A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor LY3022855 in Combination With Durvalumab (MEDI4736) or Tremelimumab in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Eli Lilly and Company

Protocol I5F-MC-JSCC (c) 
 
A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor 
LY3022855 in Combination with Durvalumab (MEDI4736) or Tremelimumab in Patients with 
Advanced Solid Tumors 
 
NCT02718911 
 
Approval Date: 02-Feb-2018 

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
1. Protocol I5F-MC-JSCC(c)
A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor
LY3022855 in Combination with 
Durvalumab (MEDI4736) or Tremelimumab 
in Patients with Advanced Solid Tumors
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3022855, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3022855
This Phase 1a/1b study is a multicenter, nonrandomized, open-label, dose-escalation study
followed by dose expansion (disease-specific expansion cohorts) of intravenous (I.V.) 
LY3022855 in combination with I.V. durvalumab (MEDI4736) or I.V. tremelimumab in 
patients with advanced cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 26 February 2016
Amendment (a) Electronically Signed and Approved by Lilly on 31 May 2016
Amendment (b) Electronically Signed and Approved by Lilly on 01 August 2017
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 02-Feb-2018 GMT

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2.
Synopsis
Protocol Title:
A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor LY3022855 in Combination with Durvalumab (MEDI4736)
or Tremelimumab in Patients with Advanced Solid Tumors
Rationale:
Checkpoint inhibitors of programmed cell death-1 protein (PD-1)/programmed cell death-ligand 1 (PD-L1) and 
cytotoxic T-lymphocyte associated protein 4 (CTLA-4) pathways have demonstrated proven, clinically meaningful 
improvement in survival for patients with various tumor types.  Preclinical data demonstrate significant interplay 
between the innate and adaptive immune systems.  Targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) 
may lead to disruption of the immunosuppressive effects of innate immune cells expressing CSF-1R.  Combining a 
checkpoint inhibitor with an inhibitor of the CSF-1 pathway may potentiate the antitumor response.  This trial will 
investigate the effects of CSF-1R inhibition using LY3022855 (anti-CSF-1R monoclonal antibody) in combination 
with durvalumab (MEDI4736, anti-PD-L1 monoclonal antibody) or tremelimumab (anti-CTLA-4 monoclonal 
antibody) in patients with advanced cancers.
Objectives:
The primary objectives of this study are:

To characterize the safety profile and tolerability of each combination, LY3022855 with durvalumab 
(MEDI4736), and LY3022855 with tremelimumab, in the treatment of patients with advanced solid tumors.

To define a recommended Phase 2 dose (RP2D) for LY3022855 with durvalumab combination, in the 
treatment of patients with advanced solid tumors.
The secondary objectives of this study are:

To document the antitumor activity of each combination, LY3022855 with durvalumab, and LY3022855 
with tremelimumab, in the treatment of patients with advanced solid tumors.

To assess the development of antibodies against LY3022855, durvalumab, and tremelimumab 
(immunogenicity).

To characterize the single-dose and multiple-dose pharmacokinetics (PK) of LY3022855 in combination 
with either durvalumab or tremelimumab, and the single-dose and multiple-dose PK of durvalumab and 
tremelimumab, each in combination with LY3022855.

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Overall Design:
Study I5F-MC-JSCC is a Phase 1a/1b, open-label, nonrandomized, dose-escalation (Part A for both durvalumab or
tremelimumab), followed by dose-expansion (Part B) study of intravenous (I.V.) LY3022855 in combination with 
only I.V. durvalumab, in patients with advanced solid tumors.  A cycle is defined as 28 days (4 weeks).  Eligible 
patients will receive treatment as follows:

LY3022855 (once weekly [QW] OR once on Days 1, 8, and 15 of each cycle OR once every 2 weeks 
[Q2W]), in combination with:
o
durvalumab Q2W
OR
o
tremelimumab once every 4 weeks (Q4W); after 6 doses, tremelimumab once every 12 weeks 
(Q12W) until discontinuation from study treatment
The following description applies to each combination therapy:
During Part A, patients will be enrolled in a 3+3 design.  In the LY3022855-plus-durvalumab regimen, LY3022855 
will be administered at increasing dose levels, as tolerated; durvalumab will be administered at a fixed dose.  In the 
LY3022855-plus-tremelimumab regimen, both LY3022855 and tremelimumab will be administered at increasing 
dose levels, as tolerated.  In the event dose-limiting toxicities (DLTs) prevent further dose escalation (LY3022855 
[in both combinations] and tremelimumab only), additional dosages between the highest dose tested and the 
previously identified safe dosage may be explored after further discussion among the investigators, sponsor, and 
collaborator.  Once a maximum tolerated dose (MTD) has been identified for LY3022855-plus-durvalumab, 
enrollment to the 2 disease-specific expansion cohorts in part B of the study consisting of 20 patients each will begin
for ovarian cancer and non-small cell lung cancer (NSCLC).  Patients in Part B will be treated at the MTD for the
LY3022855-plus-durvalumab combination.  Upon completion of Part B, which is intended to confirm tolerability of 
a combination dose, the RP2D will be declared/defined.

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Abbreviations:  MTD = maximum tolerated dose; NSCLC = non-small cell lung 
cancer; pts = patients.
Note for Part A:  Only LY3022855 (in both combinations) and tremelimumab, but not
durvalumab, are dose escalated.
JSCC study design.
Number of Patients:
Planned Number of 
Patients
Part A
(Phase 1a, dose escalation)
Part B
(Phase 1b, disease-specific expansion)
Enrolleda
Up to 78
Approximately 20 per cohort (2 cohorts)
Evaluableb
Up to 78
Note:  Nonevaluable patients will be 
replaced to ensure enough patients 
are enrolled in Part A.
Not applicable
Note:  The concept of “evaluable” (and, thus, 
replacement of patients) does not apply to 
patients in Part B.
a
Patients who are enrolled in the trial are those who have been assigned to a treatment and have received at least one dose of
study treatment.  The assumption is that every patient who is enrolled in Part A is evaluable.
b
Patients in Part A who receive all doses of study treatment for Cycle 1 (DLT-evaluation period) will be considered evaluable 
for the assessment of a dose level, provided it can be documented whether the patient did or did not experience a DLT within 
28 days of Cycle 1, Day 1.

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Treatment Arms and Duration:
For both Parts A and B, the planned duration of treatment is not fixed; patients will remain on study until they fulfill 
one of the criteria for study discontinuation.
Part A (Dose Escalation) Dose Regimens for the LY3022855-plus-Durvalumab Combination, by Cohort
Cohort
LY3022855
Durvalumab
Dose (mg)
Frequency
Dose (mg)
Frequency
D1a
25
QW
750
Q2W
D1ba
25
Days 1, 8, and 15 of each cycle
750
Q2W
D1c
25
Q2W
750
Q2W
D2a
50
QW
750
Q2W
D2ba
50
Days 1, 8, and 15 of each cycle
750
Q2W
D2c
50
Q2W
750
Q2W
D3a
75
QW
750
Q2W
D3ba
75
Days 1, 8, and 15 of each cycle
750
Q2W
D3c
75
Q2W
750
Q2W
D4a
100
QW
750
Q2W
D4ba
100
Days 1, 8, and 15 of each cycle
750
Q2W
D4c
100
Q2W
750
Q2W
Abbreviations:  QW = weekly; Q2W = every 2 weeks.
Note:  A cycle is defined as 28 days (4 weeks).  QW refers to dosing on Days 1, 8, 15, and 22 of each cycle; Q2W 
refers to dosing on Days 1 and 15 of each cycle.
a
Enrollment to the Dnb cohort will occur only if ≥2 DLTs are observed after Cycle 1, Day 21 of the 
corresponding Dna cohort.

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Part A (Dose Escalation) Dose Regimens for the LY3022855-plus-Tremelimumab Combination, by Cohort
Cohort
LY3022855
Tremelimumab
Dose (mg)
Frequency
Dose (mg)
Frequencya
T1a
50
QW
75
Q4W
T1bb
50
Days 1, 8, and 15 of each cycle
75
Q4W
T1c
50
Q2W
75
Q4W
T2a
100
QW
75
Q4W
T2bb
100
Days 1, 8, and 15 of each cycle
75
Q4W
T2c
75
Q2W
75
Q4W
T3a
100
QW
225
Q4W
T3bb
100
Days 1, 8, and 15 of each cycle
225
Q4W
T3c
100
Q2W
225
Q4W
T3d
75
QW
225
Q4W
T4a
100
QW
750
Q4W
T4b
100
Q2W
750
Q4W
T4c
100
Days 1, 8, 15 of each cycle
750
Q4W
T4d
75
QW
750
Q4W
Abbreviations:  QW = weekly; Q2W = every 2 weeks; Q4W = every 4 weeks.
Note:  A cycle is defined as 28 days (4 weeks).  QW refers to dosing on Days 1, 8, 15, and 22 of each cycle; Q2W 
refers to dosing on Days 1 and 15 of each cycle; Q4W refers to dosing on Day 1 of each cycle.
a
After 6 doses, tremelimumab to be dosed once every 12 weeks until discontinuation.
b
Enrollment to the Tnb cohort will occur only if ≥2 DLTs are observed after Cycle 1, Day 21 of the corresponding 
Tna cohort.
Treatment for Part B (Disease-Specific Dose Expansion Cohorts):  LY3022855 plus Durvalumab 
Patients in Part B will be treated at the MTD identified for LY3022855 in combination with durvalumab in Part A, 
unless otherwise specified by the sponsor.
Key Study Definitions
enter:  Patients who are entered in the trial are those who have signed the informed consent form directly or through 
their legally acceptable representatives.
enroll:  Patients who are enrolled in the trial are those who have been assigned to a treatment and have received at 
least 1 dose of study treatment.
interim analysis:  An analysis of clinical study data that is conducted before the final reporting database is 
authorized for data lock.
study completion:  This study will be considered complete when the primary and secondary objectives have been 
met.
continued access period:  The period between study completion and end of trial during which patients on study 
treatment who continue to experience clinical benefit and no undue risks may continue to receive study treatment 
until one of the criteria for discontinuation is met.

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end of trial:  End of trial is the date of the last visit or last scheduled procedure for the last patient.
Notable Statistical Methods:
The analyses for this study will be descriptive; no p values will be calculated.  Data analyses will be provided by 
cohort and treatment, whenever appropriate.  For continuous variables, summary statistics will include the number 
of patients, mean, median, standard deviation, minimum, and maximum.  Categorical endpoints will be summarized 
using the number of patients and percentages.  Missing data will not be imputed.
Tumor response data, according to RECIST 1.1, will be tabulated by cohorts.  Particularly, the antitumor effect will 
be summarized by best overall response, including the overall response rate (ORR) and disease control rate (DCR; 
complete response [CR]+ partial response [PR]+ stable disease [SD]).

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3.
Table of Contents
A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor 
LY3022855 in Combination with Durvalumab (MEDI4736) or 
Tremelimumab in Patients with Advanced Solid Tumors
Section
Page
1.
Protocol I5F-MC-JSCC(c)  A Phase 1a/1b Trial Investigating the 
CSF-1R Inhibitor LY3022855 in Combination with 
Durvalumab (MEDI4736) or Tremelimumab 
in Patients with Advanced Solid Tumors.............................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................8
4.
Abbreviations and Definitions...........................................................................................15
5.
Introduction ......................................................................................................................21
5.1.
Rationale and Justification for the Study ......................................................................21
5.1.1.
Summary of the Rationale for Amendment (a) .....................................................21
5.1.2.
Summary of the Rationale for Amendment (b).....................................................21
5.1.3.
Summary of the Rationale for Amendment (c) .....................................................23
5.2.
Objectives ....................................................................................................................23
5.2.1.
Primary Objectives...............................................................................................23
5.2.2.
Secondary Objectives...........................................................................................25
5.2.3.
Exploratory Objectives.........................................................................................25
5.3.
General Introduction to LY3022855, Durvalumab, and 
Tremelimumab.............................................................................................................25
5.4.
Rationale for Selection of Dose....................................................................................31
5.4.1.
LY3022855..........................................................................................................31
5.4.2.
Durvalumab .........................................................................................................36
5.4.3.
Tremelimumab.....................................................................................................37
6.
Investigational Plan...........................................................................................................39
6.1.
Study Population..........................................................................................................39
6.1.1.
Inclusion Criteria .................................................................................................39
6.1.2.
Exclusion Criteria ................................................................................................44
6.1.3.
Lifestyle Restrictions ...........................................................................................46
6.2.
Summary of Study Design............................................................................................46
6.2.1.
Study Completion and End of Trial......................................................................49
6.2.2.
Continued Access Period......................................................................................49
6.3.
Discontinuations ..........................................................................................................51

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6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................52
6.3.2.
Discontinuation of Patients from Study and/or Study 
Treatment.............................................................................................................52
6.3.3.
Patients Lost to Follow-Up...................................................................................53
6.3.4.
Discontinuation of Study Sites .............................................................................53
6.3.5.
Discontinuation of the Study................................................................................53
7.
Treatment..........................................................................................................................54
7.1.
Materials and Supplies .................................................................................................54
7.1.1.
LY3022855..........................................................................................................54
7.1.2.
Durvalumab .........................................................................................................54
7.1.3.
Tremelimumab.....................................................................................................55
7.2.
Study Drug Administration ..........................................................................................55
7.2.1.
Dosing Schedule ..................................................................................................56
7.2.1.1.
LY3022855 ....................................................................................................56
7.2.1.2.
Durvalumab....................................................................................................56
7.2.1.3.
Tremelimumab ...............................................................................................57
7.2.2.
Part A:  Dose Escalation (Phase 1a)......................................................................58
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................61
7.2.2.2.
Dose-Escalation Method.................................................................................64
7.2.3.
Part B:  Disease-Specific Expansion (Phase 1b) ...................................................65
7.2.4.
Dose Adjustments, Interruptions, and Delays .......................................................65
7.2.4.1.
Dose Delays for Adverse Events.....................................................................66
7.2.4.1.1.
Specific Adverse Events ...........................................................................67
7.3.
Method of Assignment to Treatment ............................................................................69
7.3.1.
Part A:  Dose Escalation (Phase 1a)......................................................................69
7.3.2.
Part B:  Disease-Specific Expansion (Phase 1b) ...................................................69
7.4.
Blinding .......................................................................................................................69
7.5.
Concomitant Therapy...................................................................................................69
7.5.1.
Excluded Concomitant Therapy ...........................................................................70
7.5.2.
Permitted Concomitant Therapy...........................................................................70
7.6.
Treatment Compliance .................................................................................................71
7.6.1.
Evaluable Patients................................................................................................71
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................72
8.1.
Safety Evaluations........................................................................................................72
8.1.1.
Safety Data Collection and Review ......................................................................72
8.1.2.
Adverse Events ....................................................................................................73

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8.1.2.1.
Serious Adverse Events ..................................................................................74
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................75
8.1.2.2.1.
Prior to Administration of Study Drug(s) ..................................................75
8.1.2.2.2.
While on Study Treatment ........................................................................75
8.1.2.2.3.
During the 30-Day and 90-Day Follow-Up Visits .....................................75
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................76
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................76
8.1.2.5.
Pregnancy, including Maternal and Paternal Exposure....................................78
8.1.3.
Overdose..............................................................................................................79
8.1.4.
Other Safety Measures .........................................................................................79
8.1.4.1.
Electrocardiogram ..........................................................................................79
8.1.4.2.
Multigated Acquisition Scan or Echocardiogram............................................80
8.1.5.
Safety Monitoring ................................................................................................80
8.1.6.
Complaint Handling.............................................................................................80
8.2.
Sample Collection and Testing.....................................................................................81
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................81
8.2.2.
Samples for Drug Concentration Measurements 
(Pharmacokinetics)...............................................................................................81
8.2.3.
Samples for Pharmacogenetics .............................................................................82
8.2.4.
Samples for Pharmacodynamic and Tailoring Biomarkers....................................82
8.2.4.1.
Blood Samples................................................................................................83
8.2.4.2.
Tumor Tissue Samples ...................................................................................83
8.2.5.
Samples for Immunogenicity Research.................................................................85
8.3.
Efficacy Evaluations ....................................................................................................85
8.4.
Procedure/Sampling Compliance..................................................................................86
9.
Data Management Methods...............................................................................................87
9.1.
Data Quality Assurance................................................................................................87
9.2.
Data Capture Systems ..................................................................................................87
9.2.1.
Case Report Form ................................................................................................87
9.2.2.
Ancillary Data......................................................................................................88
10.
Data Analyses...................................................................................................................89
10.1. General Considerations ................................................................................................89
10.2. Patient Disposition .......................................................................................................90
10.3. Patient Characteristics ..................................................................................................90
10.4. Safety Analyses............................................................................................................91
10.4.1.
Immunogenicity Analyses....................................................................................91
10.5. Pharmacokinetic Analyses............................................................................................91
10.6. Pharmacodynamic Analyses.........................................................................................92

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10.7. Pharmacokinetic/Pharmacodynamic Analyses..............................................................92
10.8. Efficacy........................................................................................................................92
10.9. Tailoring Biomarker Analyses......................................................................................92
10.10. Interim Analyses ..........................................................................................................93
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................94
11.1. Informed Consent.........................................................................................................94
11.2. Ethical Review.............................................................................................................94
11.3. Regulatory Considerations ...........................................................................................95
11.3.1.
Investigator Information.......................................................................................95
11.3.2.
Protocol Signatures ..............................................................................................95
11.3.3.
Final Report Signature .........................................................................................95
12.
References ........................................................................................................................96

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List of Tables
Table
Page
Table JSCC.1.
Part A (Dose Escalation) Dose Regimens for the LY3022855-plus-
Durvalumab Combination, by Cohort ............................................................60
Table JSCC.2.
Part A (Dose Escalation) Dose Regimens for the LY3022855-plus-
Tremelimumab Combination, by Cohort........................................................61
Table JSCC.3.
MTD Determination for the Combination of LY3022855 plus 
Durvalumab...................................................................................................65
Table JSCC.4.
AE and SAE Reporting Guidelines for Study JSCC.......................................77
Table JSCC.5.
Estimated Incidence Rate and 2-Sided 95% CI ..............................................89

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List of Figures
Figure
Page
Figure JSCC.1.
Treatment of murine MC38 tumors with anti-murine CSF-1R antibody 
(CS7).............................................................................................................28
Figure JSCC.2.
Combination therapy of anti-murine CSF-1R (CS7) and CTLA-4 
(9H10) antibodies. .........................................................................................29
Figure JSCC.3.
Combination therapy of anti-murine CSF-1R (CS7) and PD-L1 
antibodies. .....................................................................................................30
Figure JSCC.4.
Profile review of circulating CSF-1 levels in response to LY3022855 
treatment........................................................................................................32
Figure JSCC.5.
Profile review of circulating CD14DIM CD16BR MONO (cells/µL) in 
response to LY3022855 treatment..................................................................33
Figure JSCC.6.
Relationship between body weight and clearance of LY3022855:  
Reported body weight versus LY3022855 drug clearance 
(as determined using noncompartmental analysis) for eligible patient 
data from Study JSCA. ..................................................................................35
Figure JSCC.7.
JSCC study design.........................................................................................48
Figure JSCC.8.
Schema for an individual patient with regard to timing of tumor tissue 
biopsies. ........................................................................................................49
Figure JSCC.9.
Continued access diagram..............................................................................51

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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JSCC Study Schedule ......................................................................99
Attachment 2.
Protocol JSCC Clinical Laboratory Tests.....................................................129
Attachment 3.
Protocol JSCC Hepatic Monitoring Tests for Treatment Emergent 
Abnormality ................................................................................................131
Attachment 4.
Protocol JSCC Recommendations for Reporting 
Serious Adverse Events ...............................................................................132
Attachment 5.
Protocol JSCC ECOG Performance Status...................................................133
Attachment 6.
Protocol JSCC Creatinine Clearance Formula..............................................134
Attachment 7.
Protocol JSCC Toxicity Management Guidelines.........................................135
Attachment 8.
Protocol JSCC Durvalumab and Tremelimumab AESIs...............................158
Attachment 9.
Protocol JSCC Durvalumab and Tremelimumab Dose Volume 
Calculations.................................................................................................163
Attachment 10.
Protocol JSCC Protocol Amendment I5F-MC-JSCC(c) Summary
A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor LY3022855 in 
Combination with Durvalumab (MEDI4736) or Tremelimumab 
in Patients with Advanced Solid Tumors......................................................165

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4.
Abbreviations and Definitions
Term
Definition
9H10
anti-murine CTLA-4 antibody
ADA
antidrug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
AESI
adverse event of special interest
ALK
anaplastic lymphoma receptor tyrosine kinase (gene)
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to last 
measurable plasma concentration
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
audit
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s).
BRAF
B-Raf proto-oncogene, serine/threonine kinase (gene)
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase (Attachment 1 and Attachment 3 only)
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
maximum plasma concentration
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.

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complaint
Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
continued access 
period
The period between study completion and end of trial during which patients on 
study treatment who continue to experience clinical benefit and no undue risks 
may continue to receive study treatment until one of the criteria for 
discontinuation is met.
CR
complete response
CRP
clinical research physician
CRS
clinical research scientist
CS7
anti-murine CSF-1R antibody
CSF-1
colony-stimulating factor 1
CSF-1R
colony-stimulating factor 1 receptor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events; also referred to as NCI-
CTCAE
CTLA-4
cytotoxic T-lymphocyte associated protein 4
DCR
disease control rate
DCSI
development core safety information (portion of an investigator’s brochure 
[IB])
DLET
dose-limiting equivalent toxicity
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
durvalumab
MEDI4736; a PD-L1 monoclonal antibody
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDTA
disodium edetate dihydrate
EGFR
epidermal growth factor receptor (gene)

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end of trial
End of trial is the date of the last visit or last scheduled procedure for the last 
patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least one dose of study treatment. 
enter
Patients who are entered in the trial are those who have signed the informed 
consent form directly or through their legally acceptable representatives.
ERB
ethical review board; see also IRB
EudraCT
European Union Drug Regulating Authorities Clinical Trials
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GFR
glomerular filtration rate
GM-CSF
granulocyte macrophage colony-stimulating factor
GnRH
gonadotropin-releasing hormone
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IgG
immunoglobulin G
IgG1
immunoglobulin G, subclass 1
IgG1κ
immunoglobulin G1 kappa subclass
IgG2
immunoglobulin G, subclass 2
IgM
immunoglobulin M
IL-34
interleukin 34
ILD
interstitial lung disease
informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the 
trial that are relevant to the patient’s decision to participate.  Informed consent 
is documented by means of a written, signed and dated informed consent form 
(ICF).

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interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for data lock.
irAE
immune-related adverse event
IRB
institutional review board; see also ERB
IRR
infusion-related reaction
I.V.
intravenous(ly)
LDH
lactate dehydrogenase
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous 
events occurring while using a drug/drug delivery system.
LVEF
left ventricular ejection fraction
LY3022855
anti-CSF-1R monoclonal antibody
MEDI4736
durvalumab; anti-PD-L1 monoclonal antibody
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition (scan)
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease (Attachment 7 only)
PD-1
programmed cell death-1 protein
PD-L1
programmed cell death-ligand 1
PFS
progression-free survival
PK
pharmacokinetic(s)
PK/PD
pharmacokinetic/pharmacodynamic

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PR
partial response
QW
weekly
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q12W
every 12 weeks
Q28D
every 28 days
Q90D
every 90 days
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s Correction Formula
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data.
re-screen
to screen a patient who was previously declared a screen failure for the same 
study
RP2D
recommended Phase 2 dose
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.
screen failure
A patient who does not meet one or more criteria required for participation in a 
trial
SD
stable disease
sPD-L1
soluble PD-L1 (programmed cell death-ligand 1)
study completion
This study will be considered complete when the primary and secondary 
objectives have been met.
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TAM
tumor-associated macrophage
TNF
tumor necrosis factor

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TPO
third-party organization
tremelimumab
anti-CTLA-4 monoclonal antibody
ULN
upper limit of normal
V/F
apparent volume of distribution
w/v
weight per volume

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A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor 
LY3022855 in Combination with Durvalumab (MEDI4736) or 
Tremelimumab in Patients with Advanced Solid Tumors
5.
Introduction
5.1.
Rationale and Justification for the Study
Checkpoint inhibitors of programmed cell death-1 protein (PD-1)/programmed cell death-
ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) pathways have 
demonstrated proven, clinically meaningful improvement in survival for patients with various 
tumor types.  Preclinical data demonstrate significant interplay between the innate and adaptive 
immune systems.  Targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) may lead to 
disruption of the immunosuppressive effects of innate immune cells expressing CSF-1R.  
Combining a checkpoint inhibitor with an inhibitor of the CSF-1 pathway may potentiate the 
antitumor response. This trial will investigate the effects of CSF-1R inhibition using 
LY3022855 (anti-CSF-1R monoclonal antibody) in combination with durvalumab (MEDI4736, 
anti-PD-L1 monoclonal antibody) or tremelimumab (anti-CTLA-4 monoclonal antibody) in 
patients with advanced cancers.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.
5.1.1. Summary of the Rationale for Amendment (a)
Amendment (a) was created to incorporate a protocol synopsis. The following changes were 
also included in this amendment:

Revised an error in Exclusion Criterion #31 regarding left ventricular ejection fraction
(LVEF).

Added Exclusion Criterion #32 to exclude patients with known ROS1 mutation in
NSCLC, as a result of newly approved therapies for this patient population.

Deleted the temperature range (23°C to 27°C) for preparation and infusion of 
LY3022855. The instructions to do this at room temperature are sufficient.

Revised the permissible electrocardiogram (ECG) window prior to the start of the 
LY3022855 infusion from 1 hour to 2 hours to accommodate clinical sites.

Other minor changes and revisions throughout the protocol to ensure clarity, internal 
consistency, and correct sentence structure and grammar.
5.1.2. Summary of the Rationale for Amendment (b)
Amendment (b) was created to incorporate the following changes:

Modification of enrollment criteria in terms of prior treatment to reflect the changing 
landscape of cancer therapies.

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
Dosing modification and toxicity management guidelines for immune-mediated, 
infusion-related, and non-immune-mediated reactions included under Table JSCC.5, 
Table JSCC.6, and Table JSCC.7 have been moved to Attachment 7 with no content 
changes.

Cohort #3 (LY3022855 in combination with durvalumab in patients with melanoma), 
Cohort #4 (LY3022855 in combination with tremelimumab in patients with 
mesothelioma), and Cohort #5 (LY3022855 in combination with tremelimumab in 
patients with melanoma) from Part B of the study was removed. These changes were 
made for strategic reasons, and not for any identified safety concerns. The dose 
escalation of LY3022855 in combination with tremelimunab in Part A of the study will 
be completed, should this combination be developed in the future.

Adverse events of special interest (AESIs) observed with durvalumab or tremelimumab 
were modified in Section 7.2.4.1.1 and Attachment 8 for consistency with durvalumab
investigator’s brochure (IB) and tremelimumab IB.

Dose-limiting toxicity (DLT) criteria (creatine kinase[CK] elevation >8×upper limit of 
normal [ULN]) for CK was added for consistency with the toxicity management and dose 
modification guidelines listed in Attachment 7 of I5F-MC-JSCC (JSCC) protocol, non-
immune-mediated reactions. These guidelines recommend different management for CK 
elevations that are > 8X ULN compared to CK elevations that are ≤ 8X ULN.

Modification of DLT criteria to allow flexibility to continue dosing with Grade ≥2 
elevations of aspartate aminotransferase (AST), CK, amylase, and lipase in certain 
situations as described in Section 7.2.2.1 based on the following rationale:
The key toxicological findings attributed to LY3022855 administration in preclinical studies 
included reversible mild-to-moderate increases in serum transaminases (AST and alanine 
aminotransferase [ALT]) and target organ effects in liver (Kupffer cell hypertrophy/hyperplasia).  
No histological changes in the liver were noted to correlate with the transaminase increases, nor 
were any changes noted in liver functional parameters (that is, alkaline phosphatase, bilirubin, or 
coagulation).  Therefore, based on the small magnitude of the elevations and their limited impact 
to the overall health of the animal, the increases in ALT and AST were not considered adverse.  
The effect on Kupffer cells, specialized macrophages in the liver that play an important role in 
the clearance of several serum enzymes, including AST and CK, was regarded as 
immunomodulatory and was possibly associated with elevations in circulating CSF-1 levels.
In clinical studies of LY3022855 monotherapy, increases in serum AST and CK levels (mostly 
Grades 1 and 2) were noted in 19 and 17 patients, respectively, who received LY3022855 (of the 
total 64 patients) as of 28 January 2017.  The majority of these patients experienced elevations in 
both enzymes and received 1.25 mg/kg Q2W, 2.5 mg/kg QW, 100 mg QW, or 150 mg QW of 
LY3022855.  One case of a dose-limiting adverse event (AE) of Grade 4 rhabdomyolysis leading 
to Grade 4 acute renal failure was reported in a patient treated with LY3022855 1.25 mg/kg QW.  
The patient recovered from the events following discontinuation of study treatment.  One of the 3 
patients administered the dose of 150 mg QW experienced a Grade 3 CK elevation with 
associated elevated levels of serum and urine myoglobin.  Although no similar observations were 
noted in additional 3 patients, the dose of 100 mg QW was selected as the recommended Phase 2 

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dose for LY3022855 due to potential safety issues related to the QW dosing of 150 mg as 
evidenced by the laboratory abnormalities induced by LY3022855.  None of the patients with 
increased levels of AST experienced clinical symptoms suggestive of hepatic toxicity, nor were 
elevations of bilirubin noted at the time of the AST elevations.  Among all patients with AST and 
CK elevations, only 1 patient who received the dose of 2.5 mg/kg QW of LY3022855 was 
discontinued from the study due to drug-related increases in CK (Grade 3), AST (Grade 3), and 
lactate dehydrogenase (LDH; Grade 1).
Comparatively, preclinical and clinical studies on CSF-1R–targeted monoclonal antibodies have 
shown asymptomatic increases in short-lived enzymes, such as LDH, CK, and AST (Cassier et 
al. 2015; Zhou et al. 2015).  These increases in the levels of serum enzymes can be the result of 
decreases in Kupffer cells, depletion of which is consistent with the expected pharmacologic 
effect of CSF-1R pathway inhibition on Kupffer cells (Radi et al. 2011).
In clinical studies of LY3022855 monotherapy, increases in serum amylase and lipase (mostly 
Grades 1 and 2) were noted in 4 and 9 patients, respectively, who received single-agent 
LY3022855 (of the total of 64 patients) as of 28 January 2017 .  These patients were treated with 
1.25 mg/kg QW, 1.25 mg/kg Q2W, 100 mg QW, or 150 mg QW of LY3022855.  One of these 
patients who was treated with LY3022855 1.25 mg/kg QW developed mild-to-moderate 
increases in amylase and lipase levels and was ultimately diagnosed with Grade 3 pancreatitis, 
determined to be dose-limiting.  The patient recovered from pancreatitis following study 
treatment interruption but was subsequently removed from study due to the event.  There were 
no other cases of pancreatitis reported with administration of a single-agent LY3022855 as of 28 
January 2017.
These data suggest that elevations of serum levels of enzymes AST, CK, amylase, and lipase, are 
not necessarily indicative of end organ damage, thus, supporting modification of the DLT criteria 
in this protocol to allow flexibility to continue dosing with Grade ≥2 elevations of AST, CK, 
amylase, and lipase in certain situations as described in Section 7.2.2.1.
5.1.3. Summary of the Rationale for Amendment (c)
Amendment (c) was created to incorporate the following changes:

Dose modification and toxicity management guidelines for durvalumab was updated per
new guidance from AstraZeneca.

Added clarification about testing for mutations in EGFR or ALK genes for patients in 
Part B (NSCLC cohort only).

Updated information about tumor biopsy samples to make it consistent across sections.

Updated treatment delay criteria to provide consistency across the protocol.
5.2.
Objectives
5.2.1. Primary Objectives
The primary objectives of the study are:

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
To characterize the safety profile and tolerability of each combination, LY3022855 with 
durvalumab (MEDI4736), and LY3022855 with tremelimumab, in the treatment of 
patients with advanced solid tumors.

To define a recommended Phase 2 dose (RP2D) for LY3022855 with durvalumab, in the 
treatment of patients with advanced solid tumors.

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5.2.2. Secondary Objectives
The secondary objectives of this study are:

To document the antitumor activity of each combination, LY3022855 with durvalumab,
and LY3022855 with tremelimumab, in the treatment of patients with advanced solid 
tumors.

To assess the development of antibodies against LY3022855, durvalumab, and 
tremelimumab (immunogenicity).

To characterize the single-dose and multiple-dose pharmacokinetics (PK) of LY3022855 
in combination with either durvalumab or tremelimumab, and the single-dose and 
multiple-dose PK of durvalumab and tremelimumab, each in combination with 
LY3022855.
5.2.3. Exploratory Objectives

To explore the effects of the combination of LY3022855 with durvalumab or 
tremelimumab in the treatment of patients with advanced solid tumors on changes in 
immune cell subset frequency and activation.

To explore the pharmacodynamic profile of each combination, LY3022855 with 
durvalumab, and LY3022855 with tremelimumab, in the treatment of patients with 
advanced solid tumors.

To explore cellular and molecular markers potentially associated with safety and 
antitumor and biological activity of the combination of LY3022855 with durvalumab or 
tremelimumab, in the treatment of patients with advanced solid tumors.
5.3.
General Introduction to LY3022855, Durvalumab, and 
Tremelimumab
LY3022855 is a recombinant human monoclonal antibody of the immunoglobulin G (IgG), 
subclass 1 (IgG1) targeting CSF-1R.  LY3022855 was originally identified from a screen of 
hybridoma candidates generated following immunization of MEDAREX HuMAb™ human 
IgG-transgenic mice with soluble human CSF-1R and NIH-3T3 cells stably expressing CSF-1R.  
The antibody comprises 2 identical gamma () heavy chains and 2 identical kappa () 
light chains.  LY3022855 was selected for having high affinity binding to CSF-1R and its ability 
to block the binding of CSF-1 and interleukin 34 (IL-34) to CSF-1R.  The LY3022855 heavy and 
light chain antibody genes were then engineered into a suitable vector for expression in Chinese 
hamster ovary cells.  Subcloning techniques were used to generate a stable clone expressing high 
levels of LY3022855 for manufacturing purposes.  The nonclinical and clinical experience is 
fully described in the current version of the LY3022855 investigator’s brochure (IB).  It is 
expected that treatment with LY3022855 will mitigate the immunosuppressive effects of cells 
expressing CSF-1R and lead to increased activation of the human immune system.

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Durvalumab (MEDI4736), a human monoclonal antibody of the immunoglobulin G1 kappa 
(IgG1κ) subclass, inhibits binding of PD-L1 and is being developed for use in the treatment of 
cancer.  As durvalumab is an engineered monoclonal antibody, it does not induce antibody-
dependent cellular cytotoxicity or complement-dependent cytotoxicity.  The proposed 
mechanism of action for durvalumab is interference of the interaction of PD-L1 with PD-1.  
Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall 
molecular weight of approximately 149 kDa.  Durvalumab contains a triple mutation in the 
constant domain of the IgG1 heavy chain that reduces binding to complement protein C1q and 
the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function.  
Durvalumab has high affinity and specificity for PD-L1.  Recently reported data demonstrated 
clinical activity with an acceptable safety profile across a range of tumors including squamous 
cell carcinoma of the head and neck, pancreatic, gastric, and non-small cell lung cancers
(NSCLC), hepatocellular carcinoma, and melanoma (Lutzky et al. 2014; Segal et al. 2014; 
Rizvi et al. 2015; Segal et al. 2015).  The nonclinical and clinical experience is fully described in 
the current version of the durvalumab IB.  It is expected that treatment with an anti-PD-L1 
antibody, such as durvalumab, will lead to increased activation of the human immune system, 
increasing antitumor activity in patients with solid tumors.
Tremelimumab is an IgG2 kappa isotype monoclonal antibody directed against CTLA-4,
also known as CD152 (cluster of differentiation 152).  This immunomodulatory therapy is being 
developed by AstraZeneca for use in the treatment of cancer.
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal, 
which limits T cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to 
B7 ligands and enhance human T cell activation as demonstrated by increased cytokine 
(interleukin 2 [IL-2] and interferon [IFN] gamma) production in vitro in whole blood or 
peripheral blood mononuclear cell (PBMC) cultures (Tarhini and Kirkwood 2008).  In addition, 
blockade of CTLA-4 binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced 
T cell activation and antitumor activity in animal models, including killing of established murine 
solid tumors and induction of protective antitumor immunity.  Therefore, it is expected that 
treatment with an anti-CTLA-4 antibody, such as tremelimumab, will lead to increased activation 
of the human immune system, increasing antitumor activity in patients with solid tumors.
An extensive program of nonclinical and clinical studies has been conducted for tremelimumab 
both as monotherapy and combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules.
The nonclinical and clinical experience is fully described in the current version of the 
tremelimumab IB.
Interactions between the innate and adaptive immune systems are critical for normal immune 
function and in the tumor microenvironment.  For example, high numbers of tumor-associated 
macrophages (TAMs) inversely correlate with infiltration by CD8+ T cells.  Targeting TAMs 
with antibodies directed against CSF-1R have been shown to significantly decrease macrophage 
infiltration of tumors (Figure JSCC.1).  Additionally, anti-CSF-1R treatment that limits 

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LY3022855
associated macrophages enhances CD8+ T cell infiltration, leading to decreases in tumor burden 
(DeNardo et al. 2011).  Moreover, in a syngeneic breast cancer model, depletion of CD8+ T cells 
rendered treatment with CSF-1R inhibition less efficacious, indicating interplay between 
macrophage activity and T cell infiltration.
Checkpoint inhibitors of PD-1/PD-L1 and CTLA-4 pathways have demonstrated clinically 
meaningful improvements in survival for patients with various tumor types.  Preclinical studies 
with CSF-1R-blocking monoclonal antibodies in combination with PD-L1- or CTLA-4-blocking 
monoclonal antibodies have demonstrated additive effects.  Figure JSCC.2 demonstrates additive 
effects of CSF-1R and CTLA-4 inhibition; Figure JSCC.3 demonstrates additive effects of 
CSF-1R and PD-L1 inhibition.  Given the immunomodulatory effects of the PD-1/PD-L1, 
CTLA-4, and CSF-1R inhibitors, the incidence of immune-related adverse events (irAEs) as 
additive effects (that is, in the combinations) may be greater than that observed with the 
individual agents.  This trial will investigate the effects of CSF-1R inhibition using LY3022855 
in combination with durvalumab or tremelimumab in patients with advanced cancers.

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Abbreviations:  CS7 = anti-murine CSF-1R antibody; CSF-1R = colony-stimulating 
factor 1 receptor; FACS = fluorescence-activated cell sorting (also referred to as flow 
cytometry); PBS = phosphate-buffered saline; PD-L1 = programmed cell death-ligand 
1; TIL = tumor-infiltrating lymphocytes.
Treatment of murine MC38 tumors with anti-murine CSF-1R antibody (CS7) results in 
reduction of tumor-infiltrating macrophages.  MC38 colon tumors were treated for 
1 week with 3 doses of CS7, and then tumors were isolated and examined for the 
presence of CD45+, CD11b+, CD11cNeg F4/80+ macrophages.  Representative FACS 
plots demonstrate an average of approximately 60% reduction in intra-tumor 
macrophages when treated with either dose of CS7.
Figure JSCC.1.
Treatment of murine MC38 tumors with anti-murine CSF-1R 
antibody (CS7).

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LY3022855
Abbreviations:  CS7 = anti-murine CSF-1R antibody; CSF-1R = colony-stimulating
factor 1 receptor; CTLA-4 = cytotoxic T-lymphocyte associated protein 4.
Combination therapy of anti-murine CSF-1R (CS7) and CTLA-4 (9H10) antibodies 
results in superior antitumor activity against 4T1 tumors.  Established murine 4T1 
triple-negative breast tumors were allowed to grow for 7 days before being treated for 
1 week with 9H10 or CS7 alone or in combination, followed by 2 weeks of continued 
CS7 alone or after combination therapy.  Combination therapy resulted in dramatically 
reduced tumor growth, which was significantly different from 9H10 or CS7 
monotherapy.  Average growth curves are shown.
Figure JSCC.2.
Combination therapy of anti-murine CSF-1R (CS7) and CTLA-4 
(9H10) antibodies.

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Abbreviations:  combo = combination; CR = complete response; CS7 = anti-murine 
CSF-1R antibody; CSF-1R = colony-stimulating factor 1 receptor; PD-L1 = 
programmed cell death-ligand 1.
Combination therapy of anti-murine CSF-1R (CS7) and PD-L1 antibodies results in
superior regression of CT26 (colon cancer) tumors.  Established murine CT26 tumors 
were allowed to grow for 6 days before being treated for 3 weeks with anti-PD-L1 or 
CS7 alone or in combination.  Combination therapy resulted in an enhanced response 
and doubling of complete tumor regressions, which was significantly different from 
PD-L1 or CS7 monotherapy. Individual tumor growth curves are shown compared 
with control (black dashed line) for CS7 (top left), PD-L1 (top right), and the 
combination (bottom).  CR rates at Day 49 are shown in the table.
Figure JSCC.3.
Combination therapy of anti-murine CSF-1R (CS7) and PD-L1 
antibodies.

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Refer to Section 5.4, as well as the respective IBs, for further details regarding the study drugs.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3022855 may be found in the LY3022855 
IB.  Information on AEs expected to be related to the investigational product LY3022855 may be 
found in Section 7 (Development Core Safety Information [DCSI]) of the LY3022855 IB.  
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate, periodically during the course of the study, may be 
found in Section 6 (Effects in Humans) of the LY3022855 IB.
5.4.
Rationale for Selection of Dose
5.4.1. LY3022855
Clinical experience with LY3022855 comprises 43 patients (as of 28 Jan 2016) who received the 
following doses intravenously (I.V.):  2.5 mg/kg weekly (QW) (n=6), 0.3 mg/kg QW (n=4), 0.6 
mg/kg QW (n=3), 1.25 mg/kg every 2 weeks (Q2W) (n=20), 1.25 mg/kg QW (n=5), and 1 mg/kg 
on Weeks 1, 2, 4, and 5 of every 6-week cycle (n=5) in 2 ongoing Lilly-sponsored Phase 1 
studies (I5F-IE-JSCA [JSCA] and I5F-MC-JSCB [JSCB]).  At the first human dose studied, 2.5 
mg/kg QW, which was also the highest dose administered, laboratory abnormalities were noted 
in 5 patients (Grade 2-3 creatine kinase or Grade 2-3 aspartate aminotransferase [AST]
elevations) but were not classified as dose-limiting toxicities (DLTs) due to the lack of clinical 
signs or symptoms of organ toxicity.  Because of these laboratory abnormalities, the study 
protocol was amended and dose escalation was restarted at a lower dose, 0.3 mg/kg QW. Three
dose-limiting toxicities (DLTs) have been observed in Study JSCA:  an event of left ventricular 
dysfunction in Cohort 4 (1.25 mg/kg Q2W) and separate events of pancreatitis and 
rhabdomyolysis in Cohort 5 (1.25 mg/kg QW).  Upon further review, the patient with the DLT of 
left ventricular dysfunction had a baseline LVEF of 35%, which obfuscated the relationship 
between LY3022855 and the DLT event; therefore, the patient was considered to be a 
suboptimal candidate for study participation.  No DLTs have occurred at the other dose levels.
In addition, elevated CK, AST, and LDH levels were observed in patients treated with 
LY3022855 at 2.5 mg/kg QW (JSCA), as previously stated, and at 1.25 mg/kg Q2W (JSCB).  
However, enzyme levels decreased to Grade <2 upon discontinuation of LY3022855, indicating 
that these effects were reversible.
In addition to safety, the pharmacodynamics of the biomarkers, plasma CSF-1, and circulating 
CD14DimCD16Bright mononuclear cells were also evaluated in Study I5F-IE-JSCA (JSCA)
(Figure JSCC.4 and Figure JSCC.5, respectively). While there were minimal changes observed 
at the 0.3-mg/kg and 0.6-mg/kg QW dose levels, CSF-1 levels were substantially increased with
1.25-mg/kg and 2.5-mg/kg doses (in a dose-dependent manner), as well as suppression of 
circulating CD14DimCD16Bright mononuclear cells, indicating sustained target engagement. 
Furthermore, these biomarker responses were maintained throughout the dosing interval by 
increasing the frequency of dosing from 1.25 mg/kg Q2W to 1.25 mg/kg QW.

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Abbreviations:  CSF-1 = colony-stimulating factor 1; I.V. = intravenous(ly).
Each line represents the profile of a single patient. Weekly I.V. dosing results in 
sustained elevation of CSF-1, an indicator of target engagement, for the duration of the 
dosing period. In contrast, dosing every 2 weeks allows CSF-1 levels to return to 
baseline, indicating reduced target engagement with a more intermittent dosing 
schedule.
Figure JSCC.4.
Profile review of circulating CSF-1 levels in response to LY3022855
treatment.
Time (Days)

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Abbreviations:  FACS = fluorescence-activated cell sorting (also referred to as 
flow cytometry); I.V. = intravenous(ly).
Each line represents the profile of a single patient.  FACS analyses revealed weekly 
I.V. dosing rapidly and continuously suppressed circulating CD14DIMCD16BR cells, in 
contrast to biweekly dosing, which resulted in an initial decrease but rapid increase to 
baseline levels prior to the next dose of LY3022855.
Figure JSCC.5.
Profile review of circulating CD14DIM CD16BR MONO (cells/µL) in 
response to LY3022855 treatment.
Preliminary analyses of the PK data obtained in Study JSCA reveal a lack of correlation between 
body weight and clearance of LY3022855 (Figure JSCC.6).  The protocol for Study JSCA has, 
therefore, been amended (as Version 7.0) to investigate the use of non-weight-based dosing in 
the LY3022855 dose escalation, starting initially with 100 mg QW.
Therefore, based on the available clinical PK, pharmacodynamic, and safety data collected for 
LY3022855 in Study JSCA and Study JSCB, and considering the lack of clinical experience with 
LY3022855 in combination with other drug treatments, dose escalation of LY3022855 will 
commence at an initial dose level of 25 mg QW (approximately equivalent to a 0.3-mg/kg QW
dose in a 75-kg patient) when in combination with durvalumab.  This LY3022855 dose was not 
associated with any DLTs in the JSCA monotherapy dose-escalation trial and is approximately 
one fourth of the currently recommended Phase 2 dose of LY3022855 (1.25 mg/kg Q2W).  
Because the planned dose of durvalumab is equal to the dose being used in Phase 3 studies and 
because there is no planned dose escalation of durvalumab, a slightly lower LY3022855 starting 
dose was selected for the combination with durvalumab, compared with that selected for the 
combination with tremelimumab.  Dose escalation of LY3022855 in combination with 
Time (Days)

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durvalumab will proceed in 25-mg increments, up to a planned maximum of 100 mg QW
(approximately equivalent to a 1.25-mg/kg QW dose in a 75-kg patient).
Dose escalation of LY3022855 when in combination with tremelimumab will commence at an 
initial dose level of 50 mg QW (approximately equivalent to a 0.6-mg/kg QW dose in a 75-kg
patient).  This LY3022855 dose was not associated with any DLTs in the JSCA monotherapy 
dose-escalation trial and is approximately one half of the currently recommended Phase 2 dose of 
LY3022855 (1.25 mg/kg Q2W).  Because the planned starting dose of tremelimumab is 
approximately one tenth of the dose being used in Phase 3 studies and because there is a planned 
dose escalation for tremelimumab, a slightly higher LY3022855 starting dose was selected for 
the combination with tremelimumab, compared with that selected for the combination with 
durvalumab.  Dose escalation of LY3022855 in combination with tremelimumab will proceed as 
a single 50-mg increment, up to a planned maximum of 100 mg QW (approximately equivalent 
to a 1.25-mg/kg QW dose in a 75-kg patient).
Furthermore, in the case where unacceptable toxicity is observed for the continuous dosing 
schedule (that is, once per week), the impact of either a reduced dose or a reduced dosing 
intensity (that is, a weeklong break in treatment) on patient safety will be evaluated.

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Abbreviations:  PK = pharmacokinetic(s); QW = weekly; Q2W = every 2 weeks.
Exploratory graphical analysis of the PK of LY3022855 samples obtained in Study 
JSCA indicates no clear relationship between body weight and drug clearance.
Figure JSCC.6.
Relationship between body weight and clearance of LY3022855:  
Reported body weight versus LY3022855 drug clearance 
(as determined using noncompartmental analysis) for eligible 
patient data from Study JSCA.

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5.4.2. Durvalumab
As of May 2015, approximately 1279 patients have received I.V. durvalumab monotherapy, the 
majority of which were enrolled on studies CD-ON-MEDI4736-1108 (n=694) and 
D4191C00003/ATLANTIC (n=303).
Following dose escalation of durvalumab in the first-human-dose study, Study CD-ON-
MEDI4736-1108 in patients with advanced solid tumors, 10 mg/kg Q2W was selected for dose 
expansion. This was the highest dose level administered in the dose-escalation phase of the 
study (with respect to total cycle dose). Treatment-related Grade 3 or higher AEs were reported 
in 378 patients (54.5%) who received 10 mg/kg Q2W and were manageable by general treatment 
guidelines described in the durvalumab study protocols. The safety profile of durvalumab 
observed in Study CD-ON-MEDI4736-1108 is consistent with that observed in Study 
D4191C00003/ATLANTIC.  In combination studies with tremelimumab, dabrafenib, or 
gefitinib, durvalumab is dosed at 10 mg/kg Q2W or 20 mg/kg every 4 weeks (Q4W) in the 
dose-expansion phases of each ongoing investigational trial.
Near-complete target saturation is expected with durvalumab ≥3 mg/kg Q2W, as indicated by 
suppression of the biomarker for PD-L1 target engagement, sPD-L1 (soluble PD-L1).
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (Study CD-ON-MEDI4736-1108; N=292; doses=0.1 to 10 mg/kg Q2W or 15 mg/kg 
every 3 weeks [Q3W]; solid tumors). Population PK analysis indicated only minor impact of 
body weight on PK of durvalumab (coefficient of ≤0.5). The impact of body weight-based 
(10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing 
predicted steady state PK concentrations (5th, median, and 95th percentiles) using the population 
PK model. A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on median 
body weight of approximately 75 kg). A total of 1000 patients were simulated using body 
weight distribution of 40 to 120 kg. Simulation results demonstrate that body weight-based and 
fixed dosing regimens yield similar median steady state PK concentrations with slightly less 
overall between-subject variability with fixed dosing regimen.
Similar findings have been reported by others (Ng et al. 2006, Wang et al. 2009, Zhang et al. 
2012, Narwal et al. 2013).  Wang and colleagues investigated 12 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better for 
7 of 12 antibodies.  In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-subject 
variability in pharmacokinetic/pharmacodynamic (PK/PD) parameters (Zhang et al. 2012).
A fixed-dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given expectation of similar PK exposure and variability, it was
considered feasible to switch to fixed-dosing regimens.
The observed PK exposures of durvalumab in the presence of tremelimumab, dabrafenib, or 
gefitinib were consistent with respective monotherapy durvalumab exposure data, indicating no 

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PK interaction between these agents.  The PK interaction between the combination of interest for 
this trial, LY3022855 and durvalumab, has not yet been clinically evaluated.
Therefore, based on the available clinical PK, pharmacodynamic, and safety data collected for
durvalumab monotherapy and combination therapy with tremelimumab, this combination trial 
will commence enrollment at a dose of 750 mg of durvalumab Q2W (equivalent to a 10-mg/kg 
Q2W dose in a 75-kg patient).
5.4.3. Tremelimumab
As of November 2014, approximately 973 patients have received I.V. tremelimumab 
monotherapy.
Following an initial multiple-dose escalation of tremelimumab (3, 6, 10 mg/kg every 28 days 
[Q28D]) in a Phase 1/2 study (Study A3671002), patients were subsequently enrolled to evaluate 
the antitumor activity of 2 alternative dosing regimens: 10 mg/kg I.V. Q28D versus 15 mg/kg 
I.V. every 90 days (Q90D). Among patients treated with 10 mg/kg Q28D or 15 mg/kg Q90D, 
the median durations of objective response were 553 days and 722 days, respectively.  
Treatment-related SAEs occurred in 25.0% of patients treated with 10 mg/kg Q28D and in 8.9% 
of patients treated with 15 mg/kg Q90D. The results of this study led to a decision to proceed 
with the dosing regimen of 15 mg/kg Q90D in subsequent studies initiated by Pfizer Inc
(previous sponsor).
However, subsequent retrospective exposure-response analyses suggested that the 15-mg/kg 
Q90D schedule could result in underexposure to tremelimumab. An intensified schedule of 
tremelimumab is now under evaluation whereby patients receive 10 mg/kg Q28D for 6 doses, 
followed by 15 mg/kg Q90D until treatment discontinuation (Calabrò et al. 2015).
In the ongoing combination study with durvalumab and tremelimumab (Study D4190C00006), 
the dose level selected for tremelimumab in the dose-expansion phase is 1 mg/kg Q4W. Doses 
higher than 1 mg/kg Q4W (that is, 3 mg/kg Q4W and 10 mg/kg Q4W) in combination with 
durvalumab at 10, 15, or 20 mg/kg Q4W were associated with increased incidence of AEs.
A population PK model was developed for tremelimumab using data from Phase 1 through 
Phase 3 studies (N=654; 0.01-15-mg/kg doses Q4W or Q90D; metastatic melanoma) 
(Wang et al. 2014). The population PK model indicated minor impact of body weight on PK of 
tremelimumab (coefficient of ≤0.5). The weight-based (1 mg/kg Q4W) and fixed-dosing (75 mg 
Q4W; based on median body weight of approximately 75 kg) regimens were compared using 
predicted PK concentrations (5th, median, and 95th percentiles) using the population PK model 
in a simulated population of 1000 patients with body weight distribution of 40 to 120 kg. Similar 
to durvalumab, simulations indicated that both body weight-based and fixed-dosing regimens of 
tremelimumab yield similar median steady-state PK concentrations with slightly less between-
subject variability with the fixed-dosing regimen.
Therefore, based on the available clinical PK and safety data collected for tremelimumab in 
monotherapy and in combination with durvalumab, this combination trial will commence 
enrollment at a dose of 75 mg of tremelimumab Q4W (equivalent to a 1-mg/kg Q4W dose in a 

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75-kg patient) for the first 6 doses, followed by dosing on an every-12-week (Q12W) schedule, 
starting 4 weeks after Dose 6 (Week 25), until treatment discontinuation.  This starting dose is 
10-fold lower than the currently recommended dose of tremelimumab monotherapy, and was 
selected to allow for an increased margin of safety, since the combination of LY3022855 and 
tremelimumab has not yet been studied in patients.
It is intended that the dose escalation of tremelimumab could reach 750 mg Q4W for the first 
6 doses, followed by dosing on a Q12W schedule (approximately equivalent to a 3-mg/kg Q4W 
dose in a 75-kg patient). This planned dose level is the currently recommended Phase 2 dose 
(RP2D) of tremelimumab for the monotherapy (10 mg/kg Q4W).

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6.
Investigational Plan
6.1.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened one time, if agreed upon by the investigator and the
sponsor.  The interval between screenings should be at least 1 week.  When re-screening is 
performed, the individual must sign a new informed consent form (ICF) and will be assigned a 
new identification number.  Repeating of laboratory tests during the screening period does not 
constitute re-screening; laboratory tests may not be repeated more than twice during the 
screening period in order to meet eligibility criteria.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
(Note:  If a specific cohort is not indicated for a criterion, the criterion applies to all patients.)
[1]
Must have histological or cytological evidence of a diagnosis of cancer that is
not amenable to curative therapy.
[2]
Part B (all cohorts):  Must have a type of malignancy that is being studied, as 
listed in the following:
[a] LY3022855 and durvalumab (MEDI4736) combination cohorts
[i] NSCLC that has relapsed or is refractory (definitions below) to
immune checkpoint inhibitor therapy and has progressed through no 
more than 3 lines of therapy (one line must have been a platinum-
containing regimen).

Relapsed: Following initial clinical benefit (that is, complete 
response [CR], partial response [PR], or stable disease [SD] on 
any scan), patients must have documented radiographic disease 
progression while receiving therapy with an immune
checkpoint inhibitor.

Refractory: Patients must have documented radiographic
disease progression ≤16 weeks after the start of treatment with
an immune checkpoint inhibitor, with no evidence of clinical 
benefit (that is, CR, PR, or SD on any scan) while receiving 
therapy.

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a.
Patients must not have a known activating mutation of the EGFR
or ALK gene.  If a site uses algorithmic testing that has eliminated 
the possibility of EGFR or ALK gene mutations, no specific 
testing for mutations in these genes is required.
b. Patients could have received only one prior immune checkpoint 
therapy (anti-PD-1/PD-L1 or anti-CTLA-4, or a single regimen 
combining anti-PD-1/PD-L1 with an anti-CTLA-4).
[ii] Ovarian cancer (epithelial ovarian cancer, fallopian tube cancer, or 
primary peritoneal cancer) that has been treated with no more than 
3 lines of therapy (with or without platinum).
[3]
Part A (all cohorts) and Part B (ovarian cancer cohort only):  Must be willing 
to undergo pretreatment and on-treatment core needle or excisional tumor 
biopsies. For patient in NSCLC Part B cohort, if newly obtained samples 
cannot be obtained such as in cases of inaccessibility or patient safety 
concern, an archived tumor sample will be requested if not restricted by local 
regulations.  The archived tumor sample must follow most recent systemic 
treatment. If no archived specimen since the most recent systemic treatment is 
available, and a new biopsy is not medically feasible, the patient should not be 
enrolled in the clinical trial.
[4]
[a] Part A (all cohorts): Have the presence of measurable and/or 
nonmeasurable disease as defined by the Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 (Eisenhauer et al. 2009).
[b] Part B (both cohorts):  Have the presence of measurable disease as defined 
by the RECIST 1.1 (Eisenhauer et al. 2009).
[5]
Are 18 years of age.
[6]
(Patient or legal representative) Have given written informed consent and any 
locally required authorization (for example, Health Insurance Portability and 
Accountability Act [HIPAA] in the United States or the European Union [EU] 
Data Privacy Directive) prior to performing any protocol-related procedures, 
including screening evaluations.
[7]
Have adequate normal organ and marrow function, including the following:

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System
Laboratory Value
Hematologic
ANC
≥1.5 × 109/L (≥1500/mm3)
Platelet count
≥100 × 109/L (≥100,000/mm3)
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L (red blood cell transfusions are not 
allowed within 7 days prior to screening hematology profile)
Renal
Creatinine
OR
Measured or calculated creatinine clearancea
(see Attachment 6)
≤1.5 × institutional ULN
OR
≥60 mL/min
Hepatic
Total bilirubin
≤1.5 × institutional ULN
AST and ALT
≤2.5 × institutional ULN OR ≤5 × institutional ULN for patients
with liver metastases
Coagulation
INR or PT
INR ≤1.5 × institutional ULN or PT ≤5 seconds above 
institutional ULN
PTT or aPTT
PTT or aPTT ≤5 seconds above institutional ULN
Thyroid
TSH OR free T4
TSH OR free T4 within the normal limits.
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; GFR = glomerular filtration rate; INR = international 
normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; T4 = thyroxine; TSH = thyroid-
stimulating hormone; ULN = upper limit of normal.
a
GFR should be estimated via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine 
equation (Levey et al. 2009).

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[8]
Have a performance status of 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (refer to Attachment 5).
[9]
Have discontinued previous treatments for cancer and recovered from the 
acute effects of therapy.
At the discretion of the investigator, patients with hormone-refractory prostate 
cancer who are stable on gonadotropin-releasing hormone (GnRH) agonist 
therapy or maintenance prednisone, and patients with breast cancer who are 
stable on antiestrogen therapy (for example, an aromatase inhibitor) may have 
that treatment continued while they are enrolled.
[10] Are reliable and willing to make themselves available for the duration of the 
study and are willing and able to comply with the protocol for the duration of 
the study, including undergoing treatment, scheduled visits and examinations 
(including follow-up), and attempted pretreatment and on-treatment tumor 
biopsies (Part A – all cohorts and Part B – ovarian cancer cohort only).
[11] Have an estimated life expectancy, in the judgment of the investigator, of at 
least 12 weeks.
[12] Male patients:
[a] who are sterile (including vasectomy)
or
[b] who are not sterile and agree to use 2 acceptable methods of effective 
contraception* during the study, starting at screening, for at least 6 months 
following last dose of study drug(s); and agree not to donate sperm during the 
study and for at least 6 months following last dose of study drug
[13] Female patients:
[a] are women not of childbearing potential due to surgical sterilization 
(at least 6 weeks postsurgical bilateral oophorectomy with or without 
hysterectomy or tubal ligation) confirmed by medical history, or 
postmenopausal by history.  Postmenopausal women include women with 
either:
[i] ≥60 years of age and spontaneous amenorrhea for at least 12 months, 
not induced by a medical condition such as anorexia nervosa and not 
taking medications during the amenorrhea that induced the 
amenorrhea (for example, oral contraceptives, hormones, GnRH, 
antiestrogens, selective estrogen receptor modulators [SERMs], or 
chemotherapy)
or
[ii] spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone (FSH) level greater than 40 mIU/mL

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[b] are women of childbearing potential who test negative for pregnancy 
within 7 days prior to enrollment based on a urine or serum pregnancy test and 
agree to use 2 acceptable methods of effective contraception* during the 
study, starting at screening, and for 6 months following the last dose of the 
study drug(s) and also must not be breastfeeding.
* Acceptable methods of effective contraception include the following, where 
2 methods must be used

Barrier methods
o
Male condom plus spermicide
o
Cap plus spermicide
o
Diaphragm plus spermicide

Intrauterine device methods
o
Copper T
o
Progesterone T (also considered to be a hormonal method)
o
Levonorgestrel-releasing intrauterine system (for example, 
Mirena®)

Hormonal methods
o
Implants
o
Hormonal shot or injection
o
Combined pill
o
Minipill
o
Patch
Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control.

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6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[14] Have received treatment with an investigational product or nonapproved use 
of a drug or device (other than the study drug used in this study) within 28 
days prior to the initial dose of study drug, or are concurrently enrolled in any 
other type of medical research judged not to be scientifically or medically 
compatible with this study.
[15] Have been involved in the planning and/or conduct of the study (applies both 
to sponsor staff and/or to staff at the study site) or have an immediate family 
member (for example, spouse, parent/legal guardian, sibling, or child) who is 
investigational site or sponsor staff directly involved with this trial, unless 
prospective institutional review board (IRB) approval (by chair or designee) is 
obtained, allowing exception to this criterion for a specific patient.
[16] Have previously been enrolled in the present study.
[17] Have had any of the following anticancer therapies prior to enrollment:
[a] small molecule therapy or chemotherapy within 14 days.
[b] radiation therapy within 14 days.
[c] monoclonal antibody treatment within 28 days.
[18] Are currently receiving or have had prior use of immunosuppressive 
medication within 28 days before the first dose of study drug, with the 
exception of intranasal and inhaled corticosteroids or systemic corticosteroids 
at physiological doses, which are not to exceed 10 mg/day of prednisone, or 
an equivalent corticosteroid.
[19] Have had major surgery within 28 days prior to enrollment.
[20] Have a serious preexisting medical condition, including, but not limited to, the 
following:
[a] Known human immunodeficiency virus (HIV) infection or acquired 
immunodeficiency syndrome (AIDS)-related illness (baseline screening 
required within 28 days prior to enrollment).
[b] History of immunodeficiency (primary and secondary).
[c] Active or prior documented autoimmune disease within the past
24 months. NOTE: Patients with vitiligo, Graves disease, or psoriasis not 
requiring systemic treatment (within the past 24 months) are not excluded.
[d] Active or prior documented inflammatory bowel disease (for example, 
Crohn’s disease, ulcerative colitis).

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[e] Uncontrolled intercurrent illness, including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer 
disease or gastritis, active bleeding diatheses including any patient known to 
have evidence of acute or chronic hepatitis B or hepatitis C.
[f] History of allogeneic organ transplant.
[g] Known history of tuberculosis.
[h] Active non-infectious pneumonitis requiring treatment with steroids, or 
history of interstitial lung disease (ILD).
[i] Active or uncontrolled clinically serious infection.
[j] Known psychiatric or substance abuse disorders, or social situations that 
would either limit compliance with study requirements or compromise the 
ability of the patient to give written informed consent.
[21] Have symptomatic central nervous system (CNS) malignancy or metastasis 
(screening not required).
Patients with treated CNS metastases are eligible for this study if they are not 
currently receiving corticosteroids greater than 10 mg per day of prednisone
or equivalent, and their disease is asymptomatic and radiographically stable 
for at least 60 days.
[22] Have a second primary malignancy that, in the judgment of the investigator 
and sponsor, may affect the interpretation of results.
[23] Have mean QT interval corrected for heart rate (QTc) ≥470 milliseconds
calculated from one baseline electrocardiogram (ECG) using Fridericia’s
Correction Formula (QTcF) and confirmed with 2 additional baseline ECGs.
[24] Have known hypersensitivity to LY3022855, durvalumab, or tremelimumab, 
or to any combination or excipient.
[25] Have received live attenuated vaccination within 30 days prior to study entry.
[26] Have any condition that, in the opinion of the investigator, would interfere 
with evaluation of study treatment or interpretation of patient safety or study 
results.
[27] Have known muscle damage due to a primary, traumatic, or other muscle 
disease or a creatine kinase greater than normal limits.
[28] Have had any prior Grade ≥3 irAE† while receiving any previous 
immunotherapy agent, have any unresolved irAE Grade >1, or any irAE that 
led to the permanent discontinuation of prior immunotherapy.

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[29] Have experienced a Grade ≥3 AE or a neurologic or ocular AE of any grade 
while receiving prior immunotherapy.  Patients with an endocrine AE 
Grade ≤2 are permitted to enroll if they are stably maintained on appropriate 
replacement therapy and are asymptomatic.
[30] Have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, have experienced recurrence of 
an AE if re-challenged, and currently require a maintenance dose of >10 mg 
prednisone or equivalent per day.
[31] Have left ventricular ejection fraction (LVEF) <50%.
[32] Have known ROS1 mutation in NSCLC (baseline screening not required).
† Immune-related AEs:  pneumonitis or ILD; diarrhea or enterocolitis; hepatitis 
(elevated liver function test); nephritis or renal dysfunction (elevated serum 
creatinine); rash (excluding bullous skin formations); endocrinopathy (for 
example, hyperthyroidism, hypothyroidism, hypopituitarism, adrenal 
insufficiency); immune-mediated neurotoxicity (including but not limited to limbic 
encephalitis, autonomic neuropathy, excluding myasthenia gravis and Guillain-
Barre); immune-mediated peripheral neuromotor syndromes, such as Guillain-
Barre and myasthenia gravis.
6.1.3. Lifestyle Restrictions
Patients should not donate blood while participating in this study until after 4 to 5 times the half-
life of study treatment(s) (that is, 6 months after the last dose).
6.2.
Summary of Study Design
Study I5F-MC-JSCC is a multicenter, nonrandomized, open-label, dose-escalation (Part A), 
followed by dose-expansion (Part B) Phase 1a/1b study of LY3022855 in combination with 
durvalumab or tremelimumab (Part A) or durvalumab only (Part B), in patients with advanced 
solid malignancies.  A cycle is defined as 28 days (4 weeks).  Eligible patients will receive 
treatment as follows:

LY3022855 (once weekly [QW] OR once on Days 1, 8, and 15 of each cycle OR once 
every 2 weeks [Q2W]), in combination with:
o
durvalumab Q2W (Parts A and B)
OR
o
tremelimumab once every 4 weeks (Q4W); after 6 doses, tremelimumab once 
every 12 weeks (Q12W) until discontinuation (Part A only)
The study will be conducted in 2 parts:

Part A – Phase 1a, dose escalation

Part B – Phase 1b, disease-specific expansion

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The following description applies to each combination therapy.
During Part A, patients will be enrolled in a 3+3 design.  In the LY3022855-plus-durvalumab 
regimen, LY3022855 will be administered at increasing dose levels, as tolerated; durvalumab 
will be administered at a fixed dose.  In the LY3022855-plus-tremelimumab regimen, both 
LY3022855 and tremelimumab will be administered at increasing dose levels, as tolerated.  In 
the event DLTs prevent further dose escalation (LY3022855 [in both combinations] and 
tremelimumab only), additional dosages between the highest dose tested and the previously 
identified safe dosage may be explored after further discussion among the investigators, sponsor, 
and collaborator.  Once a maximum tolerated dose (MTD) has been identified for the 
LY3022855-plus-durvalumab combination, enrollment to Part B (2 disease-specific expansion 
cohorts of 20 patients per cohort) will begin.  The NSCLC cohort will consist of a minimum of 
10 patients with disease refractory to checkpoint therapy and a minimum of 6 patients with 
disease relapsed on prior checkpoint therapy.  Patients in Part B will be treated at the MTD for 
LY3022855-plus-durvalumab combination.  Upon completion of Part B, which is intended to 
confirm tolerability of a combination dose, the RP2D will be declared/defined.
All patients enrolled to all cohorts of Part A or to the ovarian cancer cohort (only) of Part B will 
undergo mandatory attempted pretreatment and on-treatment (6-8 weeks after starting study 
treatment) tumor core needle or excisional biopsies.
Figure JSCC.7 presents the overall study design.  Figure JSCC.8 presents the schema for an 
individual patient with regard to timing of tumor tissue biopsies.

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Abbreviations:  MTD = maximum tolerated dose; NSCLC = non-small cell lung 
cancer; pts = patients.
Note for Part A:  Only LY3022855 (in both combinations) and tremelimumab, but not 
durvalumab, are dose escalated.
Figure JSCC.7.
JSCC study design.

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Figure JSCC.8.
Schema for an individual patient with regard to timing of tumor 
tissue biopsies.
To characterize the safety profile and tolerability and to define the RP2D of the combinations of 
LY3022855 with durvalumab or tremelimumab, an adequate sample size is required.  The actual 
sample size in Part A depends on the incidence of DLTs and is estimated to be up to 
approximately 78 patients; refer to Section 10.1 for additional details.
In Part A, after all patients who are deemed evaluable for the assessment of dose levels complete 
the DLT-evaluation period or the MTD is determined, an interim safety and PK analysis may be 
conducted for each combination for planning next studies.  After completion of enrollment to 
Part B, if it is deemed that enough data are obtained to assess the primary and secondary 
objectives, a clinical study report may be written before the last patient visit for the study.
The planned duration of treatment is not fixed; patients will remain on study until they fulfill one 
of the criteria for study discontinuation (Section 6.3).
Refer to Attachment 1 for the Study Schedule.
6.2.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study
completion]) when the primary and secondary study objectives have been met.  “End of trial”
refers to the date of the last visit or last scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up.
6.2.2. Continued Access Period
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks.
Continued access will apply to this study only if at least one patient is still on study treatment
when study completion occurs.  Lilly (the sponsor) will notify investigators when the continued 
access period begins.

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The sponsor may allow patients to enroll in an LY3022855 “rollover” protocol to provide long-
term continued access for patients enrolled in this study.
Patients must sign a new ICF before continued access is provided.
The patient's continued access to study treatment (Visits 501-5XX) will end when the patient and 
investigator agree that the patient will no longer continue to receive study treatment.  Continued 
access follow-up (Visits 901 [30-day] and 902 [90-day, only for durvalumab and tremelimumab 
safety]) will begin the day after the patient and the investigator agree that the patient will no 
longer continue to receive study treatment.  Continued access follow-up for Visit 901 lasts 
approximately 30 days (±7 days); Visit 902 occurs 90 days (±7 days) after the patient and 
investigator agree that the patient will no longer continue to receive study treatment.  Follow-up 
procedures will be performed as shown in the Continued Access Schedule in Attachment 1.

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Figure JSCC.9 presents the sequence of study periods, including continued access.
Figure JSCC.9.
Continued access diagram.
Patients who are in short-term follow-up (Visit 801 [30-day] or Visit 802 [90-day]) when the 
continued access period begins will continue in short-term follow-up until the 30-Day/90-Day 
Follow-Up visit is completed.
6.3.
Discontinuations
The reason for and date of discontinuation will be collected for all patients.  The date of 
discontinuation from study treatment is to be reported on the electronic case report form (eCRF).  
Patients who discontinue will have follow-up procedures performed as shown in the Study 
Schedule (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
Refer to Section 7.6.1 for conditions under which patients may be replaced.
Study Treatment Period
a Lilly will notify sites when the continued access period begins and ends. 
b Primary and secondary objectives have been met.  Lilly will notify sites when study completion occurs.
c End of trial occurs at the last visit or last scheduled procedure for the last patient.
Study Completionb
Patient and investigator 
agree to discontinue  
study treatment
Study treatment
Continued access 
follow-up
(approximately 30 days
[90 days for durvalumab/ 
tremelimumab safety])
Continued Access Perioda
End of Trialc

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6.3.1. Discontinuation of Patients Inadvertently Enrolled
If the sponsor or the investigator site identifies a patient who did not meet enrollment criteria and 
who was inadvertently enrolled, a discussion must occur between the sponsor’s clinical research 
physician (CRP)/clinical research scientist (CRS) and the investigator to determine if the patient 
may continue in the study.  If both agree that it is medically appropriate to continue, the
investigator must obtain documented approval from the sponsor’s CRP/CRS to allow the 
inadvertently enrolled patient to continue in the study with or without study treatment.
6.3.2. Discontinuation of Patients from Study and/or Study Treatment
Patients who are discontinued from the study treatment will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
Patients will be permanently discontinued from the study and/or from the study treatment in the 
following circumstances:

Enrollment in any other clinical trial involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study.

Investigator/Physician Decision
o
The investigator/physician decides that the patient should be discontinued from 
the study or study drug(s).
o
The patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication;
discontinuation from the study drug(s) occurs prior to introduction of the other 
agent.

Patient Decision
o
The patient or the patient’s designee (for example, parents or legal guardian) 
requests to be discontinued from the study or study drug.  No follow-up 
procedures will be performed for patients who withdraw informed consent, unless 
he or she has explicitly provided permission and consent.

Sponsor Decision
o
Lilly, in consultation with the collaborator, stops the study or stops the patient’s 
participation in the study for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.

The patient experiences a Grade ≥3 infusion reaction.

The patient has radiographic evidence of progressive disease or significant 
symptomatic disease deterioration characterized as progression of disease, in the 
opinion of investigator, in the absence of radiographic evidence of progressive 
disease.

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Exceptions for continuing study treatment beyond confirmed radiographic progression 
may be made on a case-by-case basis for patients who are believed to be clinically 
benefiting from study treatment, and the investigator and the sponsor agree that 
continuing study treatment is in the patient’s best interest.

The patient experiences unacceptable toxicity (for example, an AE that, in the 
opinion of the investigator or the sponsor, contraindicates further dosing).

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

The patient becomes pregnant or intends to become pregnant during the study.

The patient begins treatment with alternative anticancer therapy, including 
another investigational agent.

The administration of study drug is delayed for more than 28 days.
o
For the patients treated with the LY3022855-plus-tremelimumab combination, a 
delay of up to 28 days between doses is allowed for Cycles 1 through 6, and up to 
60 days between doses for Cycles 7 and beyond.
6.3.3. Patients Lost to Follow-Up
A patient would be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
6.3.4. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for any 
scientific, medical, safety, regulatory, ethical, or other reasons consistent with applicable laws, 
regulations, and GCP.
6.3.5. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges discontinuation of the study necessary for any scientific, medical, safety, 
regulatory, ethical, or other reasons consistent with applicable laws, regulations, and GCP.

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7.
Treatment
7.1.
Materials and Supplies
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.1.1. LY3022855
LY3022855 Injection for infusion is supplied at 5 mg/mL strength as a solution dosage, in glass 
vials with an elastomeric closure.  Each vial of LY3022855 Injection for infusion contains 20 mL 
of the drug product (100 mg/20-mL vial). Vials of LY3022855 Injection for infusion should be 
stored refrigerated at 2°C to 8°C.  The drug product is formulated to contain the active 
LY3022855 in 10mM histidine, 100mM glycine, 100mM arginine, and 0.01% polysorbate 80 at 
pH 6.0.  LY3022855 is a clear or slightly opalescent and colorless or slightly yellow liquid 
without visible particles.  LY3022855 will be administered as an I.V. infusion. The dose is 
prepared and infused at room temperature.  LY3022855 will be diluted in normal saline to a final 
volume of 250 mL.  Lilly instructions regarding dilution requirements should be followed.
7.1.2. Durvalumab
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. The solution contains 50 mg/mL durvalumab, 26mM histidine/histidine
hydrochloride, 275mM trehalose dihydrate, and 0.02% (weight/volume [w/v]) polysorbate 80; it 
has a pH of 6.0.  The nominal fill volume is 10 mL.
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.  
Durvalumab must be used within the individually assigned expiry date on the label.
The following applies to the preparation of durvalumab doses for administration with an I.V. 
bag.  The dose for administration must be prepared by the investigator’s or the site’s designated 
investigational product manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If in-use storage time exceeds these limits, a new dose must be prepared from new vials.  
Infusion solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration.
Refer to Attachment 9 for the durvalumab dose volume calculation.

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7.1.3. Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 20-mg/mL solution for infusion after 
dilution. The solution contains 20 mg/mL of tremelimumab, 20mM histidine/histidine 
hydrochloride, 222mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27mM disodium 
edetate dihydrate (EDTA); it has a pH of 5.5. The nominal fill volume is 20 mL. Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.  Tremelimumab 
must be used within the individually assigned expiry date on the label.
The following applies to the preparation of tremelimumab doses for administration with an I.V. 
bag.  The dose of tremelimumab for administration must be prepared by the investigator’s or the 
site’s designated investigational product manager using aseptic technique.  Total time from 
needle puncture of the tremelimumab vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
It is recommended that the prepared final I.V. bag be stored in the dark at 2ºC to 8°C (36°F to 
46°F) until needed. If storage time exceeds these limits, a new dose must be prepared from new 
vials. The refrigerated infusion solutions in the prepared final I.V. bag should be equilibrated at 
room temperature for about 2 hours prior to administration. Tremelimumab does not contain 
preservatives and any unused portion must be discarded.
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin I.V. bags have 
been observed.
Refer to Attachment 9 for the tremelimumab dose volume calculation.
7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agent(s) and planned duration of each 
individual’s treatment to the site personnel

verifying that instructions are followed properly

maintaining accurate records of study drug dispensation, and collection, and returning or 
destroying all unused medication to Lilly or its designee at the end of the study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.

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7.2.1. Dosing Schedule
Refer to Section 7.2.2 for Part A (dose escalation) dose regimens for each combination, by 
cohort.  Refer to Section 7.2.3 for Part B (disease-specific expansion) dose regimens for 
LY3022855-plus-durvalumab, by cohort.
For each combination regimen, LY3022855 will be administered first, followed by a 30-minute 
observation period.  After the observation period, durvalumab or tremelimumab will be 
administered. In this study, a cycle is defined as 4 weeks (28 days); Day 1 of a cycle is based on 
the administration of LY3022855 (rather than durvalumab or tremelimumab). A delay of study 
treatment due to holiday, weekend, bad weather, or other unforeseen circumstances will be 
permitted for a maximum of 3 days and not counted as a protocol deviation.
7.2.1.1.
LY3022855
Eligible patients will receive LY3022855 as an I.V. infusion administered over a minimum 
duration of 30 minutes and a maximum duration of 4 hours, based on the known safety and 
stability of the prepared drug. The infusion rate should not exceed 25 mg/minute. Suggested 
infusion times are as follows:

90 minutes for the first infusion; if no infusion-related reaction (IRR) is observed, 
decrease the infusion time to 60 minutes for the second infusion

60 minutes for the second infusion; if no IRR is observed, decrease the infusion time to 
30 minutes for the third infusion

30 minutes for the third and subsequent infusions
If, at any time, a patient experiences an IRR, the infusion time should not be decreased.  
Premedication is not recommended to be administered prior to the first infusion of LY3022855.  
However, if the patient experiences a Grade 1 or 2 IRR, premedication must be provided prior to 
any subsequent doses of LY3022855. The choice of premedication is to be made after 
discussion and agreement between the investigator and sponsor.  In such cases (Grade 1 or 2 
IRRs), administration of steroids should be avoided, if possible.  If an IRR Grade ≤2 occurs 
during or after LY3022855 administration and the patient’s condition allows it, treatment with 
durvalumab or tremelimumab will proceed as planned.  Patients experiencing an IRR Grade ≥3 
will be permanently discontinued from study treatment.
LY3022855 may be administered up to 3 days AFTER the scheduled dosing date and up to 4
days BEFORE the next scheduled dosing date to accommodate for patient vacations, holidays, 
inclement weather or other unforeseen circumstances.  If, at any time, a dose is to be 
administered beyond the 3-day window, that dose is to be skipped.  A maximum of 28 days 
between administered doses is allowed for delays due to adverse events.
7.2.1.2.
Durvalumab
Patients are to receive durvalumab I.V. on Days 1 and 15 of every cycle.  Durvalumab may be 
administered up to 3 days AFTER the scheduled dosing date.  If, at any time, a dose is 
administered beyond the 3-day window, that dose is considered a dose delay.  A maximum delay 
of 28 days between administered doses is allowed (for dose delay in case of immune-related AE 

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please refer to Section 7.2.4.1).  Note that a maximum of 12 months/26 doses of durvalumab 
treatment is permitted.
Refer to Attachment 9 for the durvalumab dose volume calculation.
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein.  Following preparation of 
durvalumab, the entire contents of the I.V. bag should be administered as an I.V. infusion over 
approximately 60 minutes (±5 minutes), using a 0.2- or 0.22-μm in-line filter.  Less than 
55 minutes is considered a deviation.
The I.V. line will be flushed with a volume of I.V. solution (0.9% [w/v] saline) equal to the 
priming volume of the infusion set used after the contents of the I.V. 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.
A 1-hour observation period is required after the first infusion of durvalumab.  If no clinically 
significant infusion reactions are observed during or after the first cycle, subsequent infusion 
observation periods can be at the investigator’s discretion (suggested 30 minutes after each 
durvalumab infusion).
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in this study protocol.
In the event of a Grade ≤2 IRR, the infusion rate of study drug may be decreased by 50% or 
interrupted until resolution of the event and re-initiated at 50% of the initial rate until completion 
of the infusion. For patients with a Grade ≤2 IRR, subsequent infusions may be administered at 
50% of the initial rate. Acetaminophen and/or an antihistamine (for example, diphenhydramine) 
or equivalent medications per institutional standard may be administered at the discretion of the 
investigator. If the IRR is Grade ≥3 in severity, study drug will be permanently discontinued.
7.2.1.3.
Tremelimumab
Patients are to receive tremelimumab I.V. on Day 1 of every cycle for the first 6 doses
(Cycles 1-6).  Starting with Cycle 7 (4 weeks after Dose 6 [Week 25]), tremelimumab will be 
dosed once every 3 cycles (12 weeks), that is, on Day 1 of Cycles 7, 10, 13, and so on, until 
disease progression.
Tremelimumab may be administered up to 3 days AFTER the scheduled dosing date.  If, at any 
time, a dose is administered beyond the 3-day window, that dose is considered a dose delay.  A 
delay of up to 28 days between administered doses is allowed for Cycles 1 through 6, and up to 
60 days between doses for Cycles 7 and beyond.
Refer to Attachment 9 for the tremelimumab dose volume calculation.
Tremelimumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein.  Following preparation of 
tremelimumab, the entire contents of the I.V. bag should be administered as an I.V. infusion over 

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approximately 60 minutes (±5 minutes), using a 0.2- or 0.22-μm in-line filter.  Less than 
55 minutes is considered a deviation.
The I.V. line will be flushed with a volume of 0.9% (w/v) saline equal to the priming volume of 
the infusion set used after the contents of the I.V. 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.
In the event that either preparation time or infusion time exceeds the time limits presented in this 
section, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded.
A 1-hour observation period is required after the first infusion of tremelimumab.  If no clinically 
significant infusion reactions are observed during or after the first cycle, subsequent infusion 
observation periods can be at the investigator’s discretion (suggested 30 minutes after each 
tremelimumab infusion).
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in this study protocol.
In the event of a Grade ≤2 IRR, the infusion rate of study drug may be decreased by 50% or 
interrupted until resolution of the event and re-initiated at 50% of the initial rate until completion 
of the infusion. For patients with a Grade ≤2 IRR, subsequent infusions may be administered at 
50% of the initial rate. Acetaminophen and/or an antihistamine (for example, diphenhydramine) 
or equivalent medications per institutional standard may be administered at the discretion of the 
investigator. If the IRR is Grade ≥3 in severity, study drug will be permanently discontinued.
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit patients to an intensive care unit if necessary.
7.2.2. Part A:  Dose Escalation (Phase 1a)
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
MTD is determined.  Safety data, in particular AEs, will be the primary criteria for the dose 
escalation.  No dose escalation can occur without prior discussion and agreement between the 
investigator, the Lilly study team, and the collaborator; the decision will be documented in 
writing.
Based on the ongoing safety reviews, modifications to the dose-escalation strategy or other 
design elements may be made via protocol amendment to ensure patient safety. No intrapatient 
dose escalation is permitted for any patient.  Dose escalation may be ceased at any time based on
available safety and PK behavior.
In Part A, study drugs for the LY3022855-plus-durvalumab and LY3022855-plus-tremelimumab 
combinations may be administered at the dose regimens shown in Table JSCC.1 and 

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Table JSCC.2, respectively.  Refer to Section 7.2.2.2 for further details on the planned dose-
escalation method, proceeding from Cohorts D1a and T1a.

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Table JSCC.1.
Part A (Dose Escalation) Dose Regimens for the LY3022855-plus-
Durvalumab Combination, by Cohort
Cohort
LY3022855
Durvalumab
Dose (mg)
Frequency
Dose (mg)
Frequency
D1a
25
QW
750
Q2W
D1ba
25
Days 1, 8, and 15 of each cycle
750
Q2W
D1c
25
Q2W
750
Q2W
D2a
50
QW
750
Q2W
D2ba
50
Days 1, 8, and 15 of each cycle
750
Q2W
D2c
50
Q2W
750
Q2W
D3a
75
QW
750
Q2W
D3ba
75
Days 1, 8, and 15 of each cycle
750
Q2W
D3c
75
Q2W
750
Q2W
D4a
100
QW
750
Q2W
D4ba
100
Days 1, 8, and 15 of each cycle
750
Q2W
D4c
100
Q2W
750
Q2W
Abbreviations:  QW = weekly; Q2W = every 2 weeks.
Note:  A cycle is defined as 28 days (4 weeks).  QW refers to dosing on Days 1, 8, 15, and 22 of each cycle; Q2W 
refers to dosing on Days 1 and 15 of each cycle.
a
Enrollment to the Dnb cohort will occur only if ≥2 DLTs are observed after Cycle 1, Day 21 of the 
corresponding Dna cohort.

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Table JSCC.2.
Part A (Dose Escalation) Dose Regimens for the LY3022855-plus-
Tremelimumab Combination, by Cohort
Cohort
LY3022855
Tremelimumab
Dose (mg)
Frequency
Dose (mg)
Frequencya
T1a
50
QW
75
Q4W
T1bb
50
Days 1, 8, and 15 of each cycle
75
Q4W
T1c
50
Q2W
75
Q4W
T2a
100
QW
75
Q4W
T2bb
100
Days 1, 8, and 15 of each cycle
75
Q4W
T2c
75
Q2W
75
Q4W
T3a
100
QW
225
Q4W
T3bb
100
Days 1, 8, and 15 of each cycle
225
Q4W
T3c
100
Q2W
225
Q4W
T3d
75
QW
225
Q4W
T4a
100
QW
750
Q4W
T4b
100
Q2W
750
Q4W
T4c
100
Days 1, 8, 15 of each cycle
750
Q4W
T4d
75
QW
750
Q4W
Abbreviations:  QW = weekly; Q2W = every 2 weeks; Q4W = every 4 weeks.
Note:  A cycle is defined as 28 days (4 weeks).  QW refers to dosing on Days 1, 8, 15, and 22 of each cycle; Q2W 
refers to dosing on Days 1 and 15 of each cycle; Q4W refers to dosing on Day 1 of each cycle.
a
After 6 doses, tremelimumab to be dosed once every 12 weeks until discontinuation.
b
Enrollment to the Tnb cohort will occur only if ≥2 DLTs are observed after Cycle 1, Day 21 of the corresponding
Tna cohort.
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition
Dose-limiting toxicity is defined as an AE that is at least possibly related to the study drug(s) and
that occurs during Cycle 1 (the DLT-evaluation period) and does not improve to the National 
Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
(CTEP 2009) Grade ≤2 (unless stated otherwise), despite medical management, including 
steroids (if applicable).  Toxicity that is clearly and directly related to the primary disease or to 
another etiology is excluded from this definition.  The following are considered DLTs, unless 
noted otherwise:

Grade 4 neutropenia lasting ≥7 days

Grade 3 or 4 neutropenia complicated by fever or infection of any duration

Any Grade 4 thrombocytopenia

Any Grade 3 thrombocytopenia complicated by hemorrhage

Any Grade 3 or 4 anemia

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
Grade 3 or 4 nonhematologic toxicity, including:

any Grade 4 irAE

any Grade 3 or 4 colitis

any Grade 3 or 4 noninfectious pneumonitis irrespective of duration

any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade 
to Grade 2 within 3 days after onset of the event despite optimal medical 
management including systemic corticosteroids or does not downgrade to 
Grade ≤1 or baseline within 14 days

any Grade 3 or 4 non-irAE except as noted for transaminases, bilirubin, lipase,
or amylase below

any liver transaminase elevation >8 × institutional ULN or total bilirubin (TB) 
>5 × institutional ULN

creatine kinase elevation >8 × ULN

Any Grade 2 pneumonitis that does not resolve to Grade ≤1 within 3 days of the 
initiation of maximal supportive care
The DLT definition excludes the following conditions:

Grade 3 fatigue lasting ≤7 days

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the patient is asymptomatic

Grade 3 inflammatory reaction attributed to a local antitumor response (for 
example, inflammatory reaction at sites of metastatic disease, lymph nodes, etc)

Concurrent vitiligo or alopecia of any AE grade

Grade 3 IRR (first occurrence and in the absence of steroid prophylaxis) that 
resolves within 6 hours with appropriate clinical management

Grade 3 or 4 neutropenia that is not associated with fever or systemic infection 
that improves by at least 1 grade within 3 days. Grade 3 or 4 febrile neutropenia 
will be a DLT regardless of duration or reversibility

Grade 3 or 4 lymphopenia

Grade 3 thrombocytopenia that is not associated with clinically significant 
bleeding that requires medical intervention, and improves by at least 1 grade 
within 3 days

Isolated Grade 3 electrolyte abnormalities that are not associated with clinical 
signs or symptoms and are reversed with appropriate maximal medical 
intervention within 3 days

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
Isolated asymptomatic Grade 3 elevation of amylase or lipase without evidence of 
end organ damage.

Asymptomatic Grade 3 CK level (5-10 × ULN: CTCAE v4.0) that is not associated with 
elevated serum or urinary myoglobins and no evidence of rhabdomyolysis or myositis.

Asymptomatic Grade 3 AST induction that is accompanied by Grade ≤1 ALT and Grade 
≤1 TB and no change of ALT or TB from baseline levels.

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Adverse events meeting DLT criteria that occur beyond Cycle 1 are defined as dose-limiting 
equivalent toxicities (DLETs).  If a patient is believed to be benefitting from study treatment, 
patients who experience a DLT may continue to receive study treatment upon agreement of the 
investigator, sponsor, and collaborator.
For the purpose of this study, the MTD is defined as the highest tested dose that has less than 
33% probability of causing a DLT.  The MTD will be determined as shown in Table JSCC.3 and 
Table JSCC.4.
7.2.2.2.
Dose-Escalation Method
Three to 6 patients will be enrolled to Cohort 1a (that is, Cohort D1a or T1a; refer to 
Table JSCC.1 and Table JSCC.2 for LY3022855-plus-durvalumab and LY3022855-plus-
tremelimumab combinations, respectively).  If none of the first 3 patients or 1 of 6 patients in 
Cohort 1a experiences a DLT event, enrollment to the next “a” cohort will proceed (that is, to 
Cohort 2a, and so on).  However, if 1 of 3 patients in any cohort (that is, at any dose level)
experiences a DLT, up to 3 additional patients will be enrolled at that dose level.  If a DLT is 
observed in ≥2 of a maximum of 6 patients in Cohorts 1a, 2a, 3a, or 4a, concurrent enrollment of 
3 to 6 patients to each of the respective “b”, “c”, and “d” cohorts (as applicable) will occur and 
no higher dosages will be explored.  For example, if no DLTs are noted in Cohort 1a, enrollment 
to Cohort 2a will occur; however, if 2 patients in Cohort 2a experience DLTs, enrollment to 
Cohorts 2b and 2c will occur concurrently and no higher dosages will be studied.  An exception 
to this method is that enrollment to Dnb/Tnb cohorts will occur only if ≥2 DLTs are observed 
after Cycle 1, Day 21 of the corresponding Dna/Tna cohorts.  All patients will be assigned to 
treatment cohorts by the sponsor, with patients assigned sequentially to the “b”, “c”, and “d” 
cohorts.
The MTD identified for each combination therapy in Part A will then be the dosage used 
(confirmed) in Part B (Phase 1b/disease-specific expansion).  However, if each of the “b”, “c”, 
and “d” cohorts (as applicable) in Part A are observed to have a probability of causing a DLT
that is lower than 33%, the sponsor (in consultation with the collaborator) will select the dosage 
to be used in Part B, based on clinical or correlative study results.

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Table JSCC.3.
MTD Determination for the Combination of LY3022855 plus 
Durvalumab
Cohort
Number of Patients Who Experience a DLT (in Cycle 1)
0 of 3
1 of 6
≥2
D1a
Enroll to D2a
Enroll to D2a
Enroll to D1b and D1c
D1b
MTD is D1b
MTD is D1b
Not defined
D1c
MTD is D1c
MTD is D1c
Not defined
D2a
Enroll to D3a
Enroll to D3a
Enroll to D2b and D2c
D2b
MTD is D2b
MTD is D2b
MTD is D1a
D2c
MTD is D2c
MTD is D2c
MTD is D1a
D3a
Enroll to D4a
Enroll to D4a
Enroll to D3b and D3c
D3b
MTD is D3b
MTD is D3b
MTD is D2a
D3c
MTD is D3c
MTD is D3c
MTD is D2a
D4a
MTD is D4a
MTD is D4a
Enroll to D4b and D4c
D4b
MTD is D4b
MTD is D4b
MTD is D3a
D4c
MTD is D4c
MTD is D4c
MTD is D3a
Abbreviations:  DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
7.2.3. Part B:  Disease-Specific Expansion (Phase 1b)
Once the MTD for LY3022855-plus-durvalumab combination has been identified, enrollment to 
Part B (disease-specific expansion) will begin and will include 2 expansion cohorts (refer to 
Section 6.1.1, Inclusion Criterion [2]).  Patients in these expansion cohorts will be treated at the 
MTD identified for LY3022855-plus-durvalumab combination in Part A, unless otherwise 
specified by the sponsor.  If patients are treated at a dose other than the MTD, the dosage chosen 
will not exceed the MTD exposure.
Additional cohorts of patients with alternative tumor histologies may be added if clinical activity 
is observed during Part A. In the event of DLTs (Section 7.2.2.1) or DLETs occurring in 33% or 
more of patients in Part B (with a minimum enrollment of 6 patients) within a tumor-specific 
expansion cohort, investigators and the sponsor study team will assess the nature and severity of 
these toxicities. No additional patients will be accrued until this safety review is completed and 
a decision is made either to continue at the current dose or to de-escalate the dose and define a 
new dose for the expansion phase.
7.2.4. Dose Adjustments, Interruptions, and Delays
No dose reductions (of any study drug) are permitted during this study.
Dosing interruptions of study drugs are permitted for reasons not related to study treatment (for 
example, minor surgery, unrelated medical events, patient vacation, and/or holidays).  The 
reason for interruption should be documented on the case report form (eCRF).

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In addition, doses of study drug(s) may need to be delayed to manage specific AEs or other 
toxicities.  Refer to Section 7.2.4.1 for implementation of dose delays due to AEs.
All dose modifications should be documented, including the approach taken and a clear rationale 
for the need for modification.
7.2.4.1.
Dose Delays for Adverse Events
Study treatment may be held for a maximum of 28 days; see exception for an immune-related 
AE below.  If appropriate, and in the opinion of the investigator and upon agreement with the 
sponsor, study treatment may resume upon resolution of clinically significant AEs to baseline or 
improvement to Grade <2.  If AEs, see exception for an immune-related AE, do not resolve to 
baseline or improve to Grade <2 within 28 days following the last administered dose, study 
treatment should be permanently discontinued and the patient should be discontinued from the 
trial. If treatment is held, the day of treatment should continue as if no drug interruption has 
occurred.  For example, if study drug is held on D6 of a cycle and AEs have resolved by D10
(4 days later), the study drugs should be resumed per the original schedule,  If the original 
schedule results in a study drug being held for >28 days, the study drug may not be  resumed.  
One or both study drugs may be held, resumed, or discontinued.
If the AE is an immune related AE as outlined in Attachment 7, and if the treatment management 
guidelines outlined in Attachment 7 are followed and documented in the patient’s medical 
record, treatment may be held for >28 days to allow taper of high dose steroids. Treatment may
resume in this setting only upon resolution of immune AEs to baseline or improvement to Grade
<2, and only if deemed clinically appropriate by the treating physician and agreed to by the 
sponsor.  If steroids cannot be tapered as outlined in Attachment 7, and/or AEs do not resolve to 
< Grade 2, the patient may not be resumed on study treatment.
For the purposes of documentation, the investigator must assess if the toxicity is considered at 
least possibly related to study treatment (that is, the combination regimen) and if the AE is 
considered to be immune related. Investigators are encouraged to consult the sponsor for 
additional guidance.

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For AEs that are considered at least possibly related to study treatment, the following dose 
adjustment guidance may be applied:

Treat each of the toxicities with maximum supportive care (including holding the study 
drug[s] suspected of causing the toxicity where required).

If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of study drugs along with appropriate continuing supportive 
care.

All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
In addition, there are certain circumstances in which study drugs should be permanently 
discontinued (refer to Attachment 7).
Following the first dose of study drugs, subsequent administration of study drugs can be 
modified based on toxicities observed (refer to Attachment 7).
7.2.4.1.1. Specific Adverse Events
Adverse events of special interest (AESIs) observed with durvalumab and/or tremelimumab 
include colitis; pneumonitis; alanine aminotransferase (ALT)/AST increases;
hepatitis/hepatotoxicity; neuropathy/neuromuscular toxicity (that is, events of encephalitis, 
peripheral motor and sensory neuropathies, Guillain-Barré, and myasthenia gravis); 
endocrinopathy (that is, events of hypophysitis, adrenal insufficiency, hyperthyroidism, and 
hypothyroidism; type 1 diabetes mellitus); dermatitis; nephritis; and pancreatitis (or labs 
suggestive of pancreatitis-increased serum lipase or serum amylase); other inflammatory 
responses that are rare with a potential immune-mediated etiology include, but are not limited to, 
myocarditis, pericarditis, myositis/polymyositis, and uveitis.  Refer to Attachment 8 for details 
about and management of AESIs.
Guidelines for the management of immune-mediated, infusion-related, and non-immune-related 
AEs are shown in Attachment 7.
Adverse events (both nonserious and serious) associated with study drugs may represent an 
immune-related etiology, which may be based on the mechanism of action of study drugs leading 
to T cell activation and proliferation.  These irAEs may occur shortly after the first dose or 
several months after the last dose of treatment.  Potential irAEs include immune-mediated 
enterocolitis, dermatitis, hepatitis, and endocrinopathies.  Patients should be monitored for signs 
and symptoms of irAEs.  In the absence of an alternative etiology (for example, infection or 
progressive disease), signs or symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, 
myocarditis, myopathy/polymyopathy and endocrinopathy should be considered immune related.  
Refer to Attachment 7 for supportive care guidelines for immune-mediated reactions, including 
use of corticosteroids.

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Based on observations from clinical trials with LY3022855, patients receiving study treatment
should be closely monitored for signs of hepatic function impairment (for example, increases in 
transaminases, lactate dehydrogenase [LDH], bilirubin, coagulation disorders) and creatine 
kinase increases.
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit patients to an intensive care unit if necessary.  Refer to Attachment 7 for management of 
infusion-related AEs.

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7.3.
Method of Assignment to Treatment
7.3.1. Part A:  Dose Escalation (Phase 1a)
A patient who meets all criteria for enrollment will be assigned (by the sponsor) to receive study
treatment.  Before each patient’s enrollment into the study, an eligibility check must be 
conducted between the investigational site and the Lilly clinical research personnel to confirm 
that each patient meets all enrollment criteria.  Upon confirmation of eligibility, the sponsor will 
confirm the dose and identification number assignment and cohort for each patient.
If investigators have eligible patients who have consented concurrently, more than 3 patients 
may be assigned to a particular dose level provided that accrual has not ceased due to excessive 
toxicity.  This enrollment procedure is allowed because of the advanced disease state of this 
patient population and the screening involved in defining eligibility.  Assigning more than 
3 patients to a particular dose level should be approved by the sponsor following discussions 
with the investigators.
7.3.2. Part B:  Disease-Specific Expansion (Phase 1b)
A patient who meets all criteria for enrollment will be assigned (by the sponsor) to a treatment 
cohort, based on the patient’s diagnosis at baseline.
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
All concomitant medications should be recorded throughout the patient’s participation in the 
study.  The principal 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).  
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications, including herbal preparations, must be captured on the case report form (eCRF).

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7.5.1. Excluded Concomitant Therapy
Other than the study treatment to which the patient is assigned (Section 7.2) and any required 
contraceptive (Section 6.1.1), no other chemotherapy, immunotherapy, cancer-related biologic or
hormone therapy, herbal preparation intended to treat cancer, or experimental drugs will be 
permitted while the patient is on this study. Palliative radiotherapy may be allowed after 
consultation with the sponsor.  Disease progression requiring other forms of antitumor therapy 
will necessitate discontinuation of the study treatment.
The following are also not permitted during the study:

Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and tumor necrosis factor (TNF)-α blockers.
o
Use of immunosuppressive medications for the management of investigational 
product-related AEs or in patients with contrast allergies is permitted.
o
Use of inhaled and intranasal corticosteroids is permitted.
o
A temporary period of steroids will be permitted for different indications, at the 
discretion of the principal investigator (for example, chronic obstructive 
pulmonary disease, radiation, nausea, etc).

Live attenuated vaccines within 30 days of Cycle 1, Day 1 dosing (that is, 30 days prior 
to the first dose of study treatment, during study treatment, and for 30 days 
postdiscontinuation of study treatment).
o
Inactivated vaccines, such as the injectable influenza vaccine, are permitted.
7.5.2. Permitted Concomitant Therapy
Concurrent use of hormones for noncancer-related conditions (insulin for diabetes, hormone 
replacement therapy) is permitted.
Patients should receive concomitant medications or treatments deemed necessary by the 
investigator to provide adequate prophylactic or supportive care, including acetaminophen or 
diphenhydramine, antibiotics, nutritional support, growth factor support (except granulocyte 
colony-stimulating factor [G-CSF] or granulocyte macrophage colony-stimulating factor 
[GM-CSF]), or therapy for correction of metabolic disorders, optimal symptom control, and pain 
management.  If clinically indicated at any time during the study, erythropoietin and transfusions 
(packed red blood cells, whole blood, platelets, or plasma) may be used according to American 
Society of Clinical Oncology (ASCO) guidelines (Rizzo et al. 2010).
Refer to Section 7.2.1.1 for information regarding premedication for IRRs.

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7.6.
Treatment Compliance
Study treatment will be administered I.V. at the investigational site, under the direction of the 
investigator.  As a result, a patient’s compliance with study drug administration is ensured.  
Patients should attend scheduled clinic visits and must comply with study criteria under their 
control. Deviation(s) from the prescribed dosage regimen should be recorded on the eCRF.
7.6.1. Evaluable Patients
Patients in Part A who receive all doses of study treatment for Cycle 1 (DLT-evaluation period) 
will be considered evaluable for the assessment of a dose level, provided it can be documented 
whether the patient did or did not experience a DLT within 28 days of Cycle 1, Day 1.
Conversely, any patient in Part A who is discontinued from the study before completing one
cycle of study treatment will be deemed nonevaluable for assessment of a dose level, unless they 
experience a DLT prior to withdrawal.  Nonevaluable patients may be replaced to ensure that 
enough patients complete one cycle of therapy at each dose level for Part A, unless accrual to 
that cohort has stopped due to a DLT.
Patients who are not evaluable for PK but who complete one cycle of therapy may be replaced 
upon consultation with the investigator(s) and the sponsor’s CRP/CRS to ensure adequate PK 
data, unless accrual to that cohort has stopped due to a DLT.
Note that the concept of “evaluable” (and, thus, replacement of patients) does not apply to 
patients in Part B.

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8.
Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
The safety and tolerability of LY3022855, durvalumab, and tremelimumab have been assessed in 
nonclinical toxicology studies, clinical studies, and the results from these studies are detailed in 
the IBs.  This Phase 1a/1b study contains detailed safety monitoring that will permit initial 
characterization of the safety profile of the combination of LY3022855 plus durvalumab or 
LY3022855 plus tremelimumab.  Study procedures and their timing, including collection of 
blood samples, are described in the Study Schedule (Attachment 1).
Standard laboratory tests, including chemistry, hematology, coagulation, and urinalysis panels, 
will be performed.  A urine or serum pregnancy test (based on institutional standards) will be 
administered if applicable.  Other clinical laboratory tests will also be collected.  Attachment 2
lists the specific tests that will be performed for this study.
8.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue study treatment before completing the study. The patient should be followed until 
the event is resolved, the event is no longer considered drug related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JSCC.4 presents a summary of AE and SAE reporting guidelines.  Table JSCC.4 also 
shows which database or system is used to store AE and SAE data.

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8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation patient 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 medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
vital signs measurements, and so on that occur should also be reported to Lilly or its designee as 
an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect.
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE v4.0.
The NCI-CTCAE v4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms. All AEs observed 
will be graded using CTCAE v4.0.  Any minor version of CTCAE v4.0 (for example, version 
4.03) may be used for this study.  Minor CTCAE v4.0 updates from the NCI will not necessitate 
a protocol amendment. For AEs without matching terminology within the NCI-CTCAE v4.0
criteria, the investigator will be responsible for selecting the appropriate system organ class and 
assessing severity grade based on the intensity of the event.  Note that both CTCAE term (actual 
or coded) and severity grade must be selected by study site personnel and collected on the eCRF.  
This collection is in addition to verbatim text used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition,
all AEs related to protocol procedures are reported to Lilly or designee.
If a patient’s treatment is discontinued as a result of an AE, study site personnel must clearly 
report to Lilly or its designee via eCRF the circumstances and data leading to discontinuation of 
treatment.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and study drug via eCRF.

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The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1.
Serious Adverse Events
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor and the SAEs will be entered in the
Lilly Safety System.

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Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs.  Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study treatment or other protocol-required 
procedure) should not be considered SAEs.
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected (by the site, in the source document) after the patient has signed the ICF.  For patients 
who do not enroll in the trial (that is, have not received at least one dose of study drug[s]), only 
AEs and SAEs related to protocol procedures are required to be collected (captured on the eCRF, 
and, in the case of an SAE, on the SAE form).
8.1.2.2.2. While on Study Treatment
All AEs and SAEs, regardless of relatedness to study drug(s), or protocol procedures, occurring 
while the patient is receiving study drug must be collected (captured on the eCRF; in the case of 
an SAE, also on the SAE form) and reported to Lilly or its designee.  A patient is considered to 
be receiving study drug (that is, “on study treatment”) from the date of the first dose of study 
drug until the date the patient and investigator agree that the patient will no longer continue to 
receive study treatment.
8.1.2.2.3. During the 30-Day and 90-Day Follow-Up Visits
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
during the 30-Day and 90-Day Follow-Up visits (Visits 801 and 802) must be collected (captured 
on the eCRF; in the case of an SAE, also on the SAE form) and reported to Lilly or its designee.  
The 30-Day Follow-Up visit (Visit 801) begins the day after the patient and investigator agree 
that the patient will no longer continue to receive study treatment.  The duration of this follow-up 
visit is 30 days (±7 days).  At the end of the 30-Day Follow-Up visit, the patient will be required 
to have specific safety assessments (Attachment 1).  If it is deemed to be in the best interest of 
the patient to start a new anticancer treatment prior to the scheduled end of the follow-up visit, 
the duration of the visit may be shortened. In this case, the follow-up assessments should be 
completed prior to the initiation of the new therapy.

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The 90-Day Follow-Up visit (Visit 802, only for durvalumab and tremelimumab safety) occurs
90 days (±7 days) after the patient and investigator agree that the patient will no longer continue 
to receive study treatment.  Refer to Attachment 1 for specific safety assessments to be 
conducted during the 90-Day Follow-Up visit.
Following the safety assessments that mark the end of the follow-up visits (30-Day Follow-Up 
visit [Visit 801], for LY3022855, durvalumab, and tremelimumab safety, and 90-Day Follow-Up 
visit [Visit 802], only for durvalumab and tremelimumab safety), the patient will be discontinued 
from the study, unless there is an ongoing AE or SAE that is possibly related to study drug.  In 
this instance, the patient should continue to be followed by extending the duration of the follow-
up visit until the event is resolved, the event is no longer considered to be drug related, the event 
becomes stable or returns to baseline, a new treatment is initiated for the patient, or the patient 
dies or is lost to follow-up.
After the follow-up visits (30-Day Follow-Up visit [Visit 801], for LY3022855, durvalumab, and 
tremelimumab safety, and 90-Day Follow-Up visit [Visit 802], only for durvalumab and 
tremelimumab safety), AEs are not required to be reported unless the investigator feels the AEs 
were related to either study drug or a protocol procedure. If an investigator becomes aware of an 
SAE believed to be related to protocol procedures or study drug (at this point, the patient is no 
longer on the study), the investigator should report the SAE to the sponsor, and the SAE will be 
entered in the Lilly Safety System.
Refer to Table JSCC.4 for AE and SAE reporting guidelines during continued access and Section 
6.2.2 for additional details on continued access, including the Continued Access Treatment 
Period (Visits 501-5XX) and Continued Access Follow-Up (Visits 901 and 902).
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the
DCSI or in the IB and that the investigator identifies as related to study drug or procedure.  The 
United States 21 CFR 312.32, the European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulatory regulations and the 
associated detailed guidances.
8.1.2.4.
Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JSCC.4; recommendations for 
reporting SAEs are presented in Attachment 4.

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Table JSCC.4.
AE and SAE Reporting Guidelines for Study JSCC
Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Prestudy (during screening, prior to 
administration of study drug[s])
Starts at the signing of informed consent 
and ends just before the first dose of study 
drug.
Preexisting conditions
AEs related to protocol procedures
SAEs related to protocol procedures
X
X
X
X
On study treatment
Starts the day of the first dose of study 
drug and ends the day the patient and 
investigator agree that the patient will no 
longer continue to receive study treatment.
All AEs
All SAEs, regardless of relatedness
X
X
X
30-Day Follow-Up (Visit 801)
Starts the day after the patient and 
investigator agree that the patient will no 
longer continue to receive study treatment 
and ends when end-of-study safety 
assessments are completed.  This visit will 
be extended as needed to follow any 
ongoing AEs at least possibly related to 
study drug(s) or protocol procedures.
All AEs
All SAEs, regardless of relatedness
X
X
X
90-Day Follow-Up (Visit 802) (only for 
durvalumab and tremelimumab safety)
Occurs 90 days (±7 days) after the patient 
and investigator agree that the patient will 
no longer continue to receive study 
treatment.  This visit will be extended as 
needed to follow any ongoing AEs at least 
possibly related to study drug(s) or 
protocol procedures.
All AEs
All SAEs, regardless of relatedness
X
X
X

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Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Continued Access Treatment Period (Visits 
501-5XX)
Starts at the first study visit after study 
completion has occurred and ends when 
the patient and investigator agree that the 
patient will no longer continue to receive 
study treatment; applies only to patients
who have not met discontinuation criteria.
All AEs
All SAEs, regardless of relatedness
X
X
X
Continued Access Follow-Up (Visits 901
and 902)
Visit 901:  Starts the day after the patient 
and investigator agree that the patient will 
no longer continue to receive study 
treatment and ends when end-of-study 
safety assessments are completed.
Visit 902 (only for durvalumab and 
tremelimumab safety):  Occurs 90 days (±7 
days) after the patient and investigator 
agree that the patient will no longer 
continue to receive study treatment.
All AEs 
All SAEs, regardless of relatedness
X
X
X
Patient no longer on study
All SAEs related to protocol 
procedures or study drug that the 
investigator becomes aware of
X
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
8.1.2.5.
Pregnancy, including Maternal and Paternal Exposure
Although generally not an AE, cases of pregnancy that occur during maternal or paternal
exposures to study drugs and through 180 days after the decision is made to discontinue study 
treatment should be reported as SAEs, within 24 hours. Additionally, congenital
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as
SAEs. Elective terminations without complications should not be handled as AEs.
Patients who become pregnant during the study period must immediately discontinue study
treatment but will not be discontinued (withdrawn) from the study.
Data on fetal outcome, including spontaneous miscarriage, elective termination, ectopic
pregnancy, normal birth, or congenital abnormality occurring from the date of the first dose of 
study drug through 180 days after the decision is made to discontinue study treatment should be 
followed up and documented even if the patient was discontinued (withdrawn) from the study.
Pregnancy itself, or pregnancy of a patient’s partner, is regarded as an AE only if an investigator
considers that study treatment may have interfered with the effectiveness of a contraceptive
medication.

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The sponsor will endeavor to collect follow-up information on such pregnancies, provided the
partner of the study patient provides consent.
Male patients must refrain from sperm donation from screening through 180 days after the 
decision is made to discontinue study treatment.
8.1.3. Overdose
An overdose is defined as an occurrence in which a patient receives a higher dose of study drug 
than the dose that patient was assigned, as specified in this protocol.
Any overdose of LY3022855, durvalumab, or tremelimumab, with or without associated 
AEs/SAEs, is required to be reported immediately to the sponsor. If the overdose results in an 
AE, the AE must also be recorded as an AE. Overdose does not automatically make an AE
serious, but if the consequences of the overdose are serious (for example, death or 
hospitalization), the event is serious and must be recorded and reported as an SAE.
There is currently no specific treatment in the event of an overdose of LY3022855, durvalumab, 
and/or tremelimumab.
The investigator will use clinical judgment to treat any overdose.
8.1.4. Other Safety Measures
8.1.4.1.
Electrocardiogram
For each patient, a local 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.
At Screening, a triplicate ECG will be obtained, on which QTcF must be <470 milliseconds
(calculated from one ECG using Fridericia’s Correction Formula and confirmed with 2 
additional ECGs).  Thereafter, single ECGs will be obtained.  In case of clinically significant 
ECG abnormalities, including a QTcF value >470 milliseconds, 2 additional 12-lead ECGs 
should be obtained over a brief period (for example, 30 minutes) to confirm the finding.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs (more replicates) than expected at a particular time point is allowed to 
ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management, should any clinically relevant findings be identified.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study.  The investigator 

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or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation.
8.1.4.2.
Multigated Acquisition Scan or Echocardiogram
At Screening, a multigated acquisition (MUGA) scan or an echocardiogram will be performed 
for each patient as an eligibility assessment of LVEF (Section 6.1.2).  An LVEF evaluation will 
also be made at additional time points during the study, as clinically indicated.  Refer to the 
Study Schedule (Attachment 1) for details about the timing of this assessment.
8.1.5. Safety Monitoring
The Lilly CRP/CRS will monitor safety data throughout the course of the study. 
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.

If a study patient experiences elevated ALT ≥5 × ULN and elevated TB ≥2 × ULN, 
clinical and laboratory monitoring should be initiated by the investigator.

For patients entering the study with ALT ≥3 × ULN, monitoring should be triggered at 
ALT ≥2 × baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended
clinical information and follow-up laboratory tests (see Attachment 3).
Refer to Attachment 8 for details about AESIs.
Refer to Attachment 7 for additional details on Toxicology management guidelines.
8.1.6. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee.
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.

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8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study, including those for PK, 
pharmacodynamics, and immunogenicity.
Attachment 2 lists the clinical laboratory tests that will be performed for this study.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood, tissue, and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria.
Standard laboratory tests, including hematology and urinalysis panels, will be performed and
analyzed by a local laboratory. Chemistry panels will be performed and analyzed centrally.  
Enrollment decisions may be based upon chemistry results performed at a local laboratory; 
however, a sample must be sent to the central laboratory. These central chemistry laboratory 
results will be used for subsequent safety analyses. In the event of minor discrepancies between 
local and central laboratory results, the investigator may use the local results for treatment 
decisions, and the central laboratory results will remain part of the safety database. 
Discrepancies between local and central results that may have an impact on treatment decisions 
will not be considered protocol violations.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Samples for Drug Concentration Measurements
(Pharmacokinetics)
At the visits and times specified in the Study Schedule (Attachment 1), venous blood samples 
will be collected to determine the serum concentrations of LY3022855, durvalumab, and
tremelimumab (depending on treatment received).  A maximum of 5 samples may be drawn at 
additional time points during the study if warranted and agreed upon between both the 
investigator and the sponsor. Instructions for the collection and handling of blood samples will 
be provided by the sponsor.  The actual date and time (24-hour clock time) of each sampling will 
be recorded.
These samples will be analyzed at a laboratory designated by the sponsor.  Serum concentrations 
of LY3022855 will be assayed using a validated enzyme-linked immunosorbent assay (ELISA) 
method.
The PK samples will be stored at a facility designated by the sponsor.

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The remaining plasma from the samples collected for PK may be pooled and used for 
exploratory metabolism work as deemed appropriate.
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding, will be retained for a maximum of 2 years following last 
patient visit for the study.
8.2.3. Samples for Pharmacogenetics
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to study drug(s). These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response. The 
pharmacogenetic biomarker samples will be used only for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored at a facility selected by the 
sponsor for up to a maximum of 15 years after the last patient visit for the study.  The samples 
and any data generated from them can be linked back to the patient only by investigator site 
personnel.  The duration allows the sponsor to respond to regulatory requests related to the study 
drugs.
Samples will be destroyed according to a process consistent with local regulation.
8.2.4. Samples for Pharmacodynamic and Tailoring Biomarkers
Collection of samples for other biomarker research is also part of this study.  Blood and tissue
samples will be collected.
Required samples for biomarker research to be collected from all patients in this study are the 
following:

blood samples (plasma, whole blood, and serum) (refer to Sections 8.2.3 and 8.2.4.1).

pretreatment and on-treatment (6-8 weeks after starting study treatment) tumor tissue 
(newly biopsied) (all cohorts of Part A and the ovarian cancer cohort only of Part B)
(refer to Section 8.2.4.2).  If clinically feasible, the biopsies should be taken from the 
same lesion.

an archived tumor sample (following the most recent systemic treatment), if not restricted 
by local regulations (Part B NSCLC cohort only).

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Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following:

on-treatment tumor tissue (Part B NSCLC cohort only).
Samples may be stored at a facility selected by the sponsor for up to a maximum of 15 years 
after the last patient visit for the study.
Sample collection including blood (whole blood, serum, and plasma) and tumor tissue will occur
at specified time points as indicated in Attachment 1.  These samples are also described in the 
following sections.
It is possible that biomarker data for patients in the study have already been generated from 
samples that were collected and analyzed prior to enrolling in this trial. This may include data 
generated from genetic analyses. If available, these data may be requested from medical records 
for use in the research described in the following sections.
8.2.4.1.
Blood Samples
Pharmacodynamic assessments are planned to be tested from baseline over time for changes in
biomarkers that may include, but not be limited to, circulating levels of CSF-1, sPD-L1, IL-34, 
and monocyte markers.
In addition, blood samples (EDTA plasma, whole blood, and serum) will be collected and may 
be used for research on the drug targets, disease process, immune functioning, pathways 
associated with cancer, mechanisms of action of LY3022855, durvalumab, and tremelimumab, 
and/or research methods or in validating diagnostic tools or assay(s) related to cancer.  The 
analyses of these samples may include, but are not limited to, testing at baseline and changes
over time in immune cell subsets, cytokines, metabolites, and molecular markers to document the 
immunomodulatory activity of treatment in patients with LY3022855 in combination with 
durvalumab or tremelimumab. These biomarkers may be compared with observed clinical
outcomes to study drug(s). Blood will be collected at times specified in Attachment 1.
Samples may be stored at a facility selected by the sponsor for up to a maximum of 15 years 
after the last patient visit for the study.
8.2.4.2.
Tumor Tissue Samples
Tissue collection will be required for biomarker research and enrollment into the study for 
patients in Part A (all cohorts) and Part B. For patients enrolled in Part A (all cohorts) and 
Part B (ovarian cancer cohort only) of the study, tissue will be required for PD-L1 biomarker and 
other exploratory analysis from a newly obtained core or excisional biopsy of a tumor lesion 
(should be taken only after study eligibility is confirmed) or from a recent biopsy defined by 
3 years since last documented progression of disease. For the NSCLC cohort, archived tissue 
should be submitted form a recent biopsy defined by 3 years old and this biopsy follows the 
most recent systemic therapy. If such an archived biopsy sample is not available, a new biopsy 
must be obtained for the patient to be eligible to participate in study. For all cohorts, new 
archived tissue will be obtained only if not restricted by local regulations.

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In addition, an on-treatment biopsy is required if any accessible lesions remain for Part A (all 
cohorts) and Part B (ovarian cancer cohort only).  If clinically feasible, the biopsies should be 
taken from the same lesion.  For patients enrolled to NSCLC cohort of Part B, the on-treatment
biopsy is optional.
Sites must confirm the availability of adequate tumor tissue for the new biopsy from the site’s
pathology laboratory or adequate archived tumor tissue. Pretreatment formalin-fixed paraffin-
embedded (FFPE) tumor tissue should be submitted in a whole block.
In addition to the biopsies and biomarker samples discussed in Sections 8.2.4.1 and 8.2.4.2,
patients may be asked to undergo collection of an additional biopsy specimen and blood sample 
after treatment with study drug(s) has been initiated, including potentially after disease 
progression.  Such additional biopsies are optional and should be performed only if clinically 
feasible. If these additional samples are requested, they will be used to further investigate 
biomarkers that may explain treatment response and resistance mechanisms.
Details for the handling and shipping of the tumor tissue will be provided by the sponsor in a 
separate document. The tissue samples will be obtained using appropriate method. Tumor tissue 
should be submitted as a newly acquired excisional or core needle (minimum 18 gauge) biopsy 
in formalin. A minimum of 3-4 core biopsies, using an 18-gauge core needle, is recommended
during each biopsy procedure. Cytological or fine-needle aspiration specimens and decalcified 
bone are not acceptable. Due diligence should be used to ensure that tumor specimen (not 
normal adjacent or tumor margins) is provided. Pathology reports accompanying the tissue may 
also be requested.
Tissue samples will be examined for biomarkers that may include, but are not limited to the drug 
targets, disease process, immune cells/immune functioning within the disease state, and cancer-
related conditions, pathways associated with cancer and study drugs, mechanisms of action of 
LY3022855, durvalumab or tremelimumab, and/or research methods or in validating diagnostic 
tools or assays.
Tumor samples may also be analyzed to explore potential gene signature(s) associated with 
response or resistance to LY3022855 in combination therapy. In addition, sequencing of 
deoxyribonucleic acid (DNA) and/or immunohistochemistry may be performed on these tissue 
samples to evaluate expansion in clonal T cell populations and changes in immune cell 
infiltration, activation, modulation, and microenvironment, and changes in stromal and tumor 
biology in response to study treatment.  The results of this analysis may be correlated with
clinical outcome data.
The samples will be coded with the patient number and stored at a facility selected by the 
sponsor for up to a maximum of 15 years after the last patient visit for the study.  The samples 
and any data generated from them can be linked back to the patient only by investigator site 
personnel.  The duration allows the sponsor to respond to regulatory requests related to the study 
drug.
Samples will be destroyed according to a process consistent with local regulation.

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8.2.5. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine antibody production 
against study drug(s).  Immunogenicity will be assessed by a validated assay designed to detect 
antidrug antibodies (ADAs) in the presence of study drug(s).  Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of study drug(s).
Samples may be stored at a facility selected by the sponsor for up to a maximum of 15 years 
following last patient visit for the study, to enable further analysis of immune responses to study 
drug(s).  The duration allows the sponsor to respond to regulatory requests related to study 
drug(s).
8.3.
Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1
for details regarding the timing of specific efficacy measures.
Each patient will be assessed by one or more of the following radiographic tests for tumor 
measurement:

Computed tomography (CT) scan

Magnetic resonance imaging (MRI).
Each patient’s full extent of disease will also be assessed with:

Tumor measurement by RECIST 1.1 (Eisenhauer et al. 2009)

Evaluation of tumor markers, if indicated

Evaluation of performance status (refer to the ECOG scale, Attachment 5).
In rare circumstances, historical radiographic examinations for RECIST criteria that are 
performed more than 28 days prior to the first dose may be used, but this decision must be 
discussed with the sponsor and documented in writing.
To confirm objective responses, all lesions should be radiographically assessed, and the same 
radiographic method used for the initial response determination should be repeated at least 8
weeks following the initial observation of an objective response, using the sample method that 
was used at baseline.  If a patient is discontinued from the study, repeat radiographic assessments 
may be omitted if clear clinical signs of progressive disease (symptomatic deterioration) are 
present.  At the conclusion of the study, radiographic images may be requested for central 
review.

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8.4.
Procedure/Sampling Compliance
Every attempt will be made to enroll patients who have the ability to understand and comply 
with instructions.  Noncompliant patients may be discontinued from the study.
The collection times of safety assessments, PK and pharmacodynamic samples, and efficacy 
measurements are given as targets, to be achieved within reasonable limits.  The scheduled time 
points may be subject to minor alterations; however, the actual collection time must be correctly 
recorded on the eCRF.
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.

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9.
Data Management Methods
9.1.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

Provide instructional material to the study sites, as appropriate.

Sponsor start-up training to instruct the investigators and study coordinators.  This 
session will give instruction on the protocol, the completion of the eCRFs, and study 
procedures.

Make periodic visits to the study site.

Be available for consultation and stay in contact with the study site personnel by 
mail/email, telephone, and/or fax.

Review and evaluate eCRF data and/or use standard computer edits to detect errors in 
data collection.

Conduct a quality review of the database.
In addition, the sponsor or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by the sponsor or 
its representatives and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable IRB/ERBs 
with direct access to the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic case report form (eCRF) data will be encoded and stored in a clinical trial database.  
For data handled by a data management third-party organization (TPO), eCRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to the Lilly data 
warehouse, using standard Lilly file transfer processes.
For data handled by the sponsor internally, eCRF data and some or all data that are related will 
be managed by the sponsor and stored electronically in the sponsor’s system.

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9.2.2. Ancillary Data
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system. Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the central vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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10. Data Analyses
10.1. General Considerations
Up to approximately 118 patients (78 [Part A] + 40 [Part B]) may be enrolled in this multicenter, 
nonrandomized, open-label Phase 1a/1b study of LY3022855.
The sample size for Part A will be determined primarily by the incidence of DLTs prior to 
establishing the MTDs in Part A. The anticipated sample size for Part A ranges from 
approximately 12 to 36 patients in the combination of LY3022855 plus durvalumab, and 
approximately 12 to 42 patients in the combination of LY3022855 plus tremelimumab. 
Nonevaluable patients, as defined in Section 7.6.1, will be replaced to ensure enough patients are 
enrolled in Part A.
In each cohort of Part B, approximately 20 patients will be enrolled. The sample size of Part B 
has been selected to allow adequate assessment of safety and tolerability of LY3022855 in 
combination with durvalumab at the recommended dose level and can provide adequate 
precision for the estimated incidence rate of the following quantities of interest: (1) patients 
having a specified AE, or (2) patients showing a response (PR/CR) to treatment. Example point 
estimates of incidence rates and corresponding 2-sided 95% confidence intervals (CIs) are 
summarized in Table JSCC.5.  The values are provided as a reference for estimation, rather than 
a basis of any decision criteria. The RP2D may be revised based on the safety data obtained in 
Part B (Iasonos and O’Quigley 2013).
Table JSCC.5.
Estimated Incidence Rate and 2-Sided 95% CI
Number of Cases
(N=20)
Estimated Incidence
Rate
95% CIa
Lower Limit
Upper Limit
0
0.0
0.0
0.17
5
0.25
0.09
0.49
10
0.50
0.27
0.73
15
0.75
0.51
0.91
Abbreviations:  CI = confidence interval; N=number of patients.
a
95% Clopper-Pearson interval for binomial distribution with sample size of 20.

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Safety and efficacy analyses will be conducted on all patients who have received at least one 
dose of the study treatment(s), regardless of whether they are deemed evaluable for the 
assessment of a dose level.  Statistical analysis of this study will be the responsibility of Eli Lilly 
and Company.
The interpretation of the study results will be the responsibility of the investigator with the 
sponsor’s CRP/CRS, PK scientist and statistician.  The sponsor’s CRP/CRS and statistician will 
also be responsible for the appropriate conduct of an internal review for both the final study 
report and any study-related material to be authorized by Lilly for publication. The analyses for 
this study will be descriptive; no p values will be calculated. Data analyses will be provided by 
cohort and treatment, whenever appropriate. For continuous variables, summary statistics will 
include number of patients, mean, median, standard deviation, minimum, and maximum. 
Categorical endpoints will be summarized using number of patients and percentages. Missing 
data will not be imputed.
Exploratory analyses of the data not described in Sections 10.2 through 10.9 will be conducted as 
deemed appropriate.
A detailed description of data analyses will be provided in a separate statistical analysis plan 
document for this study.
10.2. Patient Disposition
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
10.3. Patient Characteristics
Patient characteristics will include a summary and listing of the following:

patient demographics

baseline disease characteristics

prior disease-related therapies

concomitant medications.
Other patient characteristics will be summarized as deemed appropriate.

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10.4. Safety Analyses
All patients who receive at least one dose of study drug(s) will be evaluated for safety and 
toxicity.  Adverse event terms and severity grades will be assigned by the investigator using 
CTCAE, v4.0.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

dose adjustments

laboratory values

vital signs

DLTs at each dose level

ECG readings

LVEF evaluation.
10.4.1. Immunogenicity Analyses
Immunogenicity data will be summarized, and correlation to drug level (each drug), activity, and 
safety will be assessed, as appropriate, respectively.  The measures that will be analyzed include 
baseline presence and level of ADA, treatment-emergent ADA, levels of neutralizing ADA, and 
incidence and levels of ADA related to IRRs.
10.5. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least one dose of 
the study drug and have had samples collected.  Pharmacokinetic parameter estimates for 
LY3022855, durvalumab, and tremelimumab will be calculated by standard noncompartmental 
methods of analysis. The primary parameters for analysis will be maximum concentration (Cmax) 
and area under the plasma concentration-time curve (AUC; AUC from time zero to last 
measurable plasma concentration [AUC0-tlast] and AUC from time zero to infinity [AUC0-∞]) of 
each of the study drugs.  Other noncompartmental parameters, such as time of half-life (t1/2), 
apparent clearance (CL/F), and apparent volume of distribution (V/F) for each study drug may be 
reported.  Additional exploratory analyses will be performed if warranted by data and other 
validated PK software programs (for example, NONMEM) may be used if appropriate and 
approved by Global Pharmacokinetic management.  The version of any software used for the 
analysis will be documented and the program will meet the Lilly requirements of software 
validation.
Pharmacokinetic parameter estimates will be evaluated to delineate the effects of dose 
proportionality, target-mediated drug disposition, and drug accumulation. Log-transformed Cmax
and AUC estimates will be assessed to estimate ratios of geometric means and the corresponding 
90% CIs. The potential effect of durvalumab-mediated PD-L1 inhibition and/or tremelimumab-
mediated CTLA-4 inhibition on the exposure of LY3022855, and the effect of LY3022855-
mediated CSF-1R inhibition on the exposure of tremelimumab and/or durvalumab will be 
assessed using historical monotherapy exposure data for each of the 3 study drugs.

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10.6. Pharmacodynamic Analyses
Characterized profiles of available longitudinal biomarkers for estimable patients will be created 
and analyzed. Pattern recognition analysis may be applied for the pharmacodynamic biomarkers 
that indicate the evidence of drug engagement. Those include, but are not limited to, circulating 
levels of CSF-1, IL-34, and monocyte markers.
10.7. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/pharmacodynamic analyses for LY3022855 may be conducted as deemed 
necessary by Global PK/PD management. These analyses may include, but are not limited to, 
establishing relationships (or lack of) between exposure and pharmacodynamic biomarkers that 
were explored or confirmed in pharmacodynamic analyses (refer to Section 10.6).
10.8. Efficacy
Tumor response data, according to RECIST 1.1 (Eisenhauer et al. 2009), will be tabulated by 
cohorts. Particularly, the antitumor effect will be summarized by best overall response,
including the overall response rate (ORR) and disease control rate (DCR; CR+PR+SD). A 
patient is considered to have a tumor response if they achieve a confirmed CR or PR. The ORR 
is estimated by the proportion of enrolled patients who have a best overall response of confirmed 
CR or PR. The DCR is estimated by the proportion of enrolled patients who have a best overall 
response of confirmed CR, confirmed PR, or stable disease. A 95% exact CI will be constructed 
to determine the level of precision of the ORR and DCR.  Time-to-event variables such as 
progression-free survival (PFS), time to response, duration of response, and overall survival (OS) 
will be tabulated if appropriate.  The Kaplan-Meier method (Kaplan and Meier 1958) will be 
used to estimate the survival curves, medians, and survival rates at specified time points, if 
applicable.
Upon completion of each Part B cohort, an analysis of safety, PK, pharmacodynamics, 
biomarkers, and efficacy may occur, once all patients have completed 4 cycles of study therapy 
or discontinued from the study.
Any cohort-specific analyses may be combined if they are expected to occur within 
approximately a month, and the analyses may also be combined with the ongoing trial-level 
safety review or annual safety review for annual safety update reporting.
10.9. Tailoring Biomarker Analyses
If applicable, efficacy measures may be summarized descriptively within subgroups of patients. 
Exploratory analyses may be applied to correlate the baseline biomarkers with clinical outcome. 
If applicable, a subset of potential predictive biomarkers associating with interpretable clinical 
benefit may be further examined with biological evidence.

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10.10.
Interim Analyses
Because this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
study, until the MTDs are determined for each combination.  The purpose of these cohort-by-
cohort reviews is to evaluate the safety data at each dose level and determine if a DLT has been 
observed that would suggest MTD has been met or exceeded.  The investigators and the Lilly
study team will make the determination regarding dose escalation based upon their review of the 
safety and tolerability data as described in this protocol.
Safety and/or PK data will be reviewed during the study if needed for dose escalation,
modifications to the dose-escalation strategy, or other design elements.
In Part A, after all patients who are deemed evaluable for the assessment of dose levels complete 
the DLT-evaluation period or the MTD is determined, an interim safety and PK analysis may be 
conducted for each combination for planning next studies.
If it is deemed that enough data are obtained to assess the primary and secondary objectives, a 
clinical study report may be written before the last patient visit for the study.  In this case, all 
data until the data cutoff date will be used for the analysis of safety, efficacy, PK, and 
pharmacodynamic biomarkers.  After the data cutoff date, all data defined in the protocol will 
continue to be collected from patients on treatment, to be listed and summarized in an updated 
clinical study report.  However, summary tables containing the data collected after the data
cutoff date will not be created; these data may be reported separately and the analyses on all 
patients, including these data, may not necessarily be performed.

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11. Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient or legal representative before the study is started.  This includes obtaining the appropriate 
signatures and dates on the ICF prior to the performance of any protocol procedures and prior to 
the administration of study drug.
In this protocol, the term “informed consent” includes all consent and assent given by patients or 
their legal representatives.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the ICH guideline on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling and updates during the course of the study

ICF

relevant curricula vitae.

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11.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 
2) the ICH GCP Guideline [E6]
3) applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other study-related data.
11.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
11.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
11.3.3. Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most analyzable patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.

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12. References
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, 
Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, 
Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, 
Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced 
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Calabrò L, Morra A, Fonsatti E, Cutaia O, Fazio C, Annesi D, Lenoci M, Amato G, Danielli R, 
Altomonte M, Giannarelli D, Di Giacomo AM, Maio M. Efficacy and safety of an intensified 
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RD, Ukarma L, Bompas E, Delord JP, Blay JY, Rüttinger D. CSF1R inhibition with 
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[CTEP] Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse 
Events, Version 4.0, DCTD, NCI, NIH, DHHS. 2009. Publish date: 29 May 2009.
DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, 
Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirström K, West BL, Coussens LM. 
Leukocyte complexity predicts breast cancer survival and functionally regulates response to 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanan JB, Gonzalez R, Robert C, 
Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel 
JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, 
Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with 
ipilimumab in patients with metastatic melanoma [published erratum appears in N Engl J Med.
2010;363(13):1290]. N Engl J Med. 2010;363(8):711-723.
Iasonos A, O’Quigley J. Design considerations for dose-expansion cohorts in phase I trials. J 
Clin Oncol. 2013;31(31):4014-4021.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat 
Assoc. 1958;53(282):457-481.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 
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Lutzky J, Antonia SJ, Blake-Haskins, A, Li X, Robbins RB, Shalabi AM, Vasselli J, 
Ibrahim RA, Khleif S, Segal NH. A phase 1 study of MEDI4736, an anti-PD-L1 antibody, in 
patients with advanced solid tumors. J Clin Oncol. 2014;32:5s. Abstract 3001.
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an
investigational anti-interferon-α monoclonal antibody, in systemic lupus erythematosus. Clin 
Pharmacokinet. 2013;52(11):1017-1027.
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in 
cancer patients based on population pharmacokinetic analysis. Pharm Res. 2006;23(6):1275-
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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655.
Radi ZA, Koza-Taylor PH, Bell RR, Obert LA, Runnels HA, Beebe JS, Lawton MP, Sadis S. 
Increased serum enzyme levels associated with kupffer cell reduction with no signs of hepatic 
or skeletal muscle injury. Am J Pathol. 2011;179(1):240-247.
Rizvi N, Brahmer J, Ou S-HI, Segal NH, Khleif SN, Hwu W-J, Gutierrez M, Schoffski P, 
Hamid O, Weiss J, Lutzky J, Maio M, Nemunaitis JJ, Jaeger D, Balmanoukian AS, 
Rebelatto M, Steele K, Li X, Blake-Haskins JA, Antonia SJ. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-
small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl). Abstract 8032.
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J,
Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR; American Society of
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epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996-5010.
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Li X, Vasselli J, Khleif S. Immunotherapy of Cancers Session, European Society for Medical
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Schoffski P, Antonia SJ, Massard C, Zandberg DP, Khleif S, Li X, Rebelatto M, Steele K, 
Robbins PB, Blake-Haskins JA, Butler MO. Safety and efficacy of MEDI4736, an anti-PD-L1 
antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) 
expansion cohort. J Clin Oncol. 2015;33(suppl). Abstract 3011.
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic 
T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with 
advanced cancers. Expert Opin Biol Ther. 2008;8(10):1583-1593.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, 
Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, 
Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, 
Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. 
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 
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Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing 
of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-1024.
Wang E, Kang D, Bae KS, Marshall MA, Pavlov D, Parivar K. Population pharmacokinetic and 
pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma. J Clin 
Pharmacol. 2014;54:1108-1116.
Weber J, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics 
of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of
therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012;52(1):18-28.
Zhou L, Sikorski R, Rogers S, Costin S, Korkosz M, Jaraczewska-Baumann M, Eva P, 
Rojkovich B, Bartalos J, Masteller E, Xiang H, Wong B, Hambleton J.: A Phase 1 Study of 
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San Francisco, CA. Abstract Number 2749.

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Attachment 1.Protocol JSCC Study Schedule
Assessments are to be performed at the times stipulated in the schedule and as clinically required 
in the management of the patient.
Screening/Baseline Assessments (Visit 0)
Relative Day Prior to 
Day 1 of Cycle 1
28
14
7
Comments
Written informed 
consent/assignment of 
patient identification 
number
X
ICF signed (prior to performance of any protocol-specific
tests/procedures).
Review of eligibility 
criteria
X
Medical history
X
Physical examination
X
Full physical examination, including assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, GI, 
urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems.
Vital signs
X
BP, temperature, RR, and PR.  Includes height (at baseline only) 
and weight.
ECOG performance 
status
X
ECG (local)
X
Triplicate ECG will be obtained, on which QTcF must be <470 ms 
(calculated from one ECG using Fridericia’s Correction Formula 
and confirmed with 2 additional ECGs).
HIV screening (local)
X
Per institutional standards.
If done within 28 days prior to Cycle 1, Day 1, as part of standard 
of care, does not need to be repeated prior to the start of Cycle 1.
Hematology (local)
X
Refer to Attachment 2.
Serum chemistry 
(central)
X
Refer to Attachment 2.
Urinalysis (local)
X
Refer to Attachment 2.
Coagulation (local)
X
Refer to Attachment 2.  Obtain prior to tumor biopsy.
Thyroid function 
(central)
X
Refer to Attachment 2.
Free T3 and free T4 will be measured only if TSH is abnormal or if 
there is clinical suspicion of an AE related to the endocrine system.
Pancreas function 
(central)
X
Refer to Attachment 2.
LVEF evaluation
X
Echocardiogram or MUGA scan.
Radiographic tumor 
assessment (CT/MRI)
X
If done within 28 d prior to Cycle 1, Day 1, as part of standard of 
care, does not need to be repeated prior to the start of Cycle 1.
Tumor measurement 
(palpable or visible)
X
CTCAE v4.0 grading 
(preexisting conditions)
X
To be reported only after study eligibility is confirmed.  Refer to 
Section 8.1.2.4 for reporting guidelines.
Concomitant 
medications
X

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Relative Day Prior to 
Day 1 of Cycle 1
28
14
7
Comments
Tumor markers (local)
X
As clinically indicated.  For example, CEA in patients with 
colorectal cancer or CA125 in patients with ovarian cancer.
Tumor tissue biopsy
X
For Part A (all cohorts) and Part B (ovarian cancer cohort only):  A 
newly obtained core or excisional biopsy of a tumor should be 
taken only after study eligibility is confirmed.  For the NSCLC 
cohort in Part B a newly obtained core or excisional biopsy should 
be obtained if an archived tumor sample following the most recent 
systemic therapy is not available.  Refer to the laboratory manual.
Archived tumor tissue
X
An archived tumor sample following most recent systemic 
treatment if not restricted by local regulations will be requested 
from all patients in Part B NSCLC cohort. If such an archived 
biopsy sample is not available, a new biopsy must be obtained for 
the patient to be eligible to participate in study.  Refer to the 
laboratory manual.
Whole blood for 
biomarkers
X
Refer to the laboratory manual.
Pregnancy test (local)
X
Applies only to women of childbearing potential.  Urine hCG or 
serum β-hCG is acceptable.
Abbreviations:  AE = adverse event; BP = blood pressure; CA125 = cancer antigen 125; CEA = carcinoembryonic 
antigen; CT = computed tomography (scan); CTCAE = Common Terminology Criteria for Adverse Events; ECG 
= electrocardiogram; ECOG = Eastern Cooperative Oncology Group; GI = gastrointestinal; hCG = human 
chorionic gonadotropin; HIV = human immunodeficiency virus; ICF = informed consent form; LVEF = left 
ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition (scan); PR = 
pulse rate; QTcF = QT interval corrected for heart rate using Fridericia’s Correction Formula; RR = respiration 
rate; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; v4.0 = Version 4.0 of CTCAE.

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On-Study Treatment and Post-Treatment (Follow-Up) Assessments for Combination Therapy: LY3022855 plus Durvalumab
Note that a maximum of 12 months/26 doses of durvalumab treatment is permitted; last infusion at Week 50.
Screening procedures performed for safety within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
Rows with italicized font indicate that there is no planned assessment for the time frame shown on the page.
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Physical examination
X
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around 
infusions as follows (allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during 
(midway through), at the end, and 30 min after the end.
Around each durvalumab infusion (based on a 60-min 
infusion):  within 30 min prior to, during (approx. 30 min 
after start of infusion), and at the end (approx. 60 min 
after start of infusion).
1-h Observation period after durvalumab infusion:  at 30 
and 60 min after the end of the infusion (90 and 120 min 
after start of infusion) for the first durvalumab infusion 
only, and for subsequent infusions as clinically indicated.
If the durvalumab infusion exceeds 60 min, monitoring of 
BP and PR should occur per the preceding principles or 
more frequently if clinically indicated.
ECOG performance status
X
Pregnancy test (local)
Every 12 wk (±7 d) after the first dose of study drug or 
according to local regulations or as clinically indicated, 
whichever is more frequent.  Urine hCG or serum β-hCG.
ECG (local)
X
Single ECG.  Obtain ECGs before any associated blood 
draws.  On dosing days, ECG should be taken within 2 h 
prior to the start of the LY3022855 infusion and at least 
one time point 0-3 h after the durvalumab infusion.  
Additional ECGs to be obtained as clinically indicated.

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LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Hematology (local)
X
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs for 
dosing
X
X
X
X
Refer to Attachment 2.  Results must be available and 
reviewed before administering study drug.
Serum chemistry (central)
X
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
Refer to Attachment 2.  To be performed at Screening, at 
C1D1, and every 4 wk thereafter.  Additional assessments 
as clinically indicated.  Results need not be available 
before administering study drug.
Coagulation (local)
Refer to Attachment 2.  As clinically indicated.
Thyroid function (central)
X
Refer to Attachment 2.  Free T3 and free T4 will be 
measured only if TSH is abnormal or if there is clinical 
suspicion of an AE related to the endocrine system.
Pancreas function (central)
Refer to Attachment 2.
Tumor markers (local)
Pharmacogenetic sample
X
Refer to the laboratory manual.  Collect once.  Sample can 
be collected at any time, if not collected on C1D1.

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LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Immunogenicity
X
X
If at any time a patient experiences an IRR, attempt to 
obtain a blood sample for immunogenicity analysis as 
close to the onset of the event as possible, at the resolution 
of the event, and 30 d following the event.  A portion of 
the sample taken for immunogenicity testing may be used 
for PK analysis.
Myoglobin (local)
X
Refer to Attachment 2.  If serum CK Grade ≥2, test for 
serum and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for 
reporting guidelines.
Concomitant medications
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.1 for dose frequency during Part A.
For LY3022855 and durvalumab:
  Part A doses:  Refer to Table JSCC.1.
  Part B doses and dose frequencies to be determined; 
refer to Section 7.2.2.2 for information.
Durvalumab administration
X
X
Pharmacokinetics
LY3022855
(predose on dosing days, unless 
noted otherwise)
X
X
2 h post-EOI 
C1D1 (±1 h)
X
24 h post-EOI 
C1D1 (±4 h)
X
48 h post-EOI 
C1D1 (±4 h)
X
X
X
The date and the time of all samples must be clearly and 
accurately recorded.
EOI = end of infusion
Durvalumab
(predose on dosing days, unless 
noted otherwise)
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
X
X
Pharmacodynamics and tailoring
Serum
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
X
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
X
X
Gene expression analysis and other exploratory research.
Flow cytometry
Immunophenotyping #1
X
X
X
X
CD14 and CD16.
Immunophenotyping #2
X
X
X
X
TBNK & T cell subset/activation panels.
Immunophenotyping #3
X
MDSC panel.
Isoenzymes (central)
Refer to Attachment 2.  Obtain at additional time points, 
as clinically indicated.

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LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
LVEF evaluation
Echocardiogram or MUGA scan.  Obtain at additional 
time points, as clinically indicated.
Radiographic tumor assessment 
(CT/MRI)
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22.
Tumor measurement (palpable or 
visible)
Tumor biopsy
For Part A (all cohorts) and Part B (ovarian cancer 
cohort only):  An on-treatment tumor core needle or 
excisional biopsy to be performed 6-8 wk after starting 
study treatment.

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LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all assessments 
to be performed preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Physical examination
X
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around 
infusions as follows (allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during (midway 
through), at the end, and 30 min after the end.
Around each durvalumab infusion (based on a 60-min infusion):  
within 30 min prior to, during (approx. 30 min after start of 
infusion), and at the end (approx. 60 min after start of infusion).
1-h Observation period after durvalumab infusion:  at 30 and 60 
min after the end of the infusion (90 and 120 min after start of 
infusion) as clinically indicated.
If the durvalumab infusion exceeds 60 min, monitoring of BP and 
PR should occur per the preceding principles or more frequently if 
clinically indicated.
ECOG performance status
X
Pregnancy test (local)
Every 12 wk (±7 d) after the first dose of study drug or according 
to local regulations or as clinically indicated, whichever is more 
frequent.  Urine hCG or serum β-hCG.
ECG (local)
X
Single ECG.  Obtain ECGs before any associated blood draws.  
ECG should be taken within 2 h prior to the start of the 
LY3022855 infusion and at least one time point 0-3 h after the 
durvalumab infusion.  Additional ECGs to be obtained as 
clinically indicated.
Hematology (local)
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs 
for dosing
X
X
X
X
Refer to Attachment 2.  Results must be available and reviewed 
before administering study drug.
Serum chemistry (central)
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
Refer to Attachment 2.  To be performed at Screening, at C1D1, 
and every 4 wk thereafter.  Additional assessments as clinically 
indicated.  Results need not be available before administering 
study drug.
Coagulation (local)
X
Refer to Attachment 2.  Obtain prior to tumor biopsy.  Additional 
assessments as clinically indicated.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 106
LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all assessments 
to be performed preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Thyroid function (central)
X
Refer to Attachment 2.  Free T3 and free T4 will be measured only 
if TSH is abnormal or if there is clinical suspicion of an AE related 
to the endocrine system.
Pancreas function (central)
X
Refer to Attachment 2.
Tumor markers (local)
X
If clinically indicated.
Pharmacogenetic sample
Refer to the laboratory manual.  Collect once.  Sample can be 
collected at any time, if not collected on C1D1.
Immunogenicity
X
If at any time a patient experiences an IRR, attempts to obtain a 
blood sample for immunogenicity analysis as close to the onset of 
the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for 
immunogenicity testing may be used for PK analysis.
Myoglobin (local)
X
X
X
X
Refer to Attachment 2.  If serum CK Grade ≥2, test for serum and
urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for reporting 
guidelines.
Concomitant medications
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.1 for dose frequency during Part A.
For LY3022855 and durvalumab:
  Part A doses:  Refer to Table JSCC.1.
  Part B doses and dose frequencies to be determined; refer to 
Section 7.2.2.2 for information.
Durvalumab administration
X
X
Pharmacokinetics
LY3022855
(predose on dosing days, unless 
noted otherwise)
X
X
X
2 h post-EOI 
C2D8 (±1 h)
X
24 h post-EOI 
C2D8 (±4 h)
X
48 h post-EOI 
C2D8 (±4 h)
X
The date and the time of all samples must be clearly and accurately 
recorded.
EOI = end of infusion
Durvalumab
(predose on dosing days, unless 
noted otherwise)
X
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Pharmacodynamics and tailoring
Serum
X
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
X
Gene expression analysis and other exploratory research.
Flow cytometry
Immunophenotyping #1
X
X
X
CD14, CD16.
Immunophenotyping #2
X
X
X
TBNK & T cell subset/activation panels.
Immunophenotyping #3
X
MDSC panel.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 107
LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all assessments 
to be performed preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Isoenzymes (central)
X
Refer to Attachment 2.  Obtain at additional time points, as 
clinically indicated.
LVEF evaluation
X
Echocardiogram or MUGA scan.  Obtain at additional time points, 
as clinically indicated.
Radiographic tumor assessment
(CT/MRI)
X
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22.
Tumor measurement (palpable or 
visible)
X
Tumor biopsy
X
For Part A (all cohorts) and Part B (ovarian cancer cohort only):  
An on-treatment tumor core needle or excisional biopsy to be 
performed 6-8 wk after starting study treatment; that is, at Cycle 2, 
between Days 8 and 22. For Part B (NSCLC cohort) an optional 
on-treatment tumor tissue should be collected from patients in the 
study where possible.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 108
LY3022855
LY3022855 plus Durvalumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 3
(Visit 3)
Cycle 4
(Visit 4)
Cycle 5
(Visit 5)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
1
8
15
22
Physical examination
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around 
infusions as follows (allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during (midway 
through), at the end, and 30 min after the end.
Around each durvalumab infusion (based on a 60-min 
infusion):  within 30 min prior to, during (approx. 30 min after 
start of infusion), and at the end (approx. 60 min after start of 
infusion).
1-h Observation period after durvalumab infusion:  at 30 and 
60 min after the end of the infusion (90 and 120 min after start 
of infusion) for the first durvalumab infusion only, and for 
subsequent infusions as clinically indicated.
If the durvalumab infusion exceeds 60 min, monitoring of BP 
and PR should occur per the preceding principles or more 
frequently if clinically indicated.
ECOG performance status
X
X
X
Pregnancy test (local)
X
Every 12 wk (±7 d) after the first dose of study drug or 
according to local regulations or as clinically indicated, 
whichever is more frequent.  Urine hCG or serum β-hCG.
ECG (local)
Additional ECGs to be obtained as clinically indicated.
Hematology (local)
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs 
for dosing
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 2.  Results must be available and 
reviewed before administering study drug.
Serum chemistry (central)
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
X
X
Refer to Attachment 2.  To be performed at Screening, at 
C1D1, and every 4 wk thereafter.  Additional assessments as 
clinically indicated.  Results need not be available before 
administering study drug.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 109
LY3022855
LY3022855 plus Durvalumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 3
(Visit 3)
Cycle 4
(Visit 4)
Cycle 5
(Visit 5)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
1
8
15
22
Coagulation (local)
Refer to Attachment 2.  As clinically indicated.
Thyroid function (central)
X
X
X
Refer to Attachment 2.  Free T3 and free T4 will be measured 
only if TSH is abnormal or if there is clinical suspicion of an 
AE related to the endocrine system.
Pancreas function (central)
X
X
Refer to Attachment 2.
Tumor markers (local)
X
X
X
If applicable.
Pharmacogenetic sample
Refer to the laboratory manual.  Collect once.  Sample can be 
collected at any time, if not collected on C1D1.
Immunogenicity
X
If at any time a patient experiences an IRR, attempts to obtain 
a blood sample for immunogenicity analysis as close to the 
onset of the event as possible, at the resolution of the event, 
and 30 days following the event.  A portion of the sample 
taken for immunogenicity testing may be used for PK 
analysis.
Myoglobin (local)
X
Refer to Attachment 2.  If serum CK Grade ≥2, test for serum 
and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
X
X
X
X
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for 
reporting guidelines.
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.1 for dose frequency during Part A.
For LY3022855 and durvalumab:
  Part A doses:  Refer to Table JSCC.1.
  Part B doses and dose frequencies to be determined; refer to 
Section 7.2.2.2 for information.
Durvalumab administration
X
X
X
X
X
X
Pharmacokinetics
LY3022855
(predose on dosing days, unless 
noted otherwise)
X
X
The date and the time of all samples must be clearly and 
accurately recorded.
Durvalumab
(predose on dosing days, unless 
noted otherwise)
X
X
Pharmacodynamics and tailoring
Serum
X
X
Serum storage for correlative studies.
Plasma
Plasma storage for correlative studies.
Flow cytometry
Immunophenotyping #1
X
X
CD14, CD16.
Immunophenotyping #2
X
X
TBNK & T cell subset/activation panels.
Immunophenotyping #3
X
MDSC panel.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 110
LY3022855
LY3022855 plus Durvalumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 3
(Visit 3)
Cycle 4
(Visit 4)
Cycle 5
(Visit 5)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
1
8
15
22
Isoenzymes (central)
Refer to Attachment 2.  Obtain at additional time points, as 
clinically indicated.
LVEF evaluation
Echocardiogram or MUGA scan.  Obtain at additional time 
points, as clinically indicated.
Radiographic tumor assessment
(CT/MRI)
X
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22.
Tumor measurement (palpable or 
visible)
X
Tumor biopsy
For Part A (all cohorts) and Part B (ovarian cancer cohort 
only):  An on-treatment tumor core needle or excisional 
biopsy to be performed 6-8 wk after starting study treatment.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 111
LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 6-n
(Visit 6-n)
Short-Term
Follow-Upa
(Visits 801 and 802)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 days, unless otherwise 
indicated.  On dosing days, all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
30-Day
(±7 d)
90-Day*
(±7 d)
*90-Day Follow-Up visit is only for durvalumab safety.
Physical examination
X
X
Targeted physical examination (on the basis of clinical observations and 
symptomatology).
Vital signs
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around infusions as follows 
(allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during (midway through), at the end, and 
30 min after the end.
Around each durvalumab infusion (based on a 60-min infusion):  within 30 min prior 
to, during (approx. 30 min after start of infusion), and at the end (approx. 60 min after 
start of infusion).
1-h Observation period after durvalumab infusion:  at 30 and 60 min after the end of the 
infusion (90 and 120 min after start of infusion) for the first durvalumab infusion only, 
and for subsequent infusions as clinically indicated.
If the durvalumab infusion exceeds 60 min, monitoring of BP and PR should occur per 
the preceding principles or more frequently if clinically indicated.
ECOG performance status
X
X
X*
*Performed at 90-day follow-up only for patients who discontinue study treatment due 
to toxicity, in the absence of confirmed disease progression.
Pregnancy test (local)
X
Every 12 wk (±7 d) after the first dose of study drug or according to local regulations or 
as clinically indicated, whichever is more frequent.  Urine hCG or serum β-hCG.
ECG (local)
X
Single ECG.  Obtain ECGs before any associated blood draws.  Additional ECGs to be 
obtained as clinically indicated.
Hematology (local)
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs for 
dosing
X
X
Refer to Attachment 2.  Results must be available and reviewed before administering 
study drug.
Serum chemistry (central)
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
X
Refer to Attachment 2.  To be performed at Screening, at C1D1, and every 4 wk
thereafter.  Additional assessments as clinically indicated.
Results need not be available before administering study drug.
Coagulation (local)
Refer to Attachment 2.  As clinically indicated.
Thyroid function (central)
X
X
Refer to Attachment 2.  Free T3 and free T4 will be measured only if TSH is abnormal 
or if there is clinical suspicion of an AE related to the endocrine system.
Pancreas function (central)
X
Refer to Attachment 2.  Only if amylase and lipase were previously elevated above 
normal limits.
Tumor markers (local)
X
If applicable.
Pharmacogenetic sample
Refer to the laboratory manual.  Collect once.  Sample can be collected at any time, if 
not collected on C1D1.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 112
LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 6-n
(Visit 6-n)
Short-Term
Follow-Upa
(Visits 801 and 802)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 days, unless otherwise 
indicated.  On dosing days, all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
30-Day
(±7 d)
90-Day*
(±7 d)
*90-Day Follow-Up visit is only for durvalumab safety.
Immunogenicity
X
X
X
If at any time a patient experiences an IRR, attempts to obtain a blood sample for 
immunogenicity analysis as close to the onset of the event as possible, at the resolution 
of the event, and 30 d following the event.  A portion of the sample taken for 
immunogenicity testing may be used for PK analysis.
To be drawn every 6 mo following Cycle 6.
Myoglobin (local)
X
Refer to Attachment 2.  If serum CK ≥ Grade 2, test for serum and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for reporting guidelines.
Concomitant medications
X
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.1 for dose 
frequency during Part A.
For LY3022855 and durvalumab:
  Part A doses:  Refer to Table JSCC.1.
  Part B doses and dose frequencies to be determined; refer to Section 7.2.2.2 for 
information.
Durvalumab administration
X
X
Pharmacokinetics
LY3022855
X
The date and the time of all samples must be clearly and accurately recorded.
Durvalumab
X
Pharmacodynamics and tailoring
Serum
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
Exploratory research.
Flow cytometry
Immunophenotyping #1 
CD14, CD16.
Immunophenotyping #2 
TBNK & T cell subset/activation panels.
Immunophenotyping #3
MDSC panel.
Isoenzymes (central)
Refer to Attachment 2.  Obtain at additional time points, as clinically indicated.
LVEF evaluation
Echocardiogram or MUGA scan.  Obtain at additional time points, as clinically 
indicated.
Radiographic tumor assessment (CT/MRI)
X
X
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22, then every 12 wk (±7 d) for 
patients who achieve disease control after 12 mo of study treatment and after Week 48 
for patients who discontinue durvalumab due to toxicity or symptomatic deterioration.  
For patients who continue on durvalumab post-confirmed progression at the 
investigator’s discretion (after consultation with the sponsor), tumor assessments 
should be performed until durvalumab is stopped.
Tumor measurement (palpable or visible)
X
X
Tumor biopsy
For Part A (all cohorts) and Part B (ovarian cancer cohort only):  An on-treatment 
tumor core needle or excisional biopsy to be performed 6-8 wk after starting study 
treatment.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 113
LY3022855
Abbreviations:  AE = adverse event; BP = blood pressure; CnDn = Cycle n, Day n (for example, C1D1 = Cycle 1, Day 1); CK = creatine kinase; CT = computed 
tomography (scan); CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EOI = end of infusion; hCG = human chorionic gonadotropin; IRR = infusion-related reaction; LVEF = left ventricular ejection fraction; LY = LY3022855; 
MDSC = myeloid-derived suppressor cell; MRI = magnetic resonance imaging; MUGA = multigated acquisition (scan); NCI = National Cancer Institute; PK 
= pharmacokinetic(s); PR = pulse rate; RR = respiration rate; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; v4.0 = Version 4.0 
of NCI-CTCAE.
a
No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 114
LY3022855
Continued Access Schedule for Combination Therapy:  LY3022855 plus Durvalumab
Continued 
Access 
Treatment 
Period
Continued 
Access 
Follow-Upa
Visit
501-5XX
901 (30 d)and 
902* (90 d)
(±7 d)
*90-Day Follow-Up visit (Visit 902) is only for durvalumab safety.
Procedureb
Instructions
AE collection
X
X
CTCAE v4.0.  Refer to Section 8.1.1 for reporting guidelines.
Pharmacokinetics and immunogenicity
X
If a patient experiences an IRR, collect blood samples for PK and 
immunogenicity analysis at the following time points:  (1) as soon as 
possible after the onset of the IRR, (2) at the resolution of the IRR, and 
(3) 30 days after the IRR.
Administer LY3022855 and durvalumab
X
Refer to Table JSCC.1 for dose frequency of LY3022855 during Part A.  
For LY3022855 and durvalumab:
  Part A doses:  Refer to Table JSCC.1.
  Part B doses and dose frequencies to be determined; refer to Section 
7.2.2.2 for information.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction; v4.0 = Version 4.0 of 
CTCAE.
a
Continued access follow-up Visit 901 begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the 
continued access period and lasts approximately 30 days. Visit 902 occurs 90 days (±7 days) after the patient and the investigator agree that the patient will 
no longer continue treatment in the continued access period.  No follow-up procedures will be performed for a patient who withdraws informed consent unless 
he or she has explicitly provided permission and consent.
b
Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 115
LY3022855
On-Study Treatment and Post-Treatment (Follow-Up) Assessments for Combination Therapy: LY3022855 plus
Tremelimumab
Tremelimumab once every 4 weeks; after 6 doses, tremelimumab once every 12 weeks until discontinuation.
Screening procedures performed within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
Rows with italicized font indicate that there is no planned assessment for the time frame shown on the page.
LY3022855 plus Tremelimumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable 
windows are ±3 days, unless otherwise indicated.  On 
dosing days, all assessments to be performed 
preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Physical examination
X
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured 
around infusions as follows (allowable window ±10 
min):
Around each LY3022855 infusion:  prior to, during 
(midway through), at the end, and 30 min after the 
end.
Around each tremelimumab infusion (based on a 60-
min infusion):  within 30 min prior to, during (approx. 
30 min after start of infusion), and at the end (approx. 
60 min after start of infusion).
1-h Observation period after tremelimumab infusion:  
at 30 and 60 min after the end of the infusion (90 and 
120 min after start of infusion) for the first 
tremelimumab infusion only, and for subsequent 
infusions as clinically indicated.
If the tremelimumab infusion exceeds 60 min, 
monitoring of BP and PR should occur per the 
preceding principles or more frequently if clinically 
indicated.
ECOG performance status
X
Pregnancy test (local)
Every 12 wk (±7 d) after the first dose of study drug or 
according to local regulations or as clinically 
indicated, whichever is more frequent.  Urine hCG or 
serum β-hCG.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 116
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable 
windows are ±3 days, unless otherwise indicated.  On 
dosing days, all assessments to be performed 
preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
ECG (local)
X
Single ECG.  Obtain ECGs before any associated 
blood draws.  ECG should be taken within 2 h prior to 
the start of the LY3022855 infusion and at least one 
time point 0-3 h after the tremelimumab infusion.  
Additional ECGs to be obtained as clinically 
indicated.
Hematology (local)
X
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs for 
dosing
X
X
X
X
Refer to Attachment 2.  Results must be available and 
reviewed before administering study drug.
Serum chemistry (central)
X
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
Refer to Attachment 2.  To be performed at Screening, 
at C1D1, and every 4 wk thereafter.  Additional 
assessments as clinically indicated.  Results need not 
be available before administering study drug.
Coagulation (local)
Refer to Attachment 2.  As clinically indicated.
Thyroid function tests (central)
X
Refer to Attachment 2.  Free T3 and free T4 will be 
measured only if TSH is abnormal or if there is 
clinical suspicion of an AE related to the endocrine 
system.
Pancreas function (central)
Refer to Attachment 2.
Tumor markers (local)
Pharmacogenetic sample
X
Refer to the laboratory manual.  Collect once.  Sample 
can be collected at any time, if not collected on C1D1.
Immunogenicity
X
X
If at any time a patient experiences an IRR, attempts 
to obtain a blood sample for immunogenicity analysis 
as close to the onset of the event as possible, at the 
resolution of the event, and 30 days following the 
event.  A portion of the sample taken for 
immunogenicity testing may be used for PK analysis.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 117
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable 
windows are ±3 days, unless otherwise indicated.  On 
dosing days, all assessments to be performed 
preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Myoglobin (local)
X
X
Refer to Attachment 2.  If serum CK Grade ≥2, test 
for serum and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1
for reporting guidelines.
Concomitant medications
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.2 for dose frequency during Part A.
For LY3022855 and tremelimumab:
  Part A doses:  Refer to Table JSCC.2.
  
Tremelimumab administration
X
Pharmacokinetics
LY3022855
(predose on dosing days, unless noted 
otherwise)
X
X
2 h post-EOI 
C1D1 (±1 h)
X
24 h post-EOI 
C1D1 (±4 h)
X
48 h post-EOI 
C1D1 (±4 h)
X
X
X
The date and the time of all samples must be clearly 
and accurately recorded.
EOI = end of infusion
Tremelimumab
(predose on dosing days, unless noted 
otherwise)
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
X
X
Pharmacodynamics and tailoring
Serum
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
X
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
X
X
Gene expression analysis and other exploratory 
research.
Flow cytometry
Immunophenotyping #1
X
X
X
X
CD14, CD16.
Immunophenotyping #2
X
X
X
X
TBNK & T cell subset/activation panels
Immunophenotyping #3
X
MDSC panel.
Isoenzymes (central)
Refer to Attachment 2.  Obtain at additional time 
points, as clinically indicated.
LVEF evaluation
Echocardiogram or MUGA scan.  Obtain at 
additional time points, as clinically indicated.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 118
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable 
windows are ±3 days, unless otherwise indicated.  On 
dosing days, all assessments to be performed 
preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Radiographic tumor assessment (CT/MRI)
Perform every 8 wk (±7 d), starting on Cycle 2, Day 
22.
Tumor measurement (palpable or visible)
Tumor biopsy
For Part A (all cohorts) and Part B (ovarian cancer 
cohort only):  An on-treatment tumor core needle or 
excisional biopsy to be performed 6-8 wk after 
starting study treatment.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 119
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are 
±3 days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Physical examination
X
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around 
infusions as follows (allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during 
(midway through), at the end, and 30 min after the end.
Around each tremelimumab infusion (based on a 60-min 
infusion):  within 30 min prior to, during (approx. 30 min 
after start of infusion), and at the end (approx. 60 min after 
start of infusion).
1-h Observation period after tremelimumab infusion:  at 30 
and 60 min after the end of the infusion (90 and 120 min 
after start of infusion) for the first tremelimumab infusion 
only, and for subsequent infusions as clinically indicated.
If the tremelimumab infusion exceeds 60 min, monitoring 
of BP and PR should occur per the preceding principles or 
more frequently if clinically indicated.
ECOG performance status
X
Pregnancy test (local)
Every 12 wk (±7 d) after the first dose of study drug or 
according to local regulations or as clinically indicated, 
whichever is more frequent.  Urine hCG or serum β-hCG.
ECG (local)
X
Single ECG.  Obtain ECGs before any associated blood 
draws.  ECG should be taken within 2 h prior to the start of 
the LY3022855 infusion and at least one time point 0-3 h 
after the tremelimumab infusion.  Additional ECGs to be 
obtained as clinically indicated.
Hematology (local)
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs 
for dosing
X
X
X
X
Refer to Attachment 2.  Results must be available and 
reviewed before administering study drug.
Serum chemistry (central)
X
X
X
X
Refer to Attachment 2.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 120
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are 
±3 days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Urinalysis (local)
X
Refer to Attachment 2.  To be performed at Screening, at 
C1D1, and every 4 wk thereafter.  Additional assessments 
as clinically indicated.  Results need not be available before 
administering study drug.
Coagulation (local)
X
Refer to Attachment 2.  Obtain prior to tumor biopsy.  
Additional assessments as clinically indicated.
Thyroid function (central)
X
Refer to Attachment 2.  Free T3 and free T4 will be 
measured only if TSH is abnormal or if there is clinical 
suspicion of an AE related to the endocrine system.
Pancreas function (central)
X
Refer to Attachment 2.
Tumor markers (local)
X
If applicable.
Pharmacogenetic sample
Refer to the laboratory manual.  Collect once.  Sample can 
be collected at any time, if not collected on C1D1.
Immunogenicity
X
If at any time a patient experiences an IRR, attempts to 
obtain a blood sample for immunogenicity analysis as close 
to the onset of the event as possible, at the resolution of the 
event, and 30 days following the event.  A portion of the 
sample taken for immunogenicity testing may be used for 
PK analysis.
Myoglobin (local)
X
X
X
X
Refer to Attachment 2.  If serum CK Grade ≥2, test for 
serum and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for 
reporting guidelines.
Concomitant medications
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.2 for dose frequency during Part A.
For LY3022855 and tremelimumab:
  Part A doses:  Refer to Table JSCC.2.
  
Tremelimumab administration
X
Pharmacokinetics
LY3022855
(predose on dosing days, unless 
noted otherwise)
X
X
X
2 h post-EOI 
C2D8 (±1 h)
X
24 h post-EOI 
C2D8 (±4 h)
X
48 h post-EOI 
C2D8 (±4 h)
X
The date and the time of all samples must be clearly and 
accurately recorded.
EOI = end of infusion
Tremelimumab
(predose on dosing days, unless 
noted otherwise)
X
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 121
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are 
±3 days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Pharmacodynamics and tailoring
Serum
X
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
X
Gene expression analysis and other exploratory research.
Flow cytometry
Immunophenotyping #1
X
X
X
CD14, CD16.
Immunophenotyping #2
X
X
X
TBNK & T cell subset/activation panels.
Immunophenotyping #3
X
MDSC panel.
Isoenzymes (central)
X
Refer to Attachment 2.  Obtain at additional time points, as 
clinically indicated.
LVEF evaluation
X
Echocardiogram or MUGA scan.  Obtain at additional time 
points, as clinically indicated.
Radiographic tumor assessment 
(CT/MRI)
X
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22.
Tumor measurement (palpable or 
visible)
X
Tumor biopsy
X
For Part A (all cohorts) and Part B (ovarian cancer cohort 
only):  An on-treatment tumor core needle or excisional 
biopsy to be performed 6-8 wk after starting study 
treatment; that is, at Cycle 2, between Days 8 and 22.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 122
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 3
(Visit 3)
Cycle 4
(Visit 4)
Cycle 5
(Visit 5)
Comments
Except for the Cycle 1, Day 1 visit, allowable 
windows are ±3 days, unless otherwise indicated.  
On dosing days, all assessments to be performed 
preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
1
8
15
22
Physical examination
X
X
X
Targeted physical examination (on the basis of 
clinical observations and symptomatology).
Vital signs
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured 
around infusions as follows (allowable window ±10 
min):
Around each LY3022855 infusion:  prior to, during 
(midway through), at the end, and 30 min after the 
end.
Around each tremelimumab infusion (based on a 
60-min infusion):  within 30 min prior to, during 
(approx. 30 min after start of infusion), and at the 
end (approx. 60 min after start of infusion).
1-h Observation period after tremelimumab
infusion:  at 30 and 60 min after the end of the 
infusion (90 and 120 min after start of infusion) for 
the first tremelimumab infusion only, and for 
subsequent infusions as clinically indicated.
If the tremelimumab infusion exceeds 60 min, 
monitoring of BP and PR should occur per the 
preceding principles or more frequently if clinically 
indicated.
ECOG performance status
X
X
X
Pregnancy test (local)
X
Every 12 wk (±7 d) after the first dose of study drug 
or according to local regulations or as clinically 
indicated, whichever is more frequent.  Urine hCG 
or serum β-hCG.
ECG (local)
Additional ECGs to be obtained as clinically 
indicated.
Hematology (local)
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs for 
dosing
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 2.  Results must be available 
and reviewed before administering study drug.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 123
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 3
(Visit 3)
Cycle 4
(Visit 4)
Cycle 5
(Visit 5)
Comments
Except for the Cycle 1, Day 1 visit, allowable 
windows are ±3 days, unless otherwise indicated.  
On dosing days, all assessments to be performed 
preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
1
8
15
22
Serum chemistry (central)
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
X
X
Refer to Attachment 2.  To be performed at 
Screening, at C1D1, and every 4 wk thereafter.  
Additional assessments as clinically indicated.  
Results need not be available before administering 
study drug.
Coagulation (local)
Refer to Attachment 2.  As clinically indicated.
Thyroid function (central)
X
X
X
Refer to Attachment 2.  Free T3 and free T4 will be 
measured only if TSH is abnormal or if there is 
clinical suspicion of an AE related to the endocrine 
system.
Pancreas function (central)
X
X
Refer to Attachment 2.
Tumor markers (local)
X
X
X
If applicable.
Pharmacogenetic sample
Refer to the laboratory manual.  Collect once.  
Sample can be collected at any time, if not collected 
on C1D1.
Immunogenicity
X
If at any time a patient experiences an IRR, attempts 
to obtain a blood sample for immunogenicity 
analysis as close to the onset of the event as 
possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken 
for immunogenicity testing may be used for PK 
analysis.
Myoglobin (local)
X
Refer to Attachment 2.  If serum CK Grade ≥2, test 
for serum and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
X
X
X
X
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1
for reporting guidelines.
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.2 for dose frequency during Part A.
For LY3022855 and tremelimumab:
  Part A doses:  Refer to Table JSCC.2.
Tremelimumab administration
X
X
X

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 124
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 3
(Visit 3)
Cycle 4
(Visit 4)
Cycle 5
(Visit 5)
Comments
Except for the Cycle 1, Day 1 visit, allowable 
windows are ±3 days, unless otherwise indicated.  
On dosing days, all assessments to be performed 
preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
1
8
15
22
Pharmacokinetics
LY3022855
(predose on dosing days, unless noted 
otherwise)
X
X
The date and the time of all samples must be clearly 
and accurately recorded.
Tremelimumab
(predose on dosing days, unless noted 
otherwise)
X
X
Pharmacodynamics and tailoring
Serum
X
X
Serum storage for correlative studies.
Plasma
Plasma storage for correlative studies.
Flow cytometry
Immunophenotyping #1
X
X
CD14, CD16.
Immunophenotyping #2
X
X
TBNK & T cell subset/activation panels.
Immunophenotyping #3
X
MDSC panel.
Isoenzymes (central)
Refer to Attachment 2.  Obtain at additional time 
points, as clinically indicated.
LVEF evaluation
Echocardiogram or MUGA scan.  Obtain at 
additional time points, as clinically indicated.
Radiographic tumor assessment 
(CT/MRI)
X
Perform every 8 wk (±7 d), starting Cycle 2, Day 
22.
Tumor measurement (palpable or visible)
X
Tumor biopsy
For Part A (all cohorts) and Part B (ovarian cancer 
cohort only):  An on-treatment tumor core needle or 
excisional biopsy to be performed 6-8 wk after 
starting study treatment.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 125
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 6
(Visit 6)
Cycle 7-n
(Visit 7-n)
Short-Term
Follow-Upa
(Visits 801 and 802)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are 
±3 days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
30-Day
(±7 d)
90-Day*
±7 d)
*90-Day Follow-Up visit is only for tremelimumab safety.
Physical examination
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around 
infusions as follows (allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during 
(midway through), at the end, and 30 min after the end.
Around each tremelimumab infusion (based on a 60-min 
infusion):  within 30 min prior to, during (approx. 30 min 
after start of infusion), and at the end (approx. 60 min after 
start of infusion).
1-h Observation period after tremelimumab infusion:  at 30 
and 60 min after the end of the infusion (90 and 120 min 
after start of infusion) for the first tremelimumab infusion 
only, and for subsequent infusions as clinically indicated.
If the tremelimumab infusion exceeds 60 min, monitoring 
of BP and PR should occur per the preceding principles or 
more frequently if clinically indicated.
ECOG performance status
X
X
X
X*
*Performed at 90-day follow-up, only for patients who 
discontinue study treatment due to toxicity, in the absence 
of confirmed disease progression.
Pregnancy test (local)
X
Every 12 wk (±7 d) after the first dose of study drug or 
according to local regulations or as clinically indicated, 
whichever is more frequent.  Urine hCG or serum β-hCG.
ECG (local)
X
Single ECG.  Obtain ECGs before any associated blood 
draws.  Additional ECGs to be obtained as clinically 
indicated.
Hematology (local)
X
X
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs 
for dosing
X
X
X
X
Refer to Attachment 2.  Results must be available and 
reviewed before administering study drug.
Serum chemistry (central)
X
X
X
X
X
X
Refer to Attachment 2.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 126
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 6
(Visit 6)
Cycle 7-n
(Visit 7-n)
Short-Term
Follow-Upa
(Visits 801 and 802)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are 
±3 days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
30-Day
(±7 d)
90-Day*
±7 d)
*90-Day Follow-Up visit is only for tremelimumab safety.
Urinalysis (local)
X
X
X
Refer to Attachment 2.  To be performed at Screening, at 
C1D1, and every 4 wk thereafter.  Additional assessments 
as clinically indicated.  Results need not be available 
before administering study drug.
Coagulation (local)
Refer to Attachment 2.  As clinically indicated.
Thyroid function (central)
X
X
X
Refer to Attachment 2.  Free T3 and free T4 will be 
measured only if TSH is abnormal or if there is clinical 
suspicion of an adverse event related to the endocrine 
system.
Pancreas function (central)
X
Refer to Attachment 2.  Only if amylase and lipase 
previously noted to be elevated above normal limits.
Tumor markers (local)
X
X
If applicable.
Pharmacogenetic sample
Refer to the laboratory manual.  Collect once.  Sample can 
be collected at any time, if not collected on C1D1.
Immunogenicity
X
X
X
If at any time a patient experiences an IRR, attempts to 
obtain a blood sample for immunogenicity analysis as 
close to the onset of the event as possible, at the resolution 
of the event, and 30 d following the event.  A portion of 
the sample taken for immunogenicity testing may be used 
for PK analysis.
To be drawn every 6 mo following Cycle 6.
Myoglobin (local)
X
Refer to Attachment 2.  If serum CK Grade ≥2, test for 
serum and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
X
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for 
reporting guidelines.
Concomitant medications
X
X
X
X
X
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.2 for dose frequency during Part A.
For LY3022855 and tremelimumab:
  Part A doses:  Refer to Table JSCC.2.
  Tremelimumab note:  Starting at C7 (that is, after 6 
doses), tremelimumab is to be administered once every 12 
wk.
Tremelimumab administration
X
X
Pharmacokinetics
LY3022855
X
The date and the time of all samples must be clearly and 
accurately recorded.
Tremelimumab
X
Pharmacodynamics and tailoring

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 127
LY3022855
LY3022855 plus Tremelimumab
Assessment (central or local 
laboratory indicated, if applicable)
Cycle 6
(Visit 6)
Cycle 7-n
(Visit 7-n)
Short-Term
Follow-Upa
(Visits 801 and 802)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are 
±3 days, unless otherwise indicated.  On dosing days, all 
assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
8
15
22
1
8
15
22
30-Day
(±7 d)
90-Day*
±7 d)
*90-Day Follow-Up visit is only for tremelimumab safety.
Serum
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
Exploratory research.
Flow cytometry
Immunophenotyping #1 
CD14, CD16.
Immunophenotyping #2 
TBNK & T cell subset / activation panels.
Immunophenotyping #3 
MDSC panel.
Isoenzymes (central)
Refer to Attachment 2.  Obtain at additional time points, 
as clinically indicated.
LVEF evaluation
Echocardiogram or MUGA scan.  Obtain at additional 
time points, as clinically indicated.
Radiographic tumor assessment 
(CT/MRI)
X
X
X
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22, 
then every 12 wk (±7 d) for patients who achieve disease 
control after 12 mo of study treatment and after Week 48 
for patients who discontinue tremelimumab due to toxicity 
or symptomatic deterioration.  For patients who continue 
on tremelimumab post-confirmed progression at the 
investigator’s discretion (after consultation with the 
sponsor), tumor assessments should be performed until 
tremelimumab is stopped.
Tumor measurement (palpable or 
visible)
X
X
X
Tumor biopsy
For Part A (all cohorts) and Part B (ovarian cancer 
cohort only):  An on-treatment tumor core needle or 
excisional biopsy to be performed 6-8 wk after starting 
study treatment.
Abbreviations:  AE = adverse event; BP = blood pressure; CnDn = Cycle n, Day n (for example, C1D1 = Cycle 1, Day 1); CK = creatine kinase; CT = computed 
tomography (scan); CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EOI = end of infusion; hCG = human chorionic gonadotropin; IRR = infusion-related reaction; LVEF = left ventricular ejection fraction; LY = LY3022855; 
MDSC = myeloid-derived suppressor cell; MRI = magnetic resonance imaging; MUGA = multigated acquisition (scan); NCI = National Cancer Institute; PK = 
pharmacokinetic(s); PR = pulse rate; RR = respiration rate; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; v4.0 = Version 4.0 of 
NCI-CTCAE.
a
No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 128
LY3022855
Continued Access Schedule for Combination Therapy:  LY3022855 plus Tremelimumab
Continued 
Access 
Treatment 
Period
Continued 
Access 
Follow-Upa
Visit
501-5XX
901 (30 d) and 
902* (90 d)
(±7 d)
*90-Day Follow-Up visit (Visit 902) is only for tremelimumab safety.
Procedureb
Instructions
AE collection
X
X
CTCAE v4.0.  Refer to Section 8.1.1 for reporting guidelines.
Pharmacokinetics and immunogenicity
X
If a patient experiences an IRR, collect blood samples for PK and 
immunogenicity analysis at the following time points:  (1) as soon as 
possible after the onset of the IRR, (2) at the resolution of the IRR, and (3)
30 days after the IRR.
Administer LY3022855 and tremelimumab
X
Refer to Table JSCC.2 for dose frequency of LY3022855 during Part A.  
For LY3022855 and tremelimumab:
  Part A doses:  Refer to Table JSCC.2.
  If the patient has reached Cycle 7 or beyond in the main study, prior to 
the start of the Continued Access period, the patient will continue to 
receive tremelimumab in the Continued Access period according to their 
most recent dosing in the main study; continue dosing every 3 cycles.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction.
a
Continued access follow-up Visit 901 begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the 
continued access period and lasts approximately 30 days. Visit 902 occurs 90 days (±7 days) after the patient and the investigator agree that the patient will 
no longer continue treatment in the continued access period.  No follow-up procedures will be performed for a patient who withdraws informed consent unless 
he or she has explicitly provided permission and consent.
b
Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 129
LY3022855
Attachment 2.Protocol JSCC Clinical Laboratory Tests
Clinical Laboratory Tests - Assayed by Local Laboratory
(local or investigator-designated laboratory)
Hematology
Serum Chemistry
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Chloride
Leukocytes (WBC)
Bicarbonate
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes 
Alanine aminotransferase (ALT)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Albumin
Platelets
Total protein
Mean corpuscular hemoglobin
Blood urea nitrogen
Mean corpuscular hemoglobin concentration
Creatinine
Mean corpuscular volume
Glucose, random
Creatine kinase
Coagulation
aPTT
PT, INR
Urinalysisa
Serum or Urine Pregnancy Test (females only)
Specific gravity
pH
Protein
Myoglobin
Glucose
Serum myoglobin
Ketones
Urine myoglobin
Blood
Urine leukocyte esterase
Serologies
Nitrites
HIV screening
Bilirubin
Color and appearance

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
Page 130
LY3022855
Clinical Laboratory Tests - Assayed by Central Laboratory b
(sponsor-designated laboratory)
Serum Chemistry
Thyroid Function
Sodium
Thyroid-stimulating hormone
Magnesium
Free T3
Potassium
Free T4
Calcium
Isoenzymes
Chloride
Alkaline phosphatase isoenzymes
Bicarbonate
Total creatine kinase
Total bilirubinc
Creatine kinase isoenzymes
Alkaline phosphatase
Total LDH
Alanine aminotransferase (ALT)
LDH isoenzymes
Aspartate aminotransferase (AST)
Gamma-glutamyl transpeptidase (GGT)d
Pancreas Function
Albumin
Amylase
Total protein
Lipase
Blood urea nitrogen
Creatinine
Uric acid
Glucose, random
Creatine kinase
Abbreviations:  aPTT = activated partial thromboplastin time; HIV = human immunodeficiency virus; INR = 
international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; T3 = triiodothyronine; T4 = 
thyroxine; ULN = upper limit of normal.
a
Microscopy should be used as appropriate to investigate WBCs and use the high power field for RBCs.
b
Results will be confirmed by the central laboratory at the time of initial testing.
c
If total bilirubin ≥2 × ULN (and no evidence of Gilbert’s syndrome), fractionate into direct and indirect bilirubin.
d
At baseline and as clinically indicated.

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Attachment 3.
Protocol JSCC Hepatic Monitoring 
Tests for Treatment Emergent Abnormality
Selected tests may be obtained in the event of a treatment emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly CRP/CRS.
Hepatic Monitoring Tests
Hepatic Chemistrya
Hepatic Serologiesa,b
Total bilirubin
Hepatitis A antibody, total
Direct bilirubin
Hepatitis A antibody, IgM
Alkaline phosphatase
Hepatitis B surface antigen
ALT
Hepatitis B surface antibody
AST
Hepatitis B core antibody
GGT
Hepatitis B virus
CK
Hepatitis C virus
Hepatitis C antibody
Haptoglobina
Hepatitis E antibody, IgG
Hepatitis E antibody, IgM
Hepatic Coagulationa
PT, INR
Anti-actin antibody
Anti-nuclear antibodya
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; CRP = 
clinical research physician; CRS = clinical research scientist; GGT = gamma-glutamyl transferase (also known as 
gamma-glutamyl transpeptidase); Ig = immunoglobulin; IgG = immunoglobulin G; IgM = immunoglobulin M; 
INR = international normalized ratio; PT = prothrombin time.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 4.
Protocol JSCC Recommendations for 
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report an SAE, please have the following information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, and weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalization), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug and Protocol Procedures
Concomitant Drug Therapy

indication, total daily dose, duration of treatment, start date, action taken
In Case of Death

cause, autopsy finding (if available), date, relationship to study drug and protocol 
procedures.

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Attachment 5.
Protocol JSCC ECOG Performance
Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out performance of a light or sedentary nature, for example,
light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair.
5
Dead.
Source:  Oken et al. 1982.

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Attachment 6.
Protocol JSCC Creatinine Clearance 
Formula
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (2009) 
is based on the same 4 variables as the Modification of Diet in Renal Disease (MDRD) Study 
equation, but uses a 2-slope spline to model the relationship between estimated glomerular 
filtration rate (GFR) and serum creatinine, and a different relationship for age, sex, and race.  
The equation was reported to perform better and with less bias than the MDRD Study equation, 
especially in patients with higher GFR.  This results in reduced misclassification of CKD.  As of 
November 2009, very few clinical laboratories report the estimated GFR using the CKD-EPI 
creatinine equation.  In the future, other GFR estimating equations may outperform CKD-EPI.
The CKD-EPI creatinine equation is as follows:
GFR = 141 X min(SCr/k, 1)α X max(SCr/k, 1)-1.209 X 0.993Age X 1.018 [if female] X 1.0159 [if black]
k = 0.7 if female
k = 0.9 if male
α = -0.329 if female
α = -0.411 if male
min = the minimum of SCr/k or 1
max = the maximum of SCr/k or 1
SCr = serum creatinine (mg/dL)
Source:  Levey et al. 2009.

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Attachment 7.Protocol JSCC Toxicity Management Guidelines
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non Immune-Mediated Reactions (Combination Therapy with LY3022855 and Durvalumab or LY3022855 and Tremelimumab) 
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 
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., 
myocarditis, or other similar events even if they are not currently noted in the 
guidelines – should implement 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 [eg, 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 (eg, 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 not currently noted in the 

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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non Immune-Mediated Reactions (Combination Therapy with LY3022855 and Durvalumab or LY3022855 and Tremelimumab) 
General Considerations
Dose Modifications
Toxicity Management
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.
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).
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 (eg, 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.
Abbreviations:  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; PO = By mouth.

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Specific Immune-Mediated Reactions
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 (eg, 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 
(eg, 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 

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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 
[eg, 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 (eg, 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 
(eg, 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 (eg, disease progression, other 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.

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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 (eg, 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 (eg, 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 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:
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 
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.

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life-threatening 
consequences)
(Grade 3 colitis:
severe abdominal pain, 
change in bowel 
habits, medical 
intervention indicated, 
peritoneal signs;
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated)
regimen can be resumed after 
completion of steroid taper.
Grade 4
Permanently discontinue 
study drug/study regimen.
−
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (eg 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)
Infliximab should not be used 
for management of immune-
related hepatitis.
Any Grade
General Guidance
For Any Grade:
−
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB.
−
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications).
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 (eg, 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 workup 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 

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For asymptomatic Grade 2 AST (only 
if accompanied by Grade ≤ 1 ALT and 
Grade ≤ 1 TB and no change of ALT 
or TB from baseline levels):

Continue dosing with both 
LY3022855 and durvalumab or 
tremelimumab
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (ie, 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
−
Monitor LFTs frequently (eg, every 1 to 2 days or as clinically 
indicated).
−
Consider hepatic consult
−
No steroids required
Grade 3 or 4
(Grade 3: AST or 
ALT >5.0×ULN and 
≤20.0×ULN and/or 
TB >3.0×ULN and 
≤10.0×ULN)
(Grade 4: AST or 
ALT >20×ULN and/or 
TB >10×ULN)
For Grade 3:
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × 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 asymptomatic Grade 3 AST up to 
≤8 × ULN (only if accompanied by 
Grade ≤ 1 ALT and Grade ≤ 1 TB and 
no change of ALT or TB from 
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 (ie, 
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

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baseline levels)

Hold LY3022855, and 
continue dosing with 
durvalumab or tremelimumab.  

If AST downgrades to Grade 
≤2, after holding LY3022855,  
resume dosing with 
LY3022855 and durvalumab 
or tremelimumab. 

If Grade 3 AST recurs after 
resumption of dosing with 
both agents, hold LY3022855 
dosing. Continue dosing 
durvalumab or tremelimumab.  
Resume treatment with the 
combination of LY3022855 
and durvalumab or 
tremelimumab if AST remains 
asymptomatic and  
downgrades to Grade ≤2.
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 (ie, 
elevated alkaline P04) and in the absence 
of any alternative cause.b
For Grade 4:
Permanently discontinue study 
drug/study regimen.
−
Monitor LFTs frequently (eg, every 1 to 2 days or as clinically 
indicated).
−
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications, history of alcohol intake).
−
Promptly seek hepatic consult as necessary. 
−
No steroids required.

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Nephritis or renal 
dysfunction
(elevated serum creatinine)
Any Grade
General Guidance
For Any Grade:
−
Consult with nephrologist.
−
Monitor for signs and symptoms that may be related to changes 
in renal function (eg, 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 (eg, 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 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

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−
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.
Grade 1
No dose modifications.
For Grade 1:
−
Consider symptomatic treatment, including oral antipruritics (eg, 
diphenhydramine or hydroxyzine) and topical therapy (eg, 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 
For Grade 2:
−
Obtain dermatology consult.
−
Consider symptomatic treatment, including oral antipruritics (eg, 
diphenhydramine or hydroxyzine) and topical therapy (eg, 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 

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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taper.
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:
Permanently discontinue study 
drug/study regimen.
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
−
Consider, as necessary, discussing with study physician.
Endocrinopathy
(eg, 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 (eg, 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 (eg, blood glucose and 
ketone levels, HbA1c).
−
For modest asymptomatic elevations in serum amylase and 

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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 (eg, 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.
−
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 (eg, 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 
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 (eg, 1 to 
2 mg/kg/day methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone replacement (eg, 
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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physician’s clinical judgement.
3.
Doses of prednisone are 
≤10 mg/day or equivalent.
−
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 judgment.
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 workup, 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 
autonomic neuropathy, 
excluding Myasthenia Gravis 
and Guillain-Barre)
Any Grade
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Patients should be evaluated to rule out any alternative etiology 
(eg, disease progression, infections, metabolic syndromes, or 
medications).
−
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness).
−
Consider appropriate diagnostic testing (eg, electromyogram and 
nerve conduction investigations).
−
Perform symptomatic treatment with neurological consult as 
appropriate.

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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 (eg, 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 (eg, 
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 4:
Permanently discontinue study 
drug/study regimen.
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 (eg, IV IG).
−
Once stable, gradually taper steroids over ≥28 days.
Peripheral neuromotor 
syndromes
(such as Guillain-Barre and 
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 

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myasthenia gravis)
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 
(eg, 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 (eg, 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:
−
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 (eg, gabapentin or duloxetine).
MYASTHENIA GRAVIS:
o
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 

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worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist.
o
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.
o
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:
o
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective.
o
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:
o
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist.
o
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG.
o
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:
o
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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o
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 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 (eg, 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 workup should include clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram (ECHO), monitoring of 
oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory workup 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 (eg, 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 workup 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 workup as clinically 
indicated.
-
Consider using steroids if clinical suspicion is high.
Grade 2, 3, or 4
(Grade 2: Symptoms 
with mild to moderate 
- 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 
For Grades 2 to 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 

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activity or exertion)
(Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention indicated)
(Grade 4: Life-
threatening 
consequences; urgent
intervention indicated 
[eg, continuous IV 
therapy or mechanical 
hemodynamic 
support])
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, 
permanently discontinue study 
drug/study regimen.
If Grade 3-4, permanently discontinue 
study drug/study regimen.
biopsy.
−
Supportive care (eg, oxygen).
−
If 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 
(eg, 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.
−
Initial workup should include clinical evaluation, creatine 

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kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory workup 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 
(eg, 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 (eg, prednisone 1 to 2 mg/kg/day PO or IV equivalent); 
if no improvement within 3 to 5 days, continue 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 
(eg, 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-

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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.
Abbreviations:  AChE = Acetylcholine esterase; ADL = Activities of daily living; AE = Adverse event; ALP = Alkaline phosphatase test; ALT = Alanine aminotransferase; 
AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; CT = Computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; HbA1C = 
glycated haemoglobin; ILD = Interstitial lung disease; imAE = immune-mediated adverse event; IG = Immunoglobulin; IV = Intravenous; GI = Gastrointestinal; 
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.
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 
(eg, 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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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 (eg, 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 (eg, 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 (eg, IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid).
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; IM = intramuscular; IV = intravenous; NCI = National Cancer Institute.

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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 (ie, 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.
For asymptomatic Grade 2 creatine kinase levels:

Hold treatment with both study agents.  Perform 
diagnostic evaluation 
If results show no evidence of end organ damage, including 
myositis and rhabdomyolysis, resume treatment with both agents.
Treat accordingly, as per institutional standard.

Perform diagnostic evaluation (serum and urine 
myoglobin, BUN and creatinine) 
Continue to monitor CK, serum and urine myoglobin, BUN and 
creatinine Weekly until creatine kinase levels return to ≤ Grade 1
or as clinically indicated.
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.
For asymptomatic Grade 3 creatine kinase levels:
Hold treatment with both LY3022855 and durvalumab or 
tremelimumab. Perform diagnostic evaluation. 

For Grade 3 elevations in CK ≤ 8X ULN with a 
diagnostic evaluation showing NO evidence of end 
organ damage including myositis or rhabdomyolysis, 
resume treatment with both agents. 

For Grade 3 elevations in CK > 8X ULN with a 
diagnostic evaluation showing NO evidence of end 
organ damage including myositis or rhabdomyolysis, , 
hold LY3022855 and resume durvalumab or 
Treat accordingly, as per institutional standard.

Perform diagnostic evaluation (serum and urine 
myoglobin, BUN and creatinine).  

Continue to monitor CK, serum and urine myoglobin, 
BUN and creatinine Weekly until CK levels return to ≤ 
Grade 1 or as clinically indicated.

Treat accordingly as per institutional standard, perform a 
full diagnostic evaluation and if there is any evidence of 
potential immune-mediated end organ damage, follow the 
guidelines for irAE management contained in this 
attachment.

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Non-Immune-Mediated Reactions
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
tremelimumab after discussion with sponsor.
If CK decreases to ≤ 8x ULN after holding LY3022855, resume 
treatment with LY3022855 and durvalumab or tremelimumab.  
o
If CK remains >8X ULN after holding 
LY3022855, permanently discontinue both 
LY3022855 and durvalumab or 
tremelimumab and discuss additional 
treatment measures with sponsor. 
In case of myositis or rhabdomyolysis, permanently discontinue 
treatment with both study agents.

  Continue to monitor CK, serum and urine myoglobin, 
BUN and creatinine weekly until CK levels return to ≤ 
Grade 1 or baseline. 
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.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.”
Abbreviations:  AE = Adverse event; BUN = elevated serum blood urea nitrogen; CK = creatinine; CTCAE = Common Terminology Criteria for Adverse Events; 
NCI = National Cancer Institute.

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Attachment 8.
Protocol JSCC Durvalumab and 
Tremelimumab AESIs
An adverse event of special interest (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.
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event 
(AE) that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the irAE. 
If the investigator has any questions in regards to an AE being an irAE, the investigator should 
promptly contact the study physician.
AESIs observed with durvalumab and tremelimumab include:
•
Diarrhea / Colitis
•
Pneumonitis / ILD (interstitial lung disease)
•
ALT/AST increases / hepatitis / hepatotoxicity
•
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis)
•
Endocrinopathy (i.e. events of hypophysitis, hypopituitarism, adrenal insufficiency, 
diabetes insipidus, type I diabetes mellitus and hyper- and hypothyroidism)
•
Rash / Dermatitis
•
Nephritis / Blood creatinine increases
•
Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase, increased serum 
amylase)
•
Other inflammatory responses that are rare with a potential immune-mediated etiology 
include, but are not limited to, myocarditis, pericarditis, myositis/polymyositis, and 
uveitis.

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Further information on these risks (eg, presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab IBs.  For durvalumab and tremelimumab, AESIs will 
comprise the following:
Pneumonitis
AEs of pneumonitis are also of interest, as pneumonitis has been observed with use of anti-PD-1 
mAbs (but not with anti-PD-L1 mAbs).  Initial work-up should include a high-resolution CT 
scan, ruling out infection, and pulse oximetry.  Pulmonary consultation is highly recommended.
Guidelines for the management of patients with immune-mediated events including pneumonitis 
are outlined in Section 7.2.4.
Infusion reactions
AEs of infusion reactions (also known as infusion-related reactions [IRRs]) are of special interest 
and are defined, for the purpose of this protocol, as all AEs occurring from the start of 
investigational product infusion up to 48 hours after the infusion start time.  For all infusion 
reactions, if they qualify as SAEs, they should be reported as SAEs as described in Section 
8.1.2.1.
Hypersensitivity reactions
Hypersensitivity reactions as well as IRRs have been reported with anti-PD-L1 and anti-PD-1 
therapy (Brahmer et al. 2012).  As with the administration of any foreign protein and/or other 
biologic agents, reactions following the infusion of mAbs can be caused by various mechanisms, 
including acute anaphylactic (IgE-mediated) and anaphylactoid reactions against the mAbs and 
serum sickness.  Acute allergic reactions may occur, may be severe, and may result in death.  
Acute allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, 
urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, 
fatigue, headache, hypertension, myalgia, vomiting, and unresponsiveness.
Guidelines for management of patients with hypersensitivity (including anaphylactic reaction) 
and IRRs are outlined in Section 7.2.4.
Hepatic function abnormalities (hepatotoxicity)
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN.  Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other.  Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (for example, cholelithiasis and 
bile duct obstruction with distended gallbladder) or an agent other than the investigational 
product.
Guidelines for management of patients with hepatic function abnormality are outlined in Section 
7.2.4.

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Gastrointestinal disorders
Diarrhea/colitis is the most commonly observed treatment-emergent SAE when tremelimumab is 
used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.
Guidelines on management of diarrhea and colitis in patients receiving study treatment are 
provided in Section 7.2.4.
Endocrine disorders
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Section 7.2.4.
Pancreatic disorders
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Section 7.2.4.
Neurotoxicity
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Section 7.2.4.
Nephritis
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to changes in 
renal function (eg, routine urinalysis, elevated serum blood urea nitrogen [BUN] and creatinine, 
decreased creatinine clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc).
Patients should be thoroughly evaluated to rule out any alternative etiology (eg, disease 
progression, infections, etc).
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.
Guidelines for the management of patients with immune-mediated neurotoxic events are 
provided in Section 7.2.4.

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Immune-related adverse events
Based on the mechanism of action of durvalumab and tremelimumab leading to T cell activation 
and proliferation, there is a possibility of observing irAEs during the conduct of this study.  
Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-
1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, 
dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (Hodi et al. 2010, 
Brahmer et al. 2012, Topalian et al. 2012).  These AEs are inflammatory in nature and can affect 
any organ.  With anti-PD-L1 and anti-CTLA-4 combination therapy, the occurrence of 
overlapping or increasing cumulative toxicities that include irAEs could potentially occur at 
higher frequencies than with either durvalumab or tremelimumab monotherapy.  Patients should 
be monitored for signs and symptoms of irAEs.  In the absence of an alternate etiology (for 
example, infection or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and endocrinopathy.  In addition to 
the dose modification guidelines provided in Section 7.2.4, it is recommended that irAEs are 
managed according to the general treatment guidelines outlined for ipilimumab (Weber et al. 
2012).  These guidelines recommend the following:
•
Patients should be evaluated to identify any alternative etiology.
•
In the absence of a clear alternative etiology, all events of an inflammatory nature should 
be considered immune related.
•
Symptomatic and topical therapy should be considered for low-grade events.
•
Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event.
•
More potent immunosuppressives should be considered for events not responding to 
systemic steroids (for example, infliximab or mycophenolate).
If the investigator has any questions in regards to an AE being an irAE, the investigator should 
immediately contact the study physician.
Myocarditis
A variety of clinical presentations, diagnostic evidence (laboratory, imaging, histopathology), 
and resulting diagnoses have been described in cases of myocarditis in the literature for other 
immune checkpoint inhibitors, including heart failure, brady- and tachyarrhythmias, and acute 
coronary syndrome-like presentations without evidence of ischemia.  Investigators should be 
aware of such rare, but severe immune-mediated adverse events including myocarditis with its 
presenting signs/symptoms (eg, decreased ejection fraction, arrhythmias, in particular 
occurrences of atrioventricular block).
Investigators should adhere to the Toxicity Management Guidelines by performing a thorough 
evaluation to rule out alternative etiologies and initiating prompt treatment with steroids and 
modification of study drug/dose regimen depending on the severity of the event.
Guidelines for the management of patients with myocarditis are provided in Attachment 7.

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Myositis/Polymyositis
Investigators should adhere to the Toxicity Management Guidelines by performing a thorough 
evaluation to rule out alternative etiologies and initiating prompt treatment with steroids and 
modification of study drug/dose regimen depending on the severity of the event. Guidelines for 
the management of patients with myositis/polymyositis are provided in Attachment 7.

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Attachment 9.
Protocol JSCC Durvalumab and 
Tremelimumab Dose Volume Calculations
Durvalumab Dose Volume Calculation
For durvalumab flat dosing:
1. Cohort dose: X g
2. Dose to be added into infusion bag:
Dose (mL) = X g × 1000 / 50 (mg/mL)
where 50 mg/mL is durvalumab nominal concentration.
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL).
3. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula:
Number of vials = Dose (mL) / 10.0 (mL/vial)
Example:
1. Cohort dose: 1.5 g
2. Dose to be added into infusion bag:
Dose (mL) = 1.5 g ×1000 / 50 (mg/mL) = 30.0 mL
3. The theoretical number of vials required for dose preparation:
Number of vials = 30.0 (mL) / 10.0 (mL/vial) = 3 vials

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Tremelimumab Dose Volume Calculation
For tremelimumab flat dosing:
1. Cohort dose: X mg
2. Dose to be added into infusion bag:
Dose (mL) = X mg / 20 (mg/mL)
where 20 mg/mL is tremelimumab nominal concentration
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 
mL).
3. The theoretical number of vials required for dose preparation is the next greatest whole
number of vials from the following formula:
Number of vials = Dose (mL) / 20 (mL/vial)
Example:
1. Cohort dose: 75 mg
2. Dose to be added into infusion bag:
Dose (mL) = 75 mg / 20 (mg/mL) = 3.8 mL
3. The theoretical number of vials required for dose preparation:
Number of vials = 3.8 (mL) / 20 (mL/vial) = 1 vial

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Attachment 10.
Protocol JSCC Protocol Amendment I5F-
MC-JSCC(c) Summary
A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor 
LY3022855 in Combination with Durvalumab (MEDI4736) or 
Tremelimumab in Patients with Advanced Solid Tumors
Overview
Protocol I5F-MC-JSCC, A Phase 1a/1b Trial Investigating the CSF-1R Inhibitor LY3022855 in 
Combination with Durvalumab (MEDI4736) or Tremelimumab in Patients with Advanced Solid
Tumors, has been amended.  The new protocol is indicated by Amendment (c) and will be used 
to conduct the study in place of any preceding version of the protocol.
Amendment (c) was created to incorporate the following changes:

Dose modification and toxicity management guidelines for durvalumab was updated per 
new guidance from AstraZeneca.

Clarification about testing for mutations in EGFR or ALK genes for patients in Part B 
(NSCLC cohort) was added.

Updated information about tumor biopsy samples to make it consistent across sections.

Updated treatment delay criteria to provide consistency across the protocol.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
5.1.3. Summary of the Rationale for Amendment (c)
Amendment (c) was created to incorporate the following changes:

Dose modification and toxicity management guidelines for durvalumab was updated per 
new guidance from AstraZeneca.

Added clarification about testing for mutations in EGFR or ALK genes for patients in 
Part B (NSCLC cohort only).

Updated information about tumor biopsy samples to make it consistent across sections.

Updated treatment delay criteria to provide consistency across the protocol.
6.1.1 Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
(Note:  If a specific cohort is not indicated for a criterion, the criterion applies to all patients.)
[1]
Must have histological or cytological evidence of a diagnosis of cancer that is
not amenable to curative therapy.
[2]
Part B (all cohorts):  Must have a type of malignancy that is being studied, as 
listed in the following:
[a] LY3022855 and durvalumab (MEDI4736) combination cohorts
[i] NSCLC that has relapsed or is refractory (definitions below) to 
immune checkpoint inhibitor therapy and has progressed through no 
more than 3 lines of therapy (one line must have been a platinum-
containing regimen).

Relapsed:  Following initial clinical benefit (that is, complete 
response [CR], partial response [PR], or stable disease [SD] on 
any scan), patients must have documented radiographic disease 
progression while receiving therapy with an immune 
checkpoint inhibitor.

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
Refractory:  Patients must have documented radiographic 
disease progression ≤16 weeks after the start of treatment with 
an immune checkpoint inhibitor, with no evidence of clinical 
benefit (that is, CR, PR, or SD on any scan) while receiving 
therapy.
a.
Patients must not have a known activating mutation of the EGFR
or ALK gene.  If a site uses algorithmic testing that has eliminated 
the possibility of EGFR or ALK gene mutations, no specific 
testing for mutations in these genes is required.
b. Patients could have received only one prior immune checkpoint 
therapy (anti-PD-1/PD-L1 or anti-CTLA-4, or a single regimen 
combining anti-PD-1/PD-L1 with an anti-CTLA-4).
[ii] Ovarian cancer (epithelial ovarian cancer, fallopian tube cancer, or 
primary peritoneal cancer) that has been treated with no more than 
3 lines of therapy (with or without platinum).
[3]
Part A (all cohorts) and Part B (ovarian cancer cohort only):  Must be willing 
to undergo pretreatment and on-treatment core needle or excisional tumor 
biopsies. For patient in NSCLC Part B cohort, if newly obtained samples 
cannot be obtained such as in cases of inaccessibility or patient safety 
concern, an archived tumor sample will be requested if not restricted by local 
regulations.  The archived tumor sample must follow most recent systemic 
treatment.  If no archived specimen since the most recent systemic treatment 
is available, and a new biopsy is not medically feasible, the patient should not 
be enrolled in the clinical trial.(Note:  An archived tumor sample will be 
requested, if not restricted by local regulations, for each patient in NSCLC 
Part B cohort).
7.2.1.1. LY3022855
Eligible patients will receive LY3022855 as an I.V. infusion administered over a minimum 
duration of 30 minutes and a maximum duration of 4 hours, based on the known safety and 
stability of the prepared drug. The infusion rate should not exceed 25 mg/minute. Suggested 
infusion times are as follows:

90 minutes for the first infusion; if no infusion-related reaction (IRR) is observed, 
decrease the infusion time to 60 minutes for the second infusion

60 minutes for the second infusion; if no IRR is observed, decrease the infusion time to 
30 minutes for the third infusion

30 minutes for the third and subsequent infusions
If, at any time, a patient experiences an IRR, the infusion time should not be decreased.  
Premedication is not recommended to be administered prior to the first infusion of LY3022855.  
However, if the patient experiences a Grade 1 or 2 IRR, premedication must be provided prior to 
any subsequent doses of LY3022855. The choice of premedication is to be made after 
discussion and agreement between the investigator and sponsor.  In such cases (Grade 1 or 2 

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IRRs), administration of steroids should be avoided, if possible.  If an IRR Grade ≤2 occurs 
during or after LY3022855 administration and the patient’s condition allows it, treatment with 
durvalumab or tremelimumab will proceed as planned.  Patients experiencing an IRR Grade ≥3 
will be permanently discontinued from study treatment.
LY3022855 may be administered up to 3 days AFTER the scheduled dosing date and up to 4
days BEFORE the next scheduled dosing date to accommodate for patient vacations, holidays, 
inclement weather or other unforeseen circumstances.  If, at any time, a dose is to be 
administered beyond the 3-day window, that dose is to be skipped.  A maximum of 28 days 
between administered doses is allowed for delays due to adverse events.
7.2.1.2. Durvalumab
Patients are to receive durvalumab I.V. on Days 1 and 15 of every cycle.  Durvalumab may be 
administered up to 3 days AFTER the scheduled dosing date.  If, at any time, a dose is 
administered beyond the 3-day window, that dose is considered a dose delay.  A maximum delay 
of 28 days between administered doses is allowed (for dose delay in case of immune-related AE 
please refer to Section 7.2.4.1).  Note that a maximum of 12 months/26 doses of durvalumab 
treatment is permitted.
7.2.1.3. Tremelimumab
Patients are to receive tremelimumab I.V. on Day 1 of every cycle for the first 6 doses
(Cycles 1-6).  Starting with Cycle 7 (4 weeks after Dose 6 [Week 25]), tremelimumab will be 
dosed once every 3 cycles (12 weeks), that is, on Day 1 of Cycles 7, 10, 13, and so on, until 
disease progression.
Tremelimumab may be administered up to 3 days AFTER the scheduled dosing date.  If, at any 
time, a dose is administered beyond the 3-day window, that dose is considered a dose delay.  A 
delay of up to 28 days between administered doses is allowed for Cycles 1 through 6, and up to 
60 days between doses for Cycles 7 and beyond.
7.2.4.1. Dose Delays for Adverse Events
Study treatment may be held for a maximum of 28 days; see exception for an immune-related 
AE below.  If appropriate, and in the opinion of the investigator and upon agreement with the 
sponsor, study treatment may resume upon resolution of clinically significant AEs to baseline or 
improvement to Grade <2.  If AEs do not resolve to baseline or improve to Grade <2 within 28 
days following the last administered dose, study treatment should be permanently discontinued 
and the patient should be discontinued from the trial.  If treatment is held, the day of treatment 
should continue as if no drug interruption has occurred.  For example, if study drug is held on D6 
of a cycle and AEs have resolved by D10 (4 days later), the study drugs should be resumed per 
the original schedule,  If the original schedule results in a study drug being held for >28 days, the 
study drug may not be  resumed.  One or both study drugs may be held, resumed, or 
discontinued.

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If the AE is an immune related AE as outlined in Attachment 7 and if the treatment management 
guidelines outlined in Attachment 7 are followed and documented in the patient’s medical 
record, treatment may be held for >28 days to allow taper of high dose steroids. Treatment may 
resume in this setting only upon resolution of immune AEs to baseline or improvement to Grade 
<2, and only if deemed clinically appropriate by the treating physician and agreed to by the 
sponsor.  If steroids cannot be tapered as outlined in Attachment 7, and/or AEs do not resolve to 
< Grade 2, the patient may not be resumed on study treatment.
For the purposes of documentation, the investigator must assess if the toxicity is considered at 
least possibly related to study treatment (that is, the combination regimen) and if the AE is 
considered to be immune related. Investigators are encouraged to consult the sponsor for 
additional guidance.

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For AEs that are considered at least possibly related to study treatment, the following dose 
adjustment guidance may be applied:

Treat each of the toxicities with maximum supportive care (including holding the study 
drug[s] suspected of causing the toxicity where required).

If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of study drugs along with appropriate continuing supportive 
care.

All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
In addition, there are certain circumstances in which study drugs should be permanently 
discontinued (refer to Attachment 7).
Following the first dose of study drugs, subsequent administration of study drugs can be 
modified based on toxicities observed (refer to Attachment 7).
7.2.4.1.1.
Specific Adverse Events
Adverse events of special interest (AESIs) observed with durvalumab and/or tremelimumab 
include colitis; pneumonitis; alanine aminotransferase (ALT)/AST increases;
hepatitis/hepatotoxicity; neuropathy/neuromuscular toxicity (that is, events of encephalitis, 
peripheral motor and sensory neuropathies, Guillain-Barré, and myasthenia gravis); 
endocrinopathy (that is, events of hypophysitis, adrenal insufficiency, hyperthyroidism, and 
hypothyroidism; type 1 diabetes mellitus); dermatitis; nephritis; and pancreatitis (or labs 
suggestive of pancreatitis-increased serum lipase or serum amylase); other inflammatory 
responses that are rare with a potential immune-mediated etiology include, but are not limited to, 
myocarditis, pericarditis, myositis/polymyositis, and uveitis.  Refer to Attachment 8 for details 
about and management of AESIs.
Guidelines for the management of immune-mediated, infusion-related, and non-immune-related 
AEs are shown in Attachment 7.
Adverse events (both nonserious and serious) associated with study drugs may represent an 
immune-related etiology, which may be based on the mechanism of action of study drugs leading 
to T cell activation and proliferation.  These irAEs may occur shortly after the first dose or 
several months after the last dose of treatment.  Potential irAEs include immune-mediated 
enterocolitis, dermatitis, hepatitis, and endocrinopathies.  Patients should be monitored for signs 
and symptoms of irAEs.  In the absence of an alternative etiology (for example, infection or 
progressive disease), signs or symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, 
myocarditis, myopathy/polymyopathy, and endocrinopathy should be considered immune
related.  Refer to Attachment 7 for supportive care guidelines for immune-mediated reactions, 
including use of corticosteroids.
8.2.4.2. Tumor Tissue Samples

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Tissue collection will be required for biomarker research and enrollment into the study for 
patients in Part A (all cohorts) and Part B (ovarian cancer cohort only).  For patients enrolled in 
Part A (all cohorts) and Part B (ovarian cancer cohort only) of the study, tissue will be required
for PD-L1 biomarker and other exploratory analysis from a newly obtained core or excisional 
biopsy of a tumor lesion (should be taken only after study eligibility is confirmed) or from a 
recent biopsy defined by 3 years since last documented progression of disease will be required.  
For the NSCLC cohort, archived tissue should be submitted form a recent biopsy defined by 3 
years old and this biopsy follows the most recent systemic therapy. If such an archived biopsy 
sample is not available, a new biopsy must be obtained for the patient to be eligible to participate 
in study. For all cohorts, new archived tissue will be obtained only if not restricted by local 
regulations.
In addition, an on-treatmentstudy biopsy is required if any accessible lesions remain for Part A 
(all cohorts) and Part B (ovarian cancer cohort only).  If clinically feasible, the biopsies should 
be taken from the same lesion.  Pretreatment and/or on-treatment tumor tissue biopsies are 
optional for all Part B cohorts, except the ovarian cancer cohort, for which these biopsies are 
mandatory.  Sites should confirm the availability of adequate tumor tissue with the site’s 
pathology laboratory.  For patients enrolled to NSCLC cohort of Part B, the on-treatment biopsy 
is optionalfor whom newly obtained samples cannot be obtained such as in cases of 
inaccessibility or patient safety concern, an archived specimen following most recent systemic 
treatment should be submitted if not restricted by local regulations.
Sites must confirm the availability of adequate tumor tissue for the new biopsy from the site’s 
pathology laboratory or adequate archived tumor tissue. Pretreatment formalin-fixed paraffin-
embedded (FFPE) tumor tissue should be submitted in a whole block.

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LY3022855
Attachment 1. Protocol JSCC Study Schedule
Assessments are to be performed at the times stipulated in the schedule and as clinically required 
in the management of the patient.
Screening/Baseline Assessments (Visit 0)
Relative Day Prior to 
Day 1 of Cycle 1
28
14
7
Comments
Written informed 
consent/assignment of 
patient identification 
number
X
ICF signed (prior to performance of any protocol-specific 
tests/procedures).
Review of eligibility 
criteria
X
Medical history
X
Physical examination
X
Full physical examination, including assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, GI, 
urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems.
Vital signs
X
BP, temperature, RR, and PR.  Includes height (at baseline only) 
and weight.
ECOG performance 
status
X
ECG (local)
X
Triplicate ECG will be obtained, on which QTcF must be <470 ms 
(calculated from one ECG using Fridericia’s Correction Formula 
and confirmed with 2 additional ECGs).
HIV screening (local)
X
Per institutional standards.
If done within 28 days prior to Cycle 1, Day 1, as part of standard 
of care, does not need to be repeated prior to the start of Cycle 1.
Hematology (local) 
X
Refer to Attachment 2.
Serum chemistry 
(central)
X
Refer to Attachment 2.
Urinalysis (local)
X
Refer to Attachment 2.
Coagulation (local)
X
Refer to Attachment 2.  Obtain prior to tumor biopsy.
Thyroid function 
(central)
X
Refer to Attachment 2.
Free T3 and free T4 will be measured only if TSH is abnormal or if 
there is clinical suspicion of an AE related to the endocrine system.
Pancreas function 
(central)
X
Refer to Attachment 2.
LVEF evaluation
X
Echocardiogram or MUGA scan.
Radiographic tumor 
assessment (CT/MRI)
X
If done within 28 d prior to Cycle 1, Day 1, as part of standard of 
care, does not need to be repeated prior to the start of Cycle 1.
Tumor measurement 
(palpable or visible)
X
CTCAE v4.0 grading 
(preexisting conditions)
X
To be reported only after study eligibility is confirmed.  Refer to 
Section 8.1.2.4 for reporting guidelines.
Concomitant 
medications
X
Tumor markers (local)
X
As clinically indicated.  For example, CEA in patients with 
colorectal cancer or CA125 in patients with ovarian cancer.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
Relative Day Prior to 
Day 1 of Cycle 1
28
14
7
Comments
Tumor tissue biopsy
X
For Part A (all cohorts) and Part B (ovarian cancer cohort only):  A 
newly obtained core or excisional biopsy of a tumor should be 
taken only after study eligibility is confirmed.  For the NSCLC 
cohort in Part B a newly obtained core or excisional biopsy should 
be obtained if an archived tumor sample following the most recent 
systemic therapy is not available.  Refer to the laboratory manual.
Archived tumor tissue
X
An archived tumor sample following most recent systemic 
treatment if not restricted by local regulations will be requested 
from all patients in Part B NSCLC cohort. If such an archived 
biopsy sample is not available, a new biopsy must be obtained for 
the patient to be eligible to participate in study.  Refer to the 
laboratory manual.
Whole blood for 
biomarkers
X
Refer to the laboratory manual.
Pregnancy test (local)
X
Applies only to women of childbearing potential.  Urine hCG or 
serum β-hCG is acceptable.
Abbreviations:  AE = adverse event; BP = blood pressure; CA125 = cancer antigen 125; CEA = carcinoembryonic 
antigen; CT = computed tomography (scan); CTCAE = Common Terminology Criteria for Adverse Events; ECG 
= electrocardiogram; ECOG = Eastern Cooperative Oncology Group; GI = gastrointestinal; hCG = human 
chorionic gonadotropin; HIV = human immunodeficiency virus; ICF = informed consent form; LVEF = left 
ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition (scan); PR = 
pulse rate; QTcF = QT interval corrected for heart rate using Fridericia’s Correction Formula; RR = respiration 
rate; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; v4.0 = Version 4.0 of CTCAE.

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LY3022855
On-Study Treatment and Post-Treatment (Follow-Up) Assessments for Combination Therapy:  LY3022855 plus Durvalumab
Note that a maximum of 12 months/26 doses of durvalumab treatment is permitted; last infusion at Week 50.
Screening procedures performed for safety within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
Rows with italicized font indicate that there is no planned assessment for the time frame shown on the page.
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Physical examination
X
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around 
infusions as follows (allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during 
(midway through), at the end, and 30 min after the end.
Around each durvalumab infusion (based on a 60-min 
infusion):  within 30 min prior to, during (approx. 30 min 
after start of infusion), and at the end (approx. 60 min 
after start of infusion).
1-h Observation period after durvalumab infusion:  at 30 
and 60 min after the end of the infusion (90 and 120 min 
after start of infusion) for the first durvalumab infusion
only, and for subsequent infusions as clinically indicated.
If the durvalumab infusion exceeds 60 min, monitoring of 
BP and PR should occur per the preceding principles or 
more frequently if clinically indicated.
ECOG performance status
X
Pregnancy test (local)
Every 12 wk (±7 d) after the first dose of study drug or 
according to local regulations or as clinically indicated, 
whichever is more frequent.  Urine hCG or serum β-hCG.
ECG (local)
X
Single ECG.  Obtain ECGs before any associated blood 
draws.  On dosing days, ECG should be taken within 2 h 
prior to the start of the LY3022855 infusion and at least 
one time point 0-3 h after the durvalumab infusion.  
Additional ECGs to be obtained as clinically indicated.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Hematology (local)
X
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs for 
dosing
X
X
X
X
Refer to Attachment 2.  Results must be available and 
reviewed before administering study drug.
Serum chemistry (central)
X
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
Refer to Attachment 2.  To be performed at Screening, at 
C1D1, and every 4 wk thereafter.  Additional assessments 
as clinically indicated.  Results need not be available 
before administering study drug.
Coagulation (local)
Refer to Attachment 2.  As clinically indicated.
Thyroid function (central)
X
Refer to Attachment 2.  Free T3 and free T4 will be 
measured only if TSH is abnormal or if there is clinical 
suspicion of an AE related to the endocrine system.
Pancreas function (central)
Refer to Attachment 2.
Tumor markers (local)
Pharmacogenetic sample
X
Refer to the laboratory manual.  Collect once.  Sample can 
be collected at any time, if not collected on C1D1.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
Immunogenicity
X
X
If at any time a patient experiences an IRR, attempt to 
obtain a blood sample for immunogenicity analysis as 
close to the onset of the event as possible, at the resolution 
of the event, and 30 d following the event.  A portion of 
the sample taken for immunogenicity testing may be used 
for PK analysis.
Myoglobin (local)
X
Refer to Attachment 2.  If serum CK Grade ≥2, test for 
serum and urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for 
reporting guidelines.
Concomitant medications
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.1 for dose frequency during Part A.
For LY3022855 and durvalumab:
  Part A doses:  Refer to Table JSCC.1.
  Part B doses and dose frequencies to be determined; 
refer to Section 7.2.2.2 for information.
Durvalumab administration
X
X
Pharmacokinetics
LY3022855
(predose on dosing days, unless 
noted otherwise)
X
X
2 h post-EOI 
C1D1 (±1 h)
X
24 h post-EOI
C1D1 (±4 h)
X
48 h post-EOI 
C1D1 (±4 h)
X
X
X
The date and the time of all samples must be clearly and 
accurately recorded.
EOI = end of infusion
Durvalumab
(predose on dosing days, unless 
noted otherwise)
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
X
X
Pharmacodynamics and tailoring
Serum
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
X
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
X
X
Gene expression analysis and other exploratory research.
Flow cytometry
Immunophenotyping #1
X
X
X
X
CD14 and CD16.
Immunophenotyping #2
X
X
X
X
TBNK & T cell subset/activation panels.
Immunophenotyping #3
X
MDSC panel.
Isoenzymes (central)
Refer to Attachment 2.  Obtain at additional time points, 
as clinically indicated.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 1
(Visit 1)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows 
are ±3 days, unless otherwise indicated.  On dosing days, 
all assessments to be performed preinfusion, unless stated 
otherwise.
Relative day within a 28-day cycle:
1
2
3
8
15
22
LVEF evaluation
Echocardiogram or MUGA scan.  Obtain at additional 
time points, as clinically indicated.
Radiographic tumor assessment 
(CT/MRI)
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22.
Tumor measurement (palpable or 
visible)
Tumor biopsy
For Part A (all cohorts) and Part B (ovarian cancer 
cohort only):  An on-treatment tumor core needle or 
excisional biopsy to be performed 6-8 wk after starting 
study treatment.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all assessments 
to be performed preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Physical examination
X
X
X
X
Targeted physical examination (on the basis of clinical 
observations and symptomatology).
Vital signs
X
X
X
X
BP, temperature, RR, PR, and weight.
Vital signs (BP, RR, and PR only) to be measured around 
infusions as follows (allowable window ±10 min):
Around each LY3022855 infusion:  prior to, during (midway 
through), at the end, and 30 min after the end.
Around each durvalumab infusion (based on a 60-min infusion):  
within 30 min prior to, during (approx. 30 min after start of 
infusion), and at the end (approx. 60 min after start of infusion).
1-h Observation period after durvalumab infusion:  at 30 and 60 
min after the end of the infusion (90 and 120 min after start of 
infusion) as clinically indicated.
If the durvalumab infusion exceeds 60 min, monitoring of BP and 
PR should occur per the preceding principles or more frequently if 
clinically indicated.
ECOG performance status
X
Pregnancy test (local)
Every 12 wk (±7 d) after the first dose of study drug or according 
to local regulations or as clinically indicated, whichever is more 
frequent.  Urine hCG or serum β-hCG.
ECG (local)
X
Single ECG.  Obtain ECGs before any associated blood draws.  
ECG should be taken within 2 h prior to the start of the 
LY3022855 infusion and at least one time point 0-3 h after the 
durvalumab infusion.  Additional ECGs to be obtained as 
clinically indicated.
Hematology (local)
X
X
X
X
Refer to Attachment 2.
Serum chemistry (local) - safety labs 
for dosing
X
X
X
X
Refer to Attachment 2.  Results must be available and reviewed 
before administering study drug.
Serum chemistry (central)
X
X
X
X
Refer to Attachment 2.
Urinalysis (local)
X
Refer to Attachment 2.  To be performed at Screening, at C1D1, 
and every 4 wk thereafter.  Additional assessments as clinically 
indicated.  Results need not be available before administering 
study drug.
Coagulation (local)
X
Refer to Attachment 2.  Obtain prior to tumor biopsy.  Additional 
assessments as clinically indicated.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all assessments 
to be performed preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Thyroid function (central)
X
Refer to Attachment 2.  Free T3 and free T4 will be measured only 
if TSH is abnormal or if there is clinical suspicion of an AE related 
to the endocrine system.
Pancreas function (central)
X
Refer to Attachment 2.
Tumor markers (local)
X
If clinically indicated.
Pharmacogenetic sample
Refer to the laboratory manual.  Collect once.  Sample can be 
collected at any time, if not collected on C1D1.
Immunogenicity
X
If at any time a patient experiences an IRR, attempts to obtain a 
blood sample for immunogenicity analysis as close to the onset of 
the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for 
immunogenicity testing may be used for PK analysis.
Myoglobin (local)
X
X
X
X
Refer to Attachment 2.  If serum CK Grade ≥2, test for serum and
urine myoglobin.
CTCAE v4.0 grading
X
X
X
X
Throughout study as needed.  Refer to Section 8.1.1 for reporting 
guidelines.
Concomitant medications
X
X
X
X
Throughout study as needed.
LY3022855 administration
Refer to Table JSCC.1 for dose frequency during Part A.
For LY3022855 and durvalumab:
  Part A doses:  Refer to Table JSCC.1.
  Part B doses and dose frequencies to be determined; refer to 
Section 7.2.2.2 for information.
Durvalumab administration
X
X
Pharmacokinetics
LY3022855
(predose on dosing days, unless 
noted otherwise)
X
X
X
2 h post-EOI 
C2D8 (±1 h)
X
24 h post-EOI 
C2D8 (±4 h)
X
48 h post-EOI 
C2D8 (±4 h)
X
The date and the time of all samples must be clearly and accurately 
recorded.
EOI = end of infusion
Durvalumab
(predose on dosing days, unless 
noted otherwise)
X
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Pharmacodynamics and tailoring
Serum
X
X
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Simultaneously 
with LY PK 
sample
X
Serum storage for correlative studies.
Plasma
X
Plasma storage for correlative studies.
Whole blood
X
X
Gene expression analysis and other exploratory research.
Flow cytometry
Immunophenotyping #1
X
X
X
CD14, CD16.
Immunophenotyping #2
X
X
X
TBNK & T cell subset/activation panels.
Immunophenotyping #3
X
MDSC panel.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
LY3022855 plus Durvalumab
Assessment (central or local laboratory 
indicated, if applicable)
Cycle 2
(Visit 2)
Comments
Except for the Cycle 1, Day 1 visit, allowable windows are ±3 
days, unless otherwise indicated.  On dosing days, all assessments 
to be performed preinfusion, unless stated otherwise.
Relative day within a 28-day cycle:
1
8
9
10
15
22
Isoenzymes (central)
X
Refer to Attachment 2.  Obtain at additional time points, as 
clinically indicated.
LVEF evaluation
X
Echocardiogram or MUGA scan.  Obtain at additional time points, 
as clinically indicated.
Radiographic tumor assessment
(CT/MRI)
X
Perform every 8 wk (±7 d), starting on Cycle 2, Day 22.
Tumor measurement (palpable or 
visible)
X
Tumor biopsy
X
For Part A (all cohorts) and Part B (ovarian cancer cohort only):  
An on-treatment tumor core needle or excisional biopsy to be 
performed 6-8 wk after starting study treatment; that is, at Cycle 2, 
between Days 8 and 22. For Part B (NSCLC cohort) an optional 
on-treatment tumor tissue should be collected from patients in the 
study where possible.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
Attachment 7.
Protocol JSCC Toxicity Management Guidelines
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non Immune-Mediated Reactions (Combination Therapy with LY3022855 and Durvalumab or LY3022855 and Tremelimumab) 
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:
4.
The event stabilizes and is controlled.
5.
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement.
6.
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.
It is recommended that management of irAEsimmune-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 (eg, 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 considered 
potentiallymanaged 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., 
myocarditis, or other similar events even if they are not currently noted in the 
guidelines – should implement 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 [eg, 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 (eg, infliximab) (also 
refer to the individual sections of the irAEimAEs 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 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 

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non Immune-Mediated Reactions (Combination Therapy with LY3022855 and Durvalumab or LY3022855 and Tremelimumab) 
General Considerations
Dose Modifications
Toxicity Management
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.
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).
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 (eg, 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.
Abbreviations:  AE = Adverse event; CTC = Common Toxicity Criteria; CTCAE = Common Terminology Criteria for Adverse Events; irAE = imAE = immune-relatedmediated
adverse event; IV = intravenous; NCI = National Cancer Institute; PO = By mouth.

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Myositis
Pneumonitis/Interstitial 
Lung Disease (ILD)
Any Grade
Grade 3 or higher
Any Grade
General Guidance
Permanently discontinue study 
drug/study regimen
General Guidance
For Any Grade:
−
Check urine or serum myoglobin or hold if serum or myoglobin 
are positive.
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 (eg, 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 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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LY3022855
general guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals, or anti-
PCPPJP treatment (refer to current NCCN guidelines for 
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 
[eg, 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 (eg, 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 
(eg, 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 patients is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals, and, in 
particular, anti-PCPPJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 
2B recommendation]).a
Diarrhea/EnterocolitisColitis
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 (eg, disease progression, other 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 

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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 (eg, 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 (eg, 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 perforation and refer to infliximab 
label for general guidance before using infliximab.
−
ConsultConsider, 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-
PCPPJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(Grade 3 diarrhea:
Grade 3
Permanently discontinue study 
For Grade 3 or 4:
−
Promptly initiate empiric IV methylprednisolone 2 to 

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stool frequency of ≥7 
over baseline per day;
Grade 4 diarrhea:
life-threatening 
consequences)
(Grade 3 colitis:
severe abdominal pain, 
change in bowel 
habits, medical 
intervention indicated, 
peritoneal signs;
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated)
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.
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 (eg 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-
PCPPJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Hepatitis 
(elevated LFTs)
Infliximab should not be used 
for management of immune-
related hepatitis.
Any Grade
General Guidance
For Any Grade:
−
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB.
−
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications).
−
For isolated AST elevations see below.
Grade 1
(AST or ALT > to 
ULN and ≤3 × 
.0×ULN and/or TB > 
to 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 to .0×ULN 
and ≤5 × .0×ULN 
and/or 

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 
For Grade 2:
−
Regular and frequent checking of LFTs (eg, every 1 to 2 days) 
until elevations of these are improving or resolved.
−
If no resolution to Grade ≤1 in 1 to 2 days, discussconsider, as 
necessary, discussing with study physician.

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TB >1.5 to ×ULN and 
≤3.0 × ×ULN)
baseline, resume study drug/study 
regimen after completion of steroid 
taper.
For asymptomatic Grade 2 AST (only 
if accompanied by Grade ≤ 1 ALT and 
Grade ≤ 1 TB and no change of ALT 
or TB from baseline levels):

Continue dosing with both 
LY3022855 and durvalumab or 
tremelimumab
−
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 workup 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-
PCPPJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
−
Monitor LFTs frequently (eg, every 1 to 2 days or as clinically 
indicated).
−
Consider hepatic consult
−
No steroids required
Grade 3 or 4
(Grade 3: AST or 
ALT >5 to 
20 × .0×ULN and
≤20.0×ULN and/or 
TB >3.0 to ×ULN and  
≤10 × .0×ULN)
(Grade 4: AST or 
ALT >20×ULN and/or 
TB >10×ULN)
For Grade 3:
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × 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 
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 (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-
PCPPJP treatment (refer to current NCCN guidelines for 

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do not downgrade to Grade ≤1 or 
baseline within 14 days
For asymptomatic Grade 3 AST up to 
≤8 × ULN (only if accompanied by 
Grade ≤ 1 ALT and Grade ≤ 1 TB and 
no change of ALT or TB from 
baseline levels)

Hold LY3022855, and 
continue dosing with 
durvalumab or tremelimumab.  

If AST downgrades to Grade 
≤2, after holding LY3022855,  
resume dosing with 
LY3022855 and durvalumab 
or tremelimumab. 

If Grade 3 AST recurs after 
resumption of dosing with 
both agents, hold LY3022855 
dosing. Continue dosing 
durvalumab or tremelimumab.  
Resume treatment with the 
combination of LY3022855 
and durvalumab or 
tremelimumab if AST remains 
asymptomatic and  
downgrades to Grade ≤2.
For elevations in transaminases 
>8 × ULN or elevations in bilirubin >5 × 
ULN, discontinue LY3022855 and 
durvalumab or tremelimumab 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 
treatment of cancer-related infections [Category 2B 
recommendation]).a
−
Monitor LFTs frequently (eg, every 1 to 2 days or as clinically 
indicated).
−
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications, history of alcohol intake).
−
Promptly seek hepatic consult as necessary. 
−
No steroids required.

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initial findings of cholestasis (ie, 
elevated alkaline P04) and in the absence 
of any alternative cause.b
For Grade 4:
Permanently discontinue LY3022855 
and durvalumab or tremelimumabstudy 
drug/study regimen.
Nephritis or renal 
dysfunction
(elevated serum creatinine)
Any Grade
General Guidance
For Any Grade:
−
Consult with nephrologist.
−
Monitor for signs and symptoms that may be related to changes 
in renal function (eg, 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 (eg, 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 
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 

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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drug/study regimen after completion 
of steroid taper.
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 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-
PCPPJP 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-
PCPPJP 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.
Grade 1
No dose modifications.
For Grade 1:
−
Consider symptomatic treatment, including oral antipruritics (eg, 

I5F-MC-JSCC(c) Phase 1 Oncology Protocol
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diphenhydramine or hydroxyzine) and topical therapy (eg, 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 (eg, 
diphenhydramine or hydroxyzine) and topical therapy (eg, 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, discussconsider, 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:
Permanently discontinue study 
drug/study regimen.
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-
PCPPJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
−
DiscussConsider, as necessary, discussing with study physician.
Endocrinopathy
(eg, hyperthyroidism, 
hypothyroidism, Type 1 
diabetes mellitus, 
Any Grade
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
General Guidance
For Any Grade:
−
ConsultConsider consulting an endocrinologist for endocrine 
events.
−
Consider, as necessary, discussing with study physician.
−
Monitor patients for signs and symptoms of endocrinopathies. 

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hypophysitis, hypopituitarism, 
and adrenal insufficiency); 
exocrine event of 
amylase/lipase increased also 
included in this section)
v4.03 for defining the 
CTC grade/severity)
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 (eg, 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 labs depending on suspected 
endocrinopathy.and related labs (eg, blood glucose and ketone 
levels, HbA1c).
−
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 (eg, 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.
−
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 
endocrinology consult.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 
For Grade 2 (including those with symptomatic endocrinopathy):
−
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids.
−
Initiate hormone replacement as needed for management.
−
EvaluateConsult endocrinologist to guide evaluation of
endocrine function, and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider pituitary 

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resumed once event stabilizes and after 
completion of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (eg, 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.
scan.
−
For all patients with abnormal endocrine work up, except for 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an  endocrinologist, consider short-term 
corticosteroids (eg, 1 to 2 mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment with relevant 
hormone replacement (eg, levothyroxine,eg, hydrocortisone, or 
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 the patient ispatients on steroids are improving, gradually 
taper steroids immunosuppressive steroids (as appropriate and 
with guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PCPPJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
−
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.
For Grade 3 or 4:
−
Consult endocrinologist.
−
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 may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids.
−
or Type 1 DM, and as guided by an  endocrinologist, promptly 
initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent
−
Administer, as well as relevant hormone replacement therapy as 
necessary.(eg, hydrocortisone, sex hormones).
−
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 

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2. The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgment.
3. Doses of prednisone are ≤10 mg/day 
or equivalent.
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 the patient ispatients 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-PCPPJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
Discuss with study physician.
Neurotoxicity
(to include but not be limited 
to limbic encephalitis and 
autonomic neuropathy, 
excluding Myasthenia Gravis 
and Guillain-Barre)
Any Grade
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Patients should be evaluated to rule out any alternative etiology 
(eg, disease progression, infections, metabolic syndromes, or 
medications).
−
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness).
−
Consider appropriate diagnostic testing (eg, 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 
For Grade 2:
−
DiscussConsider, as necessary, discussing with the study 
physician.
−
Obtain neurology consult.
−
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, 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 (eg, 

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Grade 3 or 4.
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid taper.
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 
irAEimAE does not resolve to Grade ≤1 
within 30 days.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
DiscussConsider, 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 (eg, IV IG).
−
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 
(eg, 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 (eg, electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 

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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:
−
DiscussConsider, 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 unless the symptoms are very minor 
and stable..
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:
−
DiscussConsider, 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 (eg, gabapentin or duloxetine).
MYASTHENIA GRAVIS:
o
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.
o
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.
o
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.

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GUILLAIN-BARRE:
o
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective.
o
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 
irAEimAE 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):
−
DiscussConsider, as necessary, discussing with study physician.
−
Recommend hospitalization.
−
Monitor symptoms and obtain neurological consult.
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist.
o
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG.
o
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:
o
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective.
o
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 of breath, 
peripheral edema). As some symptoms can overlap with lung 

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toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (eg, 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 workup should include clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram (ECHO), monitoring of 
oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory workup 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 (eg, 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 workup 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 workup 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 
or exertion; 
intervention indicated)
(Grade 4: Life-
- 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, 
permanently discontinue study 
drug/study regimen.
If Grade 3-4, permanently discontinue 
study drug/study regimen.
For Grades 2 to 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 (eg, oxygen).
−
If 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 
(eg, 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 

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threatening 
consequences; urgent
intervention indicated 
[eg, continuous IV 
therapy or mechanical 
hemodynamic 
support])
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.
−
Initial workup should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory workup as indicated, including a 
number of possible rheumatological/antibody tests (ie, 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 

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(eg, 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 (eg, prednisone 1 to 2 mg/kg/day PO or IV equivalent); 
if no improvement within 3 to 5 days, continue 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 
(eg, 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 
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 

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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.
Abbreviations:  AChE = Acetylcholine esterase; ADL = Activities of daily living; AE = Adverse event; ALP = Alkaline phosphatase test; ALT = Alanine aminotransferase; 
AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; CT = Computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; HbA1C = 
glycated haemoglobin; ILD = Interstitial lung disease; irAE = imAE = immune-relatedmediated adverse event; IG = Immunoglobulin; IV = Intravenous; 
GI = Gastrointestinal; LFT = Liver function tests; LLN = Lower limit of normal; MRI  = Magnetic resonance imaging; NCI  = National Cancer Institute; NCCN 
= National Comprehensive Cancer Network; PCP ;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.
insufficiency.
For Grade 4:
- Permanently discontinue study 
drug/study regimen.
immunosuppressive therapy such as TNF inhibitors 
(eg, 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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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 (eg, 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 (eg, 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 (eg, IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid).
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; IM = intramuscular; IV = intravenous; NCI = National Cancer Institute.

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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 (ie, 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.
For asymptomatic Grade 2 creatine kinase levels:

Hold treatment with both study agents.  Perform 
diagnostic evaluation 
If results show no evidence of end organ damage, including 
myositis and rhabdomyolysis, resume treatment with both agents.
Treat accordingly, as per institutional standard.
1.
Perform diagnostic evaluation (serum and urine myoglobin, 
BUN and creatinine) 
Continue to monitor CK, serum and urine myoglobin, BUN and 
creatinine Weekly until creatine kinase levels return to ≤ Grade 1
or as clinically indicated.
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.
For asymptomatic Grade 3 creatine kinase levels:
Hold treatment with both LY3022855 and durvalumab or 
tremelimumab. Perform diagnostic evaluation. 

For Grade 3 elevations in CK ≤ 8X ULN with a 
diagnostic evaluation showing NO evidence of end 
organ damage including myositis or rhabdomyolysis, 
resume treatment with both agents. 

For Grade 3 elevations in CK > 8X ULN with a 
diagnostic evaluation showing NO evidence of end 
organ damage including myositis or rhabdomyolysis, , 
hold LY3022855 and resume durvalumab or 
Treat accordingly, as per institutional standard.

Perform diagnostic evaluation (serum and urine 
myoglobin, BUN and creatinine).  

Continue to monitor CK, serum and urine myoglobin, 
BUN and creatinine Weekly until CK levels return to ≤ 
Grade 1 or as clinically indicated.

Treat accordingly as per institutional standard, perform a 
full diagnostic evaluation and if there is any evidence of 
potential immune-mediated end organ damage, follow the 
guidelines for irAE management contained in this 
attachment.

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Non-Immune-Mediated Reactions
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
tremelimumab after discussion with sponsor.
If CK decreases to ≤ 8x ULN after holding LY3022855, resume 
treatment with LY3022855 and durvalumab or tremelimumab.  
o
If CK remains >8X ULN after holding 
LY3022855, permanently discontinue both 
LY3022855 and durvalumab or 
tremelimumab and discuss additional 
treatment measures with sponsor. 
In case of myositis or rhabdomyolysis, permanently discontinue 
treatment with both study agents.

  Continue to monitor CK, serum and urine myoglobin, 
BUN and creatinine weekly until CK levels return to ≤ 
Grade 1 or baseline. 
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.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.”
Abbreviations:  AE = Adverse event; BUN = elevated serum blood urea nitrogen; CK = creatinine; CTCAE = Common Terminology Criteria for Adverse Events; 
NCI = National Cancer Institute.

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Attachment 8.
Protocol JSCC Durvalumab and Tremelimumab AESIs
An adverse event of special interest (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.
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event 
(AE) that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the irAE. 
If the investigator has any questions in regards to an AE being an irAE, the investigator should 
promptly contact the study physician.
AESIs observed with durvalumab and tremelimumab include:
•
Diarrhea / Colitis
•
Pneumonitis / ILD (interstitial lung disease)
•
ALT/AST increases / hepatitis / hepatotoxicity
•
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis)
•
Endocrinopathy (i.e. events of hypophysitis, hypopituitarism, adrenal insufficiency, 
diabetes insipidus, type I diabetes mellitus and hyper- and hypothyroidism)
•
Rash / Dermatitis
•
Nephritis / Blood creatinine increases
•
Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase, increased serum 
amylase)
•
Other inflammatory responses that are rare with a potential immune-mediated etiology 
include, but are not limited to, myocarditis, pericarditis, myositis/polymyositis, and 
uveitis.
Further information on these risks (eg, presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab IBs.  For durvalumab and tremelimumab, AESIs will 
comprise the following:

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Pneumonitis
AEs of pneumonitis are also of interest, as pneumonitis has been observed with use of anti-PD-1 
mAbs (but not with anti-PD-L1 mAbs).  Initial work-up should include a high-resolution CT 
scan, ruling out infection, and pulse oximetry.  Pulmonary consultation is highly recommended.
Guidelines for the management of patients with immune-mediated events including pneumonitis 
are outlined in Section 7.2.4.
Infusion reactions
AEs of infusion reactions (also known as infusion-related reactions [IRRs]) are of special interest 
and are defined, for the purpose of this protocol, as all AEs occurring from the start of 
investigational product infusion up to 48 hours after the infusion start time.  For all infusion 
reactions, if they qualify as SAEs, they should be reported as SAEs as described in Section 
8.1.2.1.
Hypersensitivity reactions
Hypersensitivity reactions as well as IRRs have been reported with anti-PD-L1 and anti-PD-1 
therapy (Brahmer et al. 2012).  As with the administration of any foreign protein and/or other 
biologic agents, reactions following the infusion of mAbs can be caused by various mechanisms, 
including acute anaphylactic (IgE-mediated) and anaphylactoid reactions against the mAbs and 
serum sickness.  Acute allergic reactions may occur, may be severe, and may result in death.  
Acute allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, 
urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, 
fatigue, headache, hypertension, myalgia, vomiting, and unresponsiveness.
Guidelines for management of patients with hypersensitivity (including anaphylactic reaction) 
and IRRs are outlined in Section 7.2.4.
Hepatic function abnormalities (hepatotoxicity)
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN.  Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other.  Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (for example, cholelithiasis and 
bile duct obstruction with distended gallbladder) or an agent other than the investigational 
product.
Guidelines for management of patients with hepatic function abnormality are outlined in Section 
7.2.4.

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Gastrointestinal disorders
Diarrhea/colitis is the most commonly observed treatment-emergent SAE when tremelimumab is 
used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.
Guidelines on management of diarrhea and colitis in patients receiving study treatment are 
provided in Section 7.2.4.
Endocrine disorders
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Section 7.2.4.
Pancreatic disorders
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Section 7.2.4.
Neurotoxicity
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Section 7.2.4.
Nephritis
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to changes in 
renal function (eg, routine urinalysis, elevated serum blood urea nitrogen [BUN] and creatinine, 
decreased creatinine clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc).
Patients should be thoroughly evaluated to rule out any alternative etiology (eg, disease 
progression, infections, etc).
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.
Guidelines for the management of patients with immune-mediated neurotoxic events are 
provided in Section 7.2.4.

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Immune-related adverse events
Based on the mechanism of action of durvalumab and tremelimumab leading to T cell activation 
and proliferation, there is a possibility of observing irAEs during the conduct of this study.  
Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-
1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, 
dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (Hodi et al. 2010, 
Brahmer et al. 2012, Topalian et al. 2012).  These AEs are inflammatory in nature and can affect 
any organ.  With anti-PD-L1 and anti-CTLA-4 combination therapy, the occurrence of 
overlapping or increasing cumulative toxicities that include irAEs could potentially occur at 
higher frequencies than with either durvalumab or tremelimumab monotherapy.  Patients should 
be monitored for signs and symptoms of irAEs.  In the absence of an alternate etiology (for 
example, infection or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and endocrinopathy.  In addition to 
the dose modification guidelines provided in Section 7.2.4, it is recommended that irAEs are 
managed according to the general treatment guidelines outlined for ipilimumab (Weber et al. 
2012).  These guidelines recommend the following:
•
Patients should be evaluated to identify any alternative etiology.
•
In the absence of a clear alternative etiology, all events of an inflammatory nature should 
be considered immune related.
•
Symptomatic and topical therapy should be considered for low-grade events.
•
Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event.
•
More potent immunosuppressives should be considered for events not responding to 
systemic steroids (for example, infliximab or mycophenolate).
If the investigator has any questions in regards to an AE being an irAE, the investigator should 
immediately contact the study physician.
Myocarditis
A variety of clinical presentations, diagnostic evidence (laboratory, imaging, histopathology), 
and resulting diagnoses have been described in cases of myocarditis in the literature for other 
immune checkpoint inhibitors, including heart failure, brady- and tachyarrhythmias, and acute 
coronary syndrome-like presentations without evidence of ischemia.  Investigators should be 
aware of such rare, but severe immune-mediated adverse events including myocarditis with its 
presenting signs/symptoms (eg, decreased ejection fraction, arrhythmias, in particular 
occurrences of atrioventricular block).
Investigators should adhere to the Toxicity Management Guidelines by performing a thorough 
evaluation to rule out alternative etiologies and initiating prompt treatment with steroids and 
modification of study drug/dose regimen depending on the severity of the event.
Guidelines for the management of patients with myocarditis are provided in Attachment 7.

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LY3022855
Myositis/Polymyositis
Investigators should adhere to the Toxicity Management Guidelines by performing a thorough 
evaluation to rule out alternative etiologies and initiating prompt treatment with steroids and 
modification of study drug/dose regimen depending on the severity of the event. Guidelines for 
the management of patients with myositis/polymyositis are provided in Attachment 7.

Leo Document ID = fa3901a0-21cf-4b79-b05c-07e280b3d13c
Approver: 
Approval Date & Time: 02-Feb-2018 15:46:37 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 02-Feb-2018 17:47:54 GMT
Signature meaning: Approved
PPD
PPD