A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination Therapies in Subjects With Previously Treated Advanced EGFRm NSCLC
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: MedImmune LLC

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A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to 
Evaluate Novel Combination Therapies in Subjects with 
Previously Treated Advanced EGFRm NSCLC
Sponsor Protocol Number: D6070C00004
Application Number:
IND 135539
Investigational Product:
Oleclumab (MEDI9447), Osimertinib (Tagrisso®), and 
AZD4635
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC
One MedImmune Way
Gaithersburg, Maryland 20878
USA
Medical Monitor:
 
MedImmune
Phone: 
Contract Research Organization: ICON Clinical Research Ltd
Protocol History, Date:
Original Protocol, 31Aug2017
Amendment 1, 17Oct2017
Amendment 2, 01May2018
Amendment 3, 12Nov2018
Amendment 4, 01Feb2021
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune.
PPD
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PROTOCOL SYNOPSIS
TITLE
A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination Therapies in Subjects 
with Previously Treated Advanced EGFRm NSCLC
HYPOTHESIS
Novel combinations of immunotherapeutics and epidermal growth factor receptor (EGFR) tyrosine kinase 
inhibitors (TKIs) will demonstrate adequate safety, tolerability, and antitumor activity in subjects with 
previously treated advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer 
(NSCLC).
OBJECTIVES
Primary objectives:
Part 1:
•
To investigate the safety and tolerability of novel combination therapies administered in subjects with 
advanced EGFRm NSCLC and confirm the combination dose(s) for further clinical evaluation
Part 2:
•
To investigate the antitumor activity of novel combination therapies administered in subjects with 
advanced EGFRm NSCLC by evaluation of tumor response based on Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1
•
To investigate the safety and tolerability of novel combination therapies administered in subjects with 
advanced EGFRm NSCLC
Secondary objectives:
Parts 1 and 2
1.  To obtain a preliminary assessment of the antitumor activity of novel combination therapies administered 
in subjects with advanced EGFRm NSCLC by evaluation of tumor response based on RECIST version 1.1
2.  To evaluate the antitumor activity of novel combination therapies administered in subjects with advanced 
EGFRm NSCLC based upon T790M testing at baseline confirmed by a central lab
3.  To determine the pharmacokinetic (PK) profile of individual analytes of novel combination therapies 
(oleclumab [investigational name MEDI9447], osimertinib, and AZD4635) administered in subjects with 
advanced EGFRm NSCLC
4.  To determine the immunogenicity of oleclumab administered in subjects with advanced EGFRm NSCLC
Exploratory objectives:
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STUDY ENDPOINTS
Primary endpoints:
Part 1
•
Incidence of adverse events (AEs) and serious adverse events (SAEs)
•
Dose-limiting toxicities (DLTs)
•
Clinically meaningful changes from baseline in laboratory parameters, vital signs, and electrocardiogram 
(ECG) results
Part 2
•
Objective response (OR) according to RECIST version 1.1
•
Incidence of AEs and SAEs
•
Clinically meaningful changes from baseline in laboratory parameters, vital signs, and ECG results
Secondary endpoints:
Parts 1 and 2:
•
Duration of response (DoR), disease control (DC), progression-free survival (PFS), and overall survival 
(OS). RECIST version 1.1 will be used for assessment of tumor response.
•
OR and DC by T790M status at baseline (determined by a central lab) in archival and/or fresh tumor 
biopsies
•
Summary PK for all therapies and/or their metabolites
•
Development of detectable antidrug antibodies (ADAs)
Exploratory endpoints:
STUDY DESIGN
This is a multiarm, open-label, multicenter, Phase 1b/2 study to evaluate novel combination therapies in subjects 
with previously treated advanced EGFRm NSCLC. The study is divided into 2 parts. In Part 1 the safety and 
tolerability of novel combination therapies will be evaluated and a recommended Phase 2 dose (RP2D) for 
combination therapy will be identified. In Part 2 the safety, tolerability, and preliminary antitumor activity of 
novel combination therapies will be evaluated. Subjects will be treated in Arm A (oleclumab and osimertinib 
combination therapy) or Arm B (oleclumab and AZD4635 combination therapy). The allocation of subjects to 
treatment arms will be dependent upon the subject’s EGFR mutation status and prior therapies.
A total of up to approximately 98 subjects will be enrolled in this study at approximately 15 sites globally: up to 
approximately 46 subjects in Arm A and up to approximately 52 subjects in Arm B. 
Arm A will investigate the safety, tolerability, and antitumor activity of oleclumab given intravenously (IV) 
every 2 weeks (Q2W) in combination with osimertinib given orally (PO) once daily (QD) in subjects with 
advanced EGFRm NSCLC who have progressed on an approved first or second generation EGFR TKI therapy 
and who are T790M mutation negative and who have not received osimertinib.
During Part 1, dose escalation will be performed to determine the maximum tolerated dose (MTD) for 
oleclumab and osimertinib combination therapy. Dose escalation will begin with enrollment of at least 
3 subjects (and up to 6 subjects) at dose level 1 (oleclumab 1500 mg IV Q2W and osimertinib 80 mg PO QD). 
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Enrollment will be staggered for the first 2 subjects so that the administration of the first dose of investigational 
product is separated by at least 24 hours. The dose escalation committee (DEC) will monitor subjects for DLTs 
during the 28-day DLT-evaluation period and will make decisions for enrollment of additional subjects at a dose 
level, dose escalation to the next dose level, or dose de-escalation.
If no DLTs are observed in a cohort of 3 to 6 evaluable subjects then dose escalation to the next higher dose 
cohort will be permitted after review of all available safety data. At dose level 1 only, dose escalation to the next 
higher dose cohort will be permitted after review of all available safety data from a minimum of 3 evaluable 
subjects in that treatment arm and a minimum of 6 evaluable subjects across both treatment arms (Arms A 
and B). If 1 subject in a dose-level cohort of 3 or more evaluable subjects experiences a DLT, that dose-level 
cohort will be expanded to a total of 6 subjects. If no more than 1 of 6 subjects in the dose-level cohort 
experiences a DLT, dose escalation will continue to the next higher dose-level cohort. If ≥2 subjects in a 
dose-level cohort experience a DLT, the MTD will be exceeded and no further subjects will be enrolled into that 
dose-level cohort. If this occurs, the preceding dose-level cohort will be evaluated for the MTD and a total of 
6 subjects will be treated at the preceding dose level if not already expanded. If ≤ 1 of 6 subjects experiences a 
DLT at the preceding dose level, then this dose level will be the MTD. 
Intra-subject dose escalation will not be allowed. Intra-subject dose de-escalation will not be allowed during the 
DLT-evaluation period. 
If the MTD is exceeded at the starting dose level, then a lower dose level of oleclumab 750 mg Q2W and 
osimertinib 80 mg PO QD may be evaluated.
Based on emerging safety, efficacy, and PK data from this study as well as other ongoing studies of oleclumab 
and osimertinib, the sponsor may choose any safe dose for evaluation in Part 2 (Dose Expansion). Once the 
RP2D has been confirmed, enrollment into the Part 2 dose expansion may proceed. The DEC will continue to 
monitor the emerging data from the study. 
To ensure subject safety, continuous monitoring of interstitial lung disease events that occur in subjects enrolled 
in Arm A will be performed during the study.
During Part 2 (Dose Expansion) the RP2D confirmed from Part 1 will be administered in approximately 10 to 
40 subjects (including subjects dosed at the RP2D in Part 1). Continuous interim monitoring will begin after 
10 subjects are response-evaluable (including subjects dosed at the RP2D in Part 1).
Arm B will investigate the safety, tolerability, and antitumor activity of oleclumab given IV Q2W in 
combination with AZD4635 PO QD in subjects with advanced EGFRm NSCLC who have received 2 to 4 lines 
of prior therapy and who have progressed on either an approved first or second generation EGFR TKI or 
osimertinib.
During Part 1, dose escalation will be performed to determine the MTD for oleclumab and AZD4635 
combination therapy. Dose escalation will begin with enrollment of at least 3 subjects (and up to 6 subjects) at 
dose level 1 (oleclumab 1500 mg IV Q2W and AZD4635 75 mg PO QD). Enrollment will be staggered for the 
first 2 subjects so that the administration of the first dose of investigational product is separated by at least 
24 hours. The DEC will monitor subjects for DLTs during the 28-day DLT-evaluation period and will make 
decisions for enrollment of additional subjects at a dose level, dose escalation to the next dose level, or dose 
de-escalation.
If no DLTs are observed in a cohort of 3 to 6 evaluable subjects then dose escalation to the next higher dose 
cohort will be permitted after review of all available safety data. At dose level 1 only, dose escalation to the next 
higher dose cohort will be permitted after review of all available safety data from a minimum of 3 evaluable 
subjects in that treatment arm and a minimum of 6 evaluable subjects across both treatment arms (Arms A 
and B). A minimum of 3 evaluable subjects will be required at subsequent dose levels. If 1 subject in a 
dose-level cohort of 3 or more evaluable subjects experiences a DLT, that dose-level cohort will be expanded to 
a total of 6 subjects. If no more than 1 of 6 subjects in the dose-level cohort experiences a DLT, dose escalation 
will continue to the next higher dose-level cohort. If ≥2 subjects in a dose-level cohort experience a DLT, the 

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MTD will be exceeded and no further subjects will be enrolled into that dose-level cohort. If this occurs, the 
preceding dose-level cohort will be evaluated for the MTD and a total of 6 subjects will be treated at the 
preceding dose level if not already expanded. If ≤ 1 of 6 subjects experiences a DLT at the preceding dose level, 
then this dose level will be the MTD. 
Intra-subject dose escalation will not be allowed. Intra-subject dose de-escalation will not be allowed during the 
DLT-evaluation period. 
If the MTD is exceeded at the starting dose level, then lower dose levels will be evaluated (see Treatment 
Groups and Regimens).
Based on emerging safety, efficacy, and PK data from this study as well as other ongoing studies of oleclumab 
and AZD4635, the sponsor may choose any safe dose for evaluation in Part 2 (Dose Expansion). Once the 
RP2D has been confirmed, enrollment into the Part 2 dose expansion may proceed. The DEC will continue to 
monitor the emerging data from the study.
During Part 2 (Dose Expansion) the RP2D confirmed from Part 1 will be administered in approximately 20 to 
40 subjects (including subjects dosed at the RP2D in Part 1). Continuous interim monitoring will begin after 
20 subjects are response-evaluable (including subjects dosed at the RP2D in Part 1).
TARGET SUBJECT POPULATION
Male or female subjects ≥ 18 years of age with histologically or cytologically-confirmed locally 
advanced/metastatic NSCLC with EGFR mutation known to be associated with EGFR TKI sensitivity 
(including G719X, exon 19 deletion, L858R, L861Q). All subjects must have received and then progressed on at 
least one approved first or second generation EGFR TKI (eg, erlotinib or gefitinib [first generation] or afatanib 
[second generation]). Subjects in Arm A must have received 1 prior line of EGFR TKI therapy in the locally 
advanced/metastatic setting, be T790M mutation negative, and osimertinib naïve. Subjects in Arm B must have 
received at least 2 but not more than 4 prior lines of therapy in the locally advanced/metastatic setting. 
NOTE: For subjects in Arm B who received osimertinib as first-line treatment, then treatment with a first or 
second generation EGFR TKI is not required, and these subjects may enroll after having received and 
progressed on osimertinib alone but can still have received no more than 4 prior lines of therapy.
TREATMENT GROUPS AND REGIMENS
For Arm A
•
Part 1: Up to approximately 12 subjects will be treated in dose escalation. The planned dose levels are:

Dose Level 1 (3 to 6 subjects): Oleclumab 1500 mg IV Q2W and osimertinib 80 mg PO QD

Dose Level 2 (6 subjects): Oleclumab 3000 mg IV Q2W and osimertinib 80 mg PO QD 

Dose Level -1 (3 to 6 subjects): If the MTD is exceeded at the starting dose level (dose level 1), a 
lower dose level of oleclumab 750 mg IV Q2W and osimertinib 80 mg PO QD may be evaluated.
•
Part 2: The RP2D confirmed from Part 1 will be administered in approximately 10 to 40 subjects 
(including subjects dosed at the RP2D in Part 1).
For Arm B
•
Part 1: Up to approximately 18 subjects will be treated in dose escalation. The planned dose levels are:

Dose Level 1 (3 to 6 subjects): Oleclumab 1500 mg IV Q2W and AZD4635 75 mg PO QD

Dose Level 2 (3 to 6 subjects): Oleclumab 3000 mg IV Q2W and AZD4635 75 mg PO QD

Dose Level 3 (6 subjects): Oleclumab 3000 mg IV Q2W and AZD4635 100 mg PO QD

If the MTD is exceeded at Dose Level 1:
Dose Level -1 (3 to 6 subjects): Oleclumab 1500 mg IV Q2W and AZD4635 50 mg PO QD
Dose Level -1a (6 subjects): Oleclumab 3000 mg IV Q2W and AZD4635 50 mg PO QD

If the MTD is exceeded at Dose Level -1:
Dose Level -2 (3 to 6 subjects): Oleclumab 1500 mg IV Q2W and AZD4635 25 mg PO QD
Dose Level -2a (6 subjects): Oleclumab 3000 mg IV Q2W and AZD4635 25 mg PO QD

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•
Part 2: The RP2D confirmed from Part 1 will be administered in approximately 20 to 40 subjects 
(including subjects dosed at the RP2D in Part 1).
All subjects will remain on their respective treatments until documentation of disease progression, intolerable 
toxicity, or other reason for subject withdrawal develops. The assigned investigational product may be 
continued in the setting of progressive disease (PD) as long as the subject does not meet any of the 
investigational product discontinuation criteria and the treatment criteria in the setting of PD are met. Subjects 
with PD who are eligible to continue receiving investigational product will be made aware of the potential 
benefits and risks of continuing treatment in the setting of PD and must provide a separate written informed 
consent prior to treatment.
STATISTICAL METHODS
Sample size: A total of up to approximately 98 subjects will be enrolled in this study: up to approximately 
46 subjects in Arm A and up to approximately 52 subjects in Arm B.
Statistical analyses:
Safety
Safety data, including DLTs, AEs, SAEs, laboratory evaluations, vital signs, cardiac left ventricular function
(Arm A only), and ECG results will be summarized based on the As-treated Population, defined as all subjects 
who receive any investigational product, analyzed according to treatment received. Summary statistics will be 
provided for AEs, SAEs, AE grade (severity) and relationship to investigational product(s), clinical laboratory 
parameters, vital signs, cardiac left ventricular function (Arm A only), and ECG. Adverse events will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Efficacy
The efficacy analyses of antitumor activity will be based on the As-treated Population. The rates of OR and DC 
based on RECIST version 1.1 will be summarized with 95% confidence interval based on the exact binomial 
distribution. Time-to-event endpoints (DoR, PFS, and OS) will be analyzed using the Kaplan-Meier method. 
Additional analyses of antitumor activity may be conducted in the Response-evaluable Population, defined as all 
subjects who receive any investigational product, had measurable disease at baseline and at least 1 post-baseline 
tumor assessment, or who died from any cause or who discontinued due to clinical PD prior to any post-baseline 
tumor assessment.
Pharmacokinetics
Individual concentrations will be tabulated by dose cohort along with descriptive statistics. Non-compartmental 
PK data analysis will be performed from each dose cohort with scheduled PK sample collection where data 
allow. Relevant descriptive statistics of non-compartmental PK parameters will be provided for individual 
compounds.
Anti-drug antibodies/immunogenicity
For each arm, the immunogenic potential of oleclumab will be assessed by summarizing the number and 
percentage of subjects who develop detectable ADAs. 
 
 Samples will be collected for potentially evaluating the neutralizing capacity of ADAs in the future.
 
Interim analysis: Bayesian predictive probabilities will be used for continuous interim monitoring by 
estimating the probability of observing a targeted treatment effect or futility of the treatment if the trial were to 
continue to its predefined maximum sample size.
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ......................................................................................................2
LIST OF ABBREVIATIONS..............................................................................................13
1
INTRODUCTION ............................................................................................16
1.1
Disease Background..........................................................................................16
1.2
Oleclumab, Osimertinib, and AZD4635 Background.........................................16
1.2.1
Oleclumab Background.....................................................................................17
1.2.2
Osimertinib Background ...................................................................................17
1.2.3
AZD4635 Background ......................................................................................17
1.3
Summary of Nonclinical Experience .................................................................17
1.3.1
Oleclumab Nonclinical Experience....................................................................17
1.3.2
Osimertinib Nonclinical Experience..................................................................19
1.3.3
AZD4635 Nonclinical Experience.....................................................................19
1.4
Summary of Clinical Experience.......................................................................21
1.4.1
Oleclumab Clinical Experience .........................................................................21
1.4.1.1
Study D6070C00001.........................................................................................21
1.4.1.2
Study D6070C00004.........................................................................................23
1.4.2
Osimertinib Clinical Experience........................................................................24
1.4.3
AZD4635 Clinical Experience...........................................................................27
1.5
Rationale for Conducting the Study...................................................................29
1.6
Benefit-Risk and Ethical Assessment ................................................................31
1.7
Research Hypotheses.........................................................................................33
2
OBJECTIVES AND ENDPOINTS ...................................................................34
2.1
Primary Objectives and Associated Endpoints...................................................34
2.2
Secondary Objectives and Associated Endpoints...............................................35
2.3
Exploratory Objectives and Associated Endpoints.............................................36
3
STUDY DESIGN..............................................................................................36
3.1
Description of the Study....................................................................................36
3.1.1
Overview………...............................................................................................36
3.1.2
Treatment Regimen...........................................................................................38
3.1.2.1
Treatment Regimen: Arm A..............................................................................39
3.1.2.2
Treatment Regimen: Arm B ..............................................................................40
3.1.3
Dose Escalation, Cohort Progression, and Dose-limiting Toxicity.....................41
3.1.3.1
Dose Escalation Committee (Arms A and B).....................................................41
3.1.3.2
Rules for Dose Escalation and Cohort Progression (Arms A and B) ..................41
3.1.3.3
Dose-Limiting Toxicity (Arms A and B)...........................................................42
3.1.4
Management of Study Medication Related Toxicities........................................43
3.1.4.1
For Toxicity That Occurs While on Oleclumab and Osimertinib (Arm A) .........44
3.1.4.2
For Toxicity That Occurs While on Oleclumab and AZD4635 (Arm B) ............44
3.2
Rationale for Dose, Population, and Endpoints..................................................45
3.2.1
Dose Rationale..................................................................................................45

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3.2.2
Rationale for Study Population..........................................................................46
3.2.2.1
Rationale for Study Population (Arm A) ...........................................................47
3.2.2.2
Rationale for Study Population (Arm B)............................................................47
3.2.3
Rationale for Endpoint(s) ..................................................................................48
4
MATERIALS AND METHODS.......................................................................49
4.1
Subjects.............................................................................................................49
4.1.1
Number of Subjects...........................................................................................49
4.1.2
Inclusion Criteria...............................................................................................49
4.1.3
Exclusion Criteria .............................................................................................51
4.1.4
Subject Enrollment............................................................................................55
4.1.5
Withdrawal from the Study ...............................................................................55
4.1.6
Discontinuation of Investigational Product........................................................55
4.1.7
Treatment Beyond Progression..........................................................................56
4.1.8
Replacement of Subjects ...................................................................................57
4.1.9
Withdrawal of Informed Consent for Data and Biological Samples ...................57
4.2
Schedule of Study Procedures ...........................................................................58
4.2.1
Enrollment/Screening Period.............................................................................58
4.2.2
Treatment Period...............................................................................................60
4.2.3
Follow-up Period...............................................................................................69
4.3
Description of Study Procedures .......................................................................70
4.3.1
Efficacy……….................................................................................................70
4.3.1.1
 
4.3.1.2
4.3.2
Medical History, Physical Examination, Ophthalmologic Examination, 
Electrocardiogram, Echocardiogram/MUGA, Weight, and Vital Signs..............76
4.3.3
Clinical Laboratory Tests ..................................................................................77
4.3.4
Pharmacokinetic Evaluation and Methods .........................................................79
4.3.5
Immunogenicity Evaluation and Methods..........................................................79
4.3.6
4.3.7
Estimate of Volume of Blood to Be Collected ...................................................81
4.4
Expected Start and End of Study .......................................................................81
4.5
Study Suspension or Termination......................................................................82
4.6
Investigational Products ....................................................................................83
4.6.1
Identity of Investigational Product(s).................................................................83
4.6.1.1
Investigational Product Inspection.....................................................................84
4.6.1.2
Oleclumab (MEDI9447) IV Bag Preparation and Administration......................84
4.6.1.3
Treatment Administration .................................................................................86
4.6.1.4
Monitoring of Dose Administration...................................................................87
4.6.1.5
Reporting Product Complaints...........................................................................87
4.6.2
Additional Study Medications ...........................................................................88
4.6.3
Labeling………. ...............................................................................................88
4.6.4
Storage………. .................................................................................................88
4.6.5
Treatment Compliance ......................................................................................88
4.6.6
Accountability...................................................................................................89
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4.7
Treatment Assignment and Blinding .................................................................89
4.7.1
Methods for Assigning Treatment Groups.........................................................89
4.7.2
Methods to Ensure Blinding ..............................................................................89
4.8
Restrictions During the Study and Concomitant Treatment(s)............................89
4.8.1
Permitted Concomitant Medications..................................................................89
4.8.2
Prohibited Concomitant Medications.................................................................90
4.9
Statistical Evaluation.........................................................................................92
4.9.1
General Considerations .....................................................................................92
4.9.2
Sample Size ......................................................................................................92
4.9.3
Safety………. ...................................................................................................93
4.9.3.1
Analysis of Safety Endpoints.............................................................................93
4.9.4
Efficacy Analyses .............................................................................................93
4.9.4.1
Analysis of Efficacy Endpoints .........................................................................93
4.9.5
Analysis of Immunogenicity/Pharmacokinetics .................................................94
4.9.6
4.9.7
Continuous Monitoring for Interstitial Lung Disease (Arm A only)...................95
4.9.8
Interim Analysis................................................................................................96
5
ASSESSMENT OF SAFETY............................................................................98
5.1
Definition of Adverse Events ............................................................................98
5.2
Definition of Serious Adverse Events................................................................99
5.3
Definition of Adverse Events of Special Interest .............................................100
5.3.1
Adverse Events of Special Interest for Oleclumab...........................................100
5.3.1.1
Infusion-related Reactions...............................................................................100
5.3.1.2
Cardiac Chest Pain, Transient Ischemic Attack, and Thromboembolism..........100
5.3.1.3
Edema………. ................................................................................................101
5.3.1.4
Immune Complex Disease...............................................................................101
5.3.2
Adverse Events of Special Interest for Osimertinib..........................................101
5.3.2.1
Interstitial Lung Disease/Pneumonitis .............................................................101
5.3.2.2
QTc Prolongation and Arrhythmias.................................................................102
5.3.2.3
Changes in Cardiac Contractility.....................................................................102
5.4
Recording of Adverse Events ..........................................................................102
5.4.1
Time Period for Collection of Adverse Events.................................................103
5.4.2
Follow-up of Unresolved Adverse Events .......................................................103
5.4.3
Deaths………. ................................................................................................103
5.4.4
Recording of Interstitial Lung Disease/Pneumonitis ........................................104
5.5
Reporting of Serious Adverse Events ..............................................................104
5.6
Other Events Requiring Immediate Reporting .................................................104
5.6.1
Overdose………. ............................................................................................104
5.6.2
Medication Error.............................................................................................105
5.6.3
Hepatic Function Abnormality ........................................................................105
5.6.4
Pregnancy………............................................................................................105
5.6.4.1
Maternal Exposure ..........................................................................................105
5.6.4.2
Paternal Exposure ...........................................................................................106
5.6.5
Interstitial Lung Disease/Pneumonitis .............................................................106
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6
STUDY AND DATA MANAGEMENT.........................................................106
6.1
Training of Study Site Personnel.....................................................................106
6.2
Monitoring of the Study ..................................................................................107
6.2.1
Source Data.....................................................................................................107
6.2.2
Study Agreements...........................................................................................107
6.2.3
Archiving of Study Documents .......................................................................107
6.3
Study Timetable and End of Study ..................................................................108
6.4
Data Management ...........................................................................................108
6.5
Medical Monitor Coverage..............................................................................108
7
ETHICAL AND REGULATORY REQUIREMENTS....................................109
7.1
Subject Data Protection...................................................................................109
7.2
Ethics and Regulatory Review.........................................................................109
7.3
Informed Consent............................................................................................110
7.4
Changes to the Protocol and Informed Consent Form......................................110
7.5
Audits and Inspections ....................................................................................110
8
REFERENCES ...............................................................................................112
9
CHANGES TO THE PROTOCOL..................................................................119
9.1
Protocol Amendment 4....................................................................................119
9.2
Protocol Amendment 3....................................................................................119
9.3
Protocol Amendment 2....................................................................................121
9.4
Protocol Amendment 1....................................................................................124
10
APPENDICES ................................................................................................127
10.1
Appendix 1 - Signatures..................................................................................127
10.2
Appendix 2 – Contraception Guidance ............................................................129
10.3
Appendix 3 - Additional Safety Guidance .......................................................130
10.4
Appendix 4 - National Institute of Allergy and Infectious Disease and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis.........134
10.5
Appendix 5 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law............................................................................135
10.5.1
Introduction.....................................................................................................135
10.5.2
Definitions ......................................................................................................135
10.5.2.1
Potential Hy’s Law..........................................................................................135
10.5.2.2
Hy’s Law ........................................................................................................135
10.5.3
Identification of Potential Hy’s Law Cases......................................................135
10.5.4
Follow-up………............................................................................................136
10.5.4.1
Potential Hy’s Law Criteria Not Met...............................................................136
10.5.4.2
Potential Hy’s Law Criteria Met......................................................................136
10.5.5
Review and Assessment of Potential Hy’s Law Cases .....................................137
10.5.6
Actions Required for Repeat Episodes of Potential Hy’s Law..........................138

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Appendix 6 – Treatment Modification and Toxicity Management Guidelines 
for Oleclumab .................................................................................................139
10.7
Appendix 7 – Exceptions to the Management of Non-immune-mediated 
Reactions for Osimertinib................................................................................165
10.8
Appendix 8 – Treatment Modification Guidelines for AZD4635 .....................166
10.9
Appendix 9 - Guidance Regarding Potential Interactions of Osimertinib with 
Concomitant Medications (Arm A) .................................................................170
10.9.1
Drugs Inducing CYP3A4 Metabolism that Sponsor Strongly Recommends 
Are Not Combined with Osimertinib...............................................................170
10.9.2
Medicines Whose Exposures May Be Affected by Osimertinib that Sponsor 
Considers May Be Allowed with Caution........................................................170
10.9.3
Drugs That May Prolong QT Interval..............................................................171
10.9.3.1
Drugs Known to Prolong QT Interval..............................................................171
10.9.3.2
Drugs That May Possibly Prolong QT Interval................................................172
10.10
Appendix 10 - Prohibited Medications for Subjects treated with AZD4635 in 
Arm B.............................................................................................................172
LIST OF TABLES
Table 1
Arm A Combination Therapies and Dose Levels (Part 1: Dose 
Escalation) ...............................................................................................39
Table 2
Schedule of Screening Procedures (All Arms)..........................................58
Table 3
Treatment Period Study Procedures – Arm A (Oleclumab + 
Osimertinib).............................................................................................61
Table 4
Treatment Period Study Procedures - Arm B (Oleclumab + AZD4635)....65
Table 5
Schedule of Follow-up Procedures (All Arms) .........................................69
Table 6
Evaluation of Overall Response ...............................................................74
Table 7
Table 8
Identification of Investigational Products .................................................83
Table 9
 
Table 10
ILD Monitoring Plan - Continuous Monitoring Based on the Potential 
Number of ILD Cases ..............................................................................96
Table 11
Methods of Contraception......................................................................129
Table 12
Treatment Modification and Toxicity Management Guidelines for 
Immune-mediated Adverse Events – General Considerations.................140
Table 13
Treatment Modification and Toxicity Management Guidelines for 
Immune-mediated Adverse Events.........................................................142
Table 14
Treatment Modification and Toxicity Management Guidelines for 
Infusion-related Reactions......................................................................163
Table 15
Treatment Modification and Toxicity Management Guidelines for Non-
immune-mediated Reactions ..................................................................164
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Exceptions to the Management of Non-immune-mediated Reactions for 
Osimertinib ............................................................................................165
Table 17
AZD4635 Dose Modifications for Hematologic Toxicities.....................167
Table 18
AZD4635 Dose Modifications and Discontinuation Criteria for Non-
hematologic Toxicities (except Hypertension and CNS Toxicities).........167
Table 19
AZD4635 Dose Modifications and Discontinuation Criteria for 
Management of Hypertension.................................................................168
Table 20
AZD4635 Dose Modifications and Discontinuation Criteria for CNS 
Toxicities (Including Seizure) ................................................................169
Table 21
Drugs Inducing CYP3A4 .......................................................................170
Table 22
Exposure, Pharmacological Action, and Toxicity May Be increased by 
Osimertinib ............................................................................................171
Table 23
Drugs Prolonging QT Interval................................................................171
Table 24
Drugs That May Prolong QT Interval.....................................................172
Table 25
Examples of potent and moderate CYP1A2 enzyme inhibitors and 
inducers .................................................................................................173
Table 26
Examples of sensitive substrates of CYP1A2, BCRP, and OAT1 ...........173
LIST OF FIGURES
Figure 1
Study Flow Diagram for Part 1: Dose Escalation......................................37
Figure 2
Study Flow Diagram for Part 2: Dose Expansion......................................38
Figure 3
Arm B Combination Therapies and Dose Levels (Part 1: Dose 
Escalation) ...............................................................................................40
Figure 4
Figure 5
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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
A1R
adenosine 1 receptor
A2AR
adenosine2A receptor
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AMP
adenosine monophosphate
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
Area under the concentration-time curve
BID
twice daily
BP
blood pressure
CD
cluster of differentiation
CI
confidence interval
CL
clearance
CL/F
Apparent plasma clearance
Cmax
maximum observed concentration
CT
computed tomography
Ctrough
trough plasma concentration 
CNS
central nervous system
CR
complete response
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
cytochrome P
DC
disease control
DCR
disease control rate
DEC
Dose Escalation Committee
DHEA
dehydroepiandrosterone
DLT
dose-limiting toxicity
DoR
duration of response
ECG
electrocardiogram
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Abbreviation or 
Specialized Term
Definition
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EGFRm
epidermal growth factor receptor mutant
FTIH
first-time-in-human
GCP
good clinical practice
GI
gastrointestinal
GLP
Good Laboratory Practice
HRCT
high resolution computed tomography
IC50
concentration giving half-maximal inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN-γ
interferon-gamma
Ig
immunoglobulin
ILD
interstitial lung disease
imAE
immune-mediated adverse event
IO
immuno-oncology
IRB
Institutional Review Board
IRR
infusion-related reaction
iRECIST
Immune Response Evaluation Criteria in Solid Tumors
IV
intravenous(ly)
IXRS
interactive voice response system/interactive web response system
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MDSC
myeloid-derived suppressor cell
MRI
magnetic resonance imaging
MSS-CRC
microsatellite stable colorectal cancer
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
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Abbreviation or 
Specialized Term
Definition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PART
Post Analysis and Reporting Team
PD
progressive disease
PD-1
programmed cell death-1
PD-L1
programmed cell death ligand-1
PFS
progression-free survival
PK
pharmacokinetic(s)
PO
per os (orally)
PR
partial response
Q2W
every 2 weeks
Q4W
every 4 weeks
QD
once daily
QTc 
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RP2D
recommended Phase 2 dose
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
stable disease
SID
subject identification
TEAE
treatment-emergent adverse event
t1/2
terminal half-life
TBL
total bilirubin
TKI
tyrosine kinase inhibitor
tmax
time to reach Cmax
Treg
regulatory T cells
ULN
upper limit of normal
Vz/F
apparent volume of distribution
w/v
weight/volume

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1
INTRODUCTION
1.1
Disease Background
Lung cancer is the most common and lethal cancer worldwide with an estimated 1.83 million 
new cases annually resulting in 1.59 million deaths (GLOBOCAN, 2015). The majority 
(80% to 85%) of these cases are non-small cell lung cancer (NSCLC). Unfortunately, most 
patients present with advanced or metastatic disease not amenable to curative treatments. 
Furthermore, many of the patients treated for early stage disease will have recurrence and die 
as a result of their lung cancer (Pisters and Le Chevalier, 2005).
Patients presenting with advanced NSCLC have a median overall survival (OS) of 10 to 
12 months (Bonomi, 2010). However, outcomes can be significantly better for patients 
whose tumors are found to harbor certain targetable molecular drivers such as epidermal 
growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase or ROS1 gene 
rearrangements. Approximately, 10% of Caucasian patients and up to 50% of Asian patients 
with NSCLC will harbor a targetable activating EGFR mutation, the most common of which 
are L858R and deletions in exon 19 (Ettinger et al, 2017). For these subjects, EGFR tyrosine 
kinase inhibitors (TKIs) are now the established first-line therapy and result in an objective 
response rate (ORR) of approximately 70% (Oxnard and Miller, 2010). Unfortunately, TKI 
resistance is inevitable and the median progression-free survival (PFS) is only 8 to 13 months 
(Mok, 2011). The emergence of a secondary T790M mutation in patients treated with a first-
generation EGFR TKI agent has been described as a major route of development of 
resistance (Kobayashi et al, 2005; Pao et al, 2005) in approximately 60% of patients 
(Yu et al, 2013). Second-line therapy for epidermal growth factor receptor mutant (EGFRm) 
NSCLC is dependent upon the presence or absence of the T790M mutation. Second-line 
therapy options include a third generation EGFR TKI such as osimertinib (Tagrisso®) for 
those with a T790M mutation, or platinum-based chemotherapy for those that lack the 
T790M mutation. In a Phase 3 trial of patients with an EGFRm T790M mutation comparing 
osimertinib to platinum-doublet therapy the ORRs were 71% and 31% with a median PFS of 
10.1 and 4.4 months, respectively (Mok et al, 2017). Currently, there is no global standard of 
care for third-line therapy in T790M negative patients or fourth-line therapy in T790M 
positive patients who have previously received osimertinib, but this may include single-agent 
chemotherapy, therapy with an alternative EGFR TKI not used during the initial treatment, or 
anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) 
monotherapy (Becker et al, 2011; Ettinger et al, 2017; Langer et al, 2013; 
Novello et al 2016).
1.2
Oleclumab, Osimertinib, and AZD4635 Background
Oleclumab (investigational name MEDI9447), osimertinib, and AZD4635 are briefly 
described below. Refer to the respective current Investigator’s Brochures for details. 

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1.2.1
Oleclumab Background
Oleclumab is a human immunoglobulin (Ig) G1 lambda monoclonal antibody (mAb) that 
selectively binds to and inhibits the ectonucleotidase activity of cluster of differentiation 
(CD)73. The triple mutation, L234F/L235E/P331S (according to European Union numbering 
convention), is encoded in the heavy chain constant region to significantly reduce IgG 
effector function. Oleclumab inhibits the catalysis of adenosine monophosphate (AMP) to 
adenosine and organic phosphate by CD73. Extracellular adenosine contributes to the 
immunosuppressive effects of both regulatory T cells (Tregs) and myeloid-derived 
suppressor cells (MDSCs), among others (Antonioli et al, 2013). The enzymatic blockade of 
CD73 caused by binding of oleclumab to CD73 may lead to increased antitumor immunity.
1.2.2
Osimertinib Background
Osimertinib is a potent, selective, central nervous system (CNS)-active, irreversible inhibitor 
of both the single EGFRm (TKI sensitivity conferring mutation) and dual EGFRm/T790M 
(TKI resistance conferring mutation) receptor forms of EGFR with a wide margin of 
selectivity against EGFR wild-type (Ballard et al, 2016; Cross et al, 2014; Goss et al, 2017; 
Ward et al, 2013; Yang et al, 2017). Therefore, osimertinib has the potential to provide 
clinical benefit to patients with advanced NSCLC harboring both the single sensitivity 
mutations and the resistance mutation following prior therapy with an EGFR TKI. 
Osimertinib is currently approved in 50 countries including the United States and South 
Korea for the treatment of patients with EGFR T790M mutation who have progressed on 
prior EGFR TKI therapy.
1.2.3
AZD4635 Background
AZD4635 is a potent, selective adenosine2A receptor (A2AR) antagonist. Adenosine, produced 
by CD73 catalysis of AMP or other extracellular enzymes, binds to A2AR and suppresses an 
immune response in order to limit tissue injury (Leone et al, 2015). AZD4635 blocks the 
ability of adenosine to bind A2AR in a dose-dependent manner and clinical trials have 
demonstrated that A2AR receptor blockade in humans leads to immune activation in the 
tumor microenvironment (Emens et al, 2017). 
1.3
Summary of Nonclinical Experience
The nonclinical experience with oleclumab, osimertinib, and AZD4635 is briefly described 
below. Refer to the respective current Investigator’s Brochures for additional details.
1.3.1
Oleclumab Nonclinical Experience
In nonclinical studies, oleclumab has been shown to:

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Activate the myeloid compartment of spleens from syngeneic CT26 tumor-bearing mice 
when administered in combination with anti-PD-1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 As CD73 is found in most tissues (Colgan et al, 2006; Resta et 
al, 1998; Zhang B., 2010), the widespread immunoreactivity of oleclumab in this study was 
anticipated.
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The ability of oleclumab (alone or in combination with durvalumab [investigational name 
MEDI4736; anti-PD-L1 mAb]) to induce cytokine release was evaluated in human in vitro 
assays using blood or peripheral blood mononuclear cell from healthy donors. Oleclumab 
alone or in combination with durvalumab, presented in solution or immobilized on plastic 
wells by dry-coating, did not induce cytokine release.
1.3.2
Osimertinib Nonclinical Experience
Carcinogenicity studies have not been performed with osimertinib. Osimertinib did not cause 
genetic damage in in vitro and in vivo assays. 
 
 
 
 
 
 
 
 
 
 
1.3.3
AZD4635 Nonclinical Experience
Key findings from the nonclinical pharmacology testing include:

AZD4635 is a potent, highly selective inhibitor of A2AR.

AZD4635 blocks cyclic AMP production in a dose-dependent manner.

AZD4635 decreases adenosine’s suppressive effect on T cells as noted by restoration of 
CD8+ cell proliferation and interferon gamma secretion in in vitro assays.
 
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1.4
Summary of Clinical Experience
The clinical experience with oleclumab, osimertinib, and AZD4635 is briefly described 
below. Refer to the respective current Investigator’s Brochures for details.
1.4.1
Oleclumab Clinical Experience
1.4.1.1
Study D6070C00001
Study D6070C00001 is a first-time-in-human (FTIH), Phase 1, multicenter, open-label, 
dose-escalation, and dose-expansion study of oleclumab to be administered as a single agent 
or in combination with durvalumab in adult subjects with selected advanced solid tumors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.4.1.2
Study D6070C00004
Arm A
 
 
 
 
 
 
 
 
 
 
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Arm B
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
1.4.2
Osimertinib Clinical Experience
The clinical experience of osimertinib is summarized below. Additional information is 
available in the Investigator’s Brochure and the local Health Authority approved Prescribing 
Information.
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1.4.3
AZD4635 Clinical Experience
A FTIH study of AZD4635 (D8730C00001) is currently being conducted.
Study D8730C0001 is a Phase 1, open-label, multicenter study to assess the safety, 
tolerability, PK, and preliminary antitumor activity of ascending doses of AZD4635 both as 
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monotherapy and in combination with durvalumab in subjects with advanced solid 
malignancies.
 
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1.5
Rationale for Conducting the Study
This is an open-label, multiarm, multicenter, Phase 1b/2 study to evaluate novel combination 
therapies in subjects with previously treated advanced EGFRm NSCLC. 
Despite therapeutic advances in recent years with both targeted and immunotherapeutic 
agents, patients who present with metastatic NSCLC still have poor OS. Of the 1.8 million 
new cases of NSCLC worldwide each year, approximately, 10% of Caucasian patients and 
up to 50% of Asian patients with NSCLC will harbor an activating EGFR mutation that 
serves as the molecular driver of their cancer. Notably, these mutations are more likely to be 
found in younger, never smokers, and females as compared to the overall population afflicted 
by NSCLC (Ettinger et al, 2017; Novello et al, 2016). 
Upon progression after the standard of care EGFR TKI, most patients will receive 
second-line (T790M negative) or third-line (T790M positive, treated with osimertinib) 
platinum-based chemotherapy. This generally provides response rates in the range of 25% to 
35% with a median PFS of 3 to 6 months (Goldberg et al, 2012; Gridelli et al, 2012; 
Maemondo et al, 2010; Mok et al, 2014; Mok et al, 2017; Wang et al, 2012b; 
Wu et al, 2011). However, this therapy is accompanied by the typical toxicities associated 
with cytotoxic therapies including nausea, vomiting, bone marrow suppression, alopecia, 
fatigue, and peripheral neuropathy. 
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Furthermore, there is no global standard of care for later lines of therapy but options include 
single-agent chemotherapy, therapy with an alternative EGFR TKI not used during the initial 
treatment, anti-PD-1/PD-L1 monotherapy, or clinical trials. In unselected NSCLC patients 
who progressed on prior platinum-containing doublet chemotherapy, low response rates 
(approximately 10%) and short PFS (median PFS, approximately 2 to 3 months) were 
observed after treatment with single agent chemotherapy such as docetaxel or pemetrexed 
(Alimita Prescribing Information, 2015; Taxotere Prescribing Information, 2016).
Re-treatment with an EGFR TKI (eg, switching to erlotinib following failure of gefitinib, or 
to afatinib following failure of erlotinib or gefitinib, or re-treatment with the same EGFR 
TKI after a period off drug) provided low response rates (approximately 10%) and PFS in a 
similar range to that of single agent chemotherapy (Hata et al, 2011; Lee et al, 2013; 
Miller et al, 2012). Similarly, anti-PD-1/PD-L1 inhibitors have demonstrated low response 
rates (approximately 10%) and their role in the treatment of EGFRm NSCLC is still being 
elucidated (Garassino et al, 2017; Lee et al, 2017). Other novel agents and combinations have 
tried to overcome the acquired resistance to EGFR TKIs with response rates generally lower 
than 10% (eg, EGFR TKI plus everolimus: response rate, 0% (Riely et al, 2007); neratinib 
response rate, 3% (Sequist et al, 2010a), IPI 504 response rate, 4% (Sequist et al, 2010b).
There is a considerable unmet clinical need for well-tolerated, efficacious therapeutic 
options, with minimal side effects, that build upon the molecular aberrations that are specific 
for patients with EGFRm NSCLC following progression on EGFR TKI therapy and to delay 
the initiation of chemotherapy and its long term consequences.
Immunotherapy in EGFRm NSCLC
Immune responses directed against tumors are one of the body’s natural defenses against the
growth and proliferation of cancer cells. However, over time and under pressure from 
immune attack, cancers develop strategies to evade immune-mediated killing allowing them 
to grow and metastasize unchecked. One such mechanism involves upregulation of surface 
proteins that deliver inhibitory signals to cytotoxic T cells. PD-L1 is one such protein, and is 
expressed in a broad range of cancers. This inhibits immune activating signals by binding 
and signaling through PD-1 and CD80 receptors on T cells. The use of mAbs against PD-L1 
or PD-1 to block this interaction and the subsequent inhibitory signals has led to significant 
improvement in the treatment of NSCLC (Brahmer et al, 2015; Fehrenbacher et al, 2016; 
Herbst et al, 2016). Unfortunately, patients with EGFRm NSCLC have not realized the same 
benefits from treatment with single-agent anti-PD-1 or PD-L1 therapy as the subset analyses 
have demonstrated no improvement in survival over chemotherapy (Brahmer et al, 2015; 
Rittmeyer et al, 2017). This suggests that EGFRm NSCLC has developed different 
mechanisms of immune escape compared to EGFR wild-type tumors necessitating innovative 
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CD73 Blockade in EGFRm NSCLC
Adenosine is a regulatory autocrine and paracrine factor that accumulates in the tumor 
microenvironment, influencing immune activity, angiogenesis, and metastasis 
(Antonioli et al, 2013). Upon apoptotic or necrotic cell death, tumor cells release adenosine 
triphosphate (ATP) into the extracellular space. ATP has been shown to lead to a 
pro-inflammatory response. In order to prevent an immune reaction stimulated by cell death, 
tissues express CD39 and CD73 to enzymatically convert ATP to adenosine which induces a 
localized immunosuppressive response through pleotropic effects upon multiple immune cell 
types. Elevated levels of extracellular adenosine have been reported within the tumor 
microenvironment, in part due to up-regulation of CD73 within cancerous tissues 
(Zhang, 2010).
One mechanism by which EGFRm tumors may have evolved to evade the immune system is 
via overexpression of CD73. Recent investigations found that CD73 overexpression was 
more frequent in EGFRm NSCLC as compared to EGFR wild-type NSCLC 
(Inoue et al, 2017). Furthermore, CD73 overexpression was found to be an independent 
predictor of poor survival in 642 resected NSCLC specimens (Inoue et al, 2017). CD73 
overexpression in EGFRm NSCLC has been further corroborated and confirmed by an 
independent analysis conducted by MedImmune of The Cancer Genome Atlas database as 
well as profiling of both messenger RNA and protein expression in previously collected 
samples (Liu et al, 2012; Streicher et al, 2017; Wu et al, 2012). Of note, the majority of these 
samples were from resected specimens and thus were TKI-naïve. In addition to the results in 
NSCLC, tumor overexpression of CD73 has also been associated with poor prognosis in 
other malignancies including colorectal cancer (Liu et al, 2012; Wu et al, 2012), triple-
negative breast cancer (Loi et al, 2013), renal cell carcinoma (Yu et al, 2015), gastric cancer 
(Lu et al, 2013), high-grade serous ovarian cancer (Turcotte et al, 2015), head and neck 
squamous cell carcinoma (Ren et al, 2016), or with metastasis in prostate cancer 
(Yang et al, 2013) and melanoma (Wang et al, 2012a). Thus, there is sufficient data to 
support the hypothesis of combining anti-CD73 blockade with other treatment modalities for 
advanced EGFRm NSCLC to restore antitumor immunity.
This study will help to identify a novel therapeutic strategy for EGFRm NSCLC by 
investigating combinations of both approved and investigational agents 
(immunotherapy + TKI and immuno-oncology [IO]-IO) to improve clinical outcomes.
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 Conference of Harmonisation 
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Potential benefits
Oleclumab is a human immunoglobulin IgG1 lambda mAb that selectively binds to and 
inhibits the ectonucleotidase activity of CD73. Oleclumab inhibits the catalysis of AMP to 
adenosine and organic phosphate by CD73. The enzymatic blockade of CD73 caused by 
binding of oleclumab to CD73 may lead to increased antitumor immunity. Preliminary data 
from study D6070C00001 demonstrate that treatment with oleclumab is well tolerated 
(Section 1.4.1) and leads to a reduction in CD73 expression on circulating immune cells. As 
CD73 overexpression has been identified as a possible mechanism of immune escape for 
EGFRm NSCLC, oleclumab is a potential candidate to be combined with other active and 
novel agents to reduce CD73 expression and block adenosine-mediated immunosuppression 
thereby enhancing the therapeutic response.
Osimertinib is a potent, selective, CNS-active, irreversible inhibitor of both the single 
EGFRm and dual EGFRm/T790M receptor forms of EGFR with a significant selectivity 
margin over wild-type EGFR. Efficacy and safety findings in the AURA3 trial have shown 
that osimertinib has superior efficacy and a more favorable safety profile compared with 
platinum-doublet chemotherapy in patients with EGFR T790M mutation positive NSCLC 
who have progressed on prior EGFR-TKI therapy. These findings for osimertinib were 
supported by efficacy and safety data in the AURA Extension and AURA2 trials. 
Additionally, the AURA trial (Phase 1 component) demonstrated that subjects with EGFRm 
T790M negative NSCLC had an ORR of 24.6% across all osimertinib doses (20 to 240 mg 
QD) and 20.7% at osimertinib 80 mg QD (Section 1.4.2).
AZD4635 is a novel A2AR antagonist agent that acts against cancer by blocking 
adenosine-mediated A2AR signaling in tumor infiltrating cells. AZD4635 blockade is 
hypothesized to modulate the tumor microenvironment so that an active antitumor immune 
response will be more effective. Therefore, AZD4635 may have the potential to provide 
benefit in terms of increased efficacy in subjects with advanced EGFRm NSCLC. 
Additionally, synergistic antitumor activity was demonstrated by the dual blockade of CD73 
and A2AR in preclinical studies (Young et al, 2016). There is no standard of care for 
third-line therapy (T790M negative patients) or fourth-line therapy (T790M positive patients 
who have previously received osimertinib) for EGFRm NSCLC. The most common 
treatment is docetaxel with an ORR of approximately 10%, however, this therapy has a 
significant toxicity profile. In the advanced cancer setting, prolonged survival rates are very 
low and there is considerable unmet clinical need for novel therapeutic agents and 
combinations (Section 1.5). The combination of oleclumab and AZD4635 to block the 
adenosine pathway may lead to antitumor activity in subjects with EGFRm NSCLC.
Potential risks
 
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The study design aims to minimize potential risks to subjects participating in this study based 
on the protocol inclusion and exclusion criteria (Sections 4.1.2 and 4.1.3), restrictions on 
concomitant medication during the study (Section 4.8), safety monitoring (including review 
of all safety, PK, and other relevant data by the Dose Escalation Committee [DEC]) 
(Sections 3.1.3 and 5), toxicity management guidelines (Section 3.1.4), starting dose 
selection (Section 3.2.1), dose escalation scheme (Section 3.1.2), and stopping criteria 
(Section 4.5). Specific intensive safety monitoring is in place (Sections 3.1.4 and 5.3) for 
those risks deemed to be most likely.
1.7
Research Hypotheses
Novel combinations of immunotherapeutics and EGFR TKIs will demonstrate adequate 
safety, tolerability, and antitumor activity in subjects with previously treated advanced 
EGFRm NSCLC.
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2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objectives and Associated Endpoints
Type
Objective
Endpoint
Part 1
Safety
To investigate the safety and 
tolerability of novel combination 
therapies administered in subjects 
with advanced EGFRm NSCLC 
and confirm the combination 
dose(s) for further clinical 
evaluation
•
Incidence of AEs and SAEs
•
DLTs
•
Clinically meaningful changes from baseline in 
laboratory parameters, vital signs, and ECG 
results
Part 2
Efficacy
To investigate the antitumor 
activity of novel combination 
therapies administered in subjects 
with advanced EGFRm NSCLC by 
evaluation of tumor response based 
on RECIST version 1.1
•
OR, according to RECIST version 1.1 
Safety
To investigate the safety and 
tolerability of novel combination 
therapies administered in subjects 
with advanced EGFRm NSCLC 
•
Incidence of AEs and SAEs
•
Clinically meaningful changes from baseline in 
laboratory parameters, vital signs, and ECG 
results
AE = adverse event; DLT = dose-limiting toxicity; ECG = electrocardiogram; EGFRm = epidermal growth 
factor receptor mutant; NSCLC = non-small cell lung cancer; OR = objective response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAE = serious adverse event.

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2.2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Parts 1 and 2
Efficacy
To obtain a preliminary assessment of the 
antitumor activity of novel combination 
therapies administered in subjects with 
advanced EGFRm NSCLC by evaluation of 
tumor response based on RECIST version 1.1
•
DoR, DC, PFS, and OS. 
RECIST version 1.1 will be 
used for assessment of tumor 
response. 
To evaluate the antitumor activity of novel 
combination therapies administered in subjects 
with advanced EGFRm NSCLC based upon 
T790M testing at baseline confirmed by a 
central lab 
•
OR and DC by T790M status at 
baseline (determined by a 
central lab) in archival and/or 
fresh tumor biopsies
Pharmacokinetic
To determine the PK profile of individual 
analytes of novel combination therapies 
(oleclumab, osimertinib, and AZD4635) 
administered in subjects with advanced EGFRm 
NSCLC
•
Summary PK for all therapies 
and/or their metabolites
Immunogenicity
To determine the immunogenicity of oleclumab 
administered in subjects with advanced EGFRm 
NSCLC
•
Development of detectable 
ADAs
ADA = antidrug antibody(ies); DC = disease control; DLT = dose-limiting toxicity; DoR = duration of 
response; ECG = electrocardiogram; EGFRm = epidermal growth factor receptor mutant; NSCLC = non-
small cell lung cancer; OR = objective response; OS = overall survival; PFS = progression-free survival; PK 
= pharmacokinetic(s); RECIST = Response Evaluation Criteria in Solid Tumors.

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2.3
Exploratory Objectives and Associated Endpoints
Type
Objective
Endpoint
 
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview……….
This is a multiarm, open-label, multicenter, Phase 1b/2 study to evaluate novel combination 
therapies in subjects with previously treated advanced EGFRm NSCLC. The study is divided 
into 2 parts. In Part 1 the safety and tolerability of novel combination therapies will be 
evaluated and a RP2D for combination therapy will be identified. In Part 2 the safety,
tolerability, and preliminary antitumor activity of novel combination therapies will be 
evaluated. Subjects will be treated in Arm A (oleclumab and osimertinib combination 
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therapy) or Arm B (oleclumab and AZD4635 combination therapy). The allocation of 
subjects to treatment arms will be dependent upon the subject’s EGFR mutation status and 
prior therapies. Additional treatment arms may be added as part of this multidrug protocol as 
decisions on the most appropriate combinations to use become available and as the scientific 
understanding of EGFRm NSCLC develops. A substantial protocol amendment with relevant 
nonclinical and clinical data will be put in place before starting a new combination treatment 
arm.
A total of up to approximately 98 subjects will be enrolled in this study at approximately 
15 sites globally: up to approximately 46 subjects in Arm A and up to approximately 
52 subjects in Arm B.
During Part 2 dose expansion, Bayesian predictive probabilities will be used for continuous 
interim monitoring analysis for efficacy and safety. Subjects dosed at the RP2D in Part 1 will 
be included in this analysis (Section 4.9.8).
The study flow is presented in Figure 1 for Part 1 and in Figure 2 for Part 2. 
Figure 1
Study Flow Diagram for Part 1: Dose Escalation
EGFRm = epidermal growth factor receptor mutant; EGFR TKI = epidermal growth factor receptor tyrosine 
kinase inhibitor; IV = intravenously; N = number; NSCLC = non-small cell lung cancer; PO = orally; Q2W = 
every 2 weeks; QD = once daily.
NOTE: For both Arms A and Arm B, subjects must have received treatment with an approved first or second 
generation EGFR TKI except for subjects in Arm B who received osimertinib as first-line treatment, in which 
case, treatment with a first or second generation EGFR TKI is not required, and these subjects may enroll after 
having received and progressed on osimertinib alone (but can still have received no more than 4 prior lines of 
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Figure 2
Study Flow Diagram for Part 2: Dose Expansion
EGFRm = epidermal growth factor receptor mutant; EGFR TKI = epidermal growth factor receptor tyrosine 
kinase inhibitor; IV = intravenously; N = number; NSCLC = non-small cell lung cancer; PO = orally; Q2W = 
every 2 weeks; QD = once daily; RP2D = recommended Phase 2 dose.
NOTE: For both Arms A and Arm B, subjects must have received treatment with an approved first or second 
generation EGFR TKI except for subjects in Arm B who received osimertinib as first-line treatment, in which 
case, treatment with a first or second generation EGFR TKI is not required, and these subjects may enroll after 
having received and progressed on osimertinib alone (but can still have received no more than 4 prior lines of 
therapy).
Response-evaluable subjects are subjects who receive any investigational product, had measurable disease at
baseline and at least 1 post-baseline tumor assessment, or who died from any cause or who discontinued due to 
clinical progressive disease prior to any post-baseline tumor assessment.
a
Including subjects dosed at the RP2D in Part 1
b
Arm A: Continuous interim monitoring will begin after 10 subjects are response-evaluable (including 
subjects dosed at the RP2D in Part 1).
c
Arm B: Continuous interim monitoring will begin after 20 subjects are response-evaluable (including 
subjects dosed at the RP2D in Part 1).
The endpoints to be measured in this study are described in Section 2.
3.1.2
Treatment Regimen
The treatment arms are described below. All subjects will remain on their respective 
treatments until documentation of disease progression, intolerable toxicity, or other reason 
for subject withdrawal develops (Section 4.1.6).
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive investigational product. Investigational product will be provided via an 
extension of the study, a rollover study requiring approval by a responsible health authority 
and ethics committee, or through another mechanism at the discretion of the sponsor. The 
sponsor reserves the right to terminate access to investigational product if any of the 
following occur: a) the marketing application is rejected by responsible health authority; b) 
the study is terminated due to safety concerns; c) the subject can obtain medication from a 

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government sponsored or private health program; or d) therapeutic alternatives become 
available in the local market.
3.1.2.1
Treatment Regimen: Arm A
Arm A will investigate the safety, tolerability, and antitumor activity of oleclumab IV Q2W 
in combination with osimertinib PO QD in subjects with advanced EGFRm NSCLC who 
have progressed on an approved first or second generation EGFR TKI therapy and who are 
T790M mutation negative and who have not received osimertinib.
During Part 1, dose escalation will be performed to determine the MTD for oleclumab and 
osimertinib combination therapy. Dose escalation will begin with enrollment of at least 
3 subjects (and up to 6 subjects) at dose level 1 (oleclumab 1500 mg IV Q2W and 
osimertinib 80 mg PO QD) (Table 1). The DEC (Section 3.1.3.1) will monitor subjects for 
DLTs during the DLT-evaluation period as defined in Section 3.1.3.3. Enrollment of 
additional subjects at a dose level, dose escalation to the next dose level, or dose 
de-escalation will progress according to the rules outlined in Section 3.1.3.2. If the MTD is 
exceeded at the starting dose level, then a lower dose level of oleclumab 750 mg Q2W and 
osimertinib 80 mg QD may be evaluated (Table 1).
Based on emerging safety, efficacy, and PK data from this study as well as other ongoing 
studies of oleclumab and osimertinib, the sponsor may choose any safe dose for evaluation in 
Part 2 (Dose Expansion). Once the RP2D has been confirmed, enrollment into the Part 2 dose 
expansion may proceed. The DEC will continue to monitor the emerging data from the study.
Table 1
Arm A Combination Therapies and Dose Levels (Part 1: Dose 
Escalation)
Agents
Dose Level a
Dose Level -1
N = 3-6 subjects
Dose Level 1 b
N = 3-6 subjects
Dose Level 2
N = 6 subjects
Oleclumab
750 mg IV Q2W
1500 mg IV Q2W
3000 mg IV Q2W
Osimertinib
80 mg PO QD
80 mg PO QD
80 mg PO QD
IV = intravenously; PO = orally; QD = once daily; Q2W = every 2 weeks.
a
Administration of the first dose of investigational product must be staggered by a minimum of 24 hours 
for the first 2 subjects in each dose level.
b
Starting dose level
Continuous monitoring of ILD events will be performed as described in Section 4.9.7.
During Part 2 (Dose Expansion), the RP2D confirmed from Part 1 will be administered in 
approximately 10 to 40 subjects (including subjects dosed at the RP2D in Part 1). Continuous 
interim monitoring will begin after 10 subjects are response-evaluable (including subjects 
dosed at the RP2D in Part 1) (Sections 4.9.1 and 4.9.8).

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3.1.2.2
Treatment Regimen: Arm B
Arm B will investigate the safety, tolerability, and antitumor activity of oleclumab IV Q2W 
in combination with AZD4635 PO QD in subjects with advanced EGFRm NSCLC who have 
received 2 to 4 lines of prior therapy and who have progressed on either an approved first or 
second generation EGFR TKI or osimertinib.
During Part 1, dose escalation will be performed to determine the MTD for oleclumab and 
AZD4635 combination therapy. Dose escalation will begin with enrollment of at least 
3 subjects (and up to 6 subjects) at dose level 1 (oleclumab 1500 mg IV Q2W and AZD4635 
75 mg PO QD) (Figure 3). The DEC (Section 3.1.3.1) will monitor subjects for DLTs during 
the DLT-evaluation period as defined in Section 3.1.3.3. Enrollment of additional subjects at 
a dose level, dose escalation to the next dose level, or dose de-escalation will progress 
according to the rules outlined in Section 3.1.3.2. If the MTD is exceeded at the starting dose 
level, then lower dose levels will be evaluated as shown in Figure 3.
Based on emerging safety, efficacy, and PK data from this study as well as other ongoing 
studies of oleclumab and AZD4635, the sponsor may choose any safe dose for evaluation in 
Part 2 (Dose Expansion). Once the RP2D has been confirmed, enrollment into the Part 2 dose 
expansion may proceed. The DEC will continue to monitor the emerging data from the study.
Figure 3
Arm B Combination Therapies and Dose Levels (Part 1: Dose 
Escalation)
IV = intravenous; MTD = maximum tolerated dose; PK = pharmacokinetic; PO = oral; QD = once daily; 
Q2W = every 2 weeks.
Administration of the first dose of investigational product must be staggered by a minimum of 24 hours for the 
first 2 subjects in each dose level.
Based on emerging safety, efficacy, and PK data from this study as well as other ongoing studies of oleclumab 
and AZD4635, the sponsor may choose any safe dose for evaluation in Part 2 (Dose Expansion).
During Part 2 (Dose Expansion) the RP2D confirmed from Part 1 will be administered in 
approximately 20 to 40 subjects (including subjects dosed at the RP2D in Part 1). Continuous 

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interim monitoring will begin after 20 subjects are response-evaluable (including subjects 
dosed at the RP2D in Part 1) (Sections 4.9.1and 4.9.8).
3.1.3
Dose Escalation, Cohort Progression, and Dose-limiting Toxicity
3.1.3.1
Dose Escalation Committee (Arms A and B)
Subjects will be followed for safety throughout the study. A study-specific DEC (including at 
a minimum the sponsor medical monitor/clinical lead and all participating investigators who 
have enrolled subjects in that dose level) will provide ongoing safety surveillance of the 
study, with regularly scheduled reviews of safety and other relevant data. 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 dose 
escalation or dose de-escalation decisions and recommendations regarding further conduct of 
the study. All decisions by this committee will be documented and shared with all 
participating sites in writing.
3.1.3.2
Rules for Dose Escalation and Cohort Progression (Arms A and B)
In Part 1 of this study novel combination therapies without previously defined dosing 
schedules will be evaluated. The following rules will be applicable to dose escalation in 
Arms A and B. The study design and planned dose levels are described in Section 3.1.2.1
(Arm A) and Section 3.1.2.2 (Arm B).
1
The MTD will be determined based on the assessment of DLT during the
DLT-evaluation period (Section 3.1.3.3). Subjects who do not meet the criteria for the 
DLT-evaluable population will be replaced (Sections 4.9.1 and 4.1.8). 
2
Administration of the first dose of investigational product must be staggered by a 
minimum of 24 hours for the first 2 subjects in each cohort. Intra-subject dose escalation 
will not be allowed. Intra-subject dose de-escalation will not be allowed during the 
DLT-evaluation period.
3
A minimum of 3 subjects will be enrolled in each dose-level cohort. If no DLTs are 
observed in a cohort of 3 to 6 evaluable subjects, then dose escalation may occur. At 
dose level 1 only, dose escalation to the next higher dose cohort will be permitted after 
review of all available safety data from a minimum of 3 evaluable subjects in that 
treatment arm and a minimum of 6 evaluable subjects across both treatment arms 
(Arms A and B). At subsequent dose levels, dose escalation to the next higher dose 
cohort will be permitted after review of all available safety data from a minimum of 
3 evaluable subjects in that treatment arm.
4
If 1 subject in a dose-level cohort of 3 or more evaluable subjects experiences a DLT, 
that dose-level cohort will be expanded to a total of 6 subjects. If no more than 1 of 
6 subjects in the dose-level cohort experiences a DLT, dose escalation will continue to 
the next higher dose-level cohort.
5
If ≥2 subjects in a dose-level cohort experience a DLT, the MTD will be exceeded and 
no further subjects will be enrolled into that dose-level cohort. If this occurs, the 
preceding dose-level cohort will be evaluated for the MTD and a total of 6 subjects will 

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be treated at the preceding dose level if not already expanded. If ≤1 of 6 subjects 
experiences a DLT at the preceding dose level, then this dose level will be the MTD. 
6
If ≥2 subjects in the first dose cohort experience a DLT, then no further subjects will be 
enrolled into that dose-level cohort. A dose de-escalation (Dose Level -1) will then be 
evaluated for the MTD in 6 subjects. 
7
If the highest protocol-defined dose level is reached and no DLTs are observed in a 
minimum of 3 evaluable subjects, the sponsor may choose to evaluate the previous dose 
level in the dose expansion phase or expand the highest protocol-defined dose level to 
6 subjects. In the latter case, if ≤1 of 6 subjects experiences a DLT, then the highest 
protocol-defined dose level may be selected for further evaluation in the dose expansion 
phase.
8
At the discretion of the sponsor, dose escalation may be stopped before an MTD is 
reached. In this case, an expanded cohort dose may be chosen based on an assessment of 
PK, 
 safety, and antitumor activity data. 
9
With the exception of dose level 1 as described in Rule 3, dose escalation proceeds 
independently between the arms of this study.
3.1.3.3
Dose-Limiting Toxicity (Arms A and B)
Dose-limiting toxicities will be evaluated during the dose-escalation phase of Arms A and B. 
The period for DLT evaluation will be from the first dose of both investigational products 
until the planned administration of the third dose of oleclumab (ie, through Day 28 post 
Dose 1). Subjects who do not complete the DLT-evaluation period for reasons other than 
DLT, did not receive all planned doses of oleclumab, or did not receive at least 75% of the 
daily administrations of osimertinib (Arm A) or AZD4635 (Arm B) during this time will be 
considered nonevaluable for DLT assessment and will be replaced with another subject at the 
same dose level (Sections 4.1.8 and 4.9.1). Grading of DLTs will be according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). 
A DLT will be defined as any Grade 3 or higher toxicity or any of the events listed below
that occurs during the DLT-evaluation period (defined above). Toxicity that is clearly and 
directly related to the primary disease or to another etiology is excluded from this definition. 
The following will be DLTs:

Any Grade 4 immune-mediated adverse event (imAE)

Any ≥ Grade 3 colitis

Any ≥ Grade 3 nausea, vomiting, or diarrhea that does not resolve to Grade 2 or less 
within 3 days of the initiation of maximal supportive care

Any ≥Grade 3 pneumonitis or ILD

Any Grade 2 pneumonitis or ILD that does not resolve to Grade 1 or less within 3 days 
of the initiation of maximal supportive care

Any Grade 4 anemia 

Any Grade 4 thrombocytopenia or neutropenia that is present for more than 4 days
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
Grade 3 thrombocytopenia with bleeding

Any grade febrile neutropenia

Convulsions, seizures, or stroke

Isolated liver transaminase elevation ≥5 × but ≤ 8 × upper limit of normal (ULN) or 
isolated total bilirubin (TBL) ≥3 × but ≤5 × ULN that does not downgrade to Grade 2 
or less within 14 days after onset with optimal medical management, including systemic 
corticosteroids. Isolated liver transaminase elevation > 8 × ULN or isolated TBL 
> 5 × ULN regardless of duration.

Any increase in AST or ALT > 3 × ULN and concurrent increase in TBL > 2 × ULN 
(Hy’s Law [see Section 10.5.2]) without evidence of cholestasis or alternative 
explanations (eg, viral hepatitis, disease progression in the liver)

Confirmed QT interval corrected for heart rate by Fridericia’s formula (QTcF) 
prolongation (≥501 msec) on triplicate ECGs within a short period of time (eg, a total of 
3 ECGs within 30 minutes). Only if the average QTcF value, manually over-read by a 
medically qualified person based on 3 ECGs, is ≥501 msec would it be declared a DLT.

Any other toxicity that is greater than that at baseline, is clinically significant and/or 
unacceptable, and is judged to be a DLT by the DEC 
A DLT excludes the following:

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy

Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) that resolved to Grade 1 or less 
within 30 days

Concurrent vitiligo or alopecia of any AE grade

Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance that are not defined as a DLT above.  
Immune-mediated AEs are defined as AEs of an 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. If late-emerging imAEs (imAEs occurring after the DLT-evaluation 
period) are observed, these events will be considered by the DEC during data reviews for 
dose escalation or de-escalation decisions.
3.1.4
Management of Study Medication Related Toxicities
If a subject experiences a CTCAE Grade 3 and/or unacceptable toxicity including a DLT not 
attributable to the disease or disease-related processes under investigation, dosing will be 
interrupted and supportive therapy administered.

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3.1.4.1
For Toxicity That Occurs While on Oleclumab and Osimertinib (Arm A)
Following the DLT-evaluation period, the treatment modification and toxicity management 
guidelines for immune-mediated AEs, IRRs, and non-immune-mediated reactions provided 
in Section 10.6 will be followed. In addition, information for adverse events of special 
interest (AESIs) is provided in Section 5.3. 
Exceptions to the management of non-immune mediated reactions that are allowed for 
osimertinib are provided in Section 10.7. If a toxicity resolves to ≤CTCAE Grade 2 or 
baseline within 3 weeks of onset, treatment with osimertinib may be restarted at the same 
dose (80 mg) or a lower dose (40 mg) using the rules for dose modifications (Section 10.7) 
and with discussion and agreement with the medical monitor as needed. There will be no 
individual modifications to dosing schedule in response to toxicity, only potential dose 
reduction or dose interruption. If the toxicity does not resolve to ≤CTCAE Grade 2 or 
baseline after 3 weeks, then the subject should be discontinued from study treatment and 
observed until resolution of the toxicity. On resolution of toxicity within 3 weeks: If an AE 
subsequently requires dose interruption, osimertinib may be restarted at the same dose or the 
reduced dose, on resolution/improvement of the AE at the discretion of the investigator.
Subjects experiencing corneal ulceration, ILD, or QTc prolongation with signs/symptoms of 
serious arrhythmia will not be permitted to restart study treatment. To ensure subject safety, 
continuous monitoring of ILD events will be performed as described in Section 4.9.7.
If treatment-related toxicity meeting criteria for discontinuation occurs, both oleclumab and 
osimertinib must be discontinued.
3.1.4.2
For Toxicity That Occurs While on Oleclumab and AZD4635 (Arm B)
Following the DLT-evaluation period, the treatment modification and toxicity management 
guidelines for immune-mediated AEs, IRRs, and non-immune-mediated reactions provided 
in Section 10.6 will be followed. In addition, information for AESIs is provided in 
Section 5.3.
For non-immunologic toxicities, it may be possible for the investigator to ascribe relationship 
with AZD4635 dosing, but not related to oleclumab. In such a case, the investigator should 
follow guidelines for AZD4635 dose modifications in Section 10.8 (Table 17 [hematologic
toxicities], Table 18 [non-hematologic toxicities], Table 19 [hypertension], and Table 20
[CNS toxicities]) and may continue to administer oleclumab. If the toxicity resolves to 
≤CTCAE Grade 2 or baseline within 2 weeks of onset and the subject is showing clinical 
benefit per the investigator, treatment with AZD4635 may be restarted at the same dose or a 
lower dose using the rules for dose modifications (Section 10.8) and with discussion and 
agreement with the medical monitor as needed. Anticipated AZD4635 dose levels are 75 and 
100 mg QD; dose levels of AZD4635 50 mg QD (dose level -1) and 25 mg QD (dose 
level -2) are allowed for de-escalation, if needed (Figure 3). There will be no individual 

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modifications to dosing schedule in response to toxicity, only potential dose reduction or 
dose interruption. Intra-subject dose re-escalation is not permitted. If the toxicity does not 
resolve to ≤ CTCAE Grade 2 or baseline within 2 weeks, then the subject should be 
discontinued from study treatment and observed until resolution of the toxicity. Maximum 
time allowed for dose interruption is 2 weeks.
If treatment-related toxicity meeting criteria for discontinuation occurs, both oleclumab and 
AZD4635 must be discontinued.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
Oleclumab (Arms A and B)
The oleclumab starting dose of 1500 mg Q2W (equivalent to 20 mg/kg Q2W in a 75 kg 
individual) was selected based on the available clinical safety, tolerability, efficacy, and PK 
data from the ongoing Phase 1 Study D6070C00001. In this study 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 (Section 1.4.1). The oleclumab 40 mg/kg 
Q2W dose (equivalent to the oleclumab 3000 mg Q2W fixed dose for a 75 kg individual) 
was identified for evaluation with durvalumab 10 mg/kg Q2W in the dose-expansion phase 
of this study (Study D6070C00001).
Many published articles have previously reported a similarity of exposures following either 
fixed or body size-based dosing of mAbs (Narwal et al, 2013; Ng et al, 2006; 
Wang et al, 2009; Zhang et al, 2012). Wang and colleagues investigated 12 mAbs and found 
that fixed and body size-based dosing perform similarly, with fixed dosing being better for 
7 of 12 mAbs (Wang et al, 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in PK/pharmacodynamics parameters (Zhang et al, 2012). A fixed 
dosing approach is also preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given the expectation of similar PK exposure and variability, it is 
considered feasible to switch to fixed dosing regimens. Based on average body weight of 
75 kg, the fixed doses of oleclumab 1500 mg Q2W (equivalent to 20 mg/kg Q2W) and 
oleclumab 3000 mg Q2W (equivalent to 40 mg/kg Q2W) are included in the current study.
Oleclumab 1500 mg Q2W is one dose level below the highest monotherapy and combination 
weight-based dose that has been tested and declared tolerable in FTIH Study D6070C00001. 
Therefore, oleclumab 1500 mg Q2W has been selected as the starting dose to be used in 
combination with osimertinib and AZD4635. Additionally, in Arm A, a fixed dose of 
oleclumab 750 mg Q2W (equivalent to 10 mg/kg Q2W) is included as dose level -1, if 
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Osimertinib (Arm A)
The osimertinib dose of 80 mg QD is the global Health Authority approved monotherapy 
dose in patients with advanced EGFRm T790M mutation positive NSCLC. This dose is not 
the MTD as osimertinib was previously administered up to 240 mg daily with no observed 
DLTs.
Given the favorable safety profiles of both oleclumab and osimertinib and the 
non-overlapping mechanisms of action and toxicity, the fixed dose of oleclumab 1500 mg 
Q2W and the approved dose of osimertinib 80 mg QD are selected as the starting dose level 
for combination therapy in Arm A of this study.
AZD4635 (Arm B)
The AZD4635 starting dose of 75 mg QD was selected based on the available clinical safety, 
tolerability, and PK data in the ongoing FTIH Phase 1 Study D8730C00001.
 
 
 
 
 
 
AZD4635 75 mg QD is one dose level below the highest monotherapy dose that has been 
tested and declared tolerable in FTIH Study D8730C00001 and is the same dose level that 
has been tested in combination with durvalumab 1500 mg and declared tolerable in the FTIH 
study. Therefore, AZD4635 75 mg QD has been selected as the starting dose to be used in 
combination with oleclumab 1500 mg Q2W in this study. Also, AZD4635 50 mg QD (dose 
level -1) and 25 mg QD (dose level -2) are included, if needed.
3.2.2
Rationale for Study Population
Lung cancer is the most common cause of cancer-related death worldwide and the majority 
of these cases are NSCLC (Section 1.1). Approximately 10% to 30% of these patients harbor 
an EGFR mutation that serves as the molecular driver of their cancer. While this has led to 
improvements in the outcomes from early lines of therapy with targeted EGFR TKIs, upon 
progression patients have limited therapeutic options and poor survival. Furthermore, recent 
advances in immunotherapy with anti-PD-1 and anti-PD-L1 antibodies have not been 
realized to the same extent in this subset of patients. Genetic and immune profiling of these 
tumors has demonstrated that alternative gene expression such as increased CD73 expression 
may help to explain the lack of efficacy of currently approved immunotherapy. It has become 
increasingly clear that long-term therapeutic benefit in metastatic cancers can be achieved by 
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enhancing the antitumor immune response. As discussed in Section 1.5, oleclumab is a 
potential candidate to be combined with other active and novel agents to restore antitumor 
immunity and enhance the therapeutic response. 
3.2.2.1
Rationale for Study Population (Arm A)
The combination of a targeted therapy such as osimertinib with an immune-mediated therapy 
such as oleclumab provides an orthogonal approach of inhibiting tumor growth signals while 
promoting tumor immune recognition to improve antitumor activity. Currently, osimertinib is 
only approved for EGFRm NSCLC subjects who have progressed on first-line EGFR TKI 
therapy and have acquired the T790M mutation. This leaves approximately 50% of patients 
with limited targeted therapy options and most will proceed to chemotherapy. However, the 
AURA study (Phase 1 component) for osimertinib demonstrated that T790M negative tumors 
can also respond to this targeted therapy. In this trial, 69 patients without centrally detectable 
EGFR T790M received osimertinib at ranges from 20 to 240 mg QD, 29 of whom received 
osimertinib at the 80 mg dose. The investigator-assessed ORR was 24.6% across all doses 
and 20.7% in the 80 mg group (Section 1.4.2). Similarly, in the Phase 1 trial of rociletinib, an 
EGFR TKI also targeting the EGFR T790M mutation, an ORR of 29% in the centrally 
confirmed T790M negative population was reported (Sequist et al, 2015). In the Phase 1b 
trial of afatinib plus the anti-EGFR antibody cetuximab, an ORR of 25% in the EGFRm 
NSCLC T790M negative population was reported. However, this combination of dual anti-
EGFR inhibition had a significant safety and tolerability burden (Janjigian et al, 2014). 
Furthermore, disease progression and acquired resistance to all targeted therapies is 
inevitable. Unlike targeted therapy, immune-mediated therapies have demonstrated 
significantly longer DoRs and even long-term disease control (DC) in some instances. 
Therefore, this novel combination of a targeted therapy and an immune-mediated therapy 
with strong scientific support has the potential to improve the response rate to osimertinib 
alone and improve the DoR for subjects with EGFR T790M mutation-negative NSCLC 
receiving the combination, thus delaying the initiation of cytotoxic therapies.
3.2.2.2
Rationale for Study Population (Arm B)
The combination of AZD4635 with oleclumab, which both target the adenosine pathway, has 
the potential to restore the antitumor response in subjects with EGFRm NSCLC.
As described in Section 1.5, ATP is rapidly catabolized to adenosine by the enzymatic 
activity of CD39 and CD73. Once generated, in the tumor microenvironment adenosine is 
capable of binding to A2AR which is expressed on a variety of immune cell types, including 
T-effector cells, Tregs, natural killer cells, MDSCs, and tumor associated macrophages. 
Nonclinical studies have demonstrated pleotropic effects on a multitude of immune cells 
resulting in an immunosuppressive state with decreases in cytotoxic responses and 
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adenosine signaling through A2AR inhibits antitumor responses and enables immune escape 
of tumors.
Given the substantial evidence supporting the role of the adenosinergic pathway in tumor 
immune evasion, investigators evaluated the impact of inhibiting both CD73 and A2AR. In 
murine models of mammary carcinoma and melanoma, investigators found that dual 
inhibition resulted in a reduced tumor growth, increased immune infiltrates, and 
improvement in OS as compared to either placebo or each treatment as monotherapy 
(Young et al, 2016). Given the overexpression of CD73 in EGFRm NSCLC, dual inhibition 
of this pathway is a potential therapeutic approach.
AZD4635 is a potent, highly selective inhibitor of A2AR. The safety and efficacy of 
AZD4635 are currently being investigated both as a monotherapy and in combination with 
durvalumab as part of an ongoing Phase 1 study (D8730C00001) (Section 1.4.3). This study 
will identify the RP2D dose for AZD4635 and oleclumab combination therapy and evaluate 
its safety and preliminary efficacy.
3.2.3
Rationale for Endpoint(s)
The primary aim of this study is to determine the safety and tolerability of novel therapeutic 
combinations in subjects with EGFRm NSCLC, identify the MTD or highest protocol 
defined dose in the absence of establishing an MTD and assess the antitumor activity for all 
combinations for which a confirmed safe dose is established. The occurrence of DLTs will be 
used to establish the MTD and thus the standard safety endpoints, such as AEs, SAEs, 
clinically meaningful changes from baseline in laboratory parameters, vital signs, and ECGs 
will be included in the evaluation. 
The endpoints for assessment of antitumor activity are those routinely included in oncology 
studies and will include OR and DC (based on RECIST version 1.1), DoR, PFS, and OS. 
Additionally, OR and DC will be assessed by T790M status. Archival and/or fresh tumor 
biopsies will be centrally tested to determine T790M status. 
 
 
 
 
The PK parameters that will be determined for the secondary objective will be specific for 
the study treatments within each arm. These parameters may include Cmax, AUC, clearance 
(CL), and t1/2 after IV doses and Cmax, tmax, AUC, apparent plasma clearance (CL/F), apparent 
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volume of distribution (Vz/F) and t1/2 after oral doses if the data allow as well as others if 
deemed important. As oleclumab is administered on a repeating dosing schedule, the 
development of antidrug antibodies (ADA) 
 
 will also be assessed. 
 
 
 
 
 
 
 
 
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A total of up to approximately 98 subjects will be enrolled in this study: up to approximately 
46 subjects in Arm A and up to approximately 52 subjects in Arm B.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Age ≥18 years at the time of screening or age of consent according to local law.
2
Written informed consent and any locally required authorization (eg, data privacy)
obtained from the subject prior to performing any protocol-related procedures, including 
screening evaluations.
3
ECOG Performance Status of 0 or 1.
4
Weight ≥35 kg.
5
Subjects diagnosed with histologically or cytologically confirmed locally 
advanced/metastatic NSCLC with EGFR mutation known to be associated with EGFR 
TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)
(a) For Arm A: Subjects must have received 1 prior line of therapy with an EGFR TKI
in the locally advanced/metastatic setting. 
(i)
Must have received and progressed on an approved first or second generation 
EGFR TKI (eg, erlotinib or gefitinb [first generation] or afatanib [second 
generation])
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(ii) Subjects must be T790M negative by an approved testing assay on tumor 
biopsy. If plasma testing was performed, they must also be negative by this as 
well. Negative testing by plasma testing alone will not be considered sufficient 
for study entry.
(iii) Prior chemotherapy received in the neoadjuvant or adjuvant settings will not be 
considered a line of therapy.
(b) For Arm B: Subjects must have received at least 2 but not more than 4 prior lines 
of therapy (including investigational therapy) in the locally advanced/metastatic 
setting. 
(i)
Must have received and progressed on an approved first or second generation
EGFR TKI (eg, erlotinib or gefitinb [first generation] or afatanib [second 
generation]) for their known mutation status.
(ii) If subjects are known to be T790M positive and subjects had access to an 
approved third generation EGFR TKI therapy, they should have received and 
progressed on this therapy as well.
(iii) Maintenance therapy following platinum-doublet is not considered a separate 
line of therapy.
(iv) Prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation 
therapy given for locally advanced disease is considered first-line therapy only 
if recurrent (local or metastatic) disease developed within 6 months of 
completing therapy.
(v) If subjects received osimertinib as first-line treatment, then treatment with a 
first or second generation EGFR TKI is not required. In addition, these subjects 
may enroll after having received and progressed on osimertinib alone but can 
still have received no more than 4 prior lines of therapy.
6
Subjects must have at least 1 measurable lesion according to RECIST version 1.1.
(a) A previously irradiated lesion can be considered a target lesion if the lesion is well 
defined, measurable per RECIST, and has clearly progressed.
(b) Subjects must have a non-target lesion that can be biopsied at acceptable risk (if 
biopsy is required for enrollment) as judged by the investigator or if no other lesion 
is suitable for biopsy, then an RECIST target lesion used for biopsy must be ≥ 2 cm 
in longest diameter.
7
 
 
8
All subjects in the dose expansion phase of the study (Part 2) must consent to a fresh 
biopsy unless a biopsy was obtained within 3 months from screening, during or after the 
most recent line of therapy (with no intervening anticancer therapy).
 
 
 
 
 
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9
For Arm B: Normotensive or well-controlled BP (< 140/90), with or without current 
antihypertensive treatment. If diagnosis or history of hypertension, subject must have 
adequately controlled BP on a maximum of 2 antihypertensive medications, as 
demonstrated by 2 BP measurements taken in the clinical setting by a medical 
professional. 
10 Adequate organ and marrow function, as defined below. Criteria “a,” “b,” and “c” 
cannot be met with ongoing or recent blood transfusions (within 14 days of starting first 
dose) or require growth factor support (within 28 days of starting the first dose)
(a) Hemoglobin ≥ 9 g/dL
(b) Absolute neutrophil count ≥ 1,500/μL
(c) Platelet count ≥ 100,000/μL
(d) TBL ≤ 1.5 × ULN if no liver metastases or ≤3 × ULN in the presence of 
documented Gilbert’s syndrome or liver metastases 
(e) ALT and AST ≤ 2.5 × ULN if no demonstrable liver metastases or ≤5 × ULN in the 
presence of liver metastases
(f) Calculated creatinine clearance ≥ 40 mL/minute as determined by Cockcroft-Gault 
(using actual body weight) or 24-hour urine creatinine clearance
11 Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use at least one highly effective method of contraception (Section 10.2 for 
definition of females of childbearing potential and for a description of highly effective 
methods of contraception) from screening to 180 days after the final dose of concurrent 
therapy. It is strongly recommended for the male partner of a female subject to also use a 
male condom plus spermicide throughout this period. Cessation of contraception after 
this point should be discussed with a responsible physician. Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of contraception.
12 Nonsterilized male subjects who are sexually active with a female partner of 
childbearing potential must use a male condom with spermicide from screening to 
180 days after the final dose of concurrent therapy. Periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. It is 
strongly recommended for the female partner of a male subject to also use one highly
effective method of contraception throughout this period, as described in Section 10.2. In 
addition, male subjects must refrain from sperm donation while on study and for 180 
days after the final dose of combination therapy.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
Receipt of an EGFR TKI within 14 days of the first dose of study treatment.
2
Receipt of any conventional or investigational anticancer therapy not otherwise specified 
within 21 days of the planned first dose.
3
Prior receipt of any investigational immunotherapy. Subjects may have received agents 
that have local health authority approval for the disease indication.

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4
Concurrent enrollment in another therapeutic clinical study. Enrollment in observational 
studies will be allowed.
5
Any toxicity (excluding alopecia) from prior standard therapy that has not been 
completely resolved to baseline at the time of consent. Subjects with NCI CTCAE 
version 4.03 Grade 1 or 2 toxicities that are deemed stable or irreversible can be enrolled 
on a case-by-case basis with prior consultation and agreement with the medical monitor.
6
Subjects with a history of venous thrombosis within the past 3 months.
7
Subjects with prior history of myocardial infarction, transient ischemic attack, or stroke
in the last 6 months.
8
Active or prior documented autoimmune or inflammatory disorders within the past 
3 years prior to the start of 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 or psoriasis not requiring systemic treatment.
9
Subjects with confirmed HIV (even if viral load is undetectable), chronic or active 
hepatitis B or C, or active hepatitis A.
10 History of primary immunodeficiency, solid organ transplantation, or active tuberculosis.
In settings where there is a clinical or radiographic evidence of tuberculosis, active 
disease must be excluded prior to enrollment. 
11 Other invasive malignancy within 2 years. Noninvasive malignancies (ie, cervical 
carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, 
ductal carcinoma in situ of the breast that has been surgically cured) are excluded from 
this definition. 
12 Refractory nausea and vomiting, chronic GI diseases, inability to swallow the formulated 
product or previous significant bowel resection that would preclude adequate absorption 
of osimertinib or AZD4635.
13 Known allergy or hypersensitivity to investigational product formulations.
14 Uncontrolled intercurrent illness including, but not limited to ongoing or active infection 
requiring antibiotic therapy, uncontrolled hypertension, bleeding diatheses, or 
psychiatric illness/social situations that would limit compliance with study requirement, 
substantially increase risk of incurring AEs, or compromise the ability of the subject to 
give written informed consent.
15 Untreated CNS metastatic disease, leptomeningeal disease, or cord compression. Note: 
Subjects previously treated for CNS metastases that are radiographically and 
neurologically stable for at least 28 days and do not require corticosteroids (of any dose) 
for symptomatic management for at least 14 days prior to the first dose will be eligible.
Contrasted computed tomography (CT) or magnetic resonance imaging (MRI; preferred) 
scan to assess for CNS metastatic disease will be performed at screening.
16 Current or prior use of immunosuppressive medication within 14 days prior to the first
dose. The following are exceptions to this criterion:
(a) Intranasal, topical, inhaled corticosteroids or local steroid injections (eg, 
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(b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or equivalent.
(c) Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).
17 Receipt of live, attenuated vaccine within 28 days prior to the first dose of 
investigational products (Note: Subjects, if enrolled, should not receive live vaccine 
during the study and 180 days after the last dose of investigational product[s]). 
Vaccination with a killed vaccine is permitted at any time.
18 Major surgery (as defined by the investigator) within 28 days prior to first dose or still 
recovering from prior surgery. Local procedures (eg, placement of a systemic port, core 
needle biopsy, and prostate biopsy) are allowed if completed at least 24 hours prior to 
the administration of the first dose of study treatment.
19 Females who are pregnant, lactating, or intend to become pregnant during their
participation in the study.
20 Subjects who are involuntarily incarcerated or are unable to willingly provide consent or
are unable to comply with the protocol procedures.
21 Any condition that, in the opinion of the investigator or sponsor, would interfere with 
safe administration or evaluation of the investigational products or interpretation of 
subject safety or study results.
Additional Exclusion Criteria for Arm A
1
Concurrent treatment (or inability to stop therapy) with medications or herbal 
supplements known to be potent inducers of CYP3A4 (Table 21). Refer to Sections 4.8.2
and 10.9 for the list of prohibited medications.
2
Any of the following cardiovascular conditions:
(a) Mean resting QTcF > 470 msec when manually over-read by a medically qualified 
person and based on 3 ECGs 
(b) Any current clinically important abnormalities in rhythm, conduction or morphology 
of resting ECG (eg, complete left bundle branch block, third-degree heart block, 
second-degree heart block)
(c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalemia, congenital long QT syndrome, family history of 
long QT syndrome, or unexplained sudden death under 40 years of age in first-
degree relatives or concurrent treatment (or inability to stop therapy) with 
medications listed in Table 23, which are known to prolong QT interval
(d) Any clinically important abnormalities in cardiac structure or function including left 
ventricular ejection fraction (LVEF) < 50% measured by echocardiography/
multigated acquisition scan (MUGA), cardiomyopathy, or symptomatic valvular 
heart disease
3
Subject has a history of ILD, drug-induced ILD, radiation pneumonitis that required 
steroid treatment, or any evidence of clinically active ILD. 
4
Subject requires supplemental oxygen for any reason. Note: Intermittent supplemental 
oxygen required for vigorous activity or sleep is allowed.

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5
Subject has a resting SpO2 < 95% on room air.
Additional Exclusion Criteria for Arm B
1
Subject has had prescription or non-prescription drugs or other products known to be 
sensitive CYP1A2 substrates, or moderate/potent inhibitors/inducers of CYP1A2, or 
sensitive substrates of BCRP and OAT1, which cannot be discontinued 14 days prior to 
Day 1 of dosing and withheld throughout the study until 14 days after the last dose of 
AZD4635. NOTE: the use of warfarin is prohibited during treatment with AZD4635.
Refer to Sections 4.8.2 and 10.10 for the list of prohibited medications.
2
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Subjects should stop using all herbal medications 14 days prior to the first dose of 
AZD4635.
3
Concomitant medications with another A1R antagonist that would increase risk of 
seizure (eg, theophylline, aminophylline)
4
History of seizures, excluding those that occurred due to previously untreated CNS 
metastasis
5
Any of the following cardiovascular conditions:
(a) Mean resting QTcF > 470 msec when manually over-read by a medically qualified 
person and based on 3 ECGs
(b) Any current clinically important abnormalities in rhythm, conduction or morphology 
of resting ECG (eg, complete left bundle branch block, third-degree heart block, 
second-degree heart block)
(c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalemia, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death under 40 years of age in first degree 
relatives or concurrent treatment (or inability to stop therapy) with medications 
listed in Table 23 which are known to prolong QT interval
(d) Any clinically important abnormalities in cardiac structure or function including, 
cardiomyopathy, or symptomatic valvular heart disease
6
Subjects who have received prior immunotherapy are NOT permitted to enroll unless all 
of the following apply:
(a) Dose of immunotherapy must have been administered at least 28 days prior to 
planned first dose.
(b) Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy
(c) All AEs while receiving prior immunotherapy must have resolved to ≤ Grade 1 or 
baseline prior to screening. Must not have experienced a related ≥ Grade 3 AE or 
neurologic or ocular AE of any grade which was deemed to be related to the prior 
immunotherapy. Subjects with an endocrine AE of any grade are permitted to enroll 
if they are stably maintained on appropriate replacement therapy and are 
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7
Any subject with an open ulceration(s) should avoid dosing with AZD4635 oral 
suspension.
4.1.4
Subject Enrollment
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 response system/interactive 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), 
including the reason(s) for screening failure.
Subjects who do not meet all eligibility requirements within the screening period (ie, screen 
failures) may be rescreened and receive a new SID number. 
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 the study (Section 4.1.5)
2
Withdrawal of consent from further treatment with investigational product 
3
Lost to follow-up
4
Any AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing
5
Any AE that meets criteria for discontinuation from investigational product as defined in 
the Toxicity Management Guidelines (Section 3.1.4)
6
Subject experienced a DLT during the DLT-evaluation period

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7
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing treatment with investigational product might 
constitute a safety risk
8
Pregnancy (Section 5.6.4) or intent to become pregnant
9
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
10 Initiation of alternative anticancer therapy including another investigational agent
11 Confirmed or unconfirmed PD and treatment criteria in the setting of PD are not met
(Section 4.1.7)
12 Investigator determination that the subject is no longer benefiting from the treatment 
regimen
Subjects who are permanently discontinued from receiving investigational product will be 
followed for 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, the subject is enrolled in another clinical study, or the 
subject dies.
4.1.7
Treatment Beyond Progression
Subjects in all treatment arms may continue receiving their originally assigned treatment, at 
the investigator’s discretion, after the first overall time point assessment of PD by RECIST 
version 1.1 until PD is confirmed on a follow-up scan (confirmed radiological PD). A 
confirmatory scan is required following the initial assessment of PD by RECIST version 1.1, 
preferably at the next scheduled visit and no earlier than 4 weeks after the immediate 
previous assessment of PD.
For all subjects who are treated through progression, the investigator should ensure that the 
subject does not have any significant, unacceptable, or irreversible toxicities that indicate that 
continuing treatment will not further benefit the subject. 
The criteria for continuing treatment despite RECIST version 1.1-defined progression are as 
follows:

There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline of more than 1 in ECOG performance status.

There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (eg, CNS metastasis, respiratory failure due to tumor compression, or 
spinal cord compression) requiring urgent alternative medical intervention (concurrent 
radiation treatment is not permitted). NOTE: If a subject requires palliative radiation for 
isolated progression at an immunologically privileged site (eg, brain) while maintaining 
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palliative radiation is agreed to by MedImmune in a subject with isolated progression, 
protocol therapy will need to be held prior to and during the radiation.
Subjects with confirmed radiological PD may continue to receive their assigned treatment at 
the discretion of the investigator (following consultation with MedImmune) as long as they 
are gaining clinical benefit; collection of additional scans subsequent to confirmed 
radiological PD will continue according to the original imaging schedule.
Subjects with PD who are eligible to continue receiving their assigned treatment will be 
made aware of the potential benefits and risks of continuing treatment in the setting of PD 
and must provide a separate written informed consent prior to treatment. 
Subjects who MedImmune and the investigator determine may not continue treatment after 
PD will be followed up for survival. Subjects who have discontinued treatment due to 
toxicity or symptomatic deterioration will be followed up until radiological PD and for 
survival. Subjects who have commenced subsequent anticancer therapy will be followed up 
only for survival.
4.1.8
Replacement of Subjects
Subjects who do not complete the DLT-evaluation period as defined in Section 3.1.3.3 for 
reasons other than DLT, did not receive all planned doses of oleclumab, or did not receive at 
least 75% of the daily administrations of osimertinib (Arm A) or AZD4635 (Arm B) during 
this time will be considered nonevaluable for DLT assessment and will be replaced with 
another subject at the same dose level.
4.1.9
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If a 
subject withdraws consent to the use of mandatory biological samples, the samples will be 
disposed of/destroyed if possible and the action documented. If samples have already been 
analyzed, the sponsor is not required to destroy the results of this research.
 
 
 
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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, if possible. 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 2 shows all procedures to be conducted at the screening visit. 
Table 2
Schedule of Screening Procedures (All Arms)
Procedure
Screening
Visit 1
Day -28 to Day -1
Written informed consent/assignment of SID number
X
Demographics (age, race, and ethnicity)
X
Medical history (including smoking, caffeine, prior 
therapies, and prior imaging a)
X
Verify eligibility criteria
X
Assessment of AEs/SAEs
X
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Table 2
Schedule of Screening Procedures (All Arms)
Procedure
Screening
Visit 1
Day -28 to Day -1
Concomitant medications
X
Physical examination (full)
X
Height and weight
X
Vital signs (including pulse oximetry)
X
ECG b
X
ECOG performance status
X
LVEF by echocardiogram/MUGA (Arm A only)
X
Ophthalmologic examination (Arm A only)
X
Laboratory Assessments:
Serum chemistry
X
Hematology
X
TSH and free T4 (If TSH is normal then free T4 is not 
required)
X
Lipid panel
X
Urinalysis
X
Pregnancy test, serum β-HCG c
X
Coagulation parameters
X
Hepatitis B, C; HIV-1 
X
Disease Evaluation:
Contrasted CT (preferred) of the chest, abdomen and pelvis d
X
MRI (preferred) scan for brain metastases d
X
AE = adverse event; β-hCG = beta-human chorionic gonadotropin; CT = computerized tomography; 
 DICOM = Digital Imaging and Communications in Medicine; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HIV-1= human immunodeficiency virus-1; 
LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition 
scan; SAE = serious adverse event; SID = subject identification; T4 = thyroxine; THS = thyroid-stimulating 
hormone.
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a
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.
b
ECG will be obtained in triplicate within a 5-minute time period. 
c
Females of childbearing potential only 
d
Previous scans for brain metastases and baseline disease that were performed within 28 days of dosing and 
meet the protocol requirements do not need to be repeated.
4.2.2
Treatment Period
All procedures to be conducted during the treatment period are shown in Table 3 for Arm A 
and Table 4 for Arm B. 
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Table 3
Treatment Period Study Procedures – Arm A (Oleclumab + Osimertinib)
Study Period
Treatment Period
Visit Number
V2
V3
V4
V5
V6
V7-Vn
Procedure/
Study Day
Day 1
Day 15 
(± 1 day)
Day 29 
(± 1 day)
Day 43
(± 3 days)
Day 57 
(± 3 days)
Q2W (± 3 days) Starting 
on D71 (unless otherwise 
noted)
Clinical Assessments:
Verify eligibility criteria
X
Physical examination (abbreviated, 
symptom directed)
Xa
X
X
X
Q4W (± 3D) starting on 
D85
ECOG
X
X
X
Q4W (± 3D) starting on 
D85
Weight
X
X
X
Q4W (± 3D) starting on 
D85
ECGb
X
X
X
X
Q12W (± 3D) starting on 
D113
Vital signsc
X
X
X
X
X
X
LVEF by echocardiogram/MUGA
Q12W (± 3D) starting on 
D85
Assessment of AEs/SAEs
All visits
Concomitant medications
All visits
Laboratory Assessmentsd:
Serum chemistryd
X
X
X
X
X
X
Hematologyd
X
X
X
X
X
X
TSH and free T4 (If TSH is normal 
then free T4 is not required)d
X
X
X
Q4W (± 3D) starting on 
D85
Lipid Paneld
X
X
Q8W (± 3D) starting on 
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Table 3
Treatment Period Study Procedures – Arm A (Oleclumab + Osimertinib)
Study Period
Treatment Period
Visit Number
V2
V3
V4
V5
V6
V7-Vn
Procedure/
Study Day
Day 1
Day 15 
(± 1 day)
Day 29 
(± 1 day)
Day 43
(± 3 days)
Day 57 
(± 3 days)
Q2W (± 3 days) Starting 
on D71 (unless otherwise 
noted)
Pregnancy testd, e
X
X
Q8W (± 3D) starting on 
D113
Urinalysisd
X
X
Q8W (± 3D) starting on 
D113
Efficacy:
Disease assessment (scans)f
X
Q8W (± 3D) starting on 
D113 through D393 then 
Q12W (± 3D)
Study Drug Administration:
Oleclumab administrationg
X
X
X
X
X
X
Osimertinib administrationg
X (daily dosing)
Pharmacokinetics/
:
Plasma for osimertinib PKh
X
Pre-dose
X
Pre-dose
Pre-dose
Pre-dose on D113 (± 3D) 
only
Serum for oleclumab PKi
X
X
X
Q12W (± 3D) starting on 
D141
Serum for oleclumab ADAd
X
X
X
Q12W (± 3D) starting on 
D141
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Table 3
Treatment Period Study Procedures – Arm A (Oleclumab + Osimertinib)
Study Period
Treatment Period
Visit Number
V2
V3
V4
V5
V6
V7-Vn
Procedure/
Study Day
Day 1
Day 15 
(± 1 day)
Day 29 
(± 1 day)
Day 43
(± 3 days)
Day 57 
(± 3 days)
Q2W (± 3 days) Starting 
on D71 (unless otherwise 
noted)
ADA = anti-drug antibody; AE = adverse event; β-hCG = beta-human chorionic gonadotropin;
 D = Day(s); ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; LVEF = left ventricular ejection fraction; MUGA = multigated acquisition scan; PK = 
pharmacokinetics; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; SAE = serious adverse event; T4 = 
thyroxine; THS = thyroid-stimulating hormone; V = Visit.
a
Physical examination can be performed up to 24 hours prior to dosing on Day 1.
b
All ECGs will be obtained in triplicate (all within a 5-minute time period). ECGs will be recorded prior to the administration of any investigational 
product and within 30 minutes post end of oleclumab infusion.
c
On days of oleclumab investigational product administration, vital signs will be measured according to the following schedule: Within 60 minutes prior 
to start of oleclumab infusion then every 30 minutes (± 5 minutes) during the infusion, the end of infusion (± 5 minutes), and 30 minutes (± 10 minutes) 
post end of oleclumab infusion. On Day 1, additional vital sign measurements will be taken at 60 minutes (± 10 minutes) and 3 hours (± 15 minutes) post 
end of oleclumab infusion. On Day 1, subjects should remain at the site for monitoring (with immediate access to medical resuscitation equipment) for at 
least 3 hours following the end of the oleclumab infusion.
d
Assessments will be collected prior to administration of any investigational product. If screening assessments have been performed within the 5 days 
prior to Day 1 (Days -5 to -1), then assessment does not need to be performed on Day 1 pre-dose. All safety laboratory results must be reviewed by the 
investigator or physician designee prior to administration of any investigational product. 
e
Females of childbearing potential only, if urine test is positive or equivocal then serum β-hCG testing should be performed for confirmation.
f
Subjects with pelvic disease and/or brain metastases at screening or subjects who develop neurologic or other clinical symptoms that warrant imaging
must have pelvic and/or brain imaging with each disease assessment. Disease assessments will be performed during the treatment period or as indicated 
by signs/symptoms. If radiographic progression is observed in the absence of clinical deterioration, a confirmatory scan should be performed not less 
than 4 weeks later. If clinical deterioration occurs then a confirmatory scan is not required.
g
On oleclumab dosing days, the administration of osimertinib should precede the oleclumab infusion.
h
On Days 1 and 29 plasma samples for osimertinib PK will be collected pre-dose (within 90 minutes prior to dosing osimertinib) and 60 minutes 
(± 5 minutes), 2 hours (± 10 minutes), and 4 hours (± 15 minutes) post-dose. For all other visits, PK will be collected pre-dose.
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Serum samples for oleclumab PK will be collected pre-dose (within 90 minutes prior to start of oleclumab infusion) and 10 minutes (± 5 minutes) post 
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Table 4
Treatment Period Study Procedures - Arm B (Oleclumab + AZD4635)
Study Period
Treatment Period
Visit Number
V2
V2a
Dose 
Escalatio
n only
V3
V4
V5
V6
V7
V7a
Dose 
Escalatio
n Only
V8-Vn
Procedure/
Study Day
Day 1
Day 2
Day 8 
Day 15 
(± 1 day)
Day 29 
(± 1 day)
Day 43
(± 3 days)
Day 57 
(± 3 days)
Day 58
Q2W (± 3 days) 
Starting on D71 
(unless otherwise 
noted)
Clinical Assessments:
Verify eligibility 
criteria
X
Physical examination 
(abbreviated, symptom 
directed)
Xa
X
X
X
Q4W (± 3D) starting 
on D85
ECOG
X
X
X
Q4W (± 3D) starting 
on D85
Weight
X
X
X
Q4W (± 3D) starting 
on D85
ECGb
Xb
X
X
X
Xb
D113 (± 3D) only
Vital signsc
X
X
X
X
X
X
X
X
Assessment of 
AEs/SAEs
All visits
Concomitant 
medications
All visits
Laboratory Assessmentsd:
Serum chemistryd
X
X
X
X
X
X
X
Hematologyd
X
X
X
X
X
X
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Table 4
Treatment Period Study Procedures - Arm B (Oleclumab + AZD4635)
Study Period
Treatment Period
Visit Number
V2
V2a
Dose 
Escalatio
n only
V3
V4
V5
V6
V7
V7a
Dose 
Escalatio
n Only
V8-Vn
Procedure/
Study Day
Day 1
Day 2
Day 8 
Day 15 
(± 1 day)
Day 29 
(± 1 day)
Day 43
(± 3 days)
Day 57 
(± 3 days)
Day 58
Q2W (± 3 days) 
Starting on D71 
(unless otherwise 
noted)
TSH and free T4 (If 
TSH is normal then free 
T4 is not required)d
X
X
X
Q4W (± 3D) starting 
on D85
Lipid Paneld
X
X
Q8W (± 3D) starting 
on D113
Pregnancy testd, e
X
X
Q8W (± 3D) starting 
on D113
Urinalysisd
X
X
Q8W (± 3D) starting 
on D113
Efficacy:
Disease assessment 
(scans)f
X
Q8W (± 3D) starting 
on D113 through 
D393 then Q12W
(± 3D)
Study Drug Administration:
Oleclumabg
X
X
X
X
X
X
AZD4635g, h
X (daily dosing)
Pharmacokinetics/
:
Plasma for AZD4635 
PKi
X
X
Pre-dose
Pre-dose
X
X
D113 (± 3D) only
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Table 4
Treatment Period Study Procedures - Arm B (Oleclumab + AZD4635)
Study Period
Treatment Period
Visit Number
V2
V2a
Dose 
Escalatio
n only
V3
V4
V5
V6
V7
V7a
Dose 
Escalatio
n Only
V8-Vn
Procedure/
Study Day
Day 1
Day 2
Day 8 
Day 15 
(± 1 day)
Day 29 
(± 1 day)
Day 43
(± 3 days)
Day 57 
(± 3 days)
Day 58
Q2W (± 3 days) 
Starting on D71 
(unless otherwise 
noted)
Serum for oleclumab
PKj
X
X
X
Q12W (± 3D) 
starting on D141
Serum for oleclumab
ADAd
X
X
X
Q12W (± 3D) 
starting on D141
ADA = anti-drug antibody; AE = adverse event; β-hCG = beta-human chorionic gonadotropin;
 ECG = 
electrocardiogram; D = Day(s); ECOG = Eastern Cooperative Oncology Group; PK = pharmacokinetics; Q2W = every 2 weeks; Q4W = every 4 weeks; 
Q8W = every 8 weeks; Q12W = every 12 weeks; SAE = serious adverse event; T4 = thyroxine; THS = thyroid-stimulating hormone; V = Visit.
a
Physical examination can be performed up to 24 hours prior to dosing on Day 1.
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b
All ECGs will be obtained in triplicate (all within a 5-minute time period). ECGs will be recorded prior to the administration of any investigational 
product and within 30 minutes post end of oleclumab infusion. For AZD4635, triplicate ECGs will also be performed on the extensive PK sampling days 
at 1, 2, and 4 hours (±15 minutes) post-dose on Day 1 and Day 57.
c
On days of oleclumab investigational product administration, vital signs will be measured according to the following schedule: Within 60 minutes prior 
to start of oleclumab infusion then every 30 minutes (± 5 minutes) during the infusion, the end of infusion (± 5 minutes), and 30 minutes (± 10 minutes) 
post end of oleclumab infusion. On Day 1, additional vital sign measurements will be taken at 60 minutes (± 10 minutes) and 3 hours (± 15 minutes) post 
end of oleclumab infusion. On Day 1, subjects should remain at the site for monitoring (with immediate access to medical resuscitation equipment) for at 
least 3 hours following the end of the oleclumab infusion.
d
Assessments will be collected prior to administration of any investigational product. If screening assessments have been performed within the 5 days 
prior to Day 1 (Days -5 to -1), then assessment does not need to be performed on Day 1 pre-dose. All safety laboratory results must be reviewed by the 
investigator or physician designee prior to administration of any investigational product.
e
Females of childbearing potential only, if urine test is positive or equivocal then serum β-hCG testing should be performed for confirmation.
f
Subjects with pelvic disease and/or brain metastases at screening or subjects who develop neurologic or other clinical symptoms that warrant imaging
must have brain and/or pelvic imaging with each disease assessment. Disease assessments will be performed during the treatment period or as indicated 
by signs/symptoms. If radiographic progression is observed in the absence of clinical deterioration, a confirmatory scan should be performed not less 
than 4 weeks later. If clinical deterioration occurs then a confirmatory scan is not required.
g
On oleclumab dosing days, the administration of AZD4635 should precede the oleclumab infusion.
h
All doses of AZD4635 should be taken at approximately the same times each day, in a fasted state (water to drink only) from at least 2 hours prior to the 
dose to at least 1 hour post-dose.
i
For all subjects: On Day 1 and Day 57, plasma samples for AZD4635 PK will be collected pre-dose (within 90 minutes prior to dosing AZD4635) and 
60 minutes (± 5 minutes), 2 hours (± 10 minutes), and 4 hours (± 15 minutes) post-dose. On Day 15 and Day 29, plasma samples for AZD4635 PK will 
be collected pre-dose (within 90 minutes prior to dosing AZD4635). On Day 113, plasma samples for AZD4635 PK will be collected pre-dose and 
within 30 minutes (± 10 minutes) post end of oleclumab infusion to coincide with the ECG collection.
For subjects in Dose-Escalation: On Day 1 and Day 57, additional plasma samples for AZD4635 PK will be collected 6 hours (± 15 minutes) and 24 
hours (± 120 minutes) post-dose. The 24 hour (± 120 minutes) post-dose plasma sample for the Day 1 and Day 57 visits will be collected at V2a (Day 2) 
and V7a (Day 58), respectively. Visits 2a and 7a are only required for subjects in dose-escalation. 
j
Serum samples for oleclumab PK will be collected pre-dose (within 90 minutes prior to start of oleclumab infusion) and 10 minutes (± 5 minutes) post 
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4.2.3
Follow-up Period
Table 5 shows all procedures to be conducted during the follow-up period. 
Table 5
Schedule of Follow-up Procedures (All Arms)
Study Period
Follow-up Period
Visit Number
EOT-1
EOT-n
Procedure/Study Day
30 Days Post Last Dose
(± 7 Days)
Q12W (± 7 days) Starting 
90 Days Post Last Dose
Clinical Assessments:
Physical examination (abbreviated, 
symptom directed) 
X
Weight
X
ECOG
X
ECGa
X
LVEF by echocardiogram/MUGA (Arm A 
only)b
X
Vital signs
X
Assessment of AEs/SAEs
X
Only EOT-2
Concomitant medications
X
Follow-up for survival and subsequent 
anticancer treatment (telephone contact if 
visits are discontinued)
X
Laboratory Assessments:
Serum chemistry
X
Hematology
X
TSH and free T4 (If TSH is normal then 
free T4 is not required)
X
Lipid panel
X
Pregnancy testc
X
Urinalysis
X
Efficacy:
Disease assessment (scans)d
X
X
Pharmacokinetics
:
Serum for oleclumab PK
Only EOT-2
Serum for oleclumab ADA
Only EOT-2
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ADA = anti-drug antibody; AE = adverse event; β-hCG = beta-human chorionic gonadotropin;
 
 ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End 
of Treatment; LVEF = left ventricular ejection fraction; MUGA = multigated acquisition scan; PD = progressive
disease; PK = pharmacokineteic; Q12W = every 12 weeks; SAE = serious adverse event; T4 = thyroxine; THS = 
thyroid-stimulating hormone.
a
All ECGs will be obtained in triplicate (all within a 5-minute time period).
b
Echocardiogram/MUGA are only required for subjects that were enrolled in Arm A. If the subject had an 
evaluation in the preceding 4 weeks this assessment is not required. However, a follow-up assessment will 
be required if the on-treatment assessment was abnormal at the time of discontinuation of investigational 
product, to confirm reversibility of the abnormality.
c
Females of childbearing potential only, if urine test is positive or equivocal then serum β-hCG testing 
should be performed for confirmation.
d
If a subject discontinues treatment, the EOT-1 disease assessment is only required if it has been > 28 days 
since the last disease assessment. Disease assessment should then continue Q12W starting with EOT-2 date 
for subjects who discontinued treatment due to reasons other than PD.
4.3
Description of Study Procedures
4.3.1
Efficacy……….
The primary assessment of tumor response will be based on RECIST version 1.1 (Eisenhauer 
et al, 2009) and will be performed according to the schedule in Section 4.2. All images will be 
collected and stored for possible future central re-analysis. 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 5. Additional disease 
assessments may be performed as clinically indicated. All subjects will be followed for 
survival until the end of the study (defined as 2 years after the last subject begins treatment 
with investigational product or when the sponsor stops the study, whichever occurs earlier
[Section 6.3]).
Tumor assessments may include the following evaluations: physical examination (with 
photograph and measurement of skin lesions as applicable); cross-sectional imaging using CT 
or MRI scan of the chest, abdomen, pelvis; and brain. Computed tomography or MRI scan of 
the chest and abdomen will be performed with each disease assessment for all subjects. 
Additionally, CT or MRI scan of the pelvis and brain will be performed at screening for all 
subjects. Any subjects with pelvic disease and/or brain metastases at screening or any subjects 
who develop neurologic or other clinical symptoms that warrant imaging must also have 
pelvic and/or 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, 
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CT with contrast is required. The same method is preferred for all subsequent tumor 
assessments.
Physical examination

Lesions detected by physical examination will only be considered measurable if 
superficial, eg, skin nodules and palpable lymph nodes. Documentation by color 
photography including ruler is recommended for estimating the size of skin lesions.
Computed tomography scan 

Computed tomography (contrast preferred) scans of the chest, abdomen, and pelvis 
should be performed with contiguous cuts in slice thickness of 5 mm or less. Spiral CT 
should be performed using a 5-mm contiguous reconstruction algorithm. The same 
imaging device should be used for serial evaluations.
Magnetic resonance imaging scan

Magnetic resonance imaging scan of the chest, abdomen, and pelvis is acceptable for 
measurement of lesions provided that the same anatomical plane is used for serial 
assessments. 

In case of MRI, measurements will be preferably performed in the axial (transverse) plane 
on contrast-enhanced T1-weighted images. However, there are no specific sequence 
recommendations.
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows:

Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 

10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm). 

10 mm caliper measurement by clinical 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 
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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 to facilitate the exploratory iRECIST 
analysis. Other new lesions will be included into the non-tumor burden.
RECIST Version 1.1 Response Criteria
Evaluation of Target Lesions

Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” if there are target nodes). 

Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression.)

Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
Evaluation of Non-target Lesions

Complete Response - Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 

Non-complete response/Non-progressive disease - Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits.

Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of stable disease (SD) or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy (see Section 4.1.7). In the 
absence of measurable disease, change in non-measurable disease comparable in 
magnitude to the increase that would be required to declare PD for measurable disease. 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large,’ an increase in 
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Appearance of New Lesions
The appearance of new lesions is considered PD according to RECIST version 1.1. 
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions may not represent true disease progression. In the absence of rapid clinical 
deterioration, subjects may continue to receive study therapy if investigators consider that 
subjects continue to benefit from treatment (see Section 4.1.7). 
Evaluation of Overall Response
For the overall response based on RECIST version 1.1, confirmation of CR and PR is required 
by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. 
A confirmatory scan will also be required after an initial assessment of PD for the purpose of 
managing treatment 
. If a subject 
discontinues the study due to PD and begins another treatment, a confirmatory scan is not 
required. Treatment of subjects may continue between the initial assessment of PD and 
confirmation of PD (which is not required by RECIST version 1.1). These subjects may 
continue to receive study therapy beyond confirmed PD in accordance with Section 4.1.7 and 
if investigators consider that subjects continue to receive benefit from treatment. In the 
absence of clinical deterioration, such modifications to the RECIST may discourage the early 
discontinuation of treatment and provide a more complete evaluation of study therapy
antitumor activity than would be seen with conventional response criteria.
Table 6 provides overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions.
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Table 6
Evaluation of Overall Response
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Complete response
Complete response (or no non-
target lesion)
No
Complete response
No target lesion a 
Complete response
No
Complete response
Complete response
Not evaluable b
No
Partial response
Complete response
Non-complete response /
non-progressive disease
No
Partial response
Partial response
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Partial response
Stable disease
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesion a
Not all evaluated
No
Not evaluable
No target lesion a
Non-complete response /
non-progressive disease
No
Non-complete response /
non-progressive disease
Progressive disease
Any
Yes/No
Progressive disease
Any
Progressive disease
Yes/No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesion a
Unequivocal progressive disease
Yes/No
Progressive disease
No target lesion a
Any
Yes
Progressive disease
a
Defined as no target lesion at baseline.
b
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment.
4.3.1.1
 
 
 
 
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Table 7
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Table 7
4.3.1.2
 
4.3.2
Medical History, Physical Examination, Ophthalmologic Examination,
Electrocardiogram, Echocardiogram/MUGA, Weight, and Vital Signs
Medical History
Medical history will be collected at screening. Based on findings from medical history, 
ongoing current conditions will be given a baseline grade according to the procedure for AEs. 
Increases in severity of pre-existing conditions during the study will be considered AEs, with 
resolution occurring when the grade returns to the pre-study grade or below.
Physical Examinations
Physical examinations will be performed according to the schedule in Section 4.2. A complete 
physical examination will be performed at screening and should include assessments of the 
head, eyes, ears, nose, and throat, respiratory, cardiovascular, GI, musculoskeletal, 
neurological, psychiatric, dermatological, hematologic/lymphatic, endocrine systems, and 
weight to 0.1 kg; and height (at screening only). Abbreviated symptom-directed physical 
examinations will be conducted at subsequent visits post dosing.  
Ophthalmologic Examination (Arm A only)
Full ophthalmologic assessment, including slit lamp, testing of visual acuity and 
ophthalmoscopic examination, should be performed at screening and if a subject experiences 
any visual symptoms, with additional tests if clinically indicated (Section 4.2). 
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Ophthalmologic examination results should be collected in the electronic case report form 
(eCRF).
Vital Signs
Vital signs (temperature, BP, pulse rate, and respiratory rate) will be measured according to 
the schedule 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. Pulse oximetry will be 
assessed at screening only (Section 4.2.1). On Day 1, subjects should remain at the site for 
monitoring (with immediate access to medical resuscitation equipment) for at least 3 hours 
following the end of the oleclumab infusion.
Electrocardiograms
According to the schedule in Section 4.2, 12-lead ECGs will be obtained by the site in 
triplicate (all 3 within a 5-minute time period) after the subject has been in supine or 
semi-recumbent rest for 10 minutes. Electrocardiograms will be recorded prior to the 
administration of any investigational product and within 30 minutes post end of oleclumab 
infusion on the day of the visit. In Arm B, triplicate ECGs will also be performed on the 
extensive AZD4635 PK sampling days at 1, 2, and 4 hours post-dose on Day 1 and Day 57
(Table 4).
In case of clinically significant ECG, abnormalities including an ECG that demonstrates a 
QTcF value > 500 msec, 2 additional 12-lead ECGs should be obtained over a brief period 
(eg, 30 minutes) to confirm prolongation based on the average QTcF value manually 
over-read by a medically qualified person.
Cardiac Left Ventricular Function Assessed by Echocardiogram/MUGA (Arm A only)
Assessment of cardiac left ventricular function will be performed by echocardiogram/MUGA 
according to the schedule in Section 4.2. Subjects should have high quality standardized 2-D 
echocardiographic examinations performed by an experienced sonographer (preferably with 
the same sonographer performing all studies for a given subject). LVEF determinations should 
be determined quantitatively based on bi-plane measurements of end diastolic and end systolic 
left ventricular volumes.
4.3.3
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. 
Routine clinical laboratory safety tests (serum chemistry, lipid panel, hematology, urinalysis, 
thyroid function, coagulation, and pregnancy tests) will be performed in a local clinical 

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laboratory. Clinically significant abnormal laboratory results should be repeated as soon as
possible (preferably within 24 to 48 hours).
The following clinical laboratory tests will be performed at the visits specified in Section 4.2: 
Serum Chemistry
•
Sodium
•
Total bilirubin
•
Potassium
•
ALP
•
Bicarbonate
•
Albumin
•
Blood urea nitrogen
•
Gamma-glutamyl transpeptidase
•
Creatinine
•
Total protein
•
Glucose
•
Lactate dehydrogenase
•
Calcium
•
Uric acid
•
Magnesium
•
Amylase
•
AST
•
Lipase
•
ALT
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase.
Note for serum chemistry: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and 
assessed concurrently. If a site is unable to perform serum chemistry testing and all testing is available on plasma 
samples this alternative method is acceptable. 
Lipid Panel
•
Total Cholesterol
•
Triglycerides
Hematology
•
White blood cells count 
•
Absolute monocyte count
•
Absolute neutrophil count
•
Hemoglobin
•
Absolute lymphocyte count
•
Platelet count
Urinalysis
•
Protein
•
Blood 
•
Ketones 
•
If abnormal, then microscopy including 
WBC/HPF, RBC/HPF 
HPF = high power field; RBC = red blood cells; WBC = white blood cells.

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Pregnancy Test (females of childbearing potential only)
•
Urine hCG
•
Serum β-hCG (at screening only and if a urine hCG is equivocal or positive during the remainder of the 
study)
β-hCG = beta-human chorionic gonadotropin; hCG = human chorionic gonadotropin.
Other Safety Tests
•
Coagulation tests: prothrombin time, partial thromboplastin time, fibrinogen. International normalized ratio 
can be obtained instead of prothrombin time but should remain consistent throughout the study.
•
Hepatitis B testing: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, IgM 
hepatitis B core antibody. If hepatitis B core (total) antibody testing is unavailable, then the hepatitis B core 
IgG and IgM should both be obtained instead. If a test is not locally available, then standard local practice 
for assessing hepatitis B status should be utilized. If screening tests are positive, a hepatitis B virus 
(HBV)-DNA test should be obtained to assess infection status.
•
Hepatitis C antibody. If screening antibody is positive, a hepatitis C virus (HCV)-RNA test should be 
performed to assess infection status.
•
Human immunodeficiency virus-1 antibody
•
Thyroid function tests: thyroid stimulating hormone (TSH) and free thyroxine (T4). Note: If TSH is normal 
then free T4 is not required.
4.3.4
Pharmacokinetic Evaluation and Methods
Blood will be collected to evaluate PK of oleclumab in serum and PK of osimertinib and 
AZD4635 in plasma (see Section 4.2 or collection time points). The PK of oleclumab in serum 
and the PK of osimertinib and AZD4635 in plasma will be measured utilizing a validated 
assay.
Pharmacokinetic analysis of the plasma data for osimertinib, AZD4635, and their metabolites 
will be performed. The actual sampling times will be used in the parameter calculations and 
appropriate PK parameters after single and multiple doses will be derived using standard non-
compartmental methods.
Blood samples will be collected for measurement of oleclumab (see Section 4.2 for collection 
time points). Evaluations will be performed using a validated assay. 
4.3.5
Immunogenicity Evaluation and Methods
Blood samples will be collected prior to administration of any investigational product to 
evaluate ADA responses to oleclumab in serum (see Section 4.2 for collection time points). 
Evaluations will be performed using a validated assay.
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4.3.7
Estimate of Volume of Blood to Be Collected
A total of no more than 57 mL (12 teaspoons) of blood will be required for all screening tests, 
which may be conducted over 1 or more days during screening. No more than 72 mL 
(15 teaspoons) of blood will be drawn on any visit day after screening. Up to 120 mL 
(24 teaspoons) of blood will be collected between Days 1 through 28 after the first dose of 
oleclumab within any cohort. The total volume to be collected will depend on the number of 
doses administered and the length of follow-up.
4.4
Expected Start and End of Study 
The study started on 08 May 2018 (first subject screening visit). The data entry cut-off in 
support of final database lock will occur approximately 12 months + 90 days follow up after 
the last subject is administered the first dose of investigational product. Data analysis will be 
performed and a CSR will be written based on the final database lock.
Any subject still receiving investigational product at the time of this data entry cut-off will 
continue to receive investigational product within the current study through a continued 
treatment period (managed by the sponsor’s Post Analysis and Reporting Team [PART] 
program) as long as, in the Investigator’s opinion, the subject is deriving clinical benefit and 
has not fulfilled any discontinuation criteria. During this continued treatment period, 
assessments will revert to the standard of care for each individual site. Data will not be entered 
into the clinical study database after the data entry cut-off date. During this continued 
treatment period, all SAEs, overdoses, and pregnancies will be reported until 28 days after the 
last dose of investigational product. Paper based SAE reporting will be used by the study sites 
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during this period. Reported SAE data will be entered into the sponsor’s global safety 
database. Investigational product dispensation and reconciliation will be handled by the study 
site at each subject’s visit.  The investigational product accountability information must still 
be collected until all subjects have completed treatment. Individual sites will be closed after 
database lock has occurred and once their final subject completes the 28-day follow-up visit.  
The continued treatment period will remain available to subjects until the Last Subject Last 
Visit which is defined as the date of the last subject’s 28-day safety follow-up visit. 
4.5
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or permanently terminate this study or 
any treatment arm at any time. The reasons for temporarily suspending or permanently 
terminating the study or a treatment arm may include but are not limited to the following: 

The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects

Subject enrollment is unsatisfactory

Non-compliance that might significantly jeopardize the validity or integrity of the study

Sponsor decision to terminate development of the investigational product for this 
indication

Sponsor decision to terminate the study or any treatment arm based on continuous interim 
monitoring (Sections 4.9.7 and 4.9.8)
If MedImmune determines that temporary suspension or permanent termination of the study 
or any treatment arm is required, MedImmune will discuss the reasons for taking such action 
with all participating investigators (or head of the medical institution, where applicable). 
When feasible, MedImmune will provide advance notice to all participating investigators (or 
head of the medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune or its representatives 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 Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) promptly and provide the reason(s) for the suspension/termination. If the study is 
suspended for safety reasons and it is deemed appropriate by the sponsor to resume the study, 
approval from the relevant regulatory authorities (and IRBs/IECs when applicable) will be 
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4.6
Investigational Products
4.6.1
Identity of Investigational Product(s)
MedImmune will provide the investigator(s) with investigational product (Table 8) using 
designated distribution centers. 
Table 8
Identification of Investigational Products
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
Oleclumab (MEDI9447)
MedImmune
Supplied as a 200-mg sterile lyophilized 
product for infusion after reconstitution and 
dilution. After reconstitution with sterile WFI, 
the solution contains 50 mg/mL oleclumab 
(MEDI9447) in 25mM histidine/histidine 
hydrochloride, 240 mM sucrose, 0.03% (w/v) 
polysorbate 80; it has a pH of 6.0. The 
nominal fill volume is 4.0 mL.
Supplied as a 500-mg sterile solution for 
infusion after dilution. The solution contains 
50 mg/mL oleclumab (MEDI9447) in 25mM 
histidine/histidine hydrochloride, 240 mM 
sucrose, 0.03% (w/v) polysorbate 80; it has a 
pH of 6.0. The nominal fill volume is 10.0 
mL.
Osimertinib
AstraZeneca
Supplied as beige, film-coated tablets 
containing either 40 or 80 mg of osimertinib 
expressed as free base (equivalent to 47.7 and 
95.4 mg of osimertinib mesylate, 
respectively). Osimertinib tablets contain 
osimertinib mesylate, mannitol, 
microcrystalline cellulose, low-substituted 
hydroxypropyl cellulose and sodium stearyl 
fumarate. The tablet film-coat contains 
polyvinyl alcohol, titanium dioxide, 
polyethylene glycol 3350, talc, yellow iron 
oxide, red iron oxide and black iron oxide.
AZD4635
AstraZeneca
Supplied as a white powder containing 5.5% 
w/w AZD4635 drug substance, hydroxypropyl 
methyl cellulose, docusate sodium, poloxamer 
188, and sucrose.
WFI = water for injection; w/v = weight/volume; w/w = weight per weight.
Oleclumab (MEDI9447) is supplied in 10R vials as a sterile, white to off white, lyophilized 
product or a as a sterile liquid drug product. The lyophilized product, after reconstitution with 

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4.0 mL sterile water for injection (WFI), and the liquid product are both clear to opalescent, 
colorless to slightly yellow liquids, free from or practically free from visible particles and 
contain 50 mg/mL oleclumab (MEDI9447) in 25 mM histidine/histidine hydrochloride, 
240 mM sucrose, 0.03% (weight/volume [w/v]) polysorbate 80, at pH 6.0. Oleclumab 
(MEDI9447) will be diluted into an IV bag containing 0.9% (w/v) saline and administered via 
IV infusion.
Osimertinib is supplied as beige, film-coated tablets (Table 8) for oral administration. 
Osimertinib tablets are packed in high-density polyethylene bottles with child-resistant 
closures. The packaging includes bottles, caps and a label. Each investigational product bottle
has a unique number that is printed on the label. 
The AZD4635 nano-milled, spray dried powder for oral suspension is presented as a white 
powder containing 5.5% weight per weight AZD4635 drug substance (Table 8). The bulk drug 
will be weighed out at a contracted compounding pharmacy into amber polyethylene 
terephthalate bottles with child-resistant screw caps. A portion of AZD4635 powder for oral 
suspension will be supplied to sites or by delivery directly to the subject in prefilled bottles 
with child-resistant screw caps, to support clinical doses from 25 to 100 mg. The drug product 
will be constituted extemporaneously as an oral suspension by the subject immediately prior 
to dosing. The aqueous suspending vehicle contains 2 mg/mL simethicone. Further details on 
the method of constitution will be provided in the Handling Instructions.
4.6.1.1
Investigational Product Inspection
Remove the required number of oleclumab (MEDI9447) vials from storage at 2°C to 8°C 
(36°F to 46°F).

750 mg dose: 4 vials of lyophilized product or 2 vials of liquid product

1500 mg dose: 8 vials of lyophilized product or 3 vials of liquid product 

3000 mg dose: 15 vials of lyophilized product or 6 vials of liquid product
Each vial selected for dose preparation should be inspected. 
If any defects are noted with the investigational product(s), the investigator and site monitor 
should be notified immediately. Refer to the Product Complaint section (Section 4.6.1.5) for 
further instructions.
4.6.1.2
Oleclumab (MEDI9447) IV Bag Preparation and Administration
The oleclumab (MEDI9447) dose must be prepared by an investigator or site-designated 
investigational product manager using aseptic technique. 
Total time from needle puncture of the oleclumab (MEDI9447) vial to the start of 
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
24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If preparation time exceeds the time limits a new dose must be prepared from new vials. 
Oleclumab (MEDI9447) does not contain preservatives, and any unused portion must be 
discarded. 
Reconstitution Procedure for Oleclumab (MEDI9447) Lypholized Product
Oleclumab (MEDI9447) investigational product requires reconstitution with sterile WFI prior 
to use. Clean the rubber stopper of the oleclumab (MEDI9447) vial with 70% ethanol or 
equivalent and allow to air dry. Slowly add 4.0 mL of sterile water for injection by tilting the 
vial to one side such that the liquid stream is directed along the vial wall and not directly onto 
the lyophilized cake. Let the vial sit for 60 seconds before swirling the vial. Gently swirl the 
vial by rotating the vial for 60 seconds and then let it sit for 60 seconds. Repeat this procedure 
until all the solids are dissolved. DO NOT SHAKE OR VIGOROUSLY AGITATE THE
VIAL. At the end of the reconstitution invert the vial to dissolve any product that might be on 
the cap. Visually inspect the solution to ensure that entire content of lyophilized cake is 
completely reconstituted. The reconstituted solution should appear clear to opalescent. A thin 
layer of bubbles on the surface of the liquid is normal.
Oleclumab (MEDI9447) IV Bag Preparation and Administration
No incompatibilities between oleclumab (MEDI9447) and polyvinyl chloride or polyolefin IV 
bags have been observed. 
The dose of oleclumab (MEDI9447) will be administered using an IV bag containing 0.9% 
(w/v) saline, with a final in-bag oleclumab (MEDI9447) concentration ranging from 1.5 to 
30 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter. The desired dose is prepared by adding the following volume of reconstituted or liquid 
oleclumab (MEDI9447) product to the IV bag: 15.0 mL for the 750 mg dose; 30.0 mL for the 
1500 mg dose; or 60.0 mL for the 3000 mg dose. The IV bag size should be selected such that 
the final concentration is within 1.5 to 30 mg/mL. Mix the bag gently to ensure homogeneity 
of the bag.
Oleclumab (MEDI9447) will be administered at room temperature (approximately 20 to 
25°C) by controlled infusion into a peripheral or central vein. Standard infusion time for 
oleclumab (MEDI9447) is one hour, 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 
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Do not co-administer other drugs through the same infusion line.
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 and document if the 
line was not flushed.
4.6.1.3
Treatment Administration
The first day of dosing is considered Day 1. The administration of osimertinib (Arm A) or 
AZD4635 (Arm B) will precede the oleclumab (MEDI9447) infusion. 
After Day 1, at visits that coincide with oleclumab (MEDI9447) dosing days, the subject 
should bring the osimertinib or AZD4635 dose for that day to the site. On these visits, after 
predose assessments, the administration of osimertinib (Arm A) or AZD4635 (Arm B) will 
also precede the oleclumab (MEDI9447) infusion.
Whenever possible, osimertinib and AZD4635 should be taken at approximately the same 
time each day. Dosing details will be captured in the subject dosing diary.
Oleclumab (MEDI9447)
Dose preparation and administration instructions are provided in Section 4.6.1.2 for oleclumab 
(MEDI9447). A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available. Investigational product must not be administered 
via IV push or bolus but as a slow IV infusion. The entire content of each IV bag will be 
infused using an infusion pump.
Osimertinib
One bottle of osimertinib will be dispensed during select oleclumab (MEDI9447) 
administration visits. Bottles will be dispensed to subjects in the original packing provided. 
The packaging includes bottles, caps, and a label. Bottle tampers should not be broken prior to 
dispensing study drug to a subject.
Osimertinib will be administered PO QD. Osimertinib should be taken at approximately the 
same time each day and can be taken with or without food.
Should a subject miss a scheduled dose of osimertinib, the subject will be allowed to take the 
dose up to a maximum of 12 hours after the scheduled dose time. If greater than 12 hours after 
the scheduled dose time, the missed dose should not be taken and the reason noted in the 
diary. The subject should take the allotted dose at the next scheduled time.

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AZD4635
AZD4635 will be dispensed to subjects at scheduled visits to the clinic or by delivery directly 
to the subject. Dosing and handling instructions and subject emergency contact details will be 
provided to subjects in writing. 
AZD4635 will be administered orally as a nanosuspension PO QD, unless safety findings 
indicate that a change to this is required. 
Whenever possible, AZD4635 should be taken at approximately the same time each day, in a 
fasted state (water to drink only) from at least 2 hours prior to the dose to at least 1 hour 
post-dose. The recommendation is for water only during this time period, but subjects should 
also be reminded that beverages containing caffeine are to be avoided during this time period. 
The fasting requirement may be reassessed, modified, or removed based on emerging data if 
appropriate. If vomiting occurs after AZD4635 dosing, the subject should not re-dose, but 
should note it in the diary.
Should a subject miss a scheduled dose, the subject will be allowed to take the dose up to a 
maximum of 4 hours after the scheduled dose time. If greater than 4 hours after the scheduled 
dose time, the missed dose should not be taken and the reason noted in the diary. The subject 
should take the allotted dose at the next scheduled time. If a subject needs to take the dose 
earlier for any reason, the subject can take the dose up to 4 hours earlier than the scheduled 
dose time. The subject should make every reasonable effort to take the study drugs on time.
4.6.1.4
Monitoring of Dose Administration
Subjects will be monitored during and after infusion of oleclumab (MEDI9447). Vital signs 
will be measured according to the schedule described in Section 4.2.2. 
Management of investigational product-related toxicities are described in Section 3.1.4. 
Acetaminophen and/or an antihistamine (eg, diphenhydramine) may be administered at the 
discretion of the investigator. If the IRR is severe or prolonged, methylprednisolone 100 mg 
(or the equivalent) should be administered as well. Investigators may administer steroids at 
their discretion as clinically indicated and per their institution’s guidelines. The medical 
monitor should be informed if steroids are utilized for management of an IRR.
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.
4.6.1.5
Reporting Product Complaints
Any defects with the investigational product(s) must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 

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monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email:
Phone:
Fax:
Mail:
MedImmune
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878
4.6.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.6.3
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.
4.6.4
Storage……….
Oleclumab (MEDI9447) investigational product vials should be stored at 2°C to 8°C (36oF to 
46oF) and must not be frozen. Vials should be kept in secondary packaging to avoid prolonged 
exposure to light.
The AZD4635 powder for oral suspension should be stored in the pack provided according to 
the storage conditions on the label.
Osimertinib should be stored below 30°C (86°F) with desiccant.
4.6.5
Treatment Compliance
Oleclumab (MEDI9447) is administered by study site personnel, who will monitor 
compliance.
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Osimertinib and AZD4635 should only be used as directed in this protocol. Subjects should 
return all unused medication and empty containers to the investigator. 
Details of treatment with investigational products for each subject will be recorded in the 
eCRF.
4.6.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of 
upon authorization by MedImmune according to investigational site policy.
4.7
Treatment Assignment and Blinding
4.7.1
Methods for Assigning Treatment Groups
Each subject who meets the eligibility criteria will be assigned open-label investigational 
product.
An IXRS will be used for assignment of unblinded investigational product kit numbers. A 
subject is considered entered into the study when the investigator notifies the IXRS that the 
subject meets eligibility criteria and the IXRS provides the assignment of unblinded 
investigational product kit numbers to the subject.
Oleclumab must be administered within 1 business day after the investigational product is 
assigned. If there is a delay in the administration of oleclumab such that it will not be 
administered within the specified timeframe, the study monitor must be notified immediately.
4.7.2
Methods to Ensure Blinding
This study is not blinded.
4.8
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.8.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.8.2. Specifically, subjects should receive full supportive care during the 

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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 
accordance with their institutional guidelines.
Specific to Osimertinib (Arm A)
If medically feasible, subjects taking regular medication, with the exception of potent inducers 
of CYP3A4 (Section 4.8.2), should be maintained on it throughout the study period. Subjects 
taking concomitant medications whose disposition is dependent upon BCRP and which have a 
narrow therapeutic index should be closely monitored for signs of changed tolerability as a 
result of increased exposure of the concomitant medication whilst receiving osimertinib. 
Guidance on medications to avoid, medications that require close monitoring and on washout 
periods is provided (see Sections 4.8.2 and 10.9). 
Subjects taking rosuvastatin should have creatine phosphokinase levels monitored (due to 
BCRP-mediated increase in exposure). If the subject experiences any potentially relevant AEs 
suggestive of muscle toxicity including unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever, rosuvastatin must be stopped and any 
appropriate further management should be taken.
Specific to AZD4635 (Arm B):
Subjects who are already taking erythropoietin at the time of screening for the study may 
continue it provided they have been taking it for more than one month at the time 
investigational product is started. Prophylactic erythropoietin should not be started during the 
first 3 weeks of any cohort, but may be started thereafter. 
Granulocyte colony stimulating factors should not be used prophylactically during the first 
3 weeks of any cohort. Use of prophylactic colony stimulating factors may be considered 
thereafter following discussion with the Medical Monitor.
4.8.2
Prohibited Concomitant Medications
Other than the medications described above, use of concomitant medications including over-
the-counter medications, vitamins, etc is discouraged. Subjects must be instructed not to take 
any medications, including over-the-counter products, without first consulting with the 
investigator.
The following medications are considered exclusionary during the study. The sponsor must be 
notified if a subject receives any of these during the study.

Any investigational anticancer therapy

Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
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hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable. 

Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-alpha blockers. Use of immunosuppressive medications for the 
management of investigational product-related AEs or in subjects with contrast allergies 
is acceptable. In addition, use of inhaled and intranasal and 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. 

Live attenuated vaccines during the study through 180 days after the last dose of 
investigational product

Herbal supplements or herbal/natural remedies 
Specific to Osimertinib (Arm A):
Concomitant use of any medications, herbal supplements and/or ingestion of foods with 
known inducer effects on CYP3A4 is prohibited (Table 21).
The medications listed in Table 23 are known to prolong QT interval and should not be 
combined with osimertinib.
Guidance regarding prohibited medications and potential interactions with concomitant 
medications for osimertinib are presented in Section 10.9.
Specific to AZD4635 (Arm B):
The following treatments and the medications listed in Section 10.10 are prohibited or are to 
be used with caution while in this study 

Beverages containing caffeine should be avoided for a time period from 2 hours before a 
dose of AZD4635 through 1 hour post-dose. Moderate use of caffeine-containing 
beverages at other times is not restricted, but subjects should be advised not to increase 
their average daily consumption.

Contribution of CYP1A2 to AZD4635 metabolism appears to be approximately 80% 
(AZD4635 Investigator’s Brochure). Therefore, potent or moderate inhibitors or inducers 
of CYP1A2 and substrates of CYP1A2 are prohibited during administration of AZD4635. 
Refer to Section 10.10 for a list of the restricted medications.

The use of warfarin is prohibited during treatment with AZD4635 (Section 10.10).

Since AZD4635 is an in vitro inhibitor of BCRP (IC50 6.2 µM) and OAT1 (IC50 6.6 µM), 
there is a risk of drug-drug interactions with sensitive substrates of BCRP (both in the gut 
and systemically) and OAT1 (systemically). Modeling has predicted a substantial increase 
in the exposure (> 2 fold) of certain statins (simvastatin, rosuvastatin, and atorvastatin) 
when co-administered with AZD4635. Therefore, the use of sensitive substrates of BCRP 
and OAT1 is prohibited in the current study (Section 10.10). Other drugs for which the 

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disposition is mediated via BCRP/OAT1 should be administered with caution, considered 
for dose modification, or substituted with an alternative drug.

Herbal preparations/medications and certain foods that are reported to be potent 
inhibitors/inducers of CYP1A2 are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, DHEA, yohimbe, saw palmetto, and ginseng. Subjects should stop using 
all herbal medications 14 days prior to first dose of AZD4635.

Subjects should avoid medications or drugs that increase risk for seizure (eg, tricyclic 
antidepressants, pseudoephedrine, anesthetics, amphetamines, cocaine).
4.9
Statistical Evaluation
4.9.1
General Considerations
Tabular summaries will be presented by dose cohort within each treatment group. Categorical 
data will be summarized by the number and percentage of subjects in each category. 
Continuous variables will be summarized by descriptive statistics, including mean, standard 
deviation, median, minimum, and maximum. Additional details of statistical analyses will be 
described in the statistical analysis plan.
The As-treated Population is defined as all subjects who receive any investigational product, 
analyzed according to treatment received. All analyses will be performed on the As-treated 
Population unless otherwise specified.
The Response-evaluable Population is defined as all subjects who receive any investigational 
product, had measurable disease at baseline and at least 1 post-baseline tumor assessment, or 
who died from any cause or who discontinued due to clinical PD prior to any post-baseline 
tumor assessment.
The DLT-evaluable Population is defined as all subjects who receive all planned doses of 
oleclumab and at least 75% of the daily administrations of osimertinib (Arm A) or AZD4635 
(Arm B) during the DLT-evaluation period (defined in Section 3.1.3.3) and complete the 
safety follow-up through the DLT-evaluation period or experience any DLT.
4.9.2
Sample Size
A total of up to approximately 98 subjects will be enrolled in this study, up to approximately 
46 subjects in Arm A and up to approximately 52 subjects in Arm B.
 
 
 
 
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Table 9
 
4.9.3
Safety……….
4.9.3.1
Analysis of Safety Endpoints
Safety data, including DLTs, AEs, SAEs, laboratory evaluations, vital signs, cardiac left 
ventricular function (Arm A only), and ECG results will be summarized based on the 
As-treated Population defined in Section 4.9.1. Summary statistics will be provided for AEs, 
SAEs, AE grade (severity), and relationship to investigational product(s), clinical laboratory 
parameters, vital signs, cardiac left ventricular function (Arm A only) and ECG. Adverse 
events will be graded according to the NCI CTCAE version 4.03.
Summary of safety data will be based on the reporting period for each endpoint (see 
Section 5.4.1 for AEs and SAEs and Section 4.2 for laboratory parameters, vital signs, cardiac 
left ventricular function [Arm A only], and ECG results).
4.9.4
Efficacy Analyses
4.9.4.1
Analysis of Efficacy Endpoints
The efficacy analyses of antitumor activity will be based on the As-treated Population
(defined in Section 4.9.1). The rates of OR and DC based on RECIST version 1.1 will be 
summarized with 95% CI based on the exact binomial distribution. Time-to-event endpoints 
(DoR, PFS, and OS) will be analyzed using the Kaplan-Meier method. Additional analyses of 
antitumor activity may be conducted in the Response-evaluable Population (defined in 
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Section 4.9.1). More details will be provided in the statistical analysis plan. The following 
efficacy endpoints will be analyzed:

OR is defined as best overall response of confirmed CR or confirmed PR according to 
RECIST version 1.1. The best overall response is defined as the best response (in the 
order of CR, PR, SD, PD, and not evaluable) among all overall responses recorded from 
the start of treatment with investigational product until objective documentation of PD, or
the last evaluable disease assessment in the absence of PD prior to the initiation of 
subsequent anticancer therapy or end of the study, whichever occurs first. The best overall 
response of CR or PR must be confirmed, which means a response of CR/PR is recorded 
at a visit and confirmed by repeat imaging not less than 28 days (4 weeks) after the visit 
when the response was first observed with no evidence of progression between the initial 
and CR/PR confirmation visit. The ORR will be estimated by the proportion of OR, and 
its 95% CI will be estimated using the exact binomial distribution. 

DoR is defined as the duration from the first documentation of OR to the first documented 
disease progression or death due to any cause, whichever occurs first. For subjects who 
are alive and progression-free at the time of data cut-off for analysis, DoR will be 
censored at the last tumor assessment date. The DoR will only be evaluated for the 
subgroup of subjects with an OR using the Kaplan-Meier method.

DC is defined as CR, PR, or SD (if subjects maintain SD for ≥ 8 weeks [± 3 days]). DC 
will be analyzed by estimating the DCR, defined as the proportion of subjects with DC 
and its 2-sided 95% CIs using an exact probability method. 

PFS will be measured from the start of treatment with investigational product until the 
first documentation of disease progression or death due to any cause, whichever occurs 
first. For subjects who are alive and progression-free at the time of data cut-off for 
analysis, PFS will be censored at the last tumor assessment date. The Kaplan-Meier 
method (Kaplan and Meier, 1958) will be used to estimate the PFS curve and the PFS rate 
at time points of interest.

The OS will be determined as the time from the start of treatment with investigational 
product 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. The Kaplan-
Meier method will be used to estimate the OS curve and the OS rate at time points of 
interest.
Subjects’ tumor samples (archival and/or from fresh biopsies) will be analyzed for T790M 
mutation that may predict increased frequency of response or longer disease stabilization. The 
analyses will be performed to determine if there is an association between the presence of the 
T790M mutation and clinical activity.
4.9.5
Analysis of Immunogenicity/Pharmacokinetics
Individual concentrations will be tabulated by dose cohort along with descriptive statistics. 
Non-compartmental PK data analysis will be performed from each dose cohort with scheduled 
PK sample collection where data allow. Relevant descriptive statistics of non-compartmental 

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PK parameters will be provided and may include: Cmax, AUC, CL, and t1/2 after IV doses and 
Cmax, tmax, AUC, CL/F, Vz/F and t1/2 after oral doses.
For each arm, the immunogenic potential of oleclumab will be assessed by summarizing the 
number and percentage of subjects who develop detectable ADAs. 
 
 Samples will be collected for potentially evaluating the 
neutralizing capacity of ADAs in the future.
4.9.6
4.9.7
Continuous Monitoring for Interstitial Lung Disease (Arm A only)
The development of ILD-like events was prospectively identified as a potential safety concern 
from a review of osimertinib in combination with durvalumab. To ensure subject safety, 
continuous monitoring of ILD events that occur in subjects enrolled in Arm A will be 
performed. The study team, including the medical monitor, will review all potential cases of 
pneumonitis/ILD via the automatic notification system from AESI reporting by the 
investigators from the start of the trial. As these reports are required within 24 hours, this will 
facilitate a rapid detection of any potential concerns. In addition, the sponsor will 
programmatically identify any potential cases of pneumonitis/ILD in the clinical database 
from the reported AE terms. The programmatic listings will commence with the enrollment of 
the sixth subject and then occur on a regular basis every 2 months thereafter.
If either of these methods of detection identify potential ILD cases exceeding the predefined 
threshold where the posterior probability of a true ILD rate of ≥10% is more than 90%, then 
an ILD review meeting will occur to adjudicate the cases and determine if any changes to the 
trial are necessary (Table 10). In addition, an ad hoc ILD review can be triggered at any time 
at the request of the study investigators or sponsor based on evolving data.
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Table 10
ILD Monitoring Plan - Continuous Monitoring Based on the Potential 
Number of ILD Cases
Number of Potential 
ILD Cases Observed
Number of Subjects 
Enrolled
Observed ILD Rate
Posterior Probability 
Given True ILD Rate 
≥10%
2
6 – 8
25.0%
91.1%
3
9- 14
21.4%
91.3%
4
15 - 21
19.0%
90.8%
5
22 - 28
17.9%
91.0%
6
29 - 36
16.7%
90.3%
7
37 - 43
16.3%
90.9%
8
44 - 46
17.4%
94.4%
ILD = interstitial lung disease.
The ILD review meeting will be comprised of all of the investigators at active sites (ie, sites 
which are IRB/IEC approved to enroll subjects) and the sponsor study team members 
(including but not limited to the medical monitor, clinical scientist, study safety physician, and 
study biostatistician). In advance of each ILD review meeting, all available clinical data about 
the cases from the sponsor and investigators will be summarized as case narratives and an 
overall summary of all potential pneumonitis/ILD cases will be provided. Investigators will 
provide a recommendation to continue the study with or without modification, or to halt 
enrollment for safety concerns. The decision of the review team will be based on a majority 
vote. All decisions by this committee will be documented and shared with all participating 
sites in writing.
During the course of the study, ILD risk was assessed and rates were closely monitored. A 
single patient discontinued treatment due to Grade 2 pneumonitis, which is expected with 
osimertinib monotherapy in the EGFRm NSCLC population. Special further assessments will 
not be devoted to ILD but will be monitored as part of overall safety assessments. Once 
patients transition to PART, safety assessments performed by the sponsor will be performed
as outlined in Section 4.4.
4.9.8
Interim Analysis
Bayesian predictive probabilities will be used for continuous interim monitoring by estimating 
the probability of observing a targeted treatment effect or futility of the treatment if the trial 
were to continue to its predefined maximum sample size (Lee and Liu, 2008). 
. An efficacy analysis may be performed at 
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each interim analysis. The results of the efficacy analysis will not impact on the stopping rule 
but may trigger other planning activities for further development of oleclumab combinations.
For Arms A and B, different ORRs were assumed as the target response rates for decision 
making.
 
The interim 
analyses will be performed separately for each arm. In Arm A, the first interim analysis will 
be performed after 10 subjects are response-evaluable (including subjects enrolled in Part 1
who receive the expansion dose) (Figure 4). In Arm B, the first interim analysis will be 
performed after 20 subjects are response-evaluable (including subjects enrolled in Part 1 who 
receive the expansion dose) (Figure 5). Enrollment may be paused at the initial interim 
analysis for each arm to allow full analysis of results. If the No-Go criteria are NOT met, 
enrollment may continue. After the initial interim analysis, the subsequent interim analyses 
will be performed after every 5 additional subjects are response-evaluable. The interim 
analyses will be based on the Response-evaluable Population as defined in Section 4.9.1.
Figure 4
 
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Figure 5
 
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for GCP E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. 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. An abnormal laboratory finding (including ECG finding) 
that requires medical intervention by the investigator, or a finding judged by the investigator 
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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 
increased). Abnormal laboratory values that are not, in the investigator's opinion, medically 
significant and do not require intervention should not be reported as AEs.
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational 
product) or nontreatment emergent. A non-treatment-emergent adverse event (TEAE) is any 
new sign or symptom, disease, or other untoward medical event that begins after written 
informed consent has been obtained but before the subject has received investigational 
product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
Adverse Events Associated with Disease Progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of a new metastasis or progression of existing metastasis related to the primary 
cancer under study should not be considered an AE. Death clearly resulting from disease 
progression should not be reported as an SAE (see reporting guidelines in Section 5.5).
New Cancers
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in the study. New metastatic lesion(s) of the subject’s 
known cancer should not be reported as a new cancer.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity 

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
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.
Additional guidance is provided in Section 10.3.
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 
investigator to the sponsor. An AESI may be serious or nonserious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
Hepatic function abnormality meeting the definition of Hy’s Law is considered an AESI. See
Section 5.6.3 for the definition and reporting of AESIs of hepatic function abnormality. 
The management of study medication related toxicities is discussed in Section 3.1.4
5.3.1
Adverse Events of Special Interest for Oleclumab
5.3.1.1
Infusion-related Reactions
Intravenous administration of mAbs can cause an acute reaction called an IRR. Acute allergic 
reactions may also occur during the infusion of investigational product. Manifestations of IRR 
and acute allergic reactions are similar and they are managed the same way. IRRs 
predominantly occur at the first exposure to drug, and are uncommon at subsequent exposures. 
The sponsor requests the study sites to include the signs/symptoms that occur during or after 
an infusion of oleclumab. Guidelines for management of subjects with hypersensitivity 
(including anaphylactic reaction) and IRRs are provided in Section 10.6. A full definition of 
anaphylaxis is provided in Section 10.4.
5.3.1.2
Cardiac Chest Pain, Transient Ischemic Attack, and Thromboembolism
AEs of cardiac chest pain, transient ischemic attack, and thromboembolic events are of special 
interest due to oleclumab potential risks of arterial calcifications, arterial ischemic disorder, 
and thrombosis. Because of this potential risk, subjects with a prior history of myocardial 
infarction, stroke, or transient ischemic attack in the past 6 months are not eligible (see 
Section 4.1.3). These events require urgent medical management, which should be performed 
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5.3.1.3
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 as per Section 3.1.4, and therapy may be discontinued at the discretion of 
the investigator. 
5.3.1.4
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 
and with confirmed presence of ADAs will discontinue treatment. Immune-complex disease 
will be managed in accordance with standard of care.
5.3.2
Adverse Events of Special Interest for Osimertinib
5.3.2.1
Interstitial Lung Disease/Pneumonitis
Interstitial lung disease describes a group of disorders characterized by progressive scarring of 
the lung. It affects the alveolar epithelium, pulmonary capillary endothelium, basement 
membrane, perivascular and perilymphatic tissues. It may cause progressive lung stiffness, 
eventually affecting the ability to get enough oxygen into the bloodstream.
The development of ILD-like events was prospectively identified as a potential safety concern 
from a review of osimertinib in combination with durvalumab and is therefore considered a 
topic of special interest in the osimertinib clinical development program. If new or worsening 
pulmonary symptoms (eg, dyspnea, cough, fever) or radiological abnormality suggestive of 
ILD are observed, an interruption in study treatment dosing is recommended, and the medical 
monitor should be informed. It is strongly recommended to perform a full diagnostic workup, 
to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage. Additionally, it should be considered that 
NSCLC and its treatment are factors which are known to predispose subjects to the occurrence 
of ILD. In the presence of confirmatory high resolution computed tomography (HRCT) scans 
where other causes of respiratory symptoms have been excluded, a diagnosis of ILD should be 
considered and study treatment permanently discontinued. A questionnaire regarding the 
results of the full diagnostic workup (including HRCT, blood and sputum culture, 
hematological parameters) will be sent to investigators (Section 5.4.4). In the absence of a 
diagnosis of ILD, study treatment may be restarted following consultation with the medical 
monitor.
ILD/pneumonitis should be reported as an AESI and should be reported within 24 hours of 
knowledge of the event (Section 5.6.5).

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Continuous monitoring of ILD events will be performed as described in Section 4.9.7.
5.3.2.2
QTc Prolongation and Arrhythmias
QTc prolongation is a measure of delayed ventricular repolarization. Excessive QTc
prolongation can predispose the myocardium to the development of early after-
depolarizations, which in turn can predispose to the development of arrhythmias. An analysis 
performed on clinical data indicated that osimertinib leads to a small (approximately 15 msec) 
increase in QTcF at the 80 mg dose level. Subjects with QTcF prolongation to > 500 msec 
should have study treatment withheld and regular ECGs performed until resolution to < 481 
msec and then restarted at a reduced dose of 40 mg. If the toxicity does not resolve to ≤Grade 
1 within 21 days, the subject will be permanently discontinued from study treatment 
(Table 16). A manual over-read by a medically qualified person should be performed for all 
QTc values > 500 msec prior to withholding or discontinuing study treatment (Section 4.3.2).
Arrhythmias assessed as related to a QT prolongation should be reported as AESIs.
5.3.2.3
Changes in Cardiac Contractility
Across clinical trials, LVEF decreases ≥10% and a drop < 50% occurred in 3.9% (35/908) of 
subjects treated with osimertinib who had a baseline and at least one follow-up LVEF 
assessment. Cardiac monitoring for all subjects in Arm A will include LVEF assessments at 
screening and during treatment according to the schedule in Section 4.2. 
Changes in cardiac contractility should be reported as AESIs.
5.4
Recording of Adverse Events
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the event 
meets criteria of an SAE and therefore requires immediate notification to the sponsor (Section 
5.5). See Section 5.2 for the definition of SAEs and Section 10.3 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.
Infusion of biological products is commonly associated with IRRs. Anaphylaxis and IRRs
have some common manifestations and may be difficult to distinguish from each other. IRRs
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 IRRs, anaphylaxis is a rare event, usually occurring after subsequent 
exposure to an antigen, and it is most commonly accompanied by severe systemic, skin,
and/or mucosal reactions. The investigator is advised to carefully examine symptoms of 

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adverse reactions observed during or shortly after exposure to oleclumab, and consider the 
above mentioned facts prior to making a final diagnosis. Reactions occurring at the time of or 
shortly after subsequent infusions of investigational product are to be judged by the 
investigator at his/her own discretion. For the investigator’s convenience and in order to 
facilitate consistency in judgments, a copy of the National Institute of Allergy and Infectious 
Disease and Food and Allergy Anaphylaxis Network guidance for anaphylaxis diagnosis is 
provided in Section 10.4.
5.4.1
Time Period for Collection of Adverse Events
Adverse events and SAEs will be collected from time of signature of informed consent
through 90 days (± 7 days) after the last dose of investigational product.
For non-TEAEs (ie, AEs that occur during the period from the time informed consent is 
signed but prior to the subject receiving investigational product), only AEs associated with 
protocol-related procedures should be reported. After the start of treatment, all TEAEs
(Section 5.1) should be reported.
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. MedImmune retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
5.4.3
Deaths……….
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:

Death clearly the result of disease progression should be reported and documented in the 
eCRF but should not be reported as an SAE.

Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign 
main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed, a copy
of the post-mortem results should be forwarded to the sponsor representative(s) within the 
usual timeframes (refer to Section 5.5 for additional information).

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5.4.4
Recording of Interstitial Lung Disease/Pneumonitis
Adverse events of ILD and/or pneumonitis will require the completion of a comprehensive 
questionnaire to help better assess the etiology. This will include further details about the 
subject’s medical and cancer history, diagnostic workup (including HRCT, blood and sputum 
culture, hematological parameters), and final outcome to be completed in the eCRF. 
5.5
Reporting of Serious Adverse Events
All SAEs must 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 sponsor 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 
representative(s).
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. 
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 Investigator’s Brochure, 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.

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If an overdose on a MedImmune investigational product occurs during the course of the study, 
then the investigator or other site personnel inform appropriate sponsor representatives 
immediately, or no later than 24 hours 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, reporting must occur within 30 days.
5.6.2
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 (initial fatal/life-threatening or follow-up 
fatal/life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 5.5) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Section 10.3.
5.6.3
Hepatic Function Abnormality
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 may need to be 
reported as SAEs. Refer to Section 10.5 for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law. 
5.6.4
Pregnancy……….
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.4.1
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 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 

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normal birth or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from study treatment and completed end of 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 sponsor 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 paper forms 
are used to report the outcome of the pregnancy.
5.6.4.2
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 180 days after 
the last dose of investigational product should, if possible, be followed up and documented.
5.6.5
Interstitial Lung Disease/Pneumonitis
Adverse events of ILD/pneumonitis are required to be reported within 24 hours of knowledge 
of the event to MedImmune Patient Safety.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review and 
discuss the requirements of the 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).

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6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed

Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each/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 
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 MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.

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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 (Sections 4.1.5 and 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. This date will 
be approximately 2 years after the final subject is entered into the study or when the sponsor 
stops the study, whichever occurs earlier.
6.4
Data Management 
Data management will be performed by MedImmune 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.
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.

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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 (ICF) 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. Clinical data from this 
study may be combined with results from other studies for additional scientific-related 
research.
 
 
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 ICF 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 MedImmune before enrollment of any subject into the study. 
MedImmune should approve any substantive modifications to the ICF that are needed to meet 
local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually.
Before the study is initiated, MedImmune will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. MedImmune 
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 
CCI

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IRB/IEC. MedImmune 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. MedImmune will develop a core 
ICF for use by all investigators in the clinical study. MedImmune must approve any 
modifications to the ICF 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 ICF(s) is/are stored in the Investigator’s Study File.

Ensure a copy of the signed ICF is given to the subject.

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC.
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune.
Substantial changes must be documented in a study protocol amendment. MedImmune will 
distribute amended versions of the protocol to the Principal Investigator(s). Before 
implementation, amended protocols must be approved by relevant IRB/IEC (Section 7.2) and 
according to local requirements, the national regulatory authority approval. The IRB/IEC must 
also approve revisions to the ICF, advertising, and any other written information and/or 
materials resulting from the change to the protocol.
If local regulations require, any unsubstantial changes will be communicated to or approved 
by each IRB/IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 

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an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements. The investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the site.

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8
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lung cancer. J Clin Oncol. 2005;23(14):3270-8.

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9
CHANGES TO THE PROTOCOL
All changes described below have been incorporated into the current version of the protocol. 
9.1
Protocol Amendment 4
Text revisions resulting from this amendment are incorporated in the body of Protocol
Amendment 4. The primary reason for the Amendment was to add Section 4.4, to allow for 
the continuation of a subject’s treatment after the Last Subject Last Visit for the primary 
endpoint.
Substantial changes to the protocol are summarized below:
1. Section 1.6 (Benefit-Risk and Ethical Assessment): 
a.
Arterial calcifications and arterial ischemic disorder have been removed as 
important potential risks for oleclumab, and added as potential risks for 
oleclumab.
b. Erythema multiforme, Stevens-Johnson syndrome (rare) and cutaneous 
vasculitis have been added as expected adverse drug reactions for osimertinib. 
2. Section 4.4 (Expected Start and End of Study): New section added to provide guidance 
for the continuation of a subject’s treatment after the Last Subject Last Visit for the 
primary endpoint. In addition, the actual study start and the data cut-off dates for the 
primary endpoint were added.
3. Section 4.9.7 (Continuous Monitoring for Interstitial Lung Disease [Arm A only]):  
Updated to include results of ILD monitoring, and to provide guidance for continued 
ILD monitoring as part of the overall safety assessment.
Changes to the protocol considered to be non-substantial are summarized below:
1. Medical monitor updated on the title page
2. Minor formatting changes were made and the table of contents and abbreviation list 
were updated accordingly
9.2
Protocol Amendment 3
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. The main reason for this Amendment was to add dose levels for Arm B as 
detailed below. The major changes to the protocol are summarized below.
1
The protocol synopsis was updated to correspond to the body of the document.
2
Section 1.3.3 (AZD4635 Nonclinical Experience): Updated text to reflect that data from 
in vitro studies suggest the main enzyme involved in the metabolism of AZD4635 is 
CYP1A2 per AZD4635 Investigator’s Brochure edition 4.0. 

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3
Section 1.4.3 (AZD4635 Clinical Experience): Updated clinical experience for 
Study D8730C00001 as of the data cut-off of 16 January 2018 per AZD4635 
Investigator’s Brochure edition 4.0.
4
Section 1.4.1.2 (Study D6070C00004): Added new section with clinical experience for 
the current study as of the data cut-off of 05 October 2018.
5
Section 1.6 (Benefit-Risk and Ethical Assessment): Revised potential risks of AZD4635 
to align with the AZD4635 Investigator’s Brochure edition 4.0. Changes include removal 
of important potential risk of increased risk of seizures, removal of potential risks of 
tachycardia, increased serum calcium and cholesterol, reduced adenosine diphosphate 
platelet aggregation, and thyroid hypertrophy, and addition of potential risk of diarrhea.
6
Section 3.1.2.2 (Treatment Regimen: Arm B): Since the starting dose level (dose level 1 
[oleclumab 1500 mg Q2W and AZD4635 75 mg QD]) was de-escalated to dose level -1 
(oleclumab 1500 mg Q2W and AZD4635 50 mg QD) due to incidence of nausea and 
vomiting (see updated clinical experience for Study D6070C00004 in Section 1.4.1.2), the 
dose-escalation scheme was revised to add additional dose levels of -1a, -2, and -2a. 
Table 2 (Arm B Combination Therapies and Dose Levels [Part 1: Dose Escalation]) was 
replaced with Figure 3 to reflect the change in study design. The changes included:

dose escalation to dose level -1a (oleclumab 3000 mg Q2W and AZD4635 50 mg 
QD) if dose level -1 is safely tolerated

dose de-escalation to dose level -2 (oleclumab 1500 mg Q2W and AZD4635 25 mg 
QD) if the MTD is exceeded at dose-level -1

dose escalation to dose level -2a (oleclumab 3000 mg Q2W and AZD4635 25 mg 
QD) if dose level -2 is safely tolerated
7
Section 3.1.4.2 (For Toxicity That Occurs While on Oleclumab and AZD4635 [Arm B]): 
Revised text to reflect that the AZD4635 25 mg QD dose is also allowed for 
de-escalation, if needed.
8
Section 3.2.1 (Dose Rationale): Under the subheading “AZD4635 (Arm B)”, updated text 
to be consistent with the changes in Section 1.4.3 (AZD4635 Clinical Experience) and to 
reflect that the AZD4635 25 mg QD dose is also allowed for de-escalation, if needed.
9
Section 4.1.3 (Exclusion Criteria [Additional Exclusion Criteria for Arm B]): The 
following revisions were made:

Exclusion criterion 1: Restrictions for concomitant treatment with sensitive substrates 
of CYP2C9 and CYP2C19 were removed, as data from in vitro studies suggest the 
main enzyme involved in the metabolism of AZD4635 is CYP1A2 per AZD4635 
Investigator’s Brochure edition 4.0. Clarified that warfarin is prohibited during 
treatment with AZD4635.

Exclusion criterion 4: The restriction to exclude subjects with prior traumatic brain 
injury, prior stroke, or other predisposing risk of seizure was removed. Increased risk 
of seizure is not considered a potential risk for AZD4635 per AZD4635 
Investigator’s Brochure edition 4.0.

Exclusion criterion 7: Added exclusion criterion that any subject with open 
ulceration(s) should avoid dosing with AZD4635. The exclusion criterion was added 
because the healing of ulcers might be affected by the local absorption of the liquid.

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10 Section 4.3.2 (Medical History, Physical Examination, Ophthalmologic Examination, 
Electrocardiogram, Echocardiogram/MUGA, Weight, and Vital Signs): For Arm A 
echocardiographic examinations, removed requirement for Doppler as high quality 
standardized 2-D is sufficient to evaluate LVEF.
11 Section 4.5.1 (Identity of Investigational Product[s]) and Table 8 (Identification of 
Investigational Products): In Table 8, revised concentration and formulation details for 
AZD4635 to be consistent with the AZD4635 Investigator’s Brochure edition 4.0. 
Removed second sentence concerning primary packaging of AZD4635 as this level of 
detail is not included in AZD4635 Investigator’s Brochure edition 4.0. Revised text to 
reflect that AZD4635 will be supplied to support clinical doses from 25 to 100 mg 
(previously 50 to 100 mg).
12 Section 4.5.4 (Storage): Revised storage details for AZD4635 per AZD4635 
Investigator’s Brochure edition 4.0.
13 Sections 4.7.2 (Prohibited Concomitant Medications [Specific to AZD4635 (Arm A)]) 
and 10.10 (Appendix 10 - Prohibited Medications for Subjects treated with AZD4635 in 
Arm B): Data from in vitro studies suggest the main enzyme involved in the metabolism 
of AZD4635 is CYP1A2 per AZD4635 Investigator’s Brochure edition 4.0. In 
Section 4.7.2, revised second bullet to reflect that contribution of CYP1A2 to AZD4635 
metabolism appears to be approximately 80% (previously stated that no formal clinical 
drug interactions have been performed). Restrictions for concomitant treatment with 
sensitive substrates of CYP2C9 and CYP2C19 were removed in Sections 4.7.2 and 10.10.
Clarified that warfarin is prohibited during treatment with AZD4635.
14 Sections 5.3.3 (Adverse Events of Special Interest for AZD4635) and 5.3.3.1 (Seizures): 
The AESI of seizures for AZD4635 was removed. The increased risk of seizures was a 
theoretical risk and is not supported by the available clinical data from the FTIH study 
and thus is no longer considered to be a risk for AZD4635 per AZD4635 Investigator’s 
Brochure edition 4.0.
15 Section 7.1 (Subject Data Protection): Added statement that clinical data from this study 
may be combined with results from other studies for additional scientific-related research.
9.3
Protocol Amendment 2
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. The major changes to the protocol are summarized below.
1
The protocol synopsis was updated to correspond to the body of the document.
2
MEDI9447 was revised to oleclumab throughout the protocol.
3
Tables and figures were renumbered sequentially throughout the protocol (previously 
numbered sequentially by section number).
4
Section 1.4.1 (Oleclumab Clinical Experience): Updated per most recent edition of the 
oleclumab Investigator’s Brochure.
5
Section 1.4.1 (Osimertinib Clinical Experience): Updated per most recent edition of the 
osimertinib Investigator’s Brochure.

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6
Sections 1.6 (Benefit-Risk and Ethical Assessment) and 5.3.1.4 (Tuberculosis): In Section 
1.6 under the subheading “Potential Risks” (first paragraph), the important potential risk 
of reactivation of latent tuberculosis for oleclumab was removed. The text, “observation 
of CD73 expression in human tuberculosis granulomas”, was also removed. Additionally, 
the AESI of tuberculosis (prior Section 5.3.1.4) was removed and the subsequent section 
renumbered accordingly. Review of the literature determined there is insufficient 
evidence to support the original inclusion of reactivation of latent tuberculosis as an 
important potential risk. Please refer to the summary of changes section of Edition 4.0 of 
the Investigator’s Brochure for full details.
7
Section 1.6 (Benefit-Risk and Ethical Assessment): In Section 1.6 under the subheading 
“Potential Risks” (second paragraph), updated risks for osimertinib per most recent 
edition of the osimertinib Investigator’s Brochure.
8
Sections 2.3 (Exploratory Objectives and Associated Endpoints), 3.2.3 (Rationale for 
Endpoints), 4.3.1 (Efficacy), 4.3.1.1
 
 
, 4.3.1.2 
 
9
Sections 3.1.1 (Overview; Figures 1 [Study Flow Diagram for Part 1: Dose Escalation]
and 2 [Study Flow Diagram for Part 2: Dose Expansion], previously numbered 
Figures 3.1.1-1 and 3.1.1-2, respectively), 3.1.2.1 (Treatment Regimen: Arm A), and 
3.1.2.2 (Treatment Regimen: Arm B): Text and figures were revised to reflect that 
subjects in Arm B must have received at least 2 but not more than 4 prior lines of therapy 
(previously 3) and that treatment with a first or second generation EGFR TKI is not 
required for subjects in Arm B who received osimertinib as first-line treatment and these 
subjects may enroll after having received and progressed on osimertinib alone (but can 
still have received no more than 4 prior lines of therapy). The changes were made to be 
consistent with the changes to the inclusion criteria detailed below.
10 Sections 3.1.2 (Treatment Regimen): Removed text pertaining to treatment beyond 
progression. Requirements for treatment beyond progression are covered in new section 
(Section 4.1.7 [Treatment Beyond Progression]).
11 Section 4.1.2 (Inclusion Criteria): The following revisions were made:
(a) Revised inclusion criterion 5b to specify a maximum of 4 prior lines of therapy for 
Arm B for enrollment purposes. 
(b) Added inclusion criteria “v” under 5b that subjects in Arm B who received 
osimertinib as first–line treatment may be enrolled, as osimertinib is becoming 
standard of care for first-line treatment of EGFRm NSCLC.
(c) For inclusion criterion 7, clarified that archival tumor samples as core biopsies or 
larger resection, no fine-needle aspiration samples.
(d) Revised inclusion criterion 10f to require that subjects have creatinine clearance
≥40 mL/minute (previously ≥50 mL/minute). Further safety and PK data for
AZD4635 have reduced the toxicity concern for subjects with mild renal impairment.
12 Section 4.1.3 (Exclusion Criteria): The following revisions were made:
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(a) For exclusion criterion 15, clarified that scans for CNS metastatic disease will be 
performed at screening.
(b) Under the subheading “Additional Exclusion Criteria for Arm A”, exclusion 
criterion 4 was revised to clarify that “intermittent supplemental oxygen required for 
vigorous activity or sleep is allowed” per investigator feedback.
(c) Revised exclusion criteria 2a under the subheading “Additional Exclusion Criteria for 
Arm A” and 5a under the subheading“Additional Exclusion Criteria for Arm B” to 
clarify that QTcF > 470 msec must be over-read by medically qualified person.
13 Section 4.1.7 (Treatment Beyond Progression): Added new section with requirements for 
treatment beyond progression including treatment after the initial assessment of PD by 
RECIST version 1.1 until PD is confirmed on a follow-up scan as well as requirements 
for treatment beyond confirmed PD. The change was made to allow treatment beyond PD 
if a subject has clinical benefit, so that subjects with a new lesion, including CNS 
metastases, but decrease in systemic tumor burden do not necessarily have to discontinue.
Subsequent sections were renumbered accordingly.
14 Section 4.2.1 (Enrollment/Screening Period): The following revisions were made to 
Table 3 (Schedule of Screening Procedures), previously numbered Table 4.2.1-1:
(a) Included prior imaging in the assessment for medical history. Added footnote that 
prior imaging will be collected if allowed by country and includes raw imaging data 
that has been performed between 4 weeks and 6 months prior to baseline scan. The 
revision was made to provide additional data for tumor kinetics.
(b) Revised assessment for thyroid function to clarify that free thyroxine is not required 
if thyroid stimulating hormone is normal.
(c) Added footnote that previous scans for brain metastases and baseline disease 
performed within 28 days of dosing do not need to be repeated at screening.
15 Sections 4.2.2 (Treatment Period): The following revisions were made to Tables 4 
(Treatment Period Study Procedures – Arm A [MEDI9447Oleclumab + Osimertinib]) and 
5 (Treatment Period Study Procedures – Arm B [Oleclumab + AZD4635]), previously 
numbered Tables 4.2.2-1 and 4.2.2-2, respectively:
(a) Added footnote that the physical examination may be performed up to 24 hours prior 
to dosing on Day 1 to facilitate PK collection.
(b) Revised assessment for thyroid function to clarify that free thyroxine is not required 
if thyroid stimulating hormone is normal.
(c) In Table 5 (previously numbered 4.2.2-2), removed the 3-day window for the 
V7a/Day 58 visit as this visit is for 24-hour post-dose PK sample.
16 Section 4.2.3 (Follow-up Period): Revised assessment for thyroid function to clarify that 
free thyroxine is not required if thyroid stimulating hormone is normal in Table 6 
(Schedule of Follow-up Procedures [All Arms]), previously numbered Table 4.2.3-1. 
Clarified in the footnote for disease assessments that disease assessments continue Q12W 
for subjects who discontinued treatment due to reasons other than PD.
17 Section 4.3.6 
 
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18 Section 4.5 (Investigational Products): This section to be revised to also include 
oleclumab liquid formulation. Revisions included:
(a) In Section 4.5.1 (Identity of Investigational Products): The liquid formulation for 
oleclumab was added to Table 9 (Identification of investigational Products), 
previously numbered Table 4.5.1-1. Text after the table was added with details for 
the lypholized product and liquid formulation. Text for AZD4635 and osimertinib 
was moved to this section (previously located in Section 4.5.1.1).
(b) Section 4.5.1.1 (Investigational Product Inspection): Revised section title (previously 
“Investigational Product Dose Preparation”). Added details for the number of 
oleclumab vials required for lypholized and liquid product by dose. 
(c) Section 4.5.1.2 (Oleclumab [MEDI9447] IV Bag Preparation and Administration): 
Made new subsection and subsequent sections were renumbered accordingly. The 
dose preparation and administration instructions were updated and consolidated and 
instructions for liquid formulation were added. The standard infusion time was 
reduced from 80 minutes to 1 hour as clinical data demonstrate that oleclumab 
infusion has been well tolerated at 80 minutes and CMC data support a reduced 
infusion time which is more patient friendly.
(d) Section 4.5.1.3 (Treatment Administration [previously numbered 4.5.1.2]): Under 
subheading for MEDI9447, added cross references to dose preparation/administration 
instructions for oleclumab in Section 4.5.1.2 and removed administration instructions 
as this is located in Section 4.5.1.2.
(e) Section 4.5.4 (Storage): Added statement for oleclumab that vials should be kept in 
secondary packaging to avoid prolonged exposure to light.
19 Section 5.3.2.2 (QTc Prolongation and Arrhythmias): For management of subjects with 
QTc prolongation > 500 msec, removed “or recovery to baseline if baseline QTcF is 
≥481 msec” as subjects with baseline QTcF > 470 msec are excluded from the study. 
Clarified that a manual over-read by a medically qualified person should be performed for 
all QTc values > 500 msec prior to withholding or discontinuing study treatment (bold 
indicates added text) and added cross-reference to Section 4.3.2 (Medical History, 
Physical Examination, Ophthalmologic Examination, Electrocardiogram, 
Echocardiogram/MUGA, Weight, and Vital Signs). 
20 Section 5.3.2.3 (Changes in Cardiac Contractility): Updated data for LVEF per most 
recent edition of the osimertinib Investigator’s Brochure.
21 Section 5.3.2.4 (Keratitis): Removed keratitis as an AESI for osimertinib per most recent 
edition of the osimertinib Investigator’s Brochure.
22 Section 8 (References): Updated references.
23 Section 10.6 (Appendix 6 - Treatment Modification and Toxicity Management Guidelines 
for Oleclumab): Updated tables with the most recent toxicity management guidelines.
9.4
Protocol Amendment 1
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. The principal reason for this amendment is to revise the starting dose level for 
MEDI9447 from 3000 mg Q2W to 1500 mg Q2W in both treatment arms and to stipulate that 

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dose escalation cannot proceed from the starting dose level of MEDI9447 1500 mg to the 
MEDI9447 3000 mg dose level in a treatment arm until after a minimum of 3 subjects have 
been evaluated for DLTs in that treatment arm and a total of at least 6 subjects have been 
evaluated for DLTs across both treatment arms. The changes were made per request of the 
Food and Drug Administration. The major changes to the protocol are summarized below.
1
Synopsis: The Synopsis was revised to be consistent with the changes in the body of the 
protocol.
2
Figure 3.1.1-1 (Study Flow Diagram for Part 1: Dose Escalation): The figure was 
modified to reflect the changes in the study design. In Arm A, safety run-in was changed 
to dose escalation. The subject numbers were changed to n = 9 to 12 subjects for Arm A 
(previously n = 6 to 12 subjects) and n = 12 to 18 subjects for Arm B (previously n = 6 to 
18 subjects).
3
Section 3.1.2.1 (Treatment Regiment: Arm A): In Table 3.1.2.1-1(Arm A Combination
Therapies and Dose Levels [Part 1: Dose Escalation]), the dose levels and subject 
numbers were revised to MEDI9447 750 mg/osimertinib 80 mg (dose level -1 [n = 3 to 
6 subjects]), MEDI9447 1500 mg/osimertinib 80 mg (dose level 1 [n = 3 to 6 subjects]), 
and MEDI9447 3000 mg/osimertinib 80 mg (dose level 2 [n = 6 subjects]). The text in 
Section 3.1.2.1 was revised to reflect the starting dose level of MEDI9447 
1500 mg/osimertinib 80 mg and the change in study design from a safety run-in to dose 
escalation. 
4
Section 3.1.2.2 (Treatment Regimen: Arm B): In Table 3.1.2.2-1(Arm B Combination 
Therapies and Dose Levels [Part 1: Dose Escalation]), the dose levels and subject 
numbers were revised to MEDI9447 1500 mg/AZD4635 50 mg (dose level -1 [n = 3 to 
6 subjects]), MEDI9447 1500 mg/AZD4635 75 mg (dose level 1 [n = 3 to 6 subjects]), 
MEDI9447 3000 mg/AZD4635 75 mg (dose level 2 [n = 3 to 6 subjects]), and MEDI9447 
3000 mg/AZD4635 100 mg (dose level 3 [n = 6 subjects]). The text in Section 3.1.2.2 
was revised to reflect the starting dose level of MEDI9447 1500 mg/AZD4635 75 mg. A 
statement was added in the text and as a footnote in Table 3.1.2.2-1 that if the MTD is 
exceeded at dose level 2 an intermediate dose level of MEDI9447 3000 mg and AZD4635 
50 mg may be evaluated.
5
Section 3.1.3.2 (Rules for Dose Escalation and Cohort Progression [Arms A and B]): The 
text and section title were revised to state that the dose escalation rules will apply to both 
Arms A and B. The following rules were revised: 
(a) Rule 3 was modified to state that at dose level 1 only, dose escalation to the next 
higher dose cohort will be permitted after review of all available safety data from a 
minimum of 3 evaluable subjects in that treatment arm and a minimum of 6 evaluable 
subjects across both treatment arms (Arms A and B) and that at subsequent dose 
levels, dose escalation to the next higher dose cohort will be permitted after review of 
all available safety data from a minimum of 3 evaluable subjects in that treatment 
arm. 
(b) Rule 9 was revised to state that “with the exception of dose level 1 as described in 
Rule 3, dose escalation proceeds independently between the arms of this study”.

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Section 3.2.1 (Dose Rationale): Under the subheadings for MEDI9447, osimertinib, and 
AZD4635, the starting dose level of MEDI9447 was changed to 1500 mg Q2W 
(previously 3000 mg Q2W). Under the subheading for MEDI9447, a statement was added 
that the MEDI9447 1500 mg Q2W dose is one dose level below the highest monotherapy 
and combination weight-based dose that has been tested and declared tolerable in FTIH 
Study D6070C00001. Under the subheading for MEDI9447, text was revised to include a 
statement that the MEDI9447 750 mg Q2W dose (equivalent to MEDI9447 10 mg/kg 
Q2W) is included as dose level -1.
7
Section 4.2.2 (Treatment Period), Tables 4.2.2-1 (Treatment Period Study Procedures –
Arm A (MEDI9447 + Osimertinib) and 4.2.2-2 (Treatment Period Study Procedures –
Arm B (MEDI9447 + AZD4635): In both tables, under the visit column “V7-Vn”, the 
timing for disease assessments
 was changed to “Q8W (± 3D) starting on 
D113 through D393” (previously “Q8W (± 3D) starting on D113 through D365”) to 
correct an oversight.
8
Sections 4.5.1.1 (Investigational Product Dose Preparation): Under subheading 
“Investigational Product Inspection”, the number of required vials for the MEDI9447 
750 mg dose level was added. Under the subheading “Intravenous Dose Preparation”, 
instructions for the MEDI9447 750 mg dose were added.
9
Section 4.8.7 (Continuous Monitoring for Interstitial Lung Disease [Arm A only]): In 
Table 4.8.7-1 (ILD Monitoring Plan - Continuous Monitoring, Based on the Potential 
Number of ILD Cases), “after run-in phase” was removed from the title and the column 
for phase was removed as continuous interim monitoring begins after the enrollment of 
the sixth subject regardless of the study phase and safety run-in is no longer applicable for 
Arm A. The first row of the table was deleted. The number of subjects in the second row 
was changed to “6 – 8” previously (“7 – 8”). The number of subjects for the last row was 
changed to “37 – 43” (previously “37 – 40”), and the observed ILD rate and posterior 
probability were revised accordingly. A row was added for 44 – 46 subjects. The 
revisions were made as up to 46 subjects may be enrolled in Arm A.
10 Section 10.1 (Appendix 1 – Signatures): The Sponsor signature name and phone number 
were updated on the Sponsor Signature Page.
CCI

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10
APPENDICES
10.1
Appendix 1 - Signatures
Sponsor Signature(s)
A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination 
Therapies in Subjects with Previously Treated Advanced EGFRm NSCLC
I agree to the terms of this protocol.
Signature and date: 
One MedImmune Way, Gaithersburg MD, 20878, USA
Telephone number: PPD
PPD

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

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10.2
Appendix 2 – 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 methods of 
contraception are described in Table 11.

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 11
Methods of Contraception
Barrier Methods
Hormonal Methods
•
Male or female condom with or without 
spermicidea, b
•
Cap, diaphragm, or sponge with spermicidea, b
•
Copper T intrauterine deviced
•
Levonorgestrel-releasing intrauterine system (eg. 
Mirena®)c, d
•
Implantsd
•
Hormone shot or injectiond
•
Combined pilld
•
Minipilla
•
Patchd
a
Not highly effective (failure rate of ≥ 1% per year)
b
A male condom plus cap, diaphragm, or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective, birth control methods
c
Also considered a hormonal method
d
Highly effective (failure rate of < 1% per year).

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10.3
Appendix 3 - Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
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 intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) 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) Version 4.03 as provided in below. 

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The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below.
Grade 1
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 or with physical or mental disabilities 
that affect or limit the ability of the subject to perform activities 
of daily living (eating, ambulation, toileting, etc).
Grade 5
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
Relationship to Investigational Product
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?

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
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? 

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? MedImmune 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.

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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).
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a 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
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the 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 fridge when it should be at room temperature 

Wrong subject received the medication (excluding IXRS errors)

Wrong drug administered to subject (excluding IXRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IXRS - 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 AZ/MedImmune product 

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
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
10.4
Appendix 4 - National Institute of Allergy and Infectious 
Disease 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.
National Institute of Allergy and Infectious Disease (NIAID) and Food Allergy and 
Anaphylaxis Network (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 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 GI symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline

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10.5
Appendix 5 - Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
10.5.1
Introduction
This appendix describes the process to be followed to identify and appropriately report cases 
of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries. Specific guidance on managing liver abnormalities can be found in 
Section 10.6 of the protocol.
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug-induced liver injury (DILI) caused by the 
investigational product. 
The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law
cases and for reporting AEs and SAEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
10.5.2
Definitions
10.5.2.1
Potential Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP.
10.5.2.2
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.  
For potential Hy’s Law and Hy’s Law, the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur.
10.5.3
Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination:

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
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 10.5.2) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
10.5.4
Follow-up……….
10.5.4.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet potential Hy’s Law criteria the investigator will:

Inform the study representative that the subject has not met potential Hy’s Law criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the study protocol.
10.5.4.2
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
The medical monitor contacts the investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. Subsequent to 
this contact the investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor. 

If at any time (in consultation with the medical monitor) the potential Hy’s Law case 
meets serious criteria, report it as an SAE using standard reporting procedures

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10.5.5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law
criteria are met.
No later than 3 weeks 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. 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.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the 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:

Report an SAE (report term ‘Hy’s Law’) according to the sponsor’s standard processes.

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the Hy’s Law case, a causality assessment 
of ‘related’ should be assigned
If, there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for Hy’s Law, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are met. Update the SAE report according to the outcome of 
the review

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10.5.6
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 10.5.4.2.
If Yes:
Determine if there has been a significant change in the subject’s condition compared with 
when potential Hy’s Law criteria were previously met:

If there is no significant change no action is required

If there is a significant change follow the process described in Section 10.5.4.2
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the medical monitor if there is any uncertainty.

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10.6
Appendix 6 – Treatment Modification and Toxicity 
Management Guidelines for Oleclumab
Table 12
Treatment Modification and Toxicity Management Guidelines for Immune-
mediated Adverse Events – General Considerations
Table 13
Treatment Modification and Toxicity Management Guidelines for Immune-
mediated Adverse Events
Table 14
Treatment Modification and Toxicity Management Guidelines for Infusion-related 
Reactions
Table 15
Treatment Modification and Toxicity Management Guidelines for Non-immune-
mediated Reactions
Version 01November 2017

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Table 12
Treatment Modification and Toxicity Management Guidelines for Immune-mediated Adverse Events –
General Considerations
General Considerations
Dose Modifications
Toxicity Management
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03.
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions:

Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen

Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing
Grade 1 No dose modification
Grade 2 Hold study drug/study regimen dose until Grade 2 resolution to Grade 
≤1.
If toxicity worsens, then treat as Grade 3 or Grade 4.
Study drug/study regimen can be resumed once event stabilizes to Grade 
≤1 after completion of steroid taper.
Patients with endocrinopathies who may require prolonged or continued 
steroid replacement can be retreated with study drug/study regimen on the 
following conditions:
1
The event stabilizes and is controlled.
2
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement.
3
Doses of prednisone are at ≤10 mg/day or equivalent.
Grade 3 Depending on the individual toxicity, study drug/study regimen may be 
permanently discontinued. Please refer to guidelines below.
Grade 4 Permanently discontinue study drug/study regimen.
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed.
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table:

It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines.

Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible 
immune-mediated event. In the absence of a clear alternative etiology, all 
such events should be managed as if they were immune related. General 
recommendations follow.

Symptomatic and topical therapy should be considered for low-grade 
(Grade 1 or 2, unless otherwise specified) events. 

For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent.

Some events with high likelihood for morbidity and/or mortality – e.g., 
myo-carditis, or other similar events even if they are not currently noted in 
the guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and 
if clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation.

If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days 
of taper).

More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) 
(also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 

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General Considerations
General Considerations
Dose Modifications
Toxicity Management
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus). 
not currently noted in the guidelines – when these events are not 
responding to systemic steroids.

With long-term steroid and other immunosuppressive use, consider need 
for Pneumocystis jirovecii pneumonia (PJP, formerly known as 
Pneumocystis carinii pneumonia) prophylaxis, gastrointestinal protection, 
and glucose monitoring.

Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph 
nodes). Continuation of study drug/study regimen in this situation should 
be based upon a benefit-risk analysis for that patient.
AE = adverse event; CTC = Common Toxicity Criteria; CTCAE = Common Terminology Criteria for Adverse Events; imAE = immune-mediated adverse event; IV = 
intravenous; NCI = National Cancer Institute; PJP = Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO = by mouth; TNF = tumor 
necrosis factor.

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Treatment Modification and Toxicity Management Guidelines for Immune-mediated Adverse Events
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Pneumonitis/Interstitial 
Lung Disease (ILD)
Any Grade
General Guidance
For Any Grade:

Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below.

Initial work-up may include clinical evaluation, monitoring 
of oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan.
Grade 1
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated)
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic work-
up for other etiologies.
For Grade 1 (radiographic changes only):

Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated.

Consider Pulmonary and Infectious disease consult.
Grade 2
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL)
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1.

If toxicity worsens, then treat 
as Grade 3 or Grade 4.

If toxicity improves to Grade 
≤1, then the decision to 
reinitiate study drug/study 
regimen will be based upon 
treating physician’s clinical 
judgment and after 
completion of steroid taper.
For Grade 2 (mild to moderate new symptoms):

Monitor symptoms daily and consider hospitalization.

Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent).

Reimage as clinically indicated.

If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started

If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PJP treatment (refer to current NCCN guidelines for 

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
treatment of cancer-related infections [Category 2B 
recommendation])a

Consider pulmonary and infectious disease consult.

Consider, as necessary, discussing with study physician.
Grade 3 or 4
(Grade 3: severe 
symptoms; limiting
self-care ADL; oxygen 
indicated)
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation])
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening):

Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.

Obtain Pulmonary and Infectious disease consult; consider, 
as necessary, discussing with study physician.

Hospitalize the patient.

Supportive care (e.g., oxygen).

If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a
Diarrhea/Colitis
Any Grade
General Guidance
For Any Grade:

Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency over 
baseline or blood in stool) or related to bowel perforation 
(such as sepsis, peritoneal signs, and ileus).

Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
medications, or infections), including testing for clostridium 
difficile toxin, etc.

Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event.

Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis.
Grade 1
(Diarrhea: stool 
frequency of <4 over 
baseline per day)
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only)
No dose modifications.
For Grade 1:

Monitor closely for worsening symptoms.

Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment.
Grade 2
(Diarrhea: stool 
frequency of 4 to 6 
over baseline per day) 
(Colitis: abdominal 
pain; mucus or blood
in stool)
Hold study drug/study regimen until 
resolution to Grade ≤1

If toxicity worsens, then treat 
as Grade 3 or Grade 4.

If toxicity improves to Grade 
≤1, then study drug/study 
regimen can be resumed after 
completion of steroid taper.
For Grade 2:

Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide.

Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.

If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
GI consult should be obtained for consideration of further 
workup, such as imaging and/or colonoscopy, to confirm 
colitis and rule out perforation, and prompt treatment with 
IV methylprednisolone 2 to 4 mg/kg/day started.

If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeksa. Caution: it is important to rule out bowel 

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
perforation and refer to infliximab label for general 
guidance before using infliximab.

Consider, as necessary, discussing with study physician if 
no resolution to Grade ≤1 in 3 to 4 days.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(Grade 3 diarrhea: 
stool frequency of ≥7 
over baseline per day;
Grade 4 diarrhea: life 
threatening 
consequences)
(Grade 3 colitis: severe 
abdominal pain, 
change in bowel habits, 
medi-cal intervention 
indi-cated, peritoneal 
signs;
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated)
Grade 3
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade ≤1 
within 14 days; study drug/study regimen 
can be resumed after completion of 
steroid taper.
Grade 4
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4:

Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent.

Monitor stool frequency and volume and maintain 
hydration.

Urgent GI consult and imaging and/or colonoscopy as 
appropriate.

If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, 
promptly start further immunosuppressives (e.g., infliximab 
at 5 mg/kg once every 2 weeks). Caution: Ensure GI 
consult to rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab.

Once the patient is improving, gradually taper steroids over
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a
Hepatitis 
(elevated LFTs)
Any Grade
General Guidance
For Any Grade:

Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB.

Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications).

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Infliximab should not be 
used for management of 
immune-related hepatitis.
Grade 1
(AST or ALT >ULN 
and ≤3.0×ULN and/or 
TB > ULN and 
≤1.5×ULN)

No dose modifications.

If it worsens, then treat as 
Grade 2 event.
For Grade 1:
Continue LFT monitoring per protocol.
Grade 2
(AST or 
ALT >3.0×ULN and 
≤5.0×ULN and/or 
TB >1.5×ULN and 
≤3.0×ULN)

Hold study drug/study 
regimen dose until Grade 2 
resolution to Grade ≤1.

If toxicity worsens, then treat 
as Grade 3 or Grade 4.

If toxicity improves to Grade 
≤1 or baseline, resume study 
drug/study regimen after 
completion of steroid taper.
For Grade 2:

Regular and frequent checking of LFTs (e.g., every 1 to 2 
days) until elevations of these are improving or resolved.

If no resolution to Grade ≤1 in 1 to 2 days, consider, as 
necessary, discussing with study physician.

If event is persistent (>3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.

If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day.

If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a
Discuss with study physician if mycophenolate mofetil is 
not available. Infliximab should NOT be used.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(Grade 3: AST or ALT 
>5.0×ULN and 
≤20.0×ULN and/or TB 
For Grade 3:
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN:
For Grade 3 or 4:

Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent.

If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with immunosuppressive therapy 

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
>3.0×ULN and 
≤10.0×ULN)
(Grade 4: AST or ALT 
>20×ULN and/or TB 
>10×ULN)

Hold study drug/study 
regimen dose until resolution 
to Grade ≤1 or baseline

Resume study drug/study 
regimen if elevations 
downgrade to Grade ≤1 or 
baseline within 14 days and 
after completion of steroid 
taper.

Permanently discontinue 
study drug/study regimen if 
the elevations do not 
downgrade to Grade ≤1 or 
baseline within 14 days
For elevations in transaminases 
>8 × ULN or elevations in bilirubin >5 × 
ULN, discontinue study drug/study 
regimen.
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria (AST and/or ALT >3 × 
ULN + bilirubin >2 × ULN without 
initial findings of cholestasis (i.e., 
elevated alkaline P04) and in the absence 
of any alternative cause.b
For Grade 4:
Permanently discontinue study 
drug/study regimen.
(i.e., mycophenolate mofetil). Discuss with study physician 
if mycophenolate is not available. Infliximab should NOT 
be used.

Perform hepatology consult, abdominal workup, and 
imaging as appropriate.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a
Nephritis or renal 
dysfunction
Any Grade
General Guidance
For Any Grade:

Consult with nephrologist.

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
(elevated serum 
creatinine)

Monitor for signs and symptoms that may be related to 
changes in renal function (e.g., routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, or 
proteinuria).

Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections).

Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event.
Grade 1
(Serum creatinine > 1 
to 1.5 × baseline; > 
ULN to 1.5 × ULN)
No dose modifications.
For Grade 1:

Monitor serum creatinine weekly and any accompanying 
symptoms.

If creatinine returns to baseline, resume its regular 
monitoring per study protocol.

If creatinine worsens, depending on the severity, treat 
as Grade 2, 3, or 4.

Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
Grade 2
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN)
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 

If toxicity worsens, then treat 
as Grade 3 or 4.

If toxicity improves to Grade 
≤1 or baseline, then resume 
study drug/study regimen 
after completion of steroid 
taper.
For Grade 2:

Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.

Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted.

Consult nephrologist and consider renal biopsy if clinically 
indicated.

If event is persistent (>3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.

If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt 

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Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
treatment with IV methylprednisolone at 2 to 4 mg/kg/day 
started.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a

When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol.
Grade 3 or 4
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 
to 6.0 × ULN;
Grade 4: serum 
creatinine >6.0 × ULN)
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:

Carefully monitor serum creatinine on daily basis.

Consult nephrologist and consider renal biopsy if clinically 
indicated.

Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.

If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt 
treatment with IV methylprednisolone 2 to 4 mg/kg/day 
started.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a
Rash
(excluding bullous skin 
formations)
Any Grade
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade:

Monitor for signs and symptoms of dermatitis (rash and 
pruritus).

IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED AND 
STUDY DRUG DISCONTINUED.

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Grade 1
No dose modifications.
For Grade 1:
Consider symptomatic treatment, including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea 
cream).
Grade 2
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline.

If toxicity worsens, then treat 
as Grade 3.

If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper.
For Grade 2:

Obtain dermatology consult.

Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream).

Consider moderate-strength topical steroid.

If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment 
and/or use of moderate strength topical steroid, consider, as 
necessary, discussing with study physician and promptly 
start systemic steroids such as prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.

Consider skin biopsy if the event is persistent for >1 to 
2 weeks or recurs.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study 
drug/study regimen.
For Grade 4:
For Grade 3 or 4:

Consult dermatology.

Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.

Consider hospitalization.

Monitor extent of rash [Rule of Nines].

Consider skin biopsy (preferably more than 1) as clinically 
feasible.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation]).a

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Permanently discontinue study 
drug/study regimen.

Consider, as necessary, discussing with study physician.
Endocrinopathy
(e.g., hyperthyroidism, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section)
Any Grade
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
CTC grade/severity)
General Guidance
For Any Grade:

Consider consulting an endocrinologist for endocrine 
events.

Consider, as necessary, discussing with study physician.

Monitor patients for signs and symptoms of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental status, 
vertigo, abdominal pain, unusual bowel habits, polydipsia, 
polyuria, hypotension, and weakness.

Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including 
brain metastases, or infections).

Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 
and other relevant endocrine and related labs (e.g., blood 
glucose and ketone levels, HgA1c).

For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as 
there are no other signs or symptoms of pancreatic 
inflammation.

If a patient experiences an AE that is thought to be possibly 
of autoimmune nature (e.g., thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing.
Grade 1
No dose modifications.
For Grade 1 (including those with asymptomatic TSH elevation):

Monitor patient with appropriate endocrine function tests.

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management

For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of 
early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin levels, 
as well as cosyntropin stimulation test (though it may not be 
useful in diagnosing early secondary adrenal insufficiency).

If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out 
of range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist.
Grade 2
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable.

If toxicity worsens, then treat 
as Grade 3 or Grade 4.
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions:
1
The event stabilizes and is 
controlled.
2
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement.
3
Doses of prednisone are 
≤10 mg/day or equivalent.
For Grade 2 (including those with symptomatic endocrinopathy):

Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and 
as clinically indicated, consider pituitary scan.

For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone 
or IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones).

Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids.

Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids.

Once patients on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management

For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated.
Grade 3 or 4
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) 
are controlled. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions:
1
The event stabilizes and is 
controlled.
2
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement.
3
Doses of prednisone are 
≤10 mg/day or equivalent.
For Grade 3 or 4:

Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and 
as clinically indicated, consider pituitary scan. 
Hospitalization recommended.

For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well 
as relevant hormone replacement (e.g., hydrocortisone, sex 
hormones).

For adrenal crisis, severe dehydration, hypotension, or 
shock, immediately initiate IV corticosteroids with 
mineralocorticoid activity.

Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids.

Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids.

Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
Neurotoxicity
(to include but not be 
limited to limbic 
encephalitis and 
Any Grade
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
General Guidance
For Any Grade:

Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes, or medications).

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Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre)
for defining the CTC 
grade/severity)

Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness).

Consider appropriate diagnostic testing 
(e.g., electromyogram and nerve conduction investigations).

Perform symptomatic treatment with neurological consult 
as appropriate.
Grade 1
No dose modifications.
For Grade 1:
See “Any Grade” recommendations above.
Grade 2
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade 
≤1.
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade 
≤1.
If toxicity worsens, then treat as Grade 3 
or 4.
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid taper.
For Grade 2:

Consider, as necessary, discussing with the study physician.

Obtain neurology consult.

Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine).

Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent.

If no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (e.g., IV IG).
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days.
For Grade 3 or 4:

Consider, as necessary, discussing with study physician.

Obtain neurology consult.

Consider hospitalization.

Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.

If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g., IV IG).

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Severity Grade of 
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CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
For Grade 4:
Permanently discontinue study 
drug/study regimen.

Once stable, gradually taper steroids over ≥28 days.
Peripheral neuromotor 
syndromes
(such as Guillain-Barre 
and myasthenia gravis)
Any Grade
General Guidance
For Any Grade:

The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations that 
can result in substantial morbidity or in the worst case, 
death. Special care should be taken for certain sentinel 
symptoms that may predict a more severe outcome, such as 
prominent dysphagia, rapidly progressive weakness, and 
signs of respiratory insufficiency or autonomic instability.

Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential 
confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of prompt 
and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult.

Neurophysiologic diagnostic testing (e.g., electromyogram 
and nerve conduction investigations, and “repetitive 
stimulation” if myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions and may be 
best facilitated by means of a neurology consultation.

It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be
started with IV IG and followed by plasmapheresis if not 
responsive to IV IG.
Grade 1
No dose modifications.
For Grade 1:

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management

Consider, as necessary, discussing with the study physician.

Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above.

Obtain a neurology consult.
Grade 2
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability.
For Grade 2:

Consider, as necessary, discussing with the study physician.

Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above.

Obtain a neurology consult

Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine).
MYASTHENIA GRAVIS:

Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision of 
a consulting neurologist.

Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IV IG. Such decisions 
are best made in consultation with a neurologist, taking 
into account the unique needs of each patient.

If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition to 
steroids. Such therapy, if successful, can also serve to 
reinforce the diagnosis.
GUILLAIN-BARRE:

It is important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not typically 
considered effective.

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management

Patients requiring treatment should be started with IV IG 
and followed by plasmapheresis if not responsive to IV 
IG.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency or autonomic instability.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or life-threatening events):

Consider, as necessary, discussing with study physician.

Recommend hospitalization.

Monitor symptoms and obtain neurological consult.
MYASTHENIA GRAVIS:

Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist.

Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IV IG.

If myasthenia gravis-like neurotoxicity present, consider 
starting AChE inhibitor therapy in addition to steroids. 
Such therapy, if successful, can also serve to reinforce the 
diagnosis.
GUILLAIN-BARRE:

It is important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not typically 
considered effective.

Patients requiring treatment should be started with IV IG 
and followed by plasmapheresis if not responsive to IV 
IG.
Myocarditis
Any Grade
General Guidance
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis.
For Any Grade:

The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function. 

Consider, as necessary, discussing with the study physician.

Monitor patients for signs and symptoms of myocarditis 
(new onset or worsening chest pain, arrhythmia, shortness 

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Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
of breath, peripheral edema). As some symptoms can 
overlap with lung toxicities, simultaneously evaluate for 
and rule out pulmonary toxicity as well as other causes 
(e.g., pulmonary embolism, congestive heart failure, 
malignant pericardial effusion). A Cardiology consultation 
should be obtained early, with prompt assessment of 
whether and when to complete a cardiac biopsy, including 
any other diagnostic procedures.

Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), 
monitoring of oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory work-up as indicated. 
Spiral CT or cardiac MRI can complement ECHO to assess 
wall motion abnormalities when needed.

Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections)
Grade 1
(asymptomatic with 
laboratory (e.g., BNP) 
or cardiac imaging 
abnormalities)
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0.
For Grade 1 (no definitive findings):

Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up as 
clinically indicated.

Consider using steroids if clinical suspicion is high.
Grade 2, 3 or 4
(Grade 2: Symptoms 
with mild to moderate 
activity or exertion)
(Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
If Grade 2 -- Hold study drug/study 
regimen dose until resolution to Grade 0. 
If toxicity rapidly improves to Grade 0, 
then the decision to reinitiate study 
drug/study regimen will be based upon 
treating physician’s clinical judgment 
and after completion of steroid taper. If 
toxicity does not rapidly improve, 
For Grade 2-4:

Monitor symptoms daily, hospitalize.

Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures 
including a cardiac biopsy.

Supportive care (e.g., oxygen).

If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
or exertion; 
intervention indicated)
(Grade 4: Life-
threatening 
consequences; urgent
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic 
support))
permanently discontinue study 
drug/study regimen.
If Grade 3-4, permanently discontinue 
study drug/study regimen.
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Myositis/Polymyositis 
(“Poly/myositis”)
Any Grade
General Guidance
For Any Grade:

Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal 
muscles including upper arms, thighs, shoulders, hips, neck 
and back, but rarely affects the extremities including hands 
and fingers; also difficulty breathing and/or trouble 
swallowing can occur and progress rapidly. Increased 
general feelings of tiredness and fatigue may occur, and 
there can be new-onset falling, difficulty getting up from a 
fall, and trouble climbing stairs, standing up from a seated 
position, and/or reaching up.

If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. Given 
breathing complications, refer to guidance under 
Pneumonitis/ILD. 
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation.

Consider, as necessary, discussing with the study physician.

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Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management

Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-up as indicated, 
including a number of possible rheumatological/antibody 
tests (i.e., consider whether a rheumatologist consultation is 
indicated and could guide need for rheumatoid factor, 
antinuclear antibody, anti-smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of the 
muscles, and/or a muscle biopsy. Consider Barium swallow 
for evaluation of dysphagia or dysphonia.
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections).
Grade 1
(mild pain)
No dose modifications.
For Grade 1:

Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated.

Consider Neurology consult.

Consider, as necessary, discussing with the study physician.
Grade 2
(moderate pain 
associated with 
weakness; pain 
limiting instrumental 
activities of daily 
living [ADLs])
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency.
For Grade 2:

Monitor symptoms daily and consider hospitalization.

Obtain Neurology consult, and initiate evaluation.

Consider, as necessary, discussing with the study physician.

If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly 
start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from Neurology 
consultant 

If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 

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Severity Grade of 
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CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day

If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(pain associated with 
severe weakness; 
limiting self-care 
ADLs)
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or life-threatening events):

Monitor symptoms closely; recommend hospitalization.

Obtain Neurology consult, and complete full evaluation.

Consider, as necessary, discussing with the study physician.

Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant.

If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.

Consider whether patient may require IV IG, 
plasmapheresis.

Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a

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AChE = acetylcholine esterase; ACTH = adrenocorticotropic hormone; ADL = activities of daily living; AE = adverse event; ALP = alkaline phosphatase test; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CT = computed tomography; CTC = Common 
Terminology Criteria; CTCAE = Common Terminology Criteria for Adverse Events; DM = diabetes mellitus; ECG = electrocardiogram; ECHO = echocardiogram; HgA1C = 
hemoglobin A1C; ILD = interstitial lung disease; imAE = immune-mediated adverse event; IG = immunoglobulin; INR = international normalized ratio; IV = intravenous; GI 
= gastrointestinal; LDH = lactate dehydrogenase; LFT = liver function tests; LLN = lower limit of normal; MRI = magnetic resonance imaging; NCI = National Cancer 
Institute; NCCN = National Comprehensive Cancer Network; PJP = Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO = by mouth; 
T3 = triiodothyronine; T4 = thyroxine; TB = total bilirubin; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; ULN = upper limit of normal.
a
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
b
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.

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Infusion-related Reactions
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:

Manage per institutional standard at the 
discretion of investigator.

Monitor patients for signs and symptoms of 
infusion-related reactions (e.g., fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, or skin rashes) 
and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia).
Grade 1 or 2
For Grade 1:
The infusion rate of study drug/study 
regimen may be decreased by 50% or
temporarily interrupted until resolution 
of the event.
For Grade 2:
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution 
of the event.
Subsequent infusions may be given at 
50% of the initial infusion rate.
For Grade 1 or 2:

Acetaminophen and/or antihistamines may 
be administered per institutional standard at 
the discretion of the investigator.

Consider premedication per institutional 
standard prior to subsequent doses.

Steroids should not be used for routine 
premedication of Grade ≤2 infusion 
reactions.
Grade 3 or 4
For Grade 3 or 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
Manage severe infusion-related reactions per 
institutional standards (e.g., IM epinephrine, followed 
by IV diphenhydramine and ranitidine, and IV 
glucocorticoid).
CTCAE = Common Terminology Criteria for Adverse Events; IM = intramuscular; IV = intravenous; NCI = National Cancer 
Institute.

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Table 15
Treatment Modification and Toxicity Management Guidelines for 
Non-immune-mediated Reactions
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for 
AEs not deemed to be related to study
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant.
Treat accordingly, as per institutional 
standard.
Grade 1
No dose modifications.
Treat accordingly, as per institutional 
standard.
Grade 2
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline.
Treat accordingly, as per institutional 
standard.
Grade 3
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline.
For AEs that downgrade to ≤Grade 2 within 
7 days or resolve to ≤Grade 1 or baseline 
within 14 days, resume study drug/study 
regimen administration. Otherwise, 
discontinue study drug/study regimen.
Treat accordingly, as per institutional 
standard.
Grade 4
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the 
Sponsor.).
Treat accordingly, as per institutional 
standard.
AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.

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10.7
Appendix 7 – Exceptions to the Management of 
Non-immune-mediated Reactions for Osimertinib
Table 16
Exceptions to the Management of Non-immune-mediated Reactions 
for Osimertinib
Target Organ
Adverse Reactiona
Dose Modification
Pulmonary
ILD/Pneumonitis
Hold osimertinib while ILD/pneumonitis is being 
evaluated and if ILD/pneumonitis is confirmed 
permanently discontinue osimertinib
Cardiac
QTc > 500 msec on at least 2 separate ECGs
Withhold osimertinib until QTc < 481 msec or 
recovery to baseline if baseline QTc ≥481 msec, 
then restart at a reduced dose (40 mg).
QTc prolongation with signs/symptoms of life 
threatening arrhythmia
Permanently discontinue osimertinib.
Other
Grade 3 or higher adverse reaction
Withhold osimertinib for up to 3 weeks.
If Grade 3 or higher adverse reaction 
improves to Grade 0-2 after withholding of 
osimertinib for up to 3 weeks
Osimertinib may be restarted at the same dose 
(80 mg) or a lower dose (40 mg).
If Grade 3 or higher adverse reaction does not 
improve to Grade 0-2 after withholding of 
osimertinib for up to 3 weeks
Permanently discontinue osimertinib.
ECG = electrocardiogram; ILD = Interstitial lung disease; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; QTc = QT interval corrected for heart rate.
a
Adverse reactions graded by NCI CTCAE version 4.03. 

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10.8
Appendix 8 – Treatment Modification Guidelines for AZD4635
Table 17 AZD4635 Dose Modifications for Hematologic Toxicities
Table 18 AZD4635 Dose Modifications and Discontinuation Criteria for Non-hematologic 
Toxicities (except Hypertension and CNS Toxicities)
Table 19 AZD4635 Dose Modifications and Discontinuation Criteria for Management of 
Hypertension
Table 20 AZD4635 Dose Modifications and Discontinuation Criteria for CNS Toxicities 
(Including Seizure)

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Table 17
AZD4635 Dose Modifications for Hematologic Toxicities
Severity/Gradea
Action
AZD4635
Dose Modification
Enrolled without bone marrow involvement
Neutropenia, Grade 3
(ANC 500 to 1000/mm3)
Hold AZD4635 1 week or until 
ANC > 1000/mm3.
Restart at same dose level. If 
recurrent toxicity then restart with 
1 dose level reduction.
Thrombocytopenia
(platelets < 25 K/mm3)
Hold AZD4635 1 week or until 
platelets resolve to ≥75 K/mm3.
Restart at same dose level. If 
recurrent toxicity then restart with 
1 dose level reduction.
Febrile neutropenia
Hold AZD4635 until infection is 
resolved, antibiotics no longer 
required, and ANC > 1000/mm3.
Restart with 1 dose level reduction. 
ANC = absolute neutrophil count; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events
a
NCI CTCAE version 4.03
Table 18
AZD4635 Dose Modifications and Discontinuation Criteria for Non-
hematologic Toxicities (except Hypertension and CNS Toxicities)
Severity/Grade a
Action
Grade 1 or 2
None required
Grade 3 or 4 and/or clinically significant b
Hold AZD4635
Toxicity resolved to Grade 1, Grade 2, or baseline 
< 14 days
Toxicity remains Grade 3 to 4 or is clinically 
significant b > 14 days
Restart AZD4635 at 1 dose level reduction
Discontinue AZD4635
Recurrence of Grade 3
Reduce one more dose level if available, or if not,
discontinue study drug
Recurrence of Grade 3 cardiac event b
Discontinue AZD4635
Recurrence of Grade 4
Discontinue AZD4635
bpm = beats per minute; CK = creatine kinase; NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events; QTc = QT interval corrected for heart rate.
a
NCI CTCAE version 4.03
b
Includes significant change in CK/CK-mb ratio (relative index > 5%), increases in heart rate of +25 bpm 
(up to 100 to 125 bpm) for more than 24 hours or increase in heart rate >125 bpm for more than 12 
hours), QTc prolongation > 500 ms.

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Table 19
AZD4635 Dose Modifications and Discontinuation Criteria for 
Management of Hypertension
Severity/Gradea
Antihypertensive 
Therapy
BP Monitoring
AZD4635 Dose Modification
Grade 2
Systolic BP 140 to 159 mm 
Hg or diastolic BP 
90 to 99 mmHg; medical 
intervention indicated;
recurrent or persistent 
(≥24 hours); symptomatic 
increase by > 20 mmHg 
(diastolic) or to 
> 140/90 mmHg if previously 
within normal limits
Initiate/escalate 
antihypertensive 
medication as per local 
guidelines.
BP goal and the choice 
of the antihypertensive 
drug will be 
individualized for each 
subject.
Increase 
frequency of 
monitoring until 
stabilized to BP 
< 140/90 mmHg
None
Grade 3
(systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg); 
medical intervention 
indicated; more than one 
drug or more intensive 
therapy than previously used
indicated
Initiate or maximize BP 
therapy as per local 
guidelines.  
Consider consult with a 
BP management 
specialist 
Increase 
frequency of 
monitoring until 
stabilized to BP 
< 140/90 mmHg
May continue AZD4635 with 
optimization of 
antihypertensive management 
unless persistent BP-related 
clinical symptoms.
Hold AZD4635 if BP is not 
decreased to Grade 2 within 
48 hours after optimum 
therapy is instituted.
If BP is reduced to baseline or 
Grade 1 within 14 days and 
considered stable, AZD4635 
may be resumed at original 
dose.
Discontinue AZD4635 if BP 
does not resolve to Grade 1 
within 14 days.
Discontinue AZD4635 if BP 
systolic ≥180 mmHg and/or 
diastolic ≥110 mmHg.
Recurrence of Grade 3: 
Discontinue study drug. 

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Table 19
AZD4635 Dose Modifications and Discontinuation Criteria for 
Management of Hypertension
Severity/Gradea
Antihypertensive 
Therapy
BP Monitoring
AZD4635 Dose Modification
Grade 4
Life-threatening 
consequences
(eg, malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis); urgent 
intervention indicated
Initiate treatment per 
local guidelines, 
including 
hospitalization, ICU 
management, and IV 
therapy as necessary
Discontinue AZD4635
BP = blood pressure; ICU = intensive care unit; IV = intravenous; NCI CTCAE = National Cancer Institute 
Common Terminology Criteria for Adverse Events
a
NCI CTCAE version 4.03
Table 20
AZD4635 Dose Modifications and Discontinuation Criteria for CNS 
Toxicities (Including Seizure)
Severity/Grade a
Action
Seizure (any grade) b
Hold AZD4635.
Grade 1 or 2 CNS toxicity (other than seizure)
None
Grade 3 or 4 or clinically significant CNS toxicity 
(other than seizure)
Hold AZD4635.
Toxicity resolved to Grade 1, Grade 2, or baseline 
< 14 days
Toxicity remains Grade 3 to 4 or is clinically 
significant> 14 days
Restart AZD4635 at 1 dose level reduction.
Discontinue AZD4635.
Recurrence of Grade 3 CNS toxicity
Reduce one more dose level if available, or if not 
discontinue study drug.
Recurrence of seizure
Discontinue AZD4635
Recurrence of Grade 4 CNS toxicity
Discontinue AZD4635
CNS = central nervous system; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events
a
NCI CTCAE version 4.03
b
Hold drug for safety review. Subsequent decision for restarting AZD4635 to be based on Benefit-Risk 
ratio as assessed by Principal Investigator in collaboration with the medical monitor

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10.9
Appendix 9 - Guidance Regarding Potential Interactions of 
Osimertinib with Concomitant Medications (Arm A)
The use of any natural/herbal products or other “folk remedies” is prohibited, but use of these 
products, as well as use of all vitamins, nutritional supplements, and all other concomitant 
medications must be recorded in the eCRF.
10.9.1
Drugs Inducing CYP3A4 Metabolism that Sponsor Strongly 
Recommends Are Not Combined with Osimertinib
Osimertinib is metabolised by CYP3A4 and CYP3A5 enzymes.
A drug-drug interaction study of osimertinib evaluated in subjects showed that there is 
potential for osimertinib being a victim when co-administered with strong inducers of 
CYP3A4 (osimertinib concentrations are decreased when co-dosed with rifampicin).
The following potent inducers of CYP3A4 must not be used during this study for any subject 
receiving osimertinib.
Table 21
Drugs Inducing CYP3A4
Contraindicated Drugs
Withdrawal Period Prior to Osimertinib Start
Carbamazepine, phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentin
St John’s Wort
3 weeks
Phenobarbitone
5 weeks
This list is not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to strongly modulate CYP3A4 activity. Appropriate medical judgment is 
required. Please contact the medical monitor with any queries on this issue.
10.9.2
Medicines Whose Exposures May Be Affected by Osimertinib that 
Sponsor Considers May Be Allowed with Caution
Osimertinib may increase the concentration of sensitive BCRP substrates (concentration of the 
sensitive BCRP substrate, rosuvastatin, is increased).

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Table 22
Exposure, Pharmacological Action, and Toxicity May Be increased by 
Osimertinib
Warning of Possible Interaction
Advice
Rosuvastatin
Drugs are permitted but caution should be exercised 
and subjects monitored closely for possible drug 
interactions. Please refer to full prescribing 
information for all drugs prior to co-administration 
with osimertinib.
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan
10.9.3
Drugs That May Prolong QT Interval
The drugs listed in this section are taken from information provided by The Arizona Center 
for Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona 
and Rockville, Maryland. Ref:  https://crediblemeds.org/index.php/drugsearch.
This list shown below is not intended to be exhaustive, and a similar restriction will apply to 
other agents that are known to prolong or modulate QT interval. Appropriate medical 
judgment is required. Please contact the medical monitor with any queries on this issue.
10.9.3.1
Drugs Known to Prolong QT Interval
The following drugs are known to prolong QT interval or induce Torsades de Pointes and 
should not be combined with osimertinib. Recommended withdrawal periods following 
cessation of treatment with these agents are provided in the table.
Table 23
Drugs Prolonging QT Interval
Contraindicated Drug
Withdrawal Period Prior to Osimertinib Start
Clarithromycin, droperidol, erythromycin, 
procainamide
2 days
Cisapride, disopyramide, dofetilide, domperidone, 
ibutilide, quinidine, sotalol, sparfloxacin, thioridazine
7 days
Bepridil, chlorpromazine, halofantrine, haloperidol, 
mesoridazine
14 days
Levomethadyl, methadone, pimozide
4 days
Arsenic trioxide
6 weeksa
Pentamidine
8 weeks
Amiodarone, chloroquine
1 year
a
Estimated value as pharmacokinetics of arsenic trioxide have not been studied

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10.9.3.2
Drugs That May Possibly Prolong QT Interval
The use of the following drugs is permitted (notwithstanding other exclusions and restrictions) 
provided the subject has been stable on therapy for the periods indicated.
Table 24
Drugs That May Prolong QT Interval
Drug
Minimum Treatment Period on Medication Prior 
to Osimertinib Start
Alfuzosin, chloral hydrate, ciprofloxacin, dolasetron, 
foscarnet, galantamine, gemifloxacin, isridipine, 
ketoconazole, levofloxacin, mexiletine, nicardipine, 
octreotide, ofloxacin, ondansetron, quetiapine, 
ranolazine, telithromycin, tizanidine, vardenafil, 
venlafaxine, ziprasidone
2 days
Amantadine, amitriptyline, amoxapine, clozapine, 
doxepin, felbamate, flecainide, fluconazole, 
fosphenytoin, gatifloxacin, granisetron, imipramine, 
indapamide, lithium, moexipril/HCTZ, moxifloxacin, 
risperidone, roxithromycin, sertraline, trimethoprin-
sulfa, trimipramine, voriconazole
7 days
Azithromycin, citalopram, clomipramine, 
itraconazole, nortriptyline, paroxetine, solifenacin, 
tacrolimus
14 days
Fluoxetine
5 weeks
Protriptyline
6 weeks
Tamoxifen
8 weeks
10.10
Appendix 10 - Prohibited Medications for Subjects treated with 
AZD4635 in Arm B
The use of warfarin is prohibited during treatment with AZD4635.
Use of potent or moderate inhibitors or inducers of CYP1A2 or sensitive substrates of 
CYP1A2, BCRP, and OAT1 is not permitted from 2 weeks before the first dose of AZD4635 
until at least 2 weeks after the last dose of AZD4635.
Examples of potent or moderate CYP1A2 inhibitors/inducers are presented in Table 25. 
Examples of sensitive substrates of CYP1A2, BCRP, and OAT1 are presented in Table 26.
The lists of medications in Table 25 and Table 26 are not exhaustive and the absence of a drug 
from these lists does not imply that its combination with AZD4635 is safe. Appropriate
medical judgment is required. Please contact the medical monitor with any queries on this 
issue.

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Information on any treatment in the 4 weeks prior to starting study treatment and all 
concomitant treatments given during the study with reasons for the treatment should be 
recorded. If medically feasible, subjects taking regular medication, with the exception of 
potent or moderate inhibitors or inducers of CYP1A2 or sensitive substrates of CYP1A2, 
BCRP, and OAT1 should be maintained on it throughout the study period.
Table 25
Examples of potent and moderate CYP1A2 enzyme inhibitors and 
inducers
CYP1A2 Enzyme 
Category
Examples of drugs in the category
Potent inhibitors
ciprofloxacin, clinafloxacin,enoxacin, fluvoxamine, oltipraz, zafirlukast, rofecoxib, 
angelica root (Bai Zhi [Angelica dahurica radix])
Moderate inhibitors
methoxsalen, mexiletine ,oral contraceptives,3,4-methylene-
dioxymethamphetamine (MDMA), etintidine, genistein, idrocilamide, osilodrostat, 
phenylpropanolamine, pipemidic acid, propafenone, propranolol, troleandomycin, 
vemurafenib, grepafloxacin, piperine, zileuton
Moderate inducers
phenytoin, rifampin, ritonavir, smoking, teriflunomide
Table 26
Examples of sensitive substrates of CYP1A2, BCRP, and OAT1
Sensitive substrate category
Examples of drugs in the category
CYP1A2
alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, 
theophylline, tizanidine, pirfenidone, selegiline, tacrine
BCRP
Methotrexate, mitoxantrone, imatinib, lapatinib, sulfasalazine, topotecan, 
daunorubicin, doxorubicin, SN-38, irinotecan, prazosin, pantoprazole, 
atorvastatin, fluvastatin, rosuvastatin, and simvastatin.
OAT1
Adefovir, captopril, furosemide, lamivudine, methotrexate, oseltamivir, 
tenofovir, zalcitabine, zidovudine, ciprofloxacin, cephaloridine, 
methotrexate, pravastatin

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