A Phase Ib/II, Open-label, Multicenter Study of Novel Oncology Therapies in Combination With Chemotherapy and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1)
Phase: PHASE1
Conditions: Metastatic Microsatellite-stable Colorectal Cancer
Sponsor: MedImmune LLC

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A Phase Ib/II, Open-label, Multicenter Study of Novel Oncology 
Therapies in Combination with Chemotherapy and Bevacizumab 
as First-line Therapy in Metastatic Microsatellite-stable 
Colorectal Cancer (COLUMBIA-1)
Sponsor Protocol Number: D910CC00001
Application Number:
IND number 143363
EudraCT number 2019-000974-44
Investigational Product:
Novel oncology therapies: durvalumab (MEDI4736) and 
oleclumab (MEDI9447)
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of
AstraZeneca PLC
One MedImmune Way
Gaithersburg, Maryland, 20878, USA
Medical Monitor:
, 
,
AstraZeneca
Phone: 
Protocol History, Date:
Original Protocol, 29 April 2019
Protocol Amendment 1, 16 May 2019
Protocol Amendment 2, 12 June 2020
Protocol Amendment 3, 11 May 2022
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from AstraZeneca.
PPD
PPD
PPD
PPD
PPD

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PROTOCOL SYNOPSIS
TITLE
A Phase Ib/II, Open-label, Multicenter Study of Novel Oncology Therapies in Combination with Chemotherapy 
and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1)
HYPOTHESES
In Part 1, novel oncology therapies plus standard of care (FOLFOX [folinic acid (leucovorin), 5-fluorouracil, 
oxaliplatin] plus bevacizumab) will demonstrate adequate safety and tolerability in subjects with first-line (1L) 
metastatic microsatellite-stable (MSS) colorectal cancer (CRC) to permit further evaluation in Part 2.
In Part 2, novel oncology therapies plus standard of care (FOLFOX plus bevacizumab) will demonstrate 
superior antitumor activity to standard of care alone in subjects with 1L metastatic MSS-CRC.
OBJECTIVES AND ENDPOINTS
Type
Objective
Endpoint
PRIMARY
Safety
Part 1: To evaluate the safety and tolerability 
profile of FOLFOX + bevacizumab + novel 
oncology therapy combinations
Incidence of AEs, SAEs, DLTs, laboratory 
findings, and vital signs
Efficacy
Part 2: To compare the efficacy of FOLFOX + 
bevacizumab + novel oncology therapy 
combinations versus FOLFOX + bevacizumab
OR per RECIST v1.1
SECONDARY
Efficacy
Part 1: To investigate the preliminary 
antitumor activity of FOLFOX + bevacizumab 
+ novel oncology therapy combinations
Assessments of antitumor activity include OR, 
BOR, DoR, DC, PFS-12, and PFS as assessed 
by RECIST v1.1 and OS
Pharmacokinetics
Part 1 and 2: To describe the PK of novel 
agents
Part 1: To describe the PK of bevacizumab
Part 1 and 2: PK (drug concentration) for 
novel agents
Part 1: PK (drug concentration) for 
bevacizumab
Immunogenicity
Part 1 and 2: To describe the immunogenicity 
of applicable novel agents
Part 1: To describe the immunogenicity of 
bevacizumab
Part 1 and 2: Incidence of ADA to applicable 
novel agents 
Part 1: Incidence of ADA to bevacizumab
Safety
Part 2: To evaluate the safety and tolerability 
profile of FOLFOX + bevacizumab + novel 
oncology therapy combinations
Incidence of AEs, SAEs, laboratory findings, 
and vital signs
Efficacy
Part 2: To compare the efficacy of FOLFOX + 
bevacizumab + novel oncology therapy 
combinations versus FOLFOX + bevacizumab
Assessment of antitumor activity include BOR, 
DoR, DC, PFS-12, and PFS as assessed by 
RECIST v1.1 and OS
EXPLORATORY
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in Part 2 will depend on the evaluation of safety outcomes in Part 1. Up to approximately 30 to 40 sites globally 
will participate in this study.
Following a screening period of up to 28 days, subjects will be centrally assigned (Part 1) or randomized 
(Part 2) to one of the open study arms. In both study parts, study treatment may be administered until disease 
progression or any discontinuation criteria are met
 
 
 
Safety Run-in (Part 1)
 
 
 
 
 
 
Dose Evaluation Committee (Part 1)
A study-specific Dose Evaluation Committee (DEC; including at a minimum the medical monitor/clinical lead 
and participating investigators who have enrolled subjects) in accordance with its charter will provide ongoing 
safety surveillance of Part 1 of the study. This committee may also meet to review data at other time points (eg, 
in response to adverse events [AEs] assessed as medically relevant by the medical monitor). This committee will 
be responsible for making recommendations for safety run-in decisions. The DEC will review the totality of all 
available clinical and laboratory safety and pharmacokinetic (PK) data and all other relevant data prior to 
establishing safety run-in decisions based on the dose de-escalation rules.
Randomized Phase (Part 2)
Once Part 1 has been completed for a given arm, Part 2 will open for randomization to evaluate the efficacy and 
safety of an arm with the same treatment regimen. Randomization will be evenly distributed across all open 
arms (eg, 1:1, 1:1:1) and will be stratified based on location of the primary tumor (right sided vs left sided). 
After 50 subjects are randomized to the control arm, the control arm will continue to enroll subjects, but the 
allocation ratio to the different arms may be adjusted via protocol amendment. Enrollment to the control arm 
will pause if there is no active experimental arm. The exact subsequent allocation ratios across arms will be 
determined by the sponsor during the conduct of the study.
Safety Review Committee (Part 2)
A Safety Review Committee (SRC) will conduct safety reviews of all enrolled subjects at least twice a year. The 
SRC may make recommendations regarding continuation, modification, or termination of any study arm for 
safety concerns. The SRC will also be responsible for making recommendations for investigational product dose 
selection to ensure subjects maintain adequate exposure (eg, assessment of dose modifications, dose delays, etc) 
to standard of care treatment (FOLFOX plus bevacizumab). The committee may request additional data (eg, 
clinical efficacy) as needed. Additional safety reviews may be conducted at the discretion of the SRC.
TARGET SUBJECT POPULATION
Male and female subjects ≥18 years of age with metastatic MSS-CRC who have not received prior treatment in 
the recurrent/metastatic setting (subjects treated with prior adjuvant chemotherapy or radiochemotherapy are 
acceptable so long as progression was not within 6 months of completing the adjuvant regimen).
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TREATMENT GROUPS AND REGIMENS
In both study parts, study treatment may be administered until disease progression or any discontinuation 
criteria are met. Study treatments are described in the table below.
Part
Arm
Study Treatment
1
S1
FOLFOX + bevacizumab + durvalumab + oleclumab
E = experimental; FOLFOX = folinic acid (leucovorin), 5-fluorouracil, oxaliplatin; S = safety run-in.
FOLFOX plus bevacizumab: administered as outlined in the protocol per National Comprehensive Cancer 
Network and European Society for Medical Oncology guidelines; 5-fluorouracil will be administered as infusion 
only, with no bolus.
Durvalumab (MEDI4736):
 intravenously (IV)
Oleclumab (MEDI9447):
 IV 
 starting on Cycle 5, Day 1
STATISTICAL METHODS 
Sample size:
In Part 1, a minimum of 6 subjects (and up to 12 subjects per dose level of novel agent) will be enrolled to 
complete the safety run-in. The number of subjects to be enrolled will depend upon the toxicities observed 
during the conduct of the study.
In Part 2, up to 50 subjects per treatment arm may be enrolled into the study. After 50 subjects are randomized 
to the control arm, the control arm will continue to enroll subjects, but the allocation ratio may be adjusted via 
protocol amendment. Enrollment to the control arm will pause if there is no active experimental arm.
New combination therapy arms may be added over time via protocol amendment. Criteria for additional 
combination arms are described in the main body of the protocol.
Statistical analyses:
Efficacy
The final efficacy analyses will be based on the Intent-to-treat Population (defined as all subjects who receive 
any investigational product analyzed according to their randomized treatment group). 
 
 
 
 
 
 
 
 
 
Safety 
Safety data, including AEs, serious adverse events (SAEs), laboratory evaluations, vital signs, and 
electrocardiogram results, will be summarized based on the As-treated population (defined as all subjects who 
receive any investigational product analyzed according to treatment received). Descriptive statistics will be 
provided for AEs, SAEs, AE grade (severity), and relationship to study drug(s). AEs will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
Descriptive statistics will be provided for the clinical laboratory results and toxicities.
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Pharmacokinetics and Immunogenicity
For PK analysis, only subjects who receive at least 1 dose of medicinal product of interest (bevacizumab, 
durvalumab, or oleclumab) and/or other combination study drug and provide at least 1 post-treatment result will 
be evaluated. Individual bevacizumab and novel agent concentrations, as applicable, will be tabulated with 
descriptive statistics.
For immunogenicity assessment, only subjects who receive at least 1 dose of medicinal product of interest 
(bevacizumab, durvalumab, or oleclumab) and/or other combination study drug and provide a baseline and at 
least 1 post-treatment antidrug antibody (ADA) result will be evaluated. Immunogenicity results will be 
analyzed descriptively by summarizing the number and percentage of subjects who develop detectable ADAs to 
bevacizumab and applicable novel biologic agents. The potential impact of ADAs on PK and safety will be 
assessed if data allow. Samples confirmed positive for ADAs may also be evaluated for neutralizing antibody 
activity.
Interim analysis:
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4.8.4
Safety ............................................................................................................... 81
4.8.4.1
Analysis of Adverse Events .............................................................................. 81
4.8.4.2
Analysis of Clinical Laboratory Parameters ...................................................... 81
4.8.4.3
Analysis of Vital Signs ..................................................................................... 81
4.8.4.4
Analysis of ECOG Performance Status............................................................. 82
4.8.5
Analysis of Immunogenicity ............................................................................. 82
4.8.6
Analysis of Pharmacokinetics ........................................................................... 82
4.8.7
Analyses of Biomarkers.................................................................................... 82
4.8.8
Interim Analysis ............................................................................................... 82
5
ASSESSMENT OF SAFETY ........................................................................... 84
5.1
Definition of Adverse Events............................................................................ 84
5.2
Definition of Serious Adverse Events ............................................................... 84
5.3
Definition of Adverse Events of Special Interest............................................... 84
5.3.1
Anaphylaxis and Infusion-related Reactions...................................................... 85
5.3.2
Adverse Events of Special Interest for Durvalumab-containing Regimens ........ 85
5.3.3
Adverse Events of Special Interest Associated with Oleclumab ........................ 86
5.4
Recording of Adverse Events............................................................................ 87
5.4.1
Time Period for Collection of Adverse Events .................................................. 87
5.4.2
Follow-up of Unresolved Adverse Events......................................................... 88
5.4.3
Deaths .............................................................................................................. 88
5.4.4
Adverse Events Based on Signs and Symptoms ................................................ 88
5.4.5
Adverse Events Based on Examination and Tests.............................................. 88
5.4.6
Potential Hy’s Law and Hy’s Law..................................................................... 89
5.4.7
Disease Progression.......................................................................................... 89
5.5
Reporting of Serious Adverse Events................................................................ 90
5.6
Other Events Requiring Immediate Reporting................................................... 91
5.6.1
Overdose .......................................................................................................... 91
5.6.2
Pregnancy......................................................................................................... 91
5.6.2.1
Maternal Exposure............................................................................................ 91
5.6.2.2
Paternal Exposure............................................................................................. 92
5.6.3
Medication Error............................................................................................... 92
6
STUDY AND DATA MANAGEMENT........................................................... 94
6.1
Training of Study Site Personnel....................................................................... 94
6.2
Monitoring of the Study.................................................................................... 94
6.2.1
Source Data ...................................................................................................... 94
6.2.2
Study Agreements............................................................................................. 94
6.2.3
Archiving of Study Documents......................................................................... 95
6.3
Study Timetable and End of Study.................................................................... 95
6.4
Data Management............................................................................................. 95
6.5
Medical Monitor Coverage ............................................................................... 96
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 96
7.1
Subject Data Protection..................................................................................... 96

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7.2
Ethics and Regulatory Review .......................................................................... 96
7.3
Informed Consent ............................................................................................. 97
7.4
Changes to the Protocol and Informed Consent Form........................................ 97
7.5
Audits and Inspections...................................................................................... 98
8
REFERENCES................................................................................................. 99
9
CHANGES TO THE PROTOCOL ................................................................. 108
9.1
Protocol Amendment 3 ................................................................................... 108
9.2
Protocol Amendment 2 ................................................................................... 109
9.3
Protocol Amendment 1 ................................................................................... 111
LIST OF TABLES
Table 1
Primary Objectives and Associated Endpoints ......................................... 26
Table 2
Secondary Objectives and Associated Endpoints...................................... 26
Table 3
Exploratory Objectives and Endpoints ..................................................... 27
Table 4
Table 5
Table 6
Schedule of Screening Procedures (All Parts) .......................................... 49
Table 7
Schedule of Treatment Period Procedures Part 1...................................... 52
Table 8
Schedule of Treatment Period Procedures (Part 2) ................................... 56
Table 9
Schedule of Follow-up Procedures (All Parts).......................................... 60
Table 10
Table 11
ECOG Performance Status....................................................................... 66
Table 12
Identification of Investigational Products................................................. 72
Table A1
Highly Effective Methods of Contraception........................................... 112
Table F1
Evaluation of Overall Response Using RECIST v1.1............................. 127
Table G1
Table H1
Table H2
Toxicity Scale for the Sensory Neuropathies Associated with Oxaliplatin134
Table H3
Comparison of the Symptoms and Treatment of Pharyngo-
Laryngodysesthesias and Platinum Hypersensitivity Reactions .............. 140
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 29
Figure 2
Figure 3
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LIST OF APPENDICES
Contraception Guidance......................................................................... 112
Additional Safety Guidance ................................................................... 113
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis............ 116
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 117
Response Evaluation Criteria in Solid Tumors Version 1.1 .................... 125
Treatment Modification and Toxicity Management................................ 130
Site and Study Closure........................................................................... 142
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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
1L
first line
2L
second line
5-FU
5-fluorouracil
ADA
antidrug antibodies
AE(s)
adverse event(s)
AESI(s)
adverse event(s) of special interest
ALP
alkaline phosphatase
ALT
alanine transaminase
AMP
adenosine monophosphate
AST
aspartate transaminase
ATP
adenosine triphosphate
BOR
best overall response
CCTG
Canadian Cancer Trials Group
CD
cluster of differentiation
CI(s)
confidence interval(s)
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CR
complete response
CRC
colorectal cancer
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTL(s)
cytotoxic T lymphocyte(s)
CTLA-4
cytotoxic T-lymphocyte-associated antigen 4
DC
disease control
DCR
disease control rate
DEC
Dose Evaluation Committee
DILI
drug-induced liver injury
DLT(s)
dose-limiting toxicity(ies)
DoR
duration of response
DPD
dihydropyrimidine dehydrogenase
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Abbreviation or 
Specialized Term
Definition
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ESMO
European Society for Medical Oncology
FAAN
Food Allergy and Anaphylaxis Network
FDA
Food and Drug Administration (United States)
FFPE
formalin-fixed paraffin embedded
FOLFOX
folinic acid (leucovorin), 5-fluorouracil, oxaliplatin
GCP
Good Clinical Practice
HBV
hepatitis B virus
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
imAE
immune-mediated adverse event
IgG1
immunoglobulin G1
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous(ly)
IVRS
interactive voice response system
IWRS
interactive web response system
mAb
monoclonal antibody
MDSC(s)
myeloid-derived suppressor cell(s)
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSS
microsatellite stable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
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Abbreviation or 
Specialized Term
Definition
NIAID
National Institute of Allergy and Infectious Disease
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein 1
PD-Lx
programmed cell death ligand-x
PFS
progression-free survival
PR
partial response
PK
pharmacokinetic(s)
QTcF
QT interval corrected for heart rate using Fridericia’s formula
QxW
every x weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase II dose
RPLS
reversible posterior leukoencephalopathy syndrome
SAE(s)
serious adverse event(s)
SARS-CoV2
severe acute respiratory syndrome coronavirus 2
SD
stable disease
SID
subject identification
SRC
Safety Review Committee
TBL
total bilirubin
TGF
transforming growth factor
Treg
Regulatory T cells
TV
target value
ULN
upper limit of normal
UPC
urine protein:creatinine (ratio)
UPM
unit probability mass
USA
United States of America
VEGF
vascular endothelial growth factor
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1
INTRODUCTION
Study D910CC00001 is a Phase Ib/II, open-label, multicenter, randomized, multidrug 
platform study to evaluate the safety and efficacy of standard of care in combination with 
novel oncology therapies (durvalumab and oleclumab) in subjects with metastatic 
microsatellite stable (MSS) colorectal cancer (CRC) who have received no prior therapy in the 
recurrent/metastatic setting. New combination treatment arms can be added during the course 
of the study via protocol amendment, as novel agents of interest are available for testing in 
this population of patients (Section 1.6.4).
1.1
Disease Background
Colorectal cancer is the third most commonly diagnosed cancer in males and the second in 
females worldwide, with an estimated 1.8 million cases and 881000 deaths occurring in 2018 
(Bray et al, 2018). In the United States, there were an estimated 140250 new cases of CRC 
and 50630 deaths in 2018 (Siegel et al, 2018). Approximately 21% of CRC cases are 
metastatic at diagnosis; 5 year survival is 14% in this population (Howlader et al, 2017). 
Colorectal cancer represents a molecularly heterogeneous disease characterized by a range of 
genomic and epigenomic alterations with variable clinical outcomes. Of these, the 
microsatellite instability (MSI) is caused by a hypermutable phenotype due to loss of DNA 
mismatch repair mechanisms, and is a key factor in disease prognosis and choice of therapy 
(Mármol et al, 2017; Sinicrope et al, 2015). About 10% to 15% of CRC cases present with 
MSI tumors and exhibit sensitivity to anti-programmed cell death protein 1 (PD-1) therapy 
(Le et al, 2015). However, most CRC (85% to 90% of tumors) is defined as MSS and is 
currently resistant to monotherapy immune checkpoint blockade (Le et al, 2015).
1.1.1
Immunotherapy
1.1.1.1
Programmed Cell Death Ligand-1 
Programmed cell death protein 1, programmed cell death ligand-1 (PD-L1), and PD-L2 are 
part of a complex system of receptors and ligands that control T-cell activation. Programmed 
cell death ligand-1 expression helps tumors evade detection and elimination by the immune 
system (Chen and Mellman, 2013; Juneja et al, 2017; Keir et al, 2008; Ohaegbulam et al, 
2015). The binding of PD-L1 to PD-1 on activated T cells delivers an inhibitory signal 
preventing T cells from killing target tumor cells (Pardoll, 2012; Zou and Chen, 2008; Zou 
et al, 2016). Ipilimumab (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor) in 
combination with nivolumab (PD-1 inhibitor) in patients with MSI-high or mismatch repair-
deficient metastatic CRC that has progressed following treatment with a fluoropyrimidine, 
oxaliplatin, and irinotecan, has received Food and Drug Administration (FDA) accelerated 
approval (Yervoy® US PI, 2018). Pembrolizumab is FDA approved to treat patients with 
unresectable or metastatic solid tumors that have been identified as having a biomarker 
referred to as MSI-high or mismatch repair deficient (Keytruda® US PI, 2018).

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1.1.1.2
CD73
Adenosine is a regulatory autocrine and paracrine factor that accumulates in the tumor 
microenvironment, influencing immune activity, angiogenesis, and metastasis. Upon apoptotic 
or necrotic cell death, tumor cells release adenosine triphosphate (ATP) into the extracellular 
space. Adenosine triphosphate has been shown to lead to a pro-inflammatory response. To 
prevent an immune over activation, tissues express cluster of differentiation (CD)39 and 
CD73 to enzymatically convert ATP to adenosine, which induces a localized 
immunosuppressive response through multiple immune cell types. In the extracellular space, 
CD39 and CD73 in tandem metabolize ATP to adenosine monophosphate (AMP), and AMP 
to adenosine, respectively, and are a major source of extracellular adenosine. Extracellular 
adenosine impairs the proliferation and effector function of cytotoxic T lymphocytes (CTLs) 
while simultaneously contributing to the immunosuppressive effects of both regulatory T cells 
and myeloid-derived suppressor cells, among others (Vijayan et al, 2017). The rate-limiting 
step in the generation of extracellular adenosine is the dephosphorylation of AMP by CD73. 
One mechanism by which tumors may have evolved to evade the immune system is via 
overexpression of CD73. Overexpression of CD73 has been associated with poor prognosis in 
multiple cancer types (Hay et al, 2016; Inoue et al, 2017; Vijayan et al, 2017). In patients 
with CRC, overexpression of CD73 is an independent biomarker for predicting poor survival 
(Liu et al, 2012; Wu et al, 2012). It is hypothesized that blocking CD73 activity will reduce 
adenosine production, thus augmenting host and/or immunotherapy response to tumor.
1.2
Study Drug Background
1.2.1
Durvalumab
Durvalumab is a human immunoglobulin G1 (IgG1) kappa monoclonal antibody (mAb) that 
blocks the interaction of PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on 
immune cells and is engineered to reduce antibody-dependent cell-mediated cytotoxicity and 
complement activation. Refer to the current durvalumab Investigator’s Brochure (IB) for 
details. 
1.2.2
Oleclumab
Oleclumab (MEDI9447) is a human IgG1 lambda mAb that selectively binds to CD73 and 
inhibits adenosine production; in addition, oleclumab reduces CD73 expression through 
internalization (Geoghegan et al, 2016; Hay et al, 2016). It contains a triple mutation in the 
heavy chain constant region for reduced effector function. The enzymatic blockade of CD73 
and decreased expression caused by binding of oleclumab to CD73 may lead to increased 
antitumor immunity. Refer to the current oleclumab IB for details.

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1.3
Summary of Nonclinical Experience
A complete summary of nonclinical experience for durvalumab and oleclumab can be found 
in the IB for each agent.
1.4
Summary of Clinical Experience
A complete summary of clinical experience, including safety, efficacy, and pharmacokinetics 
(PK), for durvalumab and oleclumab can be found in the IB for each agent. A summary of 
potential benefits and risks is presented in Section 1.6.
1.5
Rationale for Conducting the Study
Despite advances in chemotherapy regimens in combination with biologics in the treatment of 
CRC, most patients still progress within 6 months after receiving either first line (1L) or 
second line (2L) chemotherapy (Saltz et al, 2008; Heinemann et al, 2014; Venook et al, 2017). 
Furthermore, almost all patients who are beyond 2L treatment progress within 3 months after 
initiation of their last line of therapy (Grothey et al, 2013; Mayer et al, 2015).
Monotherapy with checkpoint inhibitors in subjects with MSS-CRC has resulted in limited or 
no antitumor activity. For example, an objective response rate (ORR) of 0% was reported 
when pembrolizumab 10 mg/kg every 2 weeks (Q2W) was administered to subjects with 
MSS-CRC (Le et al, 2015). Combining immune checkpoint inhibitors and novel therapies 
with conventional cytotoxic drugs could theoretically provide durable anticancer responses 
and hence improve the patients’ outcome. 
In CRC nonclinical models, 5-fluorouracil (5-FU) and oxaliplatin have been shown to 
promote immunogenic cell death through calreticulin exposure (Martins et al, 2011), to 
increase CTL/regulatory T cells (Treg) ratio (Gonzalez-Aparicio et al, 2011), and to deplete 
circulating myeloid-derived suppressor cells (MDSCs; FOLFOX [folinic acid (leucovorin), 
5-FU, oxaliplatin]) (Kanterman et al, 2014; Gonzalez-Aparicio et al, 2011). Further, the 
immunomodulatory role of vascular endothelial growth factor (VEGF) targeting agents, such 
as bevacizumab, has also been explored in these colorectal models. Vascular endothelial 
growth factor A is recognized as a key mediator of the immune response by modulating the 
expression of PD-1, CTLA-4, and Tim-3 on CD8+ T cells (Voron et al, 2015). Bevacizumab 
has been demonstrated to deplete Tregs (Terme et al, 2013). Altogether, these nonclinical data 
suggest that combining durvalumab (anti-PD-L1) with FOLFOX plus bevacizumab may 
provide complementary benefit in mounting an effective antitumor immunity in patients with 
CRC. 
Checkpoint inhibitors in combination with chemotherapy have been tested in subjects with 
metastatic CRC. Studies have examined the combination of atezolizumab (an anti-PD-L1 
agent) with bevacizumab (Arm A) or atezolizumab with bevacizumab and FOLFOX at 
standard doses (Arm B) (Bendell et al, 2015), nivolumab with capecitabine and irinotecan 

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(Khemka et al, 2016), or modified FOLFOX with pembrolizumab (Shahda et al, 2017). All 
combinations appear to be safe and well tolerated. 
A variety of approaches for combining PD-1/PD-L1 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, 
durvalumab, anti-CTLA-4), immunostimulatory cytokines (eg, interferon-γ), cytotoxic 
chemotherapy, antiangiogenic inhibitors, and small-molecule molecular-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 I studies; a 
MedImmune-sponsored study (D419SC00001, unpublished data on file) and a Phase Ib study 
conducted by the Canadian Cancer Trials Group (CCTG; NCT02537418; Daaboul et al, 
2017). The combinations tested were tolerable and manageable. In addition, an ongoing 
Phase Ib/II trial is evaluating the safety, tolerability, and antitumor activity of durvalumab plus 
tremelimumab combined with FOLFOX in subjects with untreated, RAS mutation positive 
metastatic CRC (NCT03202758; Fumet et al, 2018a; Fumet et al, 2018b). After an initial 
safety run-in of 9 subjects, FOLFOX plus durvalumab and tremelimumab was tolerable with 
manageable toxicity. Preliminary results have shown encouraging clinical outcome; 
4 of 9 subjects had a partial response (PR) and 3 subjects had stable disease (SD). The results 
of the Phase I study have led to the Phase II study, which is ongoing.
In summary, the preliminary efficacy, safety, and tolerability data generated to date for 
durvalumab alone, 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 MSS-CRC and the initial promising antitumor activity seen with durvalumab in 
combination with other immuno-oncology agents in subjects with MSS-CRC and good 
tolerability, it was decided to evaluate whether this preliminary antitumor activity of 
durvalumab in combination with other novel oncology therapies could be further improved 
with acceptable tolerability by adding a standard chemotherapy regimen of FOLFOX with 
bevacizumab in subjects with 1L MSS-CRC. 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.
1.5.1
Rationale for Inclusion of Durvalumab in Combination with Oleclumab
CD73 is known to contribute to the immunosuppressive effects of both CTLs and myeloid-
derived suppressor cells, among others (Vijayan et al, 2017). High protein expression of CD73 
is associated with poor outcome in CRC patients (Wu et al, 2012). Nonclinical experiments 
have shown increased tumor growth inhibition and survival in tumor bearing mice treated with 

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anti-CD73 antibody in combination with anti-PD-1/PD-L1 antibodies (Hay et al, 2016). 
Oleclumab selectively binds to CD73, inhibits adenosine production and reduces the CD73 
expression. The combination of oleclumab with durvalumab is hypothesized to exert a 
synergistic effect on the reversal of immune suppression in the tumor microenvironment. 
Chemotherapeutic agents, including oxaliplatin, induce significant ATP release from tumor 
cells (Martins et al, 2009). Oleclumab may counteract any downstream adenosine mediated 
immunosuppressive effects induced by this ATP release. Oleclumab in combination with 
durvalumab (Study D6070C00001) and in combination with durvalumab and chemotherapy 
(Study D6070C00005) exhibited a manageable safety profile (see oleclumab IB and 
Section 1.6.2.3), further supporting exploration of this treatment combination. In addition, 
preliminary evidence of efficacy has been observed for oleclumab plus durvalumab in subjects 
with CRC (Study D6070C00001; see oleclumab IB and Section 1.6.1.1).
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.
Detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of durvalumab and each novel oncology therapy may be found 
in the respective IB for each molecule.
1.6.1
Potential Benefits
1.6.1.1
Durvalumab in Combination with Chemotherapy
An ongoing Phase Ib/II trial is evaluating the safety, tolerability, and antitumor activity of 
durvalumab plus tremelimumab combined with FOLFOX in subjects with untreated, RAS 
mutation-positive metastatic CRC (NCT03202758; Fumet et al, 2018a; Fumet et al, 2018b). 
After an initial safety run-in of 9 subjects, FOLFOX plus durvalumab and tremelimumab was 
tolerable with manageable toxicity. Preliminary results have shown encouraging clinical 
outcome; 4 of 9 subjects had a PR and 3 subjects had SD. The results of the Phase I study 
have led to the Phase II study, which is ongoing.
1.6.1.2
Oleclumab
As of 09 June 2019, 3 clinical studies are currently ongoing with oleclumab: Studies 
D6070C00001, D6070C00004, and D6070C00005. The safety and clinical activity of 
durvalumab 10 mg/kg Q2W plus oleclumab 40 mg/kg Q2W in third and fifth line MSS-CRC 
subjects is being evaluated in Study D6070C00001. Preliminary data suggest that treatment 
with oleclumab is well tolerated and leads to a reduction in CD73 expression on both tumor 
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Efficacy data from 111 response-evaluable subjects treated with oleclumab plus durvalumab 
in the dose-expansion phase of Study D6070C00001, including subjects with CRC, pancreatic 
adenocarcinoma, and non-small cell lung cancer (NSCLC) showed a confirmed ORR of 2.4% 
(1 of 42 subjects), 4.8% (2 of 42 subjects), and 11.1% (3 of 27 subjects), respectively, with a 
disease control rate (DCR) at 8 weeks of 21.4%, 23.8%, and 18.5%, respectively. The duration 
of response (DoR) was 22.1 months in the subject with CRC, 9.2 and 17.6 months in the 
2 subjects with pancreatic adenocarcinoma, respectively, and ranged between 5.5 and 
5.6 months in the 3 subjects with NSCLC. 
In addition, 11 subjects with metastatic pancreatic adenocarcinoma, in Study D6070C00005, 
have received 
 (3 subjects) or 
 (8 subjects) oleclumab 
 
, 
 durvalumab 
, and a modified regimen of FOLFOX. The 
regimen is currently being examined in dose-escalation with no dose-limiting toxicities 
(DLTs) reported and the combination has been well tolerated so far. Refer to the current 
oleclumab IB for additional information.
The plan to combine oleclumab with durvalumab, FOLFOX, and bevacizumab (Arm S1 and 
Arm E1) in the current study is supported by nonclinical and clinical studies that have 
demonstrated increases in CD73 expression and increases in extracellular ATP in response to 
chemotherapy (Samanta et al, 2018; Zhao et al, 2015). In addition, nonclinical studies have 
demonstrated synergistic benefit of chemotherapy with CD73 blockade (Loi et al, 2013). 
Furthermore, FOLFOX-bevacizumab treatment elicited a decrease in granulocytic MDSCs in 
15 of 25 patients with metastatic CRC and was associated with an improved survival outcome 
(Limagne et al, 2016). Notably, granulocytic MDSCs that expressed high levels of PD-L1, 
CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells 
present in blood, which could be reversed by blocking the CD39/CD73 and PD1/PD-L1 axes. 
Therefore, oleclumab with durvalumab combined with FOLFOX and bevacizumab therapy 
may demonstrate a clinically meaningful benefit and manageable safety profile compared with 
FOLFOX and bevacizumab alone. The overall benefit-risk profile of the proposed treatment 
combinations is expected to be favorable for subjects with MSS-CRC, therefore supporting 
the current study design.
1.6.2
Potential Risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1, aim to 
boost endogenous immune responses against tumor cells. By stimulating the immune system, 
however, there is the potential for adverse effects on normal tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and that may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
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and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ 
system and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea, 
pneumonitis/interstitial lung disease, hepatic AEs such as liver enzyme elevations, skin events 
such as rash and dermatitis, and endocrinopathies including hypo- and hyper-thyroidism.
1.6.2.1
Durvalumab Risks
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/interstitial 
lung disease, endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal 
insufficiency, hyperthyroidism, hypothyroidism, type I diabetes mellitus, and diabetes 
insipidus), hepatitis/increases in transaminases, nephritis/increases in creatinine, 
rash/dermatitis, myocarditis, myositis/polymyositis, infusion-related reactions, 
hypersensitivity reactions, pancreatitis, serious infections, and other rare or less frequent 
inflammatory events, including neuromuscular toxicities (eg, Guillain-Barré syndrome, 
myasthenia gravis).
In monotherapy clinical studies, AEs reported at an incidence of ≥20% include events such as 
fatigue, cough, decreased appetite, dyspnea, and nausea. Approximately 10% of subjects 
discontinued the drug due to an AE. Refer to the current edition of the durvalumab IB for a 
detailed summary of the monotherapy data, including AEs, serious adverse events (SAEs), 
and Grade 3 to Grade 5 AEs reported across the durvalumab program.
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment and, in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (https://tmg.azirae.com).
A detailed summary of durvalumab monotherapy AE data can be found in the current edition 
of the durvalumab IB.
1.6.2.2
Checkpoint Inhibitors in Combination with Chemotherapy 
Checkpoint Inhibitors in Combination with Chemotherapy and Bevacizumab
Checkpoint inhibitors in combination with chemotherapy have been tested in subjects with 
metastatic CRC (Section 1.5). A Phase Ib study evaluated atezolizumab (anti-PD-L1 antibody) 
with bevacizumab (Arm A) or atezolizumab with bevacizumab and FOLFOX at standard 
doses (Arm B) (NCT01633970; Bendell et al, 2015). All combinations appeared to be well 
tolerated with no unexpected toxicities. In a Phase II study (MODUL, NCT02291289) 
comparing fluoropyrimidine plus bevacizumab versus fluoropyrimidine plus bevacizumab 
with atezolizumab (Cohort 2) as 1L maintenance therapy, the safety profiles observed were 
consistent with previous findings with no new safety signals identified (Grothey et al, 2013; 
Grothey et al, 2018).

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Durvalumab in Combination with Chemotherapy with or without Other Immunotherapies
An ongoing Phase Ib/II trial is evaluating the efficacy and safety of durvalumab plus 
tremelimumab combined with FOLFOX in subjects with untreated, RAS mutation positive 
metastatic CRC (NCT03202758; ESMO 2019; Fumet et al, 2018a; Fumet et al, 2018b). 
Subjects receive FOLFOX at standard doses plus durvalumab 750 mg Q2W and 
tremelimumab 75 mg Q4W. After 6 cycles of FOLFOX, only durvalumab and tremelimumab 
continue. Nine subjects were enrolled in Phase I. Grade 3-4 treatment-related AEs occurred in 
3 of 9 subjects. The most common treatment-related Grade 3-4 AEs were neutropenia and 
diarrhea. No subjects discontinued due to a drug-related AE. 
 
 
he results of the Phase I study have led to the Phase II study, which is ongoing.
Overall, toxicities related to the chemotherapy and to durvalumab and tremelimumab were as 
expected for these agents.
1.6.2.3
Durvalumab plus Oleclumab
Overall, oleclumab and durvalumab combination therapy has demonstrated an acceptable 
safety profile (see oleclumab IB). As of 09 June 2019, 135 subjects have received oleclumab 
and durvalumab combination therapy. Of these, 111 subjects with CRC, pancreatic cancer, 
and NSCLC were treated with 40 mg/kg oleclumab Q2W plus 10 mg/kg durvalumab Q2W 
combination therapy in the dose-expansion phase of Study D6070C00001. 
Following oleclumab plus durvalumab combination therapy in the dose-expansion phase of 
Study D6070C00001, 53.2% of subjects (59 of 111) reported a treatment-related AE, with 
fatigue (14.4%), diarrhea (9.0%), pyrexia and vomiting (6.3% each), and increased aspartate 
aminotransferase (AST; 5.4%) being the most common (≥5.0%). Grade 3 or Grade 4 AEs 
were reported in 54.1% of subjects (60 of 111), with increased blood alkaline 
phosphatase (7.2%), increased gamma-glutamyl transferase and increased AST (5.4% each), 
and pneumonia (4.5%) being the most common (≥4.0%). Overall, 15.3% of subjects reported 
treatment-related Grade 3 or Grade 4 AEs. The rate of treatment-related AEs leading to 
discontinuation was 7.2%. Three subjects had AEs leading to death. One subject died of a 
treatment-related SAE of systemic inflammatory response syndrome. The other 2 subjects had 
fatal AEs of respiratory arrest and pulmonary embolism, respectively, which were considered 
unrelated to study treatment.
As of 09 June 2019, of 11 subjects with metastatic pancreatic adenocarcinoma in Study 
D6070C00005, one subject from the oleclumab 
 dose cohort experienced DLTs. This 
subject reported SAEs of nausea (Grade 3; not related to oleclumab), localized edema 
(Grade 3; related to oleclumab), bacterial infection (Grade 3; not related to oleclumab), and 
dizziness (Grade 3; not related to oleclumab), of which nausea and localized edema were 
identified as DLTs. No other DLTs were reported for this combination.
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For oleclumab, important potential risks include thrombosis and increased microvascular 
permeability, and potential risks for oleclumab include arterial ischemic disorder, arterial 
calcifications, and joint calcifications. These events were determined as potential risks for 
oleclumab based on clinical findings in individuals with CD73 deficiency and findings in 
CD73-deficient mice. Additional important potential risks include infusion-related reactions, 
anaphylaxis, hypersensitivity and serious allergic reactions, and immune complex disease, 
which are associated with the administration of mAbs. Additional potential risks associated 
with any intravenous (IV) administration are localized infection, redness, swelling, pain, and 
induration at the administration site. Given the mode of action of oleclumab, the theoretical 
risk associated with removing the inhibition of adenosine on the microenvironment favors 
increased antitumor immunity when combined with durvalumab, as well as the risk of 
emergence of autoimmune phenomena. For information on all identified and potential risks 
with oleclumab, refer to the current oleclumab IB. See Section 5.3.3 for adverse events of 
special interest (AESIs) associated with oleclumab.
1.6.3
Overall Benefit-Risk
In the 1L setting, FOLFOX plus bevacizumab is the recommended standard of care in 
metastatic CRC per National Comprehensive Cancer Network (NCCN) and European Society 
for Medical Oncology (ESMO) guidelines (NCCN, 2018; Van Cutsem et al, 2016); further 
improvement in clinical outcomes may be achieved through combination with novel therapies 
such as durvalumab and oleclumab. Clinical and nonclinical data to date have shown an 
acceptable safety profile for oleclumab in combination with durvalumab.
The design of the current study aims to minimize potential risks to subjects and include the 
protocol inclusion and exclusion criteria (Section 4.1.2 and Section 4.1.3, respectively), 
restrictions on concomitant medication during the study (Section 4.7), safety monitoring 
(including review of all safety, PK, and other relevant data by the Dose Evaluation Committee 
[DEC; Section 3.1.3.3] in Part 1 or Safety Review Committee [SRC; Section 3.1.5.2] in 
Part 2), toxicity management guidelines (Section 3.1.6 and Appendix H), study stopping 
criteria (Section 4.1.6), and rules and procedures to add new combination treatment arms 
(Section 1.6.4). Specific intensive safety monitoring is in place for those risks deemed to be 
most likely for each of the novel combination therapies. Overall, the benefit-risk assessment 
for this Phase Ib/II platform study is acceptable.
Of note, the eligibility criteria exclude participants with active severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV2) infection (see Section 4.1.3, exclusion criteria 1, 8, 
and 11). In case of an infection while on study, including SARS-CoV2, the general toxicity 
management guidelines and institutional practice guidelines should be followed.

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1.6.4
Criteria for Additional Treatment Arms
Further design elements aim to specifically minimize the risks for subjects allocated to a 
combination experimental arm. Any new combination treatment arm must adhere to the 
following elements: 

A rationale for additive or synergistic activity of the potential new candidate agent in 
combination based on its mechanism of action and/or supported by nonclinical or clinical 
evidence.

An established recommended dose for the novel agent(s).

Description of the safety profile and AESIs for the novel agent alone, in combination with 
durvalumab, and/or with chemotherapy based on previous clinical studies demonstrating a 
safety profile that would be considered acceptable for the target population in this study. 

Requirement of a protocol amendment and respective health authority and local 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approvals prior to 
implementing any new experimental arm.

Updated informed consent form with relevant information on the new combination 
experimental arm.
1.6.4.1
Regulatory Amendment for Additional Arms: Europe and Rest of World
The sponsor will provide a substantial amendment for review and approval.
1.6.4.2
Regulatory Amendment for Additional Arms: United States of America
For substantive changes that affect safety, scope, or the scientific quality of the study, the 
sponsor will provide an amendment to the FDA 30 days in advance of planned enrollment 
amendment unless the amendment contains changes to eliminate an immediate hazard to 
subjects. The sponsor will begin enrollment of subjects on new cohorts in the United States 
only after the 30-day review period is completed and after IRB approval is received.
Protocol changes needed to eliminate an apparent immediate hazard to subjects (eg, closure of 
an arm for unacceptable toxicity, modification of eligibility or monitoring to mitigate risks) 
will be implemented immediately. Both FDA and IRBs will subsequently be notified of these 
changes.
1.7
Research Hypotheses
In Part 1, novel oncology therapies plus standard of care (FOLFOX plus bevacizumab) will 
demonstrate adequate safety and tolerability in subjects with 1L metastatic MSS-CRC to 
permit further evaluation in Part 2.
In Part 2, novel oncology therapies plus standard of care (FOLFOX plus bevacizumab) will 
demonstrate superior antitumor activity to standard of care alone in subjects with 1L 
metastatic MSS-CRC.

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2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objectives and Associated Endpoints
Table 1
Primary Objectives and Associated Endpoints
Type
Objective
Endpoint
Safety
Part 1: To evaluate the safety and 
tolerability profile of FOLFOX + 
bevacizumab + novel oncology therapy 
combinations
Incidence of AEs, SAEs, DLTs, laboratory 
findings, and vital signs
Efficacy
Part 2: To compare the efficacy of 
FOLFOX + bevacizumab + novel 
oncology therapy combinations versus 
FOLFOX + bevacizumab
OR per RECIST v1.1
AE = adverse event; DLT = dose-limiting toxicity; FOLFOX = folinic acid (leucovorin), 5-fluorouracil, 
oxaliplatin; OR = objective response; RECIST v1.1 = Response Evaluation Criteria for Solid Tumors version 
1.1; SAE = serious adverse event
2.2
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Efficacy
Part 1: To investigate the preliminary 
antitumor activity of FOLFOX + 
bevacizumab + novel oncology therapy 
combinations
Assessments of antitumor activity include 
OR, BOR, DoR, DC, PFS-12, and PFS as 
assessed by RECIST v1.1 and OS
Safety
Part 2: To evaluate the safety and 
tolerability profile of FOLFOX + 
bevacizumab + novel oncology therapy 
combinations
Incidence of AEs, SAEs, laboratory 
findings, and vital signs
Efficacy
Part 2: To compare the efficacy of 
FOLFOX + bevacizumab + novel 
oncology therapy combinations versus 
FOLFOX + bevacizumab
Assessment of antitumor activity include 
BOR, DoR, DC, PFS-12, and PFS as 
assessed by RECIST v1.1 and OS
Pharmacokinetics
Part 1 and 2: To describe the PK of novel 
agents
Part 1: To describe the PK of 
bevacizumab
Part 1 and 2: PK (drug concentration) for 
novel agents
Part 1: PK (drug concentration) for 
bevacizumab
Immunogenicity
Part 1 and 2: To describe the 
immunogenicity of applicable novel agents
Part 1: To describe the immunogenicity of 
bevacizumab
Part 1 and 2: Incidence of ADA to 
applicable novel agents 
Part 1: Incidence of ADA to bevacizumab

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Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
ADA = antidrug antibody; AE = adverse event; BOR = best overall response; DC = disease control; 
DoR = duration of response; FOLFOX = folinic acid (leucovorin), 5-fluorouracil, oxaliplatin; OR =objective 
response; OS = overall survival; PFS = progression-free survival; PFS-12 = progression-free survival at 
12 months; PK = pharmacokinetics; RECIST v1.1 = Response Evaluation Criteria for Solid Tumors 
version 1.1; SAE = serious adverse event.
2.3
Exploratory Objectives and Associated Endpoints
Table 3
Exploratory Objectives and Endpoints
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Table 3
Exploratory Objectives and Endpoints
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
Study D910CC00001 is a Phase Ib/II, open-label, multicenter, randomized, multidrug 
platform study to evaluate the safety and efficacy of standard of care (FOLFOX plus 
bevacizumab) in combination with novel oncology therapies (durvalumab and oleclumab) in 
subjects with 1L metastatic MSS-CRC. The study is designed to concurrently evaluate 
potential novel combinations with clinical promise using a 2-part approach (Figure 1). Part 1 
is a Phase Ib study of safety, and Part 2 is a Phase II study of efficacy and safety. The 
treatment arms are defined in Table 4, and regimens are described in Section 3.1.2. The 
treatment regimens evaluated in Part 2 will depend on the evaluation of safety outcomes in 
Part 1.
Following a screening period of up to 28 days, subjects will be centrally assigned (Part 1) or 
randomized (Part 2) to one of the open study arms. Information on subject randomization and 
sample size is provided in Section 4.6.1 and Section 4.8.2, respectively. Up to approximately 
30 to 40 sites globally will participate in this study.
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Table 5
3.1.3.3
Dose Evaluation Committee (Part 1)
A study-specific DEC (including at a minimum the medical monitor/clinical lead and 
participating investigators who have enrolled subjects) in accordance with its charter, will 
provide ongoing safety surveillance of Part 1 of the study. This committee may also meet to 
review data at other time points (eg, in response to AEs assessed as medically relevant by the 
medical monitor). This committee will be responsible for making recommendations for safety 
run-in decisions. The DEC will review the totality of all available clinical and laboratory 
safety and PK data and all other relevant data prior to establishing safety run-in decisions 
based on the dose de-escalation rules. All decisions by this committee will be documented and 
shared in writing with all participating sites.
3.1.4
Dose-limiting Toxicity (Part 1)
Dose-limiting toxicities will be evaluated during the safety run-in phase (Part 1). The DLT 
evaluation period is defined as 28 days from the first dose of investigational product (novel 
therapy). Subjects who do not complete the DLT-evaluation period or did not receive the full 
prescribed dose of durvalumab and ≥75% of the prescribed number of doses of FOLFOX plus 
bevacizumab and the other novel oncology therapy for reasons other than DLT will be 
considered non-evaluable for DLT assessment and will be replaced with another subject in the 
same arm but will still be considered when reviewing toxicity from this arm.
Grading of DLTs will be according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0.
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A DLT will be defined as any Grade 3 or higher toxicity or any of the events listed below that 
occurs during the 28-day DLT-evaluation period. Toxicity that is clearly and directly related 
to the primary disease or to another etiology is excluded from this definition. Toxicity that is 
clearly and directly related to standard treatment (oxaliplatin, 5-FU, and/or bevacizumab) and 
not related to the novel therapy is excluded from this definition.
The following events will be DLTs: 

Grade 4 immune-mediated adverse event (imAE)

Grade 3 or Grade 4 noninfectious pneumonitis irrespective of duration

Grade 3 or Grade 4 noninfectious colitis irrespective of duration

Liver transaminase elevation:

Transaminase elevation > 8 × upper limit of normal (ULN) or total bilirubin (TBL) 
> 5 × ULN regardless of duration or reversibility

Any increase in AST or alanine transaminase (ALT) > 3 × ULN and concurrent 
increase in TBL > 2 × ULN, regardless of duration or reversibility, where no other 
reason, other than the investigational product(s), can be found to explain the 
combination of increases

Isolated liver transaminase elevation > 5 × but ≤ 8 × ULN or isolated TBL 
elevation > 3 × but ≤5 × ULN that does not downgrade to Grade 2 or less within 
14 days despite optimal management

Any Grade 3 imAE, including rash, pruritus, or diarrhea (NOTE: this excludes colitis or 
pneumonitis, as these AEs are already defined above), that does not downgrade to 
Grade ≤2 within 7 days after onset of the event despite maximal supportive care 
including systemic corticosteroids

Grade 3 nausea, vomiting, or diarrhea that does not resolve to Grade 2 or less within 
3 days of initiation of maximal supportive care

Grade 3 or Grade 4 neutropenia and/or febrile neutropenia

Grade 3 or Grade 4 febrile neutropenia regardless of duration

Grade 4 neutropenia, not associated with fever or systemic infection, lasting for 
> 7 days

Grade 3 neutropenia, not associated with fever or systemic infection, that does not 
improve by at least one grade within 7 days of onset 

Grade 3 or Grade 4 anemia

Grade 4 anemia regardless of duration

Grade 3 anemia if associated with clinical sequelae or requires transfusion 
of > 2 units of red blood cell

Grade 3 or Grade 4 thrombocytopenia

Grade 4 thrombocytopenia lasting more than 7 days

Grade 3 thrombocytopenia that does not improve by at least one grade within 7 days 
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
Grade 3 or Grade 4 thrombocytopenia, regardless of duration, associated with 
Grade 3 or higher hemorrhage or requiring transfusion or invasive intervention
The DLT definition excludes the following conditions:

Grade 3 fatigue lasting ≤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 the symptoms within 14 days after treatment onset.

Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes) that resolves to ≤Grade 1 within 
30 days after onset

Concurrent vitiligo or alopecia of any AE grade

Grade 3 infusion-related reaction: first occurrence and in the absence of steroid 
prophylaxis that resolves within 12 hours with appropriate clinical management

Grade 3 or Grade 4 lymphopenia (unless associated with clinical sequelae)

Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms (eg, hyperlipasemia or hyperamylasemia not associated with clinical signs or 
symptoms or radiographic features suggestive of pancreatitis) and are reversed with 
appropriate maximal medical intervention within 7 days 

Grade 3 rigors, chills, or fever lasting < 24 hours with appropriate maximal medical 
therapy

Grade 3 diarrhea, nausea, and/or vomiting in the absence of maximal supportive care that 
responds to therapy per institutional standards and improves by at least 1 grade within 
3 days of onset

Grade 3 hypertension that can be controlled with medical therapy (to < 160/100 mmHg 
within 7 days)
Immune-mediated AEs are defined as AEs of immune nature (ie, inflammatory) in the 
absence of a clear alternative etiology. In the absence of clinical abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT. An AE not listed above, or an AE meeting the DLT criteria above but 
occurring outside of the DLT period may be defined as a DLT after consultation with the 
sponsor and investigators based on the emerging safety profile.
3.1.5
Randomized Phase (Part 2)
Once Part 1 has been completed for a given arm, Part 2 will open for randomization to 
evaluate the efficacy and safety of an arm with the same treatment regimen. Randomization 
will be evenly distributed across all open arms (eg, 1:1, 1:1:1) and will be stratified based on 
location of the primary tumor (right sided vs left sided). After 50 subjects are randomized to 
the control arm, the control arm will continue to enroll subjects, but the allocation ratio to the 
different arms may be adjusted via protocol amendment. Enrollment to the control arm will 

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pause if there is no active experimental arm. The exact subsequent allocation ratios across 
arms will be determined by the sponsor during the conduct of the study (Section 4.6.1). 
3.1.5.1
Interim Analysis (Part 2)
 
 
3.1.5.2
Safety Review Committee (Part 2)
An SRC will conduct safety reviews of all enrolled subjects at least twice a year. The SRC 
may make recommendations regarding continuation, modification, or termination of any study 
arm for safety concerns. The SRC will also be responsible for making recommendations for 
investigational product dose selection to ensure subjects maintain adequate exposure (eg, 
assessment of dose modifications, dose delays, etc) to standard of care treatment (FOLFOX 
plus bevacizumab). The committee may request additional data (eg, clinical efficacy) as 
needed. Additional safety reviews may be conducted at the discretion of the SRC.
The SRC will consist of the following:
!
External physician not associated with the conduct of the study (SRC Chairperson)
!
Principal Investigators from a subset of active investigational sites. The number of 
sponsor representatives will not exceed the number of Principal Investigators.
!
The sponsor study medical monitor, or delegate
!
The sponsor Global Safety Physician, or delegate
!
The sponsor Study Statistician, or delegate
The Clinical Scientist, Patient Safety Scientist, and other delegates may also be invited as 
appropriate. Other internal and external experts may be consulted by the SRC as necessary. 
The membership, roles, responsibilities, and details on the process flow/communication plan 
are provided in the SRC Charter.
3.1.6
Management of Study Medication Related Toxicities
The following general guidelines should be followed for management of toxicities:
(A)Study drug treatment can be held/omitted in the context of toxicity. Omitted doses will not 
be administered at a later date. Study treatment may resume when appropriate following 
the schedule of evaluations.
(B) Study treatment modifications are to be made independently for each study drug, based on 
the specific types of toxicity that are observed, unless otherwise noted. 
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Refer to Appendix H for additional details regarding treatment modification and toxicity 
management. Actions required for any case meeting potential Hy’s Law criteria are described 
in Appendix D.
3.1.6.1
Management of Toxicities Related to Durvalumab-containing Regimens
Subjects who receive oleclumab in combination with durvalumab should follow the 
durvalumab toxicity management guidelines, which are provided as an Annex to this protocol 
as described below.
Comprehensive toxicity management guidelines have been developed to assist investigators 
with the recognition and management of toxicities associated with the use of the immune 
checkpoint inhibitors durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor). 
Given the similar underlying mechanisms of toxicities observed with these 2 compounds, 
these durvalumab ± tremelimumab guidelines are applicable to the management of subjects 
receiving either drug as monotherapy or in combination. Additionally, these guidelines are 
applicable when either drug is used alone or in combination, and is administered concurrently 
or sequentially with other anticancer drugs (ie, antineoplastic chemotherapy, targeted agents), 
as part of a protocol-specific treatment regimen. The toxicity management guidelines provide 
information for the management of immune-mediated reactions, infusion-related reactions, 
and non-immune-mediated reactions that may be observed with checkpoint inhibitor 
monotherapy or combination checkpoint inhibitor regimens, with specific instructions for dose 
modifications (including discontinuations) and treatment interventions. Investigators are 
advised, however, to use local practice guidelines and consult local references for the 
management of toxicities observed with other cancer treatment (Section 3.1.6.2). The most 
current version of the durvalumab ± tremelimumab toxicity management guidelines, entitled 
“Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and Non-Immune-Mediated Reactions (MEDI4736 Monotherapy or 
Combination Therapy with Tremelimumab or Tremelimumab Monotherapy)”, is provided to 
the investigative site as an Annex document and is maintained within the Site Master File. In 
addition, a version of the current Dosing Modification and Toxicity Management Guidelines 
is available through the following link: https://tmg.azirae.com. Please contact the study 
representative for information on how to gain access to this website.
Subjects should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune-related. In addition, there are certain circumstances in which durvalumab 
should be permanently discontinued. Following the first dose of investigational product, 
subsequent administration of durvalumab can be modified based on toxicities observed as 
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have been prepared by the sponsor to assist the investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities. These guidelines apply to AEs considered 
causally related to a durvalumab-containing regimen by the reporting investigator. 
Dose reductions are not permitted. In case of doubt, the investigator should consult with the 
medical monitor.
3.1.6.2
Management of Toxicities Related to Standard of Care Therapies
Detailed guidelines regarding treatment modification and toxicity management for standard of 
care therapies are provided in Appendix H. Actions required for any case meeting potential 
Hy’s Law criteria are described in Appendix D.
3.1.7
Post-study Access to Investigational Product(s)
Any subjects still receiving investigational product at the time of the data cutoff (for the final 
analysis in the clinical study report [CSR]) will be able to continue to receive investigational 
product, 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) or equivalent 
program.

Assessments will revert to the standard of care for each individual site. 

Data will not be entered into the clinical study database after the data cutoff 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.
In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed by 
AstraZeneca with the Investigator. AstraZeneca will work with the Investigator to transition 
the participant(s) to alternative supply, where possible.
The sponsor reserves the right to terminate access to investigational product(s) if any of the 
following occur: a) the marketing application is rejected by the responsible Health Authority; 
b) the study is terminated due to safety concerns; c) the subject can obtain investigational 
product(s) from a government sponsored or private health program; or d) therapeutic 
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3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
3.2.1.1
Durvalumab Dose Rationale
The dose and schedule of durvalumab 
 as monotherapy and in combination 
therapy has been selected based on PK/pharmacodynamics, safety, and efficacy data from 
numerous studies. As detailed in the durvalumab IB, a fixed dose of 
 is being 
used in numerous ongoing studies. Clinical studies across a range of solid tumors found 
durvalumab 10 mg/kg Q2W and 20 mg/kg Q4W to be well tolerated both in monotherapy and 
in combination (see Section 5.2.2, durvalumab IB). Durvalumab PK exposures observed in 
combination therapy were consistent with the observed monotherapy exposures (see 
Section 5.1, durvalumab IB). Previous studies and PK simulations of durvalumab have 
indicated a similar area under the concentration curve at steady state (4 weeks) is expected 
following both 10 mg/kg Q2W and 20 mg/kg Q4W. Additionally, only minor impact of body 
weight on PK of durvalumab (coefficient of ≤ 0.5) was indicated from these data. Simulation 
results demonstrated that body weight-based (20 mg/kg Q4W) and fixed dosing (
 
) regimens yield similar median steady-state exposures and variability.
3.2.1.2
Oleclumab Dose Rationale
The oleclumab regimen of 
 was selected based on data 
from the Phase I Study D6070C00001. In that study, oleclumab doses of 5, 10, 20, and 
40 mg/kg Q2W were examined both as a monotherapy and in combination with durvalumab 
10 mg/kg Q2W. Oleclumab was well tolerated and there were no observed DLTs either as 
monotherapy or in combination with durvalumab. Additionally, both oleclumab and 
durvalumab exposures in combination were comparable to monotherapy exposures. The 
oleclumab 40 mg/kg Q2W dose was selected for evaluation with durvalumab 10 mg/kg Q2W 
in the dose-expansion phase of that study. 
A fixed dose of oleclumab 
 is currently being explored based on 
simulations that oleclumab might achieve similar exposures to those observed with the 
40 mg/kg Q2W dose schedule. The subsequent 
 schedule at 
 is predicted to 
result in adequate long-term exposures with median trough concentration above the estimated 
CD73 saturating concentration of approximately 40 μg/mL (100-fold of estimated Michaelis-
Menten constant from the population PK model) to maintain optimal CD73 saturation at 
steady state.
3.2.2
Rationale for Study Population
CRC is the third most common cancer worldwide and a significant cause of cancer-related 
mortality (Bray et al, 2018). Approximately 85% of CRC tumors are MSS and minimally 
responsive to PD-(L)1-targeted agents. Since 2005, the standard of care for 1L metastatic 
MSS-CRC has been 5-FU doublet chemotherapy (most often FOLFOX) with bevacizumab 
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(all) or cetuximab (KRAS wild type only). Median overall survival (OS) for 1L metastatic 
MSS-CRC remains approximately 2 years (Chong et al, 2019; Tran et al, 2011). There is 
clinical need for improved treatment options for 1L MSS-CRC.
Several reasons may explain why MSS-CRC is poorly immunogenic. First, approximately 
40% to 50% of MSS-CRC present a genetic inactivation of the transforming growth factor 
(TGF) β receptors (TGFBR1 and TGFBR2) or of the SMAD intracellular mediators (SMAD4, 
SMAD2 and SMAD3). This results in a paradoxical increase in TGFβ (TGFB1) production 
(Calon et al, 2015) and drives T-cell exclusion (Tauriello et al, 2018). Second, up to 70% of 
MSS-CRC tumors feature defects in the beta-catenin pathway (eg, activating CTNNB1 or 
inactivating mutations in Axin1, Axin2, APC1, and APC2), preventing the migration of 
effector T cells into tumors, via a mechanism of failed Batf3-dendritic cells recruitment (Luke 
et al, 2016; Spranger et al, 2017; Spranger and Gajewski, 2018). Third, downregulation of 
MHC-1 impairs the immunosurveillance of tumors. This defect (ie, low or lack of MHC-1 
expression) is often observed in colorectal tumors and is associated with poor prognosis 
(Watson et al, 2006; Simpson et al, 2010). Finally, liver metastases may also be involved in 
driving the lack of immune response to anti-PD-1/PD-L1 (Tumeh et al, 2017; Paz-Ares et al, 
2017). Such findings appear crucial, since up to 65% of patients with metastatic CRC present 
liver metastases. 
FOLFOX plus bevacizumab is the recommended standard of care in 1L metastatic patients per 
NCCN and ESMO guidelines (NCCN, 2018; Van Cutsem et al, 2016). An increasing body of 
evidence suggests that combining novel immunotherapies with FOLFOX plus bevacizumab 
could improve the outcome of patients with CRC. In the CRC setting, FOLFOX has been 
shown to: (i) promote immunogenic cell death through calreticulin exposure (Martins et al, 
2011); (ii) to increase the CTL/Treg ratio (Gonzalez-Aparicio et al, 2011); and (iii) to deplete 
of circulating MDSCs (Kanterman et al, 2014; Gonzalez-Aparicio et al, 2011). Further, 
targeting the VEGF pathway with bevacizumab also modulates the immune context of tumors. 
Indeed, it is recognized that VEGF-A modulates the expression of PD-1, CTLA-4, and Tim-3 
on CD8+ T cells (Voron et al, 2015). Further, bevacizumab was described to deplete Tregs 
(Terme et al, 2013). Finally, the combination of anti-PD-L1 targeting with bevacizumab 
recently demonstrated improved patient benefit in metastatic NSCLC and advanced 
hepatocellular carcinoma (Socinski et al, 2018; Stein et al, 2018).
All together, these arguments suggest that combining novel immune oncology assets such as 
oleclumab plus durvalumab with FOLFOX and bevacizumab, may improve the outcome of 
metastatic CRC patients by inducing immunogenic tumor cell death, stimulating the innate 
immune system, and reversing immune suppression within the tumor microenvironment. 
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 
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3.2.3
Rationale for Endpoint(s)
The primary objective of Part 1 is to evaluate the safety and tolerability of FOLFOX and 
bevacizumab in combination with novel oncology therapies in subjects with metastatic 
MSS-CRC. This will be accomplished through confirming the recommended Phase II dose 
(RP2D) for all combinations tested. The occurrence of DLTs will be used to confirm the 
RP2D and thus standard safety endpoints, such as AEs, SAEs, clinically meaningful changes
from baseline in laboratory parameters, and vital signs will be included in the evaluation. In 
addition, PK parameters may be considered when confirmed the RP2D, along with emerging 
safety data. 
The primary objective of Part 2 is to compare the efficacy of FOLFOX and bevacizumab plus 
novel oncology therapy combinations versus FOLFOX plus bevacizumab in subjects with 
metastatic MSS-CRC. The endpoints for assessment of antitumor activity are those routinely 
included in oncology studies for the evaluation of clinical response to investigational product 
and will include objective response (OR) as a primary endpoint, while best overall response 
(BOR), DoR, disease control (DC), progression-free survival (PFS) per the Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1, and OS, will be considered secondary 
endpoints.
3.2.3.1
3.2.3.2
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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
In Part 1, a minimum of 6 subjects (and up to 12 subjects per dose level of novel agent) will 
be enrolled to complete the safety run-in. The number of subjects to be enrolled will depend 
upon the toxicities observed during the conduct of the study.
In Part 2, up to 50 subjects per treatment arm may be enrolled into the study. After 50 subjects 
are randomized to the control arm, the control arm will continue to enroll subjects, but the 
allocation ratio may be adjusted at the discretion of the sponsor (Section 4.6.1). Enrollment to 
the control arm will pause if there is no active experimental arm.
New combination therapy arms may be added over time via protocol amendment 
(Section 1.6.4). Details regarding the specifics of a new combination arm will be provided via 
protocol amendment.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
Informed consent
1
Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act [HIPAA] in the United States of America [USA]) 
obtained from the subject/legal representative prior to performing any protocol-related 
procedures, including screening evaluations.
Age
2
Age ≥ 18 years at the time of screening.
Type of subject and disease characteristics
3
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4
Subjects must have histologic documentation of advanced or metastatic CRC and:
(a) A documented mutation test during screening and confirmed tumor locations from 
disease assessment for enrollment.
(b) Subjects must NOT have defective DNA mismatch repair (MSI) as documented by 
testing. Testing may be performed locally, and prior documentation of this testing is 
acceptable in lieu of repeating the test. Defective DNA mismatch repair is defined by 
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(i)
High-frequency MSI with changes detected in 2 or more panels of microsatellite 
markers (BAT-25, BAT-26, NR-21, NR-24, or MONO-27), or
(ii) Immunohistochemical analysis demonstrating absence of protein expression of 
any one or more of the following proteins: MLH1, MSH2, MSH6, or PMS2.
(c) Subjects must not have received any prior systemic therapy for recurrent/metastatic 
disease (prior adjuvant chemotherapy or radiochemotherapy is acceptable so long as
progression was not within 6 months of completing the adjuvant regimen).
5
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 the most 
recent therapy.
(b) Up to 20 subjects per arm at select centers undergoing pre-treatment and on-
treatment tumor biopsy must have a non-target, non-lymph node lesion that can be 
biopsied at acceptable risk as judged by the investigator or a target, non-lymph node 
lesion that can be biopsied and is ≥ 2 cm in longest diameter. Sites must confirm the 
nature of the tumor material (fresh vs archived formalin-fixed paraffin embedded 
[FFPE]) before treatment assignment. Refer to the laboratory manual for details.
6
Subjects must have adequate organ function, as determined by:
(a) Hematological (cannot be met with blood transfusions or growth factor support 
within 2 weeks of scheduled first dose of study treatment)
(i)
Absolute neutrophil count ≥ 1.5 × 109/L
(ii) Platelet count ≥ 100 × 109/L
(iii) Hemoglobin ≥ 9.0 g/dL
(b) Renal
(i)
Calculated creatinine clearance by the modification of diet in renal disease 
equation (Levey et al, 2006) or 24 hour urine creatinine clearance > 40 mL/min
(ii) Urinalysis ≤ 1+ protein. Subjects discovered to have ≥2+ proteinuria at baseline 
must undergo a 24-hour urine collection that must demonstrate < 1 g of 
protein/24 hours or have a urine protein:creatinine (UPC) ratio < 1.0
(c) Hepatic
(i)
TBL ≤ 1.5 × ULN if no demonstrable liver metastases or ≤3 ULN in the 
presence of documented Gilbert’s syndrome or liver metastases
(ii) ALT and AST ≤ 2.5 × ULN if no demonstrable liver metastases or ≤5 × ULN in 
the presence of liver metastasis
(d) Coagulation
(i)
International normalized ratio (INR) < 1.5 × ULN with the exception of subjects 
on systemic anticoagulation (see criterion #7)
(ii) Partial thromboplastin time (or activated partial thromboplastin 
time) < 1.5 × ULN
7
Subjects with medical conditions requiring systemic anticoagulation (eg, atrial 
fibrillation) are eligible provided that both of the following criteria are met:

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
The subject has an in-range INR (usually between 2 and 3) on a stable dose of oral 
anticoagulant or be on a stable dose of low molecular weight heparin.

The subject has no active bleeding or pathological condition that carries a high risk of 
bleeding (eg, tumor involving major vessels or known varices).

NOTE: Subjects receiving antiplatelet agents including daily prophylactic aspirin 
(≤325 mg/day) are permitted to enroll. In addition, 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 scheduled first dose of study treatment.
Weight
8
Body weight > 35 kg
Lifestyle/Reproduction
9
Females of childbearing potential who are sexually active with a nonsterilized male 
partner must have used at least one highly effective method of contraception (see 
Appendix A for definition of females of childbearing potential and for a description of 
highly effective methods of contraception) from screening through 180 days 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 (except in countries where 
spermicides are not approved) 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 contraception. 
In addition, female subjects must refrain from egg cell donation and breastfeeding while 
on study and for 180 days after the final dose of investigational product.
10 Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use a male condom with spermicide (except in countries where 
spermicides are not approved) from screening through 180 days after receipt of the final 
dose of investigational product. It is strongly recommended for the female partner of a 
male subject to also use a highly effective method of contraception throughout this 
period, as described in Appendix A. In addition, male subjects must refrain from sperm 
donation while on study and for 180 days after the final dose of investigational product.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
Medical conditions
1
Any condition that, in the opinion of the investigator, would interfere with evaluation of 
the investigational product or interpretation of subject safety or study results.
2
History of allogeneic organ transplantation.

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3
Active or prior documented autoimmune disorders within the past 5 years prior to the 
scheduled first dose of study treatment. 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 with celiac disease controlled by diet alone.
4
History of venous thrombosis within the past 3 months prior to the scheduled first dose of 
study treatment.
5
Cardiovascular criteria:
(a) Presence of acute coronary syndrome including myocardial infarction or unstable 
angina pectoris, other arterial thrombotic event including cerebrovascular accident or 
transient ischemic attack or stroke within the past 6 months prior to the scheduled 
first dose of study treatment.
(b) New York Heart Association class II or greater congestive heart failure, serious 
cardiac arrhythmia requiring medication, or uncontrolled hypertension (≥160 mmHg 
systolic and/or ≥100 mmHg diastolic, despite appropriate antihypertensive 
medication).
(c) History of hypertensive crisis/hypertensive encephalopathy within the past 6 months 
prior to the scheduled first dose of study treatment.
6
Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms 
calculated from 3 electrocardiograms (ECGs) obtained within a 5-minute period at least 
1 minute apart.
7
No significant history of bleeding events or gastrointestinal perforation:
(a) History of significant bleeding episodes (eg, hemoptysis, upper or lower 
gastrointestinal bleeding) within the past 6 months unless the source of bleeding has 
been resected.
(b) History of gastrointestinal perforation within the past 12 months prior to the 
scheduled first dose of study treatment.
8
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
interstitial lung disease, serious chronic gastrointestinal conditions associated with 
diarrhea, or psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs or compromise the ability of the 
patient to give written informed consent.
9
History of another primary malignancy except for:
(a) Malignancy treated with curative intent and with no known active disease ≥5 years 
prior to the scheduled first dose of study treatment and of low potential risk for 
recurrence.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease.
(c) Adequately treated carcinoma in situ without evidence of disease.
10 History of active primary immunodeficiency

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11 Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 
practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, 
or human immunodeficiency virus (positive HIV 1/2 antibodies). NOTE: Subjects with 
a past or resolved HBV infection (defined as the presence of hepatitis B core antibody 
[anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C virus 
(HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
12 Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients.
13 Any unresolved toxicity NCI CTCAE Grade > 1 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria.
14 History of leptomeningeal disease or cord compression.
15 Untreated central nervous system (CNS) metastases identified either on the baseline brain 
imaging obtained during the screening period or identified prior to signing the informed 
consent form. NOTE: Subjects whose brain metastases have been treated may participate 
provided they show radiographic stability (defined as 2 brain images, both of which are 
obtained after treatment to the brain metastases. These imaging scans should both be 
obtained at least 4 weeks apart and show no evidence of intracranial progression). In 
addition, any neurologic symptoms that developed either as a result of the brain 
metastases or their treatment must have resolved or be stable either, without the use of 
steroids for at least 14 days prior to the scheduled first dose of study treatment. Brain 
metastases will not be recorded as RECIST target lesions at baseline.
16 Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or 
inability to take oral medication.
17 Known dihydropyrimidine dehydrogenase (DPD) deficiency. Testing for DPD deficiency 
must be performed where required by local regulations, using a validated method that is 
approved by local health authorities.
Prior/concomitant therapy
18 Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for 
cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions 
(eg, hormone replacement therapy) is acceptable.
19 Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation within 4 weeks prior to the scheduled first dose of study treatment
20 Prior receipt of any immune-mediated therapy including, but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1 antibodies and agents targeting CD73, CD39, or 
adenosine receptors, excluding therapeutic anticancer vaccines.
21 Prior receipt of anti-angiogenics, including, but not limited to, VEGF/VEGF receptor 
inhibitors.
22 Receipt of live attenuated vaccine within 30 days prior to the scheduled first dose of study 
treatment.

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23 Major surgical procedure, open biopsy, or significant traumatic injury (all as defined by 
the investigator) within 28 days prior to the scheduled first dose of study treatment, or 
anticipation of the need for major surgical procedure during the course of the study. 
NOTE: Local surgery of isolated lesions for palliative intent is acceptable.
24 Current or prior use of immunosuppressive medication within 14 days prior to the 
scheduled first dose of study treatment. The following are exceptions to this criterion:
(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular 
injection).
(b) Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
[CT] scan premedication or chemotherapy premedication per institutional practice).
Prior/concurrent clinical study experience
25 Participation in another clinical study with an investigational product administered within 
28 days prior to the scheduled first dose of study treatment.
26 Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study or during the follow-up period of an interventional study.
Other exclusions
27 Female subjects who are pregnant, breastfeeding, or intend to become pregnant during 
their participation in the study.
28 Involvement in the planning and/or conduct of the study (applies to both sponsor staff 
and/or staff at the study site).
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.
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 
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and/or are not randomized), including the reason(s) for screening failure. Site completion of 
the minimal set of screen failure information including demography, screen failure details, 
eligibility criteria, and any SAE is required.
Subjects who do not meet the criteria for participation in the study (ie, screening failures) may 
be rescreened (if clinically appropriate). Subjects can be rescreened a single time, but they 
cannot be re-randomized. Rescreened subjects should be assigned a new SID number. 
Rescreening should be documented so that its effect on study results, if any, can be assessed. 
These subjects should have the reason for screen failure recorded in the electronic case report 
form (eCRF).
Further details regarding randomization are provided in Section 4.6.1.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time, without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any AEs. If the subject is 
willing, the subject will be seen and assessed by the investigator. Adverse events will be 
followed up and all study medications should be returned by the subject. 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 further treatment with investigational product
2
Lost to follow-up
3
Unacceptable toxicity/AE that, in the opinion of the investigator or the sponsor, warrants 
discontinuation of further dosing or meets criteria for discontinuation from investigational 
product as defined in the toxicity management guidelines (Section 3.1.6 and Appendix H) 
or in the local prescribing information for standard of care therapies.
4
Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation at study entry and continuing treatment 
with investigational product might constitute a safety risk. 
5
Pregnancy or intent to become pregnant (Section 5.6.2)
6
Initiation of alternative anticancer therapy including another investigational agent
7
Intercurrent illness or medical condition that, in the judgment of the investigator and/or 
sponsor, warrants discontinuation of further dosing
8
Subject noncompliance (eg, refusal to adhere to visit schedule) that, in the opinion of the 
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9
Confirmed progressive disease (PD) or unconfirmed PD and treatment criteria in the 
setting of PD are not met (Section 4.1.7)
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent is 
withdrawn from further study participation (Section 4.1.5), the subject is lost to follow-up, the 
subject starts alternative treatment, or the subject is enrolled in another clinical study.
4.1.7
Treatment Beyond Progression
For all subjects, if PD (based on RECIST v1.1) occurs, the subject may continue to be treated 
with the scheduled regimen assigned after study enrollment until one of the following criteria 
is met: 

Confirmed PD: The initial assessment of PD by RECIST v1.1 (ie, the unconfirmed PD,
defined as the baseline PD assessment) will be confirmed by a repeat evaluation at the 
next tumor assessment time point, which should be no sooner than 4 weeks but no later 
than 8 weeks after the previous tumor assessment. If any subsequent tumor assessment 
time point demonstrates further increase in the tumor burden defined by any of the 
following: ≥5 mm increase in the sum of diameters of target lesions compared to the 
nadir of the unconfirmed PD assessment; any unequivocal increase in the size of the non-
target lesions; or the occurrence of new lesions compared to the nadir of unconfirmed PD; 
then the subject would be deemed as having confirmed PD.

Meets any of the investigational product discontinuation criteria (Section 4.1.6)

Clinical symptoms or signs indicating clinically significant PD such that the benefit-risk 
ratio of continuing therapy is no longer justified based on the investigator’s judgment.

Decline in ECOG performance status compared to baseline.

Rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention.
4.1.8
Replacement of Subjects
In the safety run-in phase of the study (Part 1), subjects who do not remain in the study 
through the DLT-evaluation period for reasons other than DLT (Section 3.1.4) will be 
considered non-evaluable for DLT assessment and will be replaced with another subject in the 
same arm.
In the randomized phase of the study (Part 2), withdrawn subjects may not be replaced.
4.1.9
Withdrawal of Informed Consent for Data and Biological Samples
The sponsor ensures that biological samples are returned to the source or destroyed at the end 
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If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, the 
sponsor is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study 
 
 if a subject withdraws consent to the use of 
donated biological samples, then the subject is withdrawn from further study participation.
The Principal Investigator:
!
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to the sponsor.
!
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented.
!
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented, 
and the signed document returned to the study site.
!
Ensures that the subject and the sponsor are informed about the sample disposal.
The sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
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.
4.2.1
Enrollment/Screening Period
Table 6 shows all procedures to be conducted at the screening visit.
Table 6
Schedule of Screening Procedures (All Parts)
Study Period
Screening/Baseline
Procedure
Days -28 to -1
Written informed consent/assignment of SID number
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
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Table 6
Schedule of Screening Procedures (All Parts)
Study Period
Screening/Baseline
Procedure
Days -28 to -1
Study Procedures and Examinations
Demographics
X
Medical 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, pulse rate)
X
Assessment of AEs/SAEs
X
Concomitantmedications
X
Safety Labs
Serum chemistry
X
Hematology
X
Coagulation
X
Thyroid function
X
Urinalysis
X
Serum pregnancy test e
X
Hepatitis B and C; HIV
X
AE = adverse event; BP = blood pressure; CNS = central nervous system; 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; MSS = microsatellite stable; SAE = serious adverse event; 
SID = subject identification
a
Disease assessments obtained prior to informed consent as part of standard of care treatment but within 
28 days of first dose may be submitted instead if the collection meets the study requirements, otherwise 
repeat scans should be obtained.
b
Brain MRI to be performed only if CNS involvement is suspected based on the signs and symptoms of 
individual subjects and only after study eligibility is confirmed, to detect the presence of intracranial 
metastasis.
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
ECG will be obtained in triplicate within a 5-minute period at least 1 minute apart.
e
Females of childbearing potential are required to have a serum pregnancy test within 7 days prior to the first 
dose of study drug.
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Treatment Period (Part 1)
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Table 7
Schedule of Treatment Period Procedures Part 1
Cycle #
C1
C2
C3
C4
C5
C6
Continuing
Week #
W1
W2
W3
W5
W7
W9
W11
Q2W unless 
otherwise noted
(± 5d)
Procedure/Study Day #
D1
D2
D8
(+ 2d)
D15
(± 3d)
D29
(± 3d)
D43
(± 3d)
D57
(±3 d)
D71
(±3 d)
Verify eligibility
X
Disease Assessments a
Scan (CT/MRI)
X
Q8W through 1 year 
then Q12W
CEA
X
X
Q8W for 1 year
Study Procedures and Examinations
Physical exam (focused
based on signs/symptoms)
X
X
X
X
Q4W
Weight
X
X
Q4W
ECOG performance status
X
X
Q8W
ECG b
X
X
X
Q12W
Vital signs c
X
X
X
X
X
X
X
Q2W
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
Q2W
Concomitant medications
X
X
X
X
X
X
X
X
Q2W
Safety Labs d
Serum chemistry
X d
X
X
X
X
X
X
Q2W
Hematology
X d
X
X
X
X
X
Q2W
Coagulation
X d
X
X
X
X
X
Q2W
Thyroid function tests
X d
X
X
Q4W
Urinalysis e
X d
X
X
Q4W
Pregnancy test f
X d
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Table 7
Schedule of Treatment Period Procedures Part 1
Cycle #
C1
C2
C3
C4
C5
C6
Continuing
Week #
W1
W2
W3
W5
W7
W9
W11
Q2W unless 
otherwise noted
(± 5d)
Procedure/Study Day #
D1
D2
D8
(+ 2d)
D15
(± 3d)
D29
(± 3d)
D43
(± 3d)
D57
(±3 d)
D71
(±3 d)
Plasma/Serum for PK and Immunogenicity g
Serum for durvalumab PK
X
X
W13, W25, W53
Serum for durvalumab ADA
X
X
W13, W25, W53
Serum for oleclumab PK (S1)
X
X
W13, W25, W53
Serum for oleclumab ADA 
(S1)
X
X
W13, W25, W53
Serum for bevacizumab PK
X
X
W13, W25, W53
Serum for bevacizumab ADA
X
X
W13, W25, W53
Study Drug Administration
FOLFOX
X
X
X
X
X
X
Q2W
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Table 7
Schedule of Treatment Period Procedures Part 1
Cycle #
C1
C2
C3
C4
C5
C6
Continuing
Week #
W1
W2
W3
W5
W7
W9
W11
Q2W unless 
otherwise noted
(± 5d)
Procedure/Study Day #
D1
D2
D8
(+ 2d)
D15
(± 3d)
D29
(± 3d)
D43
(± 3d)
D57
(±3 d)
D71
(±3 d)
Bevacizumab
X
X
X
X
X
X
Q2W
Durvalumab
X
X
X
Q4W
Oleclumab (S1 only)
X
X
X
X
X
Q4W
ADA = antidrug antibody; AE = adverse event; β-hCG = beta-human chorionic gonadotropin; C = cycle; CEA = carcinoembryonic antigen; CT = computed 
tomography; 
; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FOLFOX = folinic acid 
(leucovorin), 5-fluorouracil, oxaliplatin; MRI = magnetic resonance imaging; PK = pharmacokinetics; 
; QxW = every x
weeks; SAE = serious adverse event; W = week.
a
Disease assessment: brain scans must be performed if brain lesion present at baseline or symptomatic. If post-baseline radiological imaging indicates 
progressive disease, a separate consent must be signed before continuing treatment.
b
On C1D1, ECGs will be obtained in triplicate (all 3 within a 5-minute period, at least 1 minute apart) within 30 minutes prior to start of investigational 
product infusion. At all other time points, a single ECG will be obtained prior to investigational product(s) administration and as clinically indicated.
c
Vital signs: temperature, blood pressure, and pulse rate will be measured.
d
If screening laboratory assessments are performed within 3 days prior to C1D1, they do not need to be repeated at D1. All safety laboratory results must 
be reviewed by the investigator or physician designee prior to administration of study drug.
e
If bevacizumab is discontinued, urinalysis may be stopped 8 weeks after the last dose of bevacizumab. Assessments may be performed more frequently if 
clinically indicated.
f
Females of childbearing potential only. A urine or serum pregnancy test is acceptable; if urine test is positive or equivocal then serum β-hCG testing 
should be performed for confirmation.
g
Samples will be collected pre-dose. PK sampling must be within 6 hours prior to start of infusion.
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4.2.3
Treatment Period (Part 2)
Table 8 shows all procedures to be conducted during the treatment period in Part 2.

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Table 8
Schedule of Treatment Period Procedures (Part 2)
Cycle #
C1
C2
C3
C4
C5
C6
Continuing
Week #
W1
W3
W5
W7
W9
W11
Q2W unless 
otherwise noted
(± 5d)
Procedure/Study Day #
D1
D15
(± 3d)
D29
(± 3d)
D43
(± 3d)
D57
(± 3d)
D71
(± 3d)
Verify eligibility
X
Randomize (-3 day window)
X
Disease Assessments a
Scan (CT/MRI)
X
Q8W for 1 year
then Q12W
CEA
X
X
Q8W for 1 year
Study Procedures and Examinations
Physical exam (focused based on 
signs/symptoms)
X
X
X
Q4W
Weight
X
X
Q4W
ECOG performance status
X
X
Q8W
ECG b
X
X
X
Q12W
Vital signs c
X
X
X
X
X
X
Q4W
Assessment of AEs/SAEs
X
X
X
X
X
X
Q4W
Concomitant medications
X
X
X
X
X
X
Q4W
Safety Labs d
Serum chemistry
X d
X
X
X
X
X
Q2W
Hematology
X d
X
X
X
X
X
Q2W
Coagulation
X d
X
X
X
X
X
Q2W
Thyroid function tests
X d
X
X
Q8W
Urinalysis e
X d
X
X
Q4W

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Table 8
Schedule of Treatment Period Procedures (Part 2)
Cycle #
C1
C2
C3
C4
C5
C6
Continuing
Week #
W1
W3
W5
W7
W9
W11
Q2W unless 
otherwise noted
(± 5d)
Procedure/Study Day #
D1
D15
(± 3d)
D29
(± 3d)
D43
(± 3d)
D57
(± 3d)
D71
(± 3d)
Pregnancy test f
X d
As clinically indicated
Serum for PK and Immunogenicity g
Serum for durvalumab PK (except 
Control 1)
X
X
W13, W25, W53
Serum for durvalumab ADA (except 
Control 1)
X
X
W13, W25, W53
Serum for oleclumab PK (E1)
X
X
W13, W25, W53
Serum for oleclumab ADA (E1)
X
X
W13, W25, W53
Serum for bevacizumab PK
X
X
W13, W25, W53
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Table 8
Schedule of Treatment Period Procedures (Part 2)
Cycle #
C1
C2
C3
C4
C5
C6
Continuing
Week #
W1
W3
W5
W7
W9
W11
Q2W unless 
otherwise noted
(± 5d)
Procedure/Study Day #
D1
D15
(± 3d)
D29
(± 3d)
D43
(± 3d)
D57
(± 3d)
D71
(± 3d)
g
Samples will be collected pre-dose. PK sampling must be within 6 hours prior to start of infusion.
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4.2.4
Follow-up Period
Table 9 shows all procedures to be conducted during the follow-up period.
Table 9
Schedule of Follow-up Procedures (All Parts)
Procedure/Visit Day
End of 
Treatment
Visit
Day 90 Post 
Last Dose
(± 7 days)
6 Months Post 
Last Dose then 
Q3Mo
(± 14 days)
18 Months Post 
Last Dose then 
Q6Mo
(± 4 weeks)
Survival Status
X
X
X
Subsequent Anticancer 
Treatment
X
X
X
X
Disease Assessments (discontinue after confirmed PD or withdrawal of consent)
Scan (CT/MRI)
X
X
X
X
CEA
X
X
Study Procedures and Examinations 
Physical exam 
X
X
ECOG performance status
X
X
ECG
X
Vital signs
X
X
Assessment of AEs/SAEs
X
X
Concomitant medications 
X
X
Safety Labs
Serum chemistry
X
X
Hematology
X
X
Coagulation
X
X
Thyroid function tests
X
X
Urinalysis
X
X
Pregnancy test a
X
Q4W starting 8 weeks through 
28 weeks post last dose
Serum for Immunogenicity
Durvalumab ADA (except 
Control 1)
X
Oleclumab ADA (S1 and E1 
only)
X
Bevacizumab ADA
X
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Table 9
Schedule of Follow-up Procedures (All Parts)
Procedure/Visit Day
End of 
Treatment
Visit
Day 90 Post 
Last Dose
(± 7 days)
6 Months Post 
Last Dose then 
Q3Mo
(± 14 days)
18 Months Post 
Last Dose then 
Q6Mo
(± 4 weeks)
ADA = antidrug antibody; AE = adverse event; β-hCG = beta-human chorionic gonadotropin; 
CEA = carcinoembryonic antigen; CT = computed tomography; 
; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; MRI = magnetic resonance 
imaging; 
; PD = progressive disease; Q4W = every 4 weeks; QxMo = every 
x months; RECIST = Response Evaluation Criteria In Solid Tumors; SAE = serious adverse event.
a
Females of childbearing potential only. Urine pregnancy tests will be performed either on site or at 
home; the study site will contact the subject by phone to obtain results for tests performed at home. If 
urine test is positive or equivocal then serum β-hCG testing should be performed for confirmation.
4.3
Description of Study Procedures
4.3.1
Efficacy
Tumor assessments will be based on RECIST v1.1 (Appendix F) and will be performed 
according to the schedules in Section 4.2. 
 
. The assessment schedule also applies to those subjects who continue 
to receive study therapy in the setting of PD (Section 4.1.7). For those subjects who 
discontinue study therapy as a result of confirmed PD, disease evaluation will be performed at 
the end of treatment visit if clinically appropriate (ie, in the absence of rapidly deteriorating 
clinical status). After discontinuation of investigational product(s), all subjects will complete 
the end of treatment visit and enter follow-up; disease evaluation will be performed according 
to the schedule in Table 9. Additional disease assessments may be performed as clinically 
indicated.
Tumor assessments may include the following evaluations: cross-sectional imaging using CT 
or magnetic resonance imaging (MRI) scan of the chest, abdomen, pelvis; and brain. 
Computed tomography or MRI scan of the chest, abdomen, and pelvis will be performed with 
each disease assessment for all subjects. Additionally, CT or MRI scan of the brain will be 
performed at screening for all subjects with clinical concern for brain metastasis. Any subjects 
with brain metastases at screening or any subjects who develop neurologic or other clinical 
symptoms that warrant imaging must also have brain imaging with each disease assessment. 
The preferred method of 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. 
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4.3.2
Tumor Samples
Table 10
 
 
4.3.2.1
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4.3.3
Medical History, Physical Examination, Electrocardiogram, and Vital 
Signs
4.3.3.1
Medical History
A complete medical history will be obtained at screening. Findings from current medical 
history will be assigned a baseline grade according to the procedure for assessing the intensity 
of AEs, whenever applicable. As a result, increases in severity of pre-existing conditions 
during the study will be considered AEs, with resolution occurring when the grade returns to 
the baseline grade or below.
4.3.3.2
Physical Examinations
Physical examinations will be performed according to the schedules in Section 4.2. A full 
physical examination will be performed at screening according to institutional guidelines and 
should include assessments of the head, ears, nose, throat, neck, respiratory, cardiovascular, 
gastrointestinal, neurological, psychiatric, dermatological, hematologic/lymphatic, endocrine 
systems, weight (to 0.1 kg) and height (screening only). Abbreviated symptom-directed 
physical examinations will be conducted at subsequent visits post dosing.
4.3.3.3
Vital Signs
Vital signs (temperature, blood pressure, and pulse rate) performed according to the schedules 
in Section 4.2. For all vital sign measurements, subjects should rest for at least 10 minutes in a 
supine or semi-recumbent position, and all vital sign measurements should be taken prior to 
any blood draws or other procedures whenever possible. 
4.3.3.4
Electrocardiograms
Resting 12-lead ECGs will be recorded as presented in Section 4.2. Electrocardiograms should 
be obtained after the subject has been in a supine position for 5 minutes and recorded while 
the subject remains in that position.
In case of clinically significant ECG abnormalities, including a QTcF value ≥470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding based on the average of all 3 manually overread ECGs by a medically qualified 
delegate (eg, for initially prolonged QTcF value, the average QTcF value of all 3 manually 
overread ECGs should be ≥470 ms for the QTcF prolongation to be confirmed).
4.3.4
ECOG Performance Status
Performance status as determined by the ECOG scale (Oken et al, 1982) as outlined in 
Table 11, will be recorded in the eCRF per the schedule in Section 4.2.

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Table 11
ECOG Performance Status
Grade 
ECOG
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
ECOG = Eastern Cooperative Oncology Group.
Source: Oken et al, 1982
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. 
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). 
The following clinical laboratory tests will be performed (see Section 4.2 for the schedule of 
tests): 
Serum Chemistry

Albumin

Gamma-glutamyl transferase

Amylase

Glucose

ALP

Lactate dehydrogenase

ALT

Lipase

AST

Magnesium

Bicarbonate

Potassium

Blood urea nitrogen/urea

Sodium

Calcium

TBL (direct bilirubin should be obtained if TBL 
> ULN)

Chloride

Total protein

Creatinine

C-reactive protein

Creatine phosphokinase

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ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; TBL = total bilirubin; 
ULN = upper limit of normal
Note for serum chemistry: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed 
concurrently.
Hematology

Absolute lymphocyte count

Platelet count

Absolute neutrophil count

White blood cell count

Hemoglobin
Coagulation

Activated partial thromboplastin time

International normalized ratio
Note: If activated partial thromboplastin time is not available, sites may substitute a partial thromboplastin time.
If international normalized ratio is not available, sites may substitute a prothrombin time.
Urinalysis

Blood

Protein
Note: If urine protein is ≥ 2+ on dipstick urinalysis, UPC ratio (urine protein to urine creatinine) or 24-hour urine 
collection (protein) will be required.
Pregnancy Test (females of childbearing potential only)

Urine hCG

Serum β-hCG (required if urine hCG is equivocal or positive)
hCG = human chorionic gonadotropin
Note: A urine or serum pregnancy test is acceptable; if urine test is positive or equivocal, then serum β-hCG 
testing should be performed for confirmation.
Other Safety Tests

Hepatitis B, hepatitis C, and HIV: Active hepatitis B, hepatitis C, and HIV infections are defined by 
positive serologic test. Subjects positive for HBV infection are eligible if findings are compatible with past 
or resolved infection (HBsAg negative, anti-HBc positive and anti-HBs positive) or due to vaccination 
(HBsAg negative, anti-HBc negative and anti-HBs positive). Subjects positive for HCV antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA.

Thyroid function tests: TSH, T3, and T4. If TSH is normal, then free T3 or free T4 is not required.
HBc = hepatitis B core; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating 
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3
Non-compliance that might significantly jeopardize the validity or integrity of the study 
4
Sponsor decision to terminate development of durvalumab or any of the combination 
study treatments for this indication
5
Sponsor decision to terminate the study based on a planned futility analysis and/or 
recommendation from SRC (Section 4.8.8 and Section 3.1.5.2, respectively)
If the sponsor determines that temporary suspension or permanent termination of the study or 
component of the study is required, the sponsor will discuss the reasons for taking such action 
with all participating investigators (or head of the medical institution, where applicable). 
When feasible, the sponsor will provide advance notice to all participating investigators (or 
head of the medical institution, where applicable) of the impending action.
If the study or component of the study is suspended or terminated for safety reasons, the 
sponsor will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study. The sponsor will also promptly inform 
the relevant regulatory authorities of the suspension/termination along with the reasons for 
such action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. If the study or component of the study is suspended for safety reasons 
and it is deemed appropriate by the sponsor to resume the study or component of the study, 
approval from the relevant regulatory authorities (and IRBs/IECs when applicable) will be 
obtained prior to resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
The sponsor will provide the investigator(s) with investigational product (Table 12) using 
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4.5.1.2
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. See Section 4.5.1 for a description 
of investigational product presentation.
If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section for further 
instructions (Section 4.5.1.7).
4.5.1.3
Durvalumab Dose Preparation and Administration
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 the durvalumab vial to start of administration should not
exceed: 
!
!
 
A dose of 
 will be administered using an IV bag containing
 
and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter. Add 
 
durvalumab 
 to the IV bag. The IV bag size should be selected 
such that the final concentration is within 
. Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag. 
Standard infusion time is 1 hour (+ 15 minutes); however, if there are interruptions during 
infusion, the total allowed infusion time should not exceed 8 hours at room temperature. 
For experimental arms that require administration of durvalumab and the combination study 
drug on the same day, the total infusion time for both study drugs should not exceed 8 hours at 
room temperature. 
Do not coadminister other drugs through the same infusion line. For IV flushing instructions, 
refer to Section 4.5.1.5.
If either preparation time or infusion time exceeds the time limits outlined above, a new dose 
must be prepared from new vials. Durvalumab does not contain preservatives, and any unused 
portion must be discarded.
4.5.1.4
Oleclumab Dose Preparation and Administration
The dose of oleclumab for administration must be prepared by the investigator’s or site’s 
designated investigational product manager using aseptic technique. 
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Total time from needle puncture of the oleclumab vial to the start of administration should not 
exceed:
!
!
No incompatibilities between oleclumab and polyvinylchloride or polyolefin IV bags have 
been observed.
A dose of 
 will be administered using an IV bag containing 
 
 and delivered through an IV 
administration set with a 0.2- or 0.22-μm filter. Add 
 oleclumab 
 
 to the IV bag. The IV bag size should be selected such that the final concentration 
is within 
. Mix the bag by gently inverting to ensure homogeneity of the dose 
in the bag.
Standard infusion time for oleclumab is 1 hour (+ 15 minutes); however, if there are 
interruptions during infusion, the total allowed time should not exceed 4 hours at room 
temperature. If this duration is met, then the remainder of the dose should be abandoned and 
should not be completed with a second prepared dose.
See Section 4.5.1.3 for durvalumab administration. In the event of interruptions during 
infusion for either oleclumab and/or durvalumab on days when both oleclumab and 
durvalumab are administered, the total infusion duration for both study drugs should not 
exceed 8 hours. Of the total 8-hour infusion duration, a maximum of 4 hours may correspond 
to oleclumab infusion.
Do not coadminister other drugs through the same infusion line. For IV flushing instructions, 
refer to Section 4.5.1.5.
If preparation time exceeds the time limits outlined above, a new dose must be prepared from 
new vials. Oleclumab does not contain preservatives, and any unused portion must be 
discarded.
4.5.1.5
Treatment Administration
The first day of dosing with investigational product(s) is considered Week 1, Day 1 in all 
treatment arms. Where applicable, oleclumab will be administered first, followed by 
durvalumab, bevacizumab, then FOLFOX per institutional guidelines for administration. A 
wait period of at least 15 minutes must follow infusions of oleclumab and durvalumab before 
beginning administration of a subsequent infusion. If infusion reactions are noted during the 
first infusion of each agent, the wait time may be increased at the discretion of the investigator 
for subsequent coadministration days.
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No specific premedication is required for durvalumab or oleclumab. Details of any 
premedication or concomitant medication given to manage or prevent AEs should be recorded 
on the eCRF.
In all treatment arms, flush the IV line with a volume of IV diluent equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is administered.
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.
4.5.1.6
Monitoring of Dose Administration
Subjects will be monitored during and after infusion(s) of investigational product(s). Vital 
signs will be measured according to the schedules described in Section 4.2.
As with any biologic product, 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.
4.5.1.7
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the sponsor 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to the sponsor and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product(s) must be stored at labeled conditions unless otherwise instructed.
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4.5.2
Additional Study Medications
Each standard-of-care agent (folinic acid, 5-FU, oxaliplatin, and bevacizumab) will be sourced 
as commercially available material/locally sourced, prescribed according to local regulations, 
and will be administered according to prescribing information or treatment guidance in 
general use by the investigating site. Under certain circumstances when local sourcing is not 
feasible, a standard-of-care agent will be supplied centrally by the sponsor. This will be 
labeled with text translated into local languages in accordance with regulatory guidelines. The 
use of bevacizumab biosimilars is acceptable in regions/countries where their use is approved.
Refer to the Full Prescribing Information for each standard-of-care therapy for further details 
on product handling, storage, administration/dispensation, etc.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. Label text will be translated into local 
languages, as required.
4.5.4
Storage
All investigational products should be stored in a secure and dry place. Vials of investigational 
product for parenteral administration should be stored at 
 
. Drug product should be kept in original packaging until 
use to prevent excessive 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 the sponsor. All unused 
investigational product will be returned to a sponsor-authorized depot or disposed of upon 
authorization by the sponsor.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
After eligibility is confirmed, subjects will be centrally assigned (Part 1) or randomized 
(Part 2) to study treatment using an interactive voice/web response system (IXRS) that will 
assign the subject depending on open cohorts.
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In Part 2, a randomization method with dynamically changing randomization ratios will be 
employed to account for fluctuation in the number of treatment arms open for randomization 
over the course of the study. Randomization will be stratified by location of the primary tumor 
(right sided vs left sided). At the onset, the randomization scheme will use an equal ratio to all 
study treatment arms open for randomization (eg, if experimental arms are opened 
sequentially, an experimental arm is added/closed, or enrollment in an experimental arm is 
suspended). Additionally, the following considerations regarding randomization will apply:

If there is no experimental arm open for randomization, then randomization will be 
paused. Any subject who had consented previously and was in screening when the 
experimental arm(s) was closed due to safety concerns may be allowed to enter into the 
study but must be allocated to the control arm.

Once the control arm randomizes 50 subjects, a subsequent randomization scheme may be 
initiated via protocol amendment to optimize the number of subjects allocated to each 
arm.

At any point during the study, the control arm will continue to enroll subjects and have no 
less than a 30% chance to be randomized in comparison to the active experimental arm 
that has the lowest randomization ratio in the study.
Investigational product(s) must be administered within 3 days after the treatment arm is 
assigned. If there is a delay in the administration of investigational product such that it will not 
be administered within the specified timeframe, the study monitor must be notified 
immediately.
4.6.2
Methods to Ensure Blinding
This study is not blinded.
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 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 prohibited 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, anti-
emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and in 
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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 concomitant medications are 
prohibited:

Any investigational anticancer therapy

Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable.

Immunosuppressive medications including, but not limited to, methotrexate, azathioprine, 
and tumor necrosis factor-alpha blockers. The following are exceptions:

Use of immunosuppressive medications for the management of investigational 
product-related AEs, for subjects with contrast allergies, or for chemotherapy 
premedication as per institutional practice is acceptable. 

Use of inhaled, intranasal, or topical corticosteroids is permitted. 

Temporary courses of corticosteroids for treatment of underlying or concurrent 
illness or in the setting of palliative radiotherapy may be permitted upon discussion 
with the medical monitor.

Chronic, daily treatment with high-dose aspirin (> 325 mg/day)

Live attenuated vaccines during the study through 180 days after the last dose of study 
drug

Herbal and natural remedies should be avoided
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 statistical comparisons will be made between 
experimental arms and the control, but not between experimental arms.
The Intent-to-treat (ITT) Population is defined as all subjects who receive any investigational 
product. Subjects will be analyzed according to their randomized treatment group.
The As-treated population is defined as all subjects who receive any investigational product. 
Subjects will be analyzed according to the treatment received.
The DLT-evaluable Population includes subjects enrolled in the safety run-in phase (Part 1) 
who receive the full prescribed dose of durvalumab and ≥ 75% of the prescribed number of 
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evaluation period (defined as 28 days from the first dose of investigational product) or 
experience any DLT.
The Response-evaluable Population includes subjects from the As-treated population who 
have a baseline disease assessment, have the opportunity to be followed for at least 8 weeks at 
the time of the data cutoff (ie, dosed at least 8 weeks prior to the time of the data cutoff), and 
either has at least one post-baseline disease assessment and/or discontinued treatment due to 
death or disease progression.
4.8.2
Sample Size
Part 1: 
A minimum of 6 subjects (up to 12 subjects per dose level of novel agent) will be enrolled to 
complete the safety run-in. More subjects may be enrolled if dose de-escalation is needed. 
 
Part 2:
 
 
 
 
4.8.3
Efficacy
The final efficacy analyses will be based on the As-treated population for Part 1 and ITT 
Population for Part 2 as defined in Section 4.8.1. Efficacy analyses for both Part 1 and Part 2 
will provide the same or similar summary statistics, but analyses for Part 2 will provide 
further statistical comparisons between experimental arms and the control arm. Therefore, in 
this section, only Part 2 analyses are described in detail. 
The efficacy analyses will be performed on the following endpoints. 
!
BOR, defined as the best response (in the order of complete response [CR], PR, SD, PD, 
and not evaluable) among all overall responses per RECIST v1.1, recorded from 
randomization/enrollment 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 BOR 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. Tumor response will be based on the programmatically-derived response from the 
investigator’s recorded measurements for target, non-target, and new lesions according to 
RECIST v1.1.
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OR, defined as the BOR of confirmed CR or confirmed PR per RECIST v1.1.

DC, defined as the BOR of confirmed CR or confirmed PR, or SD per RECIST v1.1. The 
DCR at 16 weeks is defined as a BOR of confirmed CR, confirmed PR or having SD with 
duration of SD lasting at least 16 weeks.

DoR, defined as the time from the first documentation of a subsequently confirmed OR to 
the first documentation of a disease progression or death due to any cause, whichever 
occurs first. Only subjects who have achieved OR (confirmed CR or confirmed PR) will 
be evaluated for DoR.

PFS, defined as the time from randomization (first dose date for Part 1) until the first 
documentation of disease progression or death due to any cause, whichever occurs first, 
regardless of whether the subject receives subsequent anticancer therapy prior to 
progression. Subjects who have not progressed at the time of analysis will be censored on 
the date of their last evaluable tumor RECIST v1.1 assessment. Landmark PFS such as 
12-month PFS (PFS-12) will be estimated using the Kaplan-Meier method.

OS will be determined as the time from randomization (first dose date for Part 1) until 
death due to any cause. For subjects who are alive at the time of data cutoff, OS will be 
censored on the last date when subjects are known to be alive. 
4.8.3.1
Primary Efficacy Analysis
The primary efficacy endpoint is OR per RECIST v1.1. Objective response rate is defined as 
the proportion of subjects with OR. The 2-sided 95% confidence intervals (CIs) for ORR will 
be estimated using the exact binomial distribution. The primary analysis will compare an 
experimental arm with the control arm using the Cochran-Mantel-Haenszel (CMH) test 
stratified by the location of the primary tumor. An estimate of the odds ratio in ORR between 
the experimental arm and the control arm will be reported. 
4.8.3.2
Secondary Efficacy Analyses
Secondary efficacy endpoints include BOR, DC, DoR, PFS, and OS. Analyses of secondary 
endpoints will be performed as follows.

BOR rate is defined as the proportion of subjects with corresponding BOR. The 2-sided 
95% CI of each BOR rate will be provided using an exact probability method.

DCR is defined as the proportion of subjects with DC. The 2-sided 95% CI of DCR will 
be provided using an exact probability method. The DCR will be compared between an 
experimental arm and control arm using the CMH test stratified by the location of the 
primary tumor.

DoR will be analyzed using the log-rank test for those subjects with OR in the 
corresponding analysis populations. The median DoR with 95% CI will be estimated 
based on the Kaplan-Meier curves.

PFS according to RECIST v1.1 will be analyzed using the log-rank test stratified by the 
location of the primary tumor. The median PFS with 95% CI will be estimated based on 
the Kaplan-Meier curves. PFS-12 will be estimated based on the Kaplan-Meier curves 
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between an experimental arm and the control arm will be reported. Comparison of 
treatment arms for PFS-12 will be performed under complementary log-log 
transformation of the Kaplan-Meier estimates of PFS-12 (Klein et al, 2007).
!
OS will be compared between experimental arms and control arm using the log-rank test 
stratified by the location of the primary tumor. The median OS with 95% CI will be 
estimated based on the Kaplan-Meier curves.
4.8.3.3
Exploratory Efficacy Analyses
4.8.4
Safety
Safety analyses will be based on the As-treated population defined in Section 4.8.1.
4.8.4.1
Analysis of Adverse Events
Summary statistics will be provided for AEs, AEs leading to treatment discontinuation, SAEs, 
and AE grade, severity, and relationship to study drug(s). AEs will be graded according to 
NCI CTCAE v5.0 and coded using system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities preferred term. Specific AEs will be counted once for 
each subject when calculating rates but will be all presented in total in subject listings.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Summary statistics will be provided for clinical laboratory parameters, physical examinations, 
vital signs, and ECG. Laboratory abnormalities with toxicity grades according to the 
NCI CTCAE v5.0 will be derived and summarized.
Laboratory parameters will be assessed at baseline as well as throughout the study. 
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 from baseline to the worst post-baseline grade, will be provided for 
clinical laboratory tests. Also, laboratory parameters will be assessed by presenting tables 
containing information related to 2-grade (or greater) laboratory shifts.
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 the maximum and 
minimum post-baseline values.
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4.8.4.4
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.
4.8.5
Analysis of Immunogenicity
Subjects who receive at least 1 dose of medicinal product of interest (bevacizumab, 
durvalumab, or oleclumab) and/or other combination study drug and provide a baseline and at 
least 1 post-treatment ADA result will be evaluated. Immunogenicity results will be analyzed 
descriptively by summarizing the number and percentage of subjects who develop detectable 
ADAs to bevacizumab and applicable novel biologic agents.
The potential impact of ADAs on PK and safety will be evaluated if data allow. Samples 
confirmed positive for ADAs may also be evaluated for neutralizing antibody activity.
4.8.6
Analysis of Pharmacokinetics
Subjects who receive at least 1 dose of medicinal product of interest (bevacizumab, 
durvalumab, or oleclumab) and/or other combination study drug and provide at least 1 post-
treatment result will be evaluated. Individual bevacizumab and novel agent concentrations, as 
applicable, will be tabulated with descriptive statistics.
4.8.7
Analyses of Biomarkers
4.8.8
Interim Analysis
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5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
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.
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

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 rapid communication by the 
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AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
5.3.1
Anaphylaxis and Infusion-related Reactions
Infusion-related reactions and hypersensitivity/anaphylactic reactions are considered AESIs. 
Infusion of biological products is commonly associated with infusion-related reactions. 
Anaphylaxis and infusion-related reactions 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 of exposure to therapeutic mAbs delivered through IV 
infusion. These reactions are less common following subsequent exposures. Unlike 
infusion-related reactions, 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 adverse reactions 
observed during or shortly after exposure to investigational product and consider the 
above-mentioned facts prior to making a final diagnosis. For the investigator’s convenience 
and to facilitate consistency in judgments, a copy of the National Institute of Allergy and 
Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis Network (FAAN) guidance 
for anaphylaxis diagnosis is provided in Appendix C.
5.3.2
Adverse Events of Special Interest for Durvalumab-containing 
Regimens
Adverse events of special interest 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 is defined as an AE that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate etiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an imAE diagnosis. Appropriate 
efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic 
causes of the imAE.
If the investigator has any questions regarding an event being an imAE, the investigator 
should promptly contact the medical monitor.
Adverse events of special interest/imAEs observed with anti-PD-L/PD-1 agents, such as 
durvalumab, include:

Pneumonitis

Hepatitis

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
Diarrhea/colitis

Intestinal perforation

Endocrinopathies (ie, events of hypophysitis/hypopituitarism, type 1 diabetes mellitus, 
adrenal insufficiency, hyperthyroidism, and hypothyroidism)

Nephritis

Rash/dermatitis

Myocarditis

Myositis/polymyositis

Pancreatitis

Rare/less frequent imAEs, including neuromuscular toxicities (eg, Guillain-Barré 
syndrome 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 events, rheumatological 
events, vasculitis, noninfectious meningitis, and noninfectious encephalitis. It is possible 
that events with an inflammatory or immune-mediated mechanism could occur in nearly 
all organs.
Further information on all those risks (eg, presenting symptoms) can be found in the current 
edition of the durvalumab IB. More specific guidelines for their evaluation and treatment are 
described in detail in Section 3.1.6 and Appendix H. These guidelines have been prepared by 
the sponsor to assist the investigator in the exercise of his/her clinical judgment in treating 
these types of toxicities. These guidelines apply to AEs considered causally related to the 
study drug/study regimen by the reporting investigator.
5.3.3
Adverse Events of Special Interest Associated with Oleclumab
Cardiac Chest Pain, Transient Ischemic Attack, and Thromboembolism
AEs of cardiac chest pain, transient ischemic attack, and thromboembolism are of special 
interest due to oleclumab potential risks of arterial calcifications, arterial ischemic disorder, 
and thrombosis. As a result of this potential risk, potential subjects with a history of venous 
thrombosis in the prior 3 months, or myocardial infarction, stroke, or transient ischemic attack 
in the prior 6 months are not eligible (Section 4.1.3). These events require urgent medical 
management, which should be performed according to consensus guidelines developed by the 
American Heart Association or appropriate local standards of care.
Edema
Edema (eg, pulmonary or peripheral) is regarded as AESI due to oleclumab potential risks of 
increased microvascular permeability. For subjects who develop ≥Grade 3 edema, doses 
should be omitted, and therapy may be discontinued at the discretion of the investigator.

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Immune Complex Disease
The immune system can respond to foreign protein, even to humanized mAb by producing 
human-anti-human antibodies, which may result in formation of immune complexes and their 
deposition in blood vessels, joints, and glomeruli causing symptomatic disease (eg, vasculitis, 
glomerulonephritis, arthritis, serum sickness). Subjects will be monitored clinically and for the 
presence of ADAs. Subjects who experience an AE suspected to be immune complex-related 
will discontinue treatment. Immune complex disease will be managed in accordance with 
standard of care.
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs 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). See 
Section 5.2 for the definition of SAEs and Appendix B 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 on the SAE Report Form.
5.4.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from the time of signature of informed consent until at least 
90 days after the last dose of study treatment or until initiation of alternative cancer therapy. If 
an event that starts post the defined safety follow up period noted above is considered to be 
due to a late onset toxicity to study drug then it should be reported as an AE or SAE as 
applicable.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the investigator should notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.

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5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically indicated, 
but without further recording in the eCRF. The sponsor retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
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 sponsor representative(s) within 
the usual timeframes (refer to Section 5.5 for additional information).
5.4.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
5.4.5
Adverse Events Based on Examination and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR. An abnormal laboratory finding (including ECG finding) that requires medical 
intervention by the investigator, or a finding judged by the investigator as medically 
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 
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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
5.4.6
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. Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law. 
5.4.7
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. Death clearly resulting from disease 
progression should not be reported as an SAE (see reporting guidelines in Section 5.4.3).
The term disease progression should not be reported as an AE or SAE, however, medically 
significant individual events and/or laboratory abnormalities associated with disease 
progression (see definition of disease progression below) that fulfill the AE or SAE definition 
should be reported.
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.

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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 toward 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 according to local regulatory 
requirements and sponsor policy, and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB and/or will notify the IRB/IEC, if appropriate according to local 
requirements.
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours after becoming aware of the event.
The designated study representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor’s patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the investigators 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 
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If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed. 
The reference document for definition of expectedness/listedness is the IB for the novel agents 
and the European Union Summary of Product Characteristics for standard of care therapies: 
folinic acid (leucovorin or levoleucovorin), fluorouracil (5-FU), oxaliplatin, and bevacizumab.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the IB, unless otherwise specified in this protocol.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on any investigational product occurs during the course of the study, then the 
investigator or other site personnel should inform appropriate sponsor representatives 
immediately, but no later than 24 hours after becoming aware of the event.
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. 
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within 
30 days.
5.6.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor except if the 
pregnancy is discovered before the study subject has received any study drug.
Females of childbearing potential must have a negative pregnancy test result at screening to be 
enrolled in the study and treated with study drug.
5.6.2.1
Maternal Exposure
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 
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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 and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel will inform the appropriate sponsor representatives within 1 day, ie, immediately 
but no later than 24 hours after becoming aware of the event.
The designated study representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site 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 pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
5.6.2.2
Paternal Exposure
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality), occurring from the date of the first dose until 90 days after 
the last dose of investigational product should, if possible, be followed up and documented.
5.6.3
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca/MedImmune study drug that either causes harm to 
the subject or has the potential to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error: 

Occurred

Was identified and intercepted before the subject received the drug

Did not occur, but circumstances were recognized that could have led to an error

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Examples of events to be reported in clinical studies as medication errors:

Drug name confusion (ie, instead of receiving the investigational product, the subject 
received a drug that has a similar-sounding name)

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 

Wrong subject received the medication (excluding interactive voice response 
system/interactive web response system [IVRS/IWRS] errors)

Wrong drug administered to subject (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Subject accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca or MedImmune product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.  
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate sponsor representatives within 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 completed within 1 or 5 calendar days if there is an SAE associated with the 
medication error (Section 5.5) and within 30 days for all other medication errors. Medication 
errors should be reported using a medication error report form.

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6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a sponsor representative will review and 
discuss the requirements of the protocol 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 sponsor 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 sponsor 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/the 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 

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inconsistency between this protocol and the clinical study agreement, the terms of protocol 
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 the sponsor 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
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment (including telephone contact), 
regardless of the number of doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (Section 4.1.5 and Section 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study (ie, last subject 
last visit). The end of the study occurs after the last subject has discontinued study treatment 
and completed any applicable follow-up visit per the schedule of study procedures 
(Section 4.2), or the date the study is closed by the sponsor, whichever occurs first. Any 
subjects still receiving investigational product at the time of “study completion” may be able 
to continue to receive investigational product, as long as, in the investigator’s opinion, the 
subject is deriving clinical benefit and has not fulfilled any discontinuation criteria.
6.4
Data Management
Data management will be performed by the sponsor Data Management staff or other party
according to the Data Management Plan.
An EDC system will be used for data collection and query handling. The investigator will 
ensure that data are recorded in the eCRFs as specified in the study protocol and in accordance 
with the eCRF 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.

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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 
clinical study protocol 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 third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The informed consent 
form will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that describes how subject data will be collected, used, and distributed 
in compliance 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 informed consent.
7.2
Ethics and Regulatory Review
The IRB/IEC responsible for each site must review and approve the final study protocol, 
including the final version of the informed consent form and any other written information 
and/or materials to be provided to the subjects. The IRB/IEC must also approve all advertising 
used to recruit subjects for the study. The investigator is responsible for submitting these 
documents to the applicable IRB/IEC and distributing them to the study site staff.
The opinion of the IRB/IEC must be given in writing. The investigator must provide a copy of 
the written approval to the sponsor before enrollment of any subject into the study. 
The sponsor should approve any substantive modifications to the informed consent form that 
are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually.

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Before the study is initiated, the sponsor will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. The sponsor 
will provide safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions where relevant, to regulatory authorities, IRB/IEC, and 
Principal Investigators.
Each Principal Investigator is responsible for providing reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product to the 
IRB/IEC. The sponsor will provide this information to the Principal Investigator so that he/she 
can meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. The sponsor will develop a core 
informed consent form for use by all investigators in the clinical study. The sponsor must 
approve any modifications to the informed consent form that are needed to meet local 
requirements.
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

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 informed consent form(s) is/are stored in the investigator’s 
study file

Ensure a copy of the signed informed consent form 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 informed consent form 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 the sponsor. Any changes must be documented in a study protocol 
amendment. 
For a substantial change to the protocol, the sponsor will distribute amended versions of the 
protocol to the Principal Investigator(s). Before implementation, amended protocols must be 

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approved by relevant IRB/IEC (Section 7.2) and reviewed as per local regulatory authority 
requirements. The IRB/IEC must also approve revisions to the informed consent form, 
advertising, and any other written information and/or materials resulting from the change to 
the protocol.
Any non-substantial changes will be communicated to or approved by each IRB/IEC and local 
regulatory authority per local requirements.
7.5
Audits and Inspections
Authorized representatives of the sponsor, 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, ICH guidelines, and any 
applicable regulatory requirements. The investigator will contact the sponsor immediately if 
contacted by a regulatory agency about an inspection at the site.

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8
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Contraception Guidance
For females of childbearing potential:

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 those who are not postmenopausal (defined as 12 months with no 
menses without an alternative medical cause).

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 A1

Female subjects must refrain from egg cell donation and breastfeeding while on study and 
for 180 days after the final dose of investigational product.
Table A1
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods

Intrauterine device

Intrauterine hormone-releasing system (IUS) a

Bilateral tubal occlusion

Vasectomized partner b

Sexual abstinence c
Combined (estrogen and progestogen containing 
hormonal contraception)

Oral (combined pill)

Injectable

Transdermal (patch)
Progestogen-only hormonal contraception associated 
with inhibition of ovulation d

Injectable

Implantable

Intravaginal
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject.
d
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(eg, minipill), is not accepted as a highly effective method).

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Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event 
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization

Development of drug dependency or drug abuse
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) v5.0 as provided in below. The 

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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 Grade 5 as 
defined below.
Grade 1
An event of mild intensity 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
An event of moderate intensity 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
A severe 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
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death.
Grade 5
Death 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
A guide to Interpreting the Causality Question
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the investigational product.

Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?

Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties? 

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
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product?

No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? The sponsor would not normally recommend or 
support a re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship?
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the investigational product?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
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).

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National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
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.
NIAID and FAAN 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 blood pressure (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 mmHg or greater than 30% decrease from that 
person’s baseline

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Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
Introduction
This appendix describes the process to be followed 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.
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 sponsor 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.
Definitions
D 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 alkaline 
phosphatase (ALP).
D 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, or another drug.

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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.
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 (Section D 2) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
Follow-up
D 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.
D 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 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

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
The medical monitor contacts the investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data. 

Subsequent to this contact the investigator will:
o
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.
o
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the medical monitor.
o
Complete the relevant eCRF Modules as information becomes available
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 within 15 calendar days 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 a 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) and follow 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 the sponsor’s standard 
processes.

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
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

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 is 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
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.
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?
If No: follow the process described in Section D 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:

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
If there is no significant change, no action is required

If there is a significant change, follow the process described in Section D 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.
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):806-15.
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing 
clinical evaluation. 

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Response Evaluation Criteria in Solid Tumors Version 1.1
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 examination (when superficial).
∀
Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).
!
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10 to < 15 mm short axis). Lesions considered truly nonmeasurable 
include the following: leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
!
Target Lesions - At baseline, 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 (eg, “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
!
New Lesions - Though only certain new lesion measurements will be included in the 
tumor burden, all new lesions that can be accurately measured should be recorded. Up to 
5 additional target lesions (maximum of 2 additional lesions per organ) may be added to 
the tumor burden at each postbaseline assessment 
 
 Other new lesions will be included into the non-tumor burden.
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RECIST v1.1 Response Criteria
Evaluation of Target Lesions

CR - 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). 

PR - At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters.

PD - At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered PD.)

SD - 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

CR - Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 

Non-CR/Non-PD - Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.

PD - 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 (Section 4.1.6). In the absence of measurable disease, change 
in non-measurable disease comparable in magnitude to the increase 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 can 
nonetheless derive clinical benefit.
Evaluation of Overall Response
For the overall response based on RECIST v1.1, confirmation of CR and PR is required by a 
repeat, consecutive assessment no less than 4 weeks from the date of first documentation. If a 
subject discontinues the study due to PD and begins another treatment, a confirmatory scan is 
not required.

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Table F1 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 F1
Evaluation of Overall Response Using RECIST v1.1
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Complete response
Complete response (or no non-
target lesion)
No
Complete response
No target lesion a 
Complete response
No
Complete response
Complete response
Not evaluable b
No
Partial response
Complete response
Non-complete response /
non-progressive disease
No
Partial response
Partial response
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Partial response
Stable disease
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesion a
Not all evaluated
No
Not evaluable
No target lesion a
Non-complete response /
non-progressive disease
No
Non-complete response/
non-progressive disease
Progressive disease
Any
Yes/No
Progressive disease
Any
Progressive disease
Yes/No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesion a
Unequivocal progressive disease
Yes/No
Progressive disease
No target lesion a
Any
Yes
Progressive disease
RECIST v1.1 = Response Evaluation Criteria in Solid Tumors version 1.1.
a
Defined as no target lesion at baseline.
b
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment.
Reference: Eisenhauer et al, 2009

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Table G1
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Table G1
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Treatment Modification and Toxicity Management
General Guidelines
If the initiation of a new cycle, or therapy during a cycle, is delayed for ≥4 weeks because of 
investigational product-related toxicity, treatment with FOLFOX may be discontinued. If 
FOLFOX is discontinued or modified (eg, oxaliplatin is suspended) due to toxicity, subjects 
may continue on therapy with bevacizumab and/or novel agent(s) only until the subject meets 
the guidelines for treatment discontinuation (Section 4.1.6).
Immune-related toxicities and chemotherapy-related toxicities are recognized to have different 
underlying pathophysiology and require different management (Brahmer et al, 2018). To 
discriminate between them, investigators are invited to perform comprehensive work-up 
covering both causes in order to direct the appropriate therapeutic interventions 
(https://tmg.azirae.com). If the toxicities are clearly attributed to chemotherapy or 
immunotherapy (ie, durvalumab and oleclumab), either chemotherapy or immunotherapy may 
be delayed or discontinued, and the other may be continued (see Section H 3 for synchronized 
delay, if applicable). If the causality of toxicity is unclear, both chemotherapy and 
immunotherapy may be delayed or discontinued. There are no recommended dose reductions 
for durvalumab or oleclumab.
In the absence of clear alternative etiology, all events should be considered potentially 
immune-mediated, and the toxicity management guidelines for management of immune-
related AEs should be followed (see the Annex to Protocol or https://tmg.azirae.com).
In the event that the novel agent(s) are discontinued or delayed as part of the toxicity 
management guidance, chemotherapy and bevacizumab may still be administered as 
scheduled. 
Dose Levels
Table H1 indicates potential dose levels for each of the agents for which dose modifications 
will be allowed. Dose adjustments of each agent may be made independently based on the 
specific types of toxicities observed. Only those agents specified in the sections below should 
be dose reduced.
Table H1
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Table H1
FOLFOX Dose Modifications
!
In the event that toxicities are clearly attributed to chemotherapy, both chemotherapy 
(5-FU and oxaliplatin) and the regimen containing novel agent(s) may be delayed for up 
to 7 days; the goal of synchronized delay is to preserve the alignment of chemotherapy 
and immunotherapy. If chemotherapy cannot be resumed within 7 days after the 
originally scheduled day, the novel agent(s) may be administered for that cycle.
!
If subjects experience a toxicity clearly related to any chemotherapeutic agent 
necessitating the suspension or the discontinuation of that agent only (eg, neuropathy due 
to oxaliplatin), then the non-offending chemotherapeutic agent and novel agent(s) may 
still be continued until the subject meets the guidelines for treatment discontinuation.
!
If 5-FU is discontinued, oxaliplatin must also be discontinued.
Bevacizumab Dose Modifications
!
There are no recommended dose reductions
!
Temporary suspension is recommended for:
∀
Severe infusion reactions (≥ Grade 3; Appendix H 17)
∀
At least 4 weeks prior to and after elective surgery (ie, major surgery)
∀
Moderate to severe proteinuria (≥2 g/24 h; Appendix H 14)
∀
Persistent or symptomatic hypertension despite appropriate therapy, as defined in 
Appendix H 10
!
Permanent discontinuation is recommended for:
∀
Wound dehiscence and wound healing complications requiring intervention 
(Appendix H 16)
∀
Necrotizing fasciitis
∀
Fistula
∀
Gastrointestinal perforation (Appendix H 16)
∀
Bowel obstruction (≥ Grade 3; Appendix H 16)
∀
Intra-abdominal abscess
∀
Hypertensive crisis
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
Hypertensive encephalopathy

Serious bleeding/hemorrhage (Appendix H 13)

Severe arterial thromboembolic events (≥ Grade 3; Appendix H 12)

Life-threatening (Grade 4) venous thromboembolic events (including pulmonary 
embolism) (Appendix H 12)

Nephrotic syndrome or ≥Grade 3 proteinuria (Appendix H 14)

Reversible posterior leukoencephalopathy syndrome (RPLS; Appendix H 11)
FOLFOX/Bevacizumab Hematologic Toxicities
The following dose modifications are based on toxicity experienced during a cycle (ie, after 
Day 1 of any cycle):
Grade 3 or Grade 4 neutropenia or thrombocytopenia: Skip 5-FU and oxaliplatin.
If counts recover to an absolute neutrophil count ≥ 1.5 × 109/L and platelets ≥75 × 109/L, then 
5-FU and oxaliplatin may be resumed at one lower dose level for subsequent cycles. Skipped 
doses are not to be made up (ie, omitted doses will not be administered at a later date).
Febrile neutropenia (defined as absolute neutrophil count < 1.0 × 109/L and temperature 
≥38.5°C): Skip 5-FU and oxaliplatin. If fever and neutropenia resolve, 5-FU and oxaliplatin 
may be resumed at one lower dose level for subsequent cycles, provided an absolute 
neutrophil count ≥ 1.5 × 109/L and platelets ≥ 75 × 109/L. Omitted doses will not be 
administered at a later date.
Hematopoietic growth factors
Granulocyte-colony stimulating factor (G-CSF) is not recommended as primary prophylaxis, 
but it can be used in secondary prophylaxis in case of: 

Precedent febrile neutropenia; 

Precedent grade 4 neutropenia lasting 5 days or more; 

More than 2 delays of the planned therapy due to neutropenia. 
Anemia: Non-hemolytic ≥ Grade 2 anemia should be managed with blood transfusions or 
with the administration of erythropoietin, according to institutional guidelines. No dose 
modification of the chemotherapy or investigational product is required.
NOTE: No bevacizumab, durvalumab, or oleclumab dose modifications will be made for 
hematologic toxicity.
Continue bevacizumab and novel agent(s), when 5-FU and/or oxaliplatin are skipped for 
hematologic toxicities.

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FOLFOX/Bevacizumab Gastrointestinal Toxicities
In cases where the toxicity is deemed to be immune related, refer to the toxicity management 
guidelines annex/website (https://tmg.azirae.com). In cases where toxicity can be reasonably 
attributed to the chemotherapy and if an immune-related etiology is ruled out, consider the 
following guidelines. If the investigator is unable to determine which study drug is a more 
likely cause of the AE (ie, FOLFOX, bevacizumab, or immunotherapeutics), then the 
treatment management should cover both etiologies. 
The following dose modifications are based on toxicity experienced during a cycle (ie, 
after Day 1 of any cycle):

For Grade 2 diarrhea, reduce 5-FU one dose level for the subsequent cycles. Oxaliplatin is 
not reduced. When diarrhea has fully resolved, resume 5-FU at the previous dose level.

For Grade 3 or Grade 4 diarrhea, skip 5-FU and oxaliplatin. If diarrhea resolves to 
≤Grade 2, then 5-FU and oxaliplatin may be resumed at one lower dose level for 
subsequent cycles. Omitted doses will not be administered at a later date.
Mucositis: The following dose modifications are based on the grade of mucositis seen on the 
day of treatment for any day after Day 1 in any cycle.

For Grade 2 mucositis, reduce 5-FU and oxaliplatin one dose level for subsequent 
cycles. When mucositis has fully resolved, continue 5-FU and oxaliplatin at the previous 
dose levels.

For Grade 3 mucositis, skip 5-FU and oxaliplatin. If mucositis resolves to ≤Grade 2, 
then 5-FU and oxaliplatin may be resumed at one lower dose level for subsequent cycles. 
Omitted doses will not be administered at a later date. When mucositis has fully resolved, 
continue 5-FU at the reduced dose level from the previous cycle and resume oxaliplatin at 
the previous dose level.

For Grade 4 mucositis, skip all protocol therapy. If mucositis resolves to ≤Grade 2, then 
5-FU and oxaliplatin may be resumed at one lower dose level for subsequent cycles. 
Omitted doses will not be administered at a later date.
Nausea/vomiting: The following dose modifications are based on the grade of nausea and 
vomiting occurring during a cycle (ie, after Day 1 in any cycle):

For Grade 3 nausea or vomiting, reduce oxaliplatin one dose level for subsequent cycles.

For Grade 4 nausea or vomiting, reduce 5-FU and oxaliplatin one dose level for 
subsequent cycles.
These dose reductions for vomiting and/or nausea should be made only if they persist/occur 
despite 2 treatments with adequate (combination) antiemetic therapy. See Hesketh et al, 2017
for antiemetic practice guidelines.

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No bevacizumab or investigational product dose modifications will be made for diarrhea, 
mucositis, nausea, or vomiting. Continue bevacizumab when 5-FU and oxaliplatin are skipped 
for these gastrointestinal toxicities.
FOLFOX/Bevacizumab Pulmonary Toxicity
In cases where the toxicity is deemed to be immune related, refer to the toxicity management 
guidelines annex/website (https://tmg.azirae.com). In cases where toxicity can be reasonably 
attributed to the chemotherapy and if an immune-related etiology is ruled out, consider the 
following guidelines. If the investigator is unable to determine which study drug is a more 
likely cause of the AE (ie, FOLFOX, bevacizumab, or immunotherapeutics), then the 
treatment management should cover both etiologies. 
For Grade 2 or worsening pulmonary symptoms unrelated to underlying cancer, 
investigational product should be held until resolution to Grade 1 or less, and symptoms 
investigated to rule out a potential immune-related pneumonitis (see https://tmg.azirae.com).
For ≥ Grade 3 cough, dyspnea, hypoxia, pneumonitis, or pulmonary infiltrates unrelated to 
underlying cancer, skip oxaliplatin, bevacizumab until interstitial lung disease is ruled out. 
Investigational product should be permanently discontinued; 5-FU may be continued. 
Discontinue all protocol therapy if interstitial lung disease is confirmed.
FOLFOX/Bevacizumab Neurotoxicity
In cases where the toxicity is deemed to be immune related, refer to the toxicity management 
guidelines annex/website (https://tmg.azirae.com). In cases where toxicity can be reasonably 
attributed to the chemotherapy and if an immune-related etiology is ruled out, consider the 
following guidelines. If the investigator is unable to determine which study drug is a more 
likely cause of the AE (ie, FOLFOX, bevacizumab, or immunotherapeutics), then the 
treatment management should cover both etiologies. 
Table H2
Toxicity Scale for the Sensory Neuropathies Associated with Oxaliplatin
Grade
Symptoms
Grade 1
Paresthesias/dysesthesias a of short duration that resolve and do not interfere with function.
Grade 2
Paresthesias/dysesthesias a interfering with function, but not in activities of daily living.
Grade 3
Paresthesias/dysesthesias a with pain or with functional impairment that also interfere with 
activities of daily living.
Grade 4
Persistent paresthesias/dysesthesias a that are disabling or life threatening.
a
May be cold-induced

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11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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For Grade 2 neurotoxicity persisting between treatments: Reduce oxaliplatin by one dose 
level for subsequent cycles.
For Grade 3 neurotoxicity resolving to ≤ Grade 2 between treatments: Reduce oxaliplatin 
by one dose level for subsequent cycles.
For recurrent Grade 3 neurotoxicity resolving to ≤ Grade 2 between treatments: Reduce 
oxaliplatin by one additional dose level for subsequent cycles. Oxaliplatin will not be reduced 
beyond level –3. If further dose reduction is required for neurotoxicity, oxaliplatin will be 
discontinued. Subjects should continue to receive other protocol therapy.
For Grade 3 neurotoxicity persisting between treatments: Discontinue oxaliplatin. 
Subjects should continue to receive other protocol therapy.
For Grade 4 neurotoxicity: Discontinue oxaliplatin. Subjects should continue to receive 
other protocol therapy. 
For pharyngo-laryngeal dysesthesia: Increase the duration of oxaliplatin infusion to 6 hours 
for all subsequent treatments.
Subjects may also discontinue oxaliplatin following multiple cycles even in the absence of 
dose-limiting neurotoxicity if, in the physician’s judgment, neurotoxicity is likely to become 
problematic. Subjects should continue to receive other protocol therapy and the oxaliplatin 
may be reintroduced subsequently.
FOLFOX Extravasation
Extravasation of oxaliplatin has been associated with necrosis; if extravasation is suspected, 
the infusion should be stopped, and the drug administered at another site. Extravasation may 
be treated according to institutional guidelines.
Bevacizumab Dose Modifications for Hypertension

For hypertension controlled with medication (to < 160/100 mmHg): Continue 
bevacizumab.

For persistent or symptomatic hypertension despite appropriate therapy: skip 
bevacizumab. If bevacizumab treatment is delayed for more than 4 weeks due to 
uncontrolled hypertension, discontinue bevacizumab.

Grade 4 hypertension: Permanently discontinue bevacizumab.
Subjects who skip or discontinue bevacizumab due to hypertension may continue other 
protocol therapy.

MedImmune
Protocol D910CC00001 Amendment 3
Platform study: novel oncology therapies
11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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Template 18.0
Bevacizumab Dose Modifications for RPLS
For signs and symptoms suggestive of RPLS (eg, confusion, headache, seizures, cortical 
blindness) skip bevacizumab. Suspected RPLS should be investigated with MRI as described 
in Section H 11.1. If diagnosis of RPLS is confirmed, bevacizumab should be permanently 
discontinued.
If RPLS is ruled out via MRI, the decision on resuming bevacizumab should be based on the 
nature of the signs/symptoms. For Grade 4 events with likely relationship to bevacizumab, 
discontinue bevacizumab; for Grade 3 events, bevacizumab may be resumed if toxicities 
completely resolve within 4 weeks.
Other protocol therapy may be continued at the discretion of the treating physician.
H 11.1
Investigation of RPLS
Reversible posterior leukoencephalopathy syndrome or clinical syndromes related to 
vasogenic edema of the white matter have been reported in association with bevacizumab 
therapy. These syndromes have been seen in < 1% of patients to date. Clinical presentations 
are variable and may include altered mental status, seizure and cortical visual deficit. 
Hypertension is a common risk factor and was present in most (though not all) patients on 
bevacizumab who developed RPLS. MRI scans are key to diagnosis and typically demonstrate 
vasogenic edema (hyperintensity in T2 and FLAIR images and hypointensity in T1 images) 
predominantly in the white matter of the posterior parietal and occipital lobes; less frequently, 
the anterior distributions and the gray matter may also be involved. RPLS should be in the 
differential diagnosis in subjects presenting with unexplained mental status change, visual 
disturbance, seizure or other CNS findings. RPLS is potentially reversible, but timely 
correction of the underlying causes, including control of blood pressure and interruption of the 
offending drug, is important to prevent progression to irreversible tissue damage.
Dose Modifications for Cardiovascular Toxicities
In cases where the toxicity is deemed to be immune related, refer to the toxicity management 
guidelines annex/website (https://tmg.azirae.com). In cases where toxicity can be reasonably 
attributed to the chemotherapy and if an immune-related etiology is ruled out, consider the 
following guidelines. If the investigator is unable to determine which study drug is a more 
likely cause of the AE (ie, FOLFOX, bevacizumab, or immunotherapeutics), then the 
treatment management should cover both etiologies. 
Subjects should be carefully monitored for evidence of thromboembolic disease during 
treatment.

MedImmune
Protocol D910CC00001 Amendment 3
Platform study: novel oncology therapies
11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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Template 18.0
For Grade 3 venous thrombosis or asymptomatic pulmonary embolism: Skip bevacizumab. If 
the planned duration of full-dose anticoagulation is < 2 weeks, bevacizumab should be held 
until the full-dose anticoagulation period is over. If the planned duration of full-dose 
anticoagulation is > 2 weeks, bevacizumab may be resumed during the period of full-dose 
anticoagulation if all of the following criteria are met:

The subject must have an in-range INR (usually between 2 and 3) or be on stable dose of 
low molecular weight heparin prior to restarting bevacizumab treatment;

The subject must not have pathological conditions that carry high risk of bleeding (eg, 
tumor involving major vessels);

The subject must not have had hemorrhagic events while on study.
For Grade 4 or for recurrent/worsening venous thromboembolic events after resumption of 
bevacizumab: Discontinue all protocol therapy and notify the sponsor medical monitor.
For symptomatic pulmonary embolism, subjects will discontinue all protocol therapy.
Arterial Thrombotic Events

For Grade 2 arterial thrombotic events not present at baseline or worsened since the 
initiation of protocol therapy, discontinue bevacizumab. Subjects may continue other 
protocol therapy.

For Grade 3 cerebrovascular ischemia, and/or peripheral or visceral arterial ischemia, 
discontinue bevacizumab. Subjects may continue other protocol therapy.

For Grade 3 cardiac ischemia/infarction, discontinue all protocol therapy.

For any Grade 4 arterial thrombotic event, including cerebrovascular ischemia, cardiac 
ischemia/infarction, peripheral or visceral arterial ischemia, discontinue all protocol 
therapy.
Myocarditis, Pericarditis, Arrhythmias or Impaired Ventricular Function with Heart 
Failure Events

For Grade 3 events, discontinue bevacizumab and investigational product. FOLFOX 
should be held until resolution to ≤Grade 1. 

For Grade 4 events, discontinue all protocol therapy.
Bevacizumab Dose Modifications for Hemorrhage/bleeding

For Grade 3 hemorrhage/bleeding, discontinue bevacizumab and skip other protocol 
therapy; once hemorrhage or bleeding resolves, other protocol therapy may be continued 
at the treating physician’s discretion.

For Grade 4 hemorrhage/bleeding, discontinue all protocol therapy.

MedImmune
Protocol D910CC00001 Amendment 3
Platform study: novel oncology therapies
11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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Template 18.0
Bevacizumab Dose Modifications for Proteinuria
In cases where the toxicity is deemed to be immune related, refer to the toxicity management 
guidelines annex/website (https://tmg.azirae.com). In cases where toxicity can be reasonably 
attributed to the chemotherapy and if an immune-related etiology is ruled out, consider the 
following guidelines. If the investigator is unable to determine which study drug is a more 
likely cause of the AE (ie, FOLFOX, bevacizumab, or immunotherapeutics), then the 
treatment management should cover both etiologies. 

For proteinuria of ≥ 2+: Confirm total urine protein with a 24-hour urine collection or 
UPC ratio. For 2+ proteinuria, the scheduled dose of bevacizumab may be given while 
awaiting the results of the 24-hour collection or UPC ratio. For > 2+ proteinuria, skip 
bevacizumab while awaiting results of the 24-hour urine collection or UPC ratio. Other 
protocol therapy may be continued.

If proteinuria is ≥ 2 g/24 hours or UPC ratio ≥ 2.0, skip bevacizumab until urine protein 
recovers to < 2 g/24 hours or UPC < 2.0, continue other protocol treatment. If 
bevacizumab is delayed more than 8 weeks due to proteinuria, discontinue bevacizumab.

If nephrotic syndrome or ≥ Grade 3 proteinuria occurs, discontinue bevacizumab.
Dose Modifications for Elevated Transaminase and Alkaline 
Phosphatase Levels
Bevacizumab: After the first incidence of elevated ALT or AST levels or Grade 3 or Grade 4 
ALP, which the clinical investigator considers to be related to bevacizumab treatment, 
bevacizumab should only be resumed after laboratory values have resolved to Grade ≤1. 
Therapy with bevacizumab should be discontinued after the second incidence.
Other Bevacizumab Toxicities

For wound dehiscence requiring medical or surgical intervention: Discontinue 
bevacizumab.

For any grade gastrointestinal perforation, gastrointestinal leak, or intra-abdominal fistula: 
Discontinue bevacizumab.

For bowel obstruction: 

Grade 1: Subjects who experience partial obstruction not requiring medical 
intervention may continue on bevacizumab

Grade 2: Hold bevacizumab in subjects who experience partial obstruction requiring 
medical intervention. Resume upon complete resolution 

Grade 3/4: Discontinue bevacizumab

MedImmune
Protocol D910CC00001 Amendment 3
Platform study: novel oncology therapies
11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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Template 18.0
Hypersensitivity and Infusion Reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-(L)1 therapy (Brahmer et al, 2018). Since durvalumab is a human anti-PD-L1 mAb, 
as with any antibody, allergic reactions following the infusion are possible and can be caused 
by various mechanisms, including acute anaphylactic (IgE-mediated) and anaphylactoid 
reactions against the mAb, and serum sickness.
Severe hypersensitivity reactions should be managed according to standard clinical practice. 
At all sites, appropriate drugs and medical equipment to treat acute anaphylactic reactions 
must be immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. The study site must have immediate access to emergency resuscitation teams and 
equipment in addition to the ability to admit patients to an intensive care unit if necessary.
Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at the discretion of the Investigator.
Refer to the toxicity management guidelines annex/website (https://tmg.azirae.com) for the 
management of hypersensitivity and infusion related reactions for immune-related events.
Dose Modifications for Hypersensitivity Reactions (FOLFOX and Bevacizumab Only)

For Grade 1 hypersensitivity reactions (transient rash, drug fever < 38°C): Decrease the 
infusion rate by 50% until symptoms resolve, then resume at the initial planned rate.

For Grade 2 hypersensitivity reactions (urticaria, drug fever ≥38°C and/or asymptomatic 
bronchospasm): Stop infusion. Administer H1 and/or H2 blockers, and/or steroids 
according to institutional policy. Restart the infusion when symptoms resolve and pretreat 
before all subsequent doses. Treat according to institutional policy.

For Grade 3 or Grade 4 hypersensitivity reactions: Stop the infusion. Discontinue all 
protocol treatment and notify the sponsor medical monitor.
Oxaliplatin-induced Pharyngolaryngeal Dysesthesias
Should a subject develop oxaliplatin-induced pharyngolaryngeal dysesthesia, their oxygen 
saturation should be evaluated via a pulse oximeter; if normal, an anxiolytic agent may be 
given, and the subject observed in the clinic until the episode has resolved. Following this 
toxicity, subjects may continue protocol therapy if it is felt appropriate. A table comparing 
pharyngo-laryngodysesthesia to platinum hypersensitivity reactions is presented below 
(Table H3).

MedImmune
Protocol D910CC00001 Amendment 3
Platform study: novel oncology therapies
11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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Template 18.0
Table H3
Comparison of the Symptoms and Treatment of Pharyngo-
Laryngodysesthesias and Platinum Hypersensitivity Reactions
Clinical Symptoms
Pharyngo-Laryngeal
Dysesthesias
Platinum Hypersensitivity
Dyspnea
present
present
Bronchospasm
absent
present
Laryngospasm
absent
present
Anxiety
present
present
Oxygen saturation
normal
decreased
Difficulty swallowing
present (loss of sensation)
absent
Pruritus
absent
present
Urticaria/rash
absent
present
cold-induced symptoms
yes
no
Blood pressure
normal or increased
normal or decreased
Treatment
anxiolytics, observation in a 
controlled clinical setting until 
symptoms abate or at the 
physician’s discretion
oxygen, steroids, epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate
Bevacizumab Dose Modifications for Infusion Reactions
The initial bevacizumab dose should be administered over a minimum of 90 minutes. If no 
adverse reactions occur, the second dose should be administered over a minimum of 
60 minutes. Again, if no adverse reactions occur, the third and subsequent doses should be 
administered over a minimum of 30 minutes. If infusion-related adverse reactions occur, 
subsequent infusions should be administered over the shortest period that is well tolerated. 
Subjects may receive premedication with diphenhydramine 25 to 50 mg IV or orally 
30 minutes prior to bevacizumab if they have previously experienced mild infusion reactions. 
Acetaminophen premedication may also be used.
FOLFOX-induced Other Non-Hematologic Toxicities
For all other ≥ Grade 3 non-hematologic toxicities not described above, hold all protocol 
treatment and monitor toxicity at least weekly. If toxicity resolves to ≤Grade 1 within 
4 weeks, treatment may be resumed, with 5-FU at one lower dose level.
Dose Modification for Obese Subjects
There is no clearly documented adverse impact of treatment of obese subjects when dosing is 
performed according to actual body weight. Therefore, all applicable dosing is to be 
determined solely by the subject’s actual weight without any modification. This will eliminate 
the risk of calculation error and the possible introduction of variability in dose administration. 

MedImmune
Protocol D910CC00001 Amendment 3
Platform study: novel oncology therapies
11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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Failure to use actual body weight in the calculation of drug dosages will be considered a major 
protocol deviation. Physicians who are uncomfortable with administering chemotherapy dose 
based on actual body weight should not enroll obese subjects.

MedImmune
Protocol D910CC00001 Amendment 3
Platform study: novel oncology therapies
11 May 2022; Final
CONFIDENTIAL AND PROPRIETARY
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Site and Study Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include, but 
are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.

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