A Phase1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors
Phase: PHASE1
Conditions: Pancreatic Cancer, Colorectal Cancer, Non-Small Cell Lung Cancer
Sponsor: AmMax Bio, Inc.

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 1 of 117
CONFIDENTIAL
Title:  A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in 
Combination With Pembrolizumab in Select Advanced Solid Tumors
Amgen Protocol Number (AMG 820) 20150195
Clinical Study Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320
Telephone: (805) 447-1000
Key Sponsor Contact(s):
, MD MS
Medical Science Medical Director
Telephone: 
Clinical Research Study Manager
Telephone: 
Date:
Amendment 1 Date:
Amendment 2 Date:
11 December 2015
03 October 2016
15 June 2018
Confidentiality Notice
This document contains confidential information of Amgen Inc.
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent.
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc.
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; for all other countries, 1-805-447-1000.
NCT Number: NCT02713529
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 2 of 117
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled “A Phase 1b/2 Study Assessing Safety and 
Anti-tumor Activity of AMG 820 in Combination with Pembrolizumab in Select Solid 
Tumors,” dated 15 June 2018, and agree to abide by all provisions set forth therein.  
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.
I agree to ensure that Financial Disclosure Statements will be completed by:

me (including, if applicable, my spouse [or legal partner] and dependent children)

my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children)
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status.
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
Signature
Name of Investigator
Date (DD Month YYYY)

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 3 of 117
CONFIDENTIAL
Protocol Synopsis
Title:  A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in Combination 
with Pembrolizumab in Select Advanced Solid Tumors
Study Phase:  1b/2  
Indication:  Colorectal cancer (CRC), pancreatic cancer and non-small cell lung cancer 
(NSCLC), and other indications dependent on emerging data
Hypotheses:

AMG 820 in combination with pembrolizumab is safe and well tolerated when administered in 
subjects with select advanced solid tumors

AMG 820 can enhance the anti-tumor activity observed with pembrolizumab alone and/or 
overcome lack of response to pembrolizumab monotherapy in subjects with select advanced 
solid tumors
Primary Objective:

Evaluate the safety and tolerability of AMG 820 administered in combination with 
pembrolizumab in subjects with select advanced solid tumors

Evaluate the objective response rate (ORR) of AMG 820 and pembrolizumab combination as 
per irRECIST in subjects with select advanced solid tumors
Secondary Objective(s):  

Evaluate the anti-tumor activity of AMG 820 and pembrolizumab combination in select 
advanced solid tumors by assessing
o
ORR per RECIST1.1
o
time to response (TTR), duration of response (DOR), and time to progression (TTP) 
o
progression free survival (PFS) and overall survival (OS) at 6 and 12 months

Characterize the pharmacokinetics (PK) of AMG 820 after intravenous (IV) infusion 
administration of AMG 820 in combination with pembrolizumab

Evaluate the relationship between the immune infiltrate status in pre-study tumor biopsies vs. 
clinical response
Primary Endpoint:  

Dose limiting toxicities (DLT), treatment-emergent adverse events, treatment-related adverse 
events and clinically significant changes in vital signs, physical examinations, and clinical
laboratory tests

ORR as per irRECIST in subjects treated at the recommended combination dose
Secondary Endpoint(s):

Objective response (OR) as per RECIST 1.1; TTR, DOR and TTP; OS and PFS at 6 and 
12 months

PK parameters for AMG 820 including, but not limited to, maximum observed concentration 
(Cmax) and minimum observed concentration (Cmin). In addition, area under the 
concentration-time curve (AUC) and, if feasible, half-life (t1/2) for AMG 820.

CD4, CD8 & CD68 cells numbers in fresh pre-treatment biopsies
Study Design:  This is a multi-center Phase 1b/2 study testing the combination of AMG 820 and 
pembrolizumab in subjects with select advanced solid tumors. Phase 1b of the study (part 1) will 
have a 6+3 design aimed at assessing the safety of the selected starting dose of AMG 820 in 
combination with pembrolizumab. Phase 2 of the study (part 2) will further evaluate safety and
test whether AMG 820 can enhance the anti-tumor activity observed historically with 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 4 of 117
CONFIDENTIAL
pembrolizumab alone and/or overcome lack of response to pembrolizumab monotherapy in 
subjects with select solid tumors.
Part 1: Up to 3 cohorts will be evaluated for safety in Part 1. The initial cohort will treat subjects 
who have select advanced solid tumors with 1400 mg AMG 820 plus 200 mg pembrolizumab 
every three weeks (Q3W) using a 6+3 design. 

If 0 or 1 of the initial 6 evaluable subjects experience a dose-limiting toxicity (DLT) then the 
dose combination will be determined to be tolerable and Part 2 initiated. The study Part 1 
DLT period is 21 days.

If 2 of the initial 6 evaluable subjects experience a DLT then 3 additional evaluable subjects 
will be enrolled. 

If 3 or more of the evaluable subjects experience a DLT (eg, 33% or higher with 9 evaluable 
subjects) then the dose combination will be determined to be non-tolerable and a second 
Part 1 cohort will be enrolled to test a decreased dose of AMG 820 in combination with 
200 mg pembrolizumab. Further degree of dose modification and/or schedule of 
administration will be decided based on analysis of emerging safety and PK data.
Part 2: The evaluation of safety and efficacy in this part will include 6-9 subjects from Part 1 who
have been treated with the recommended combination dose, and will enroll additional subjects 
with select solid tumors up to 185 subjects overall. Part 2 will have 5 groups, which will be 
evaluated using a Simon two-stage design. Analysis of data in Part 2 will be done separately for 
each group (Group 1, 2, 3, 4a, 4b).

Group 1 will enroll up to 43 advanced MMR-proficient CRC subjects who are naïve to 
anti-PD-1/PD-L1/CSF-1/CSF-1R therapies. Eighteen (18) subjects will be enrolled during the 
first stage and treated with the AMG 820 plus pembrolizumab combination. If only 2 or fewer 
subjects have an objective response per irRECIST then further enrollment may be 
discontinued; otherwise, enrollment up to 43 subjects will occur.

Group 2 will enroll up to 29 advanced pancreatic cancer subjects who are naïve to 
anti-PD-1/PD-L1/CSF-1/CSF-1R therapies. Ten (10) subjects will be enrolled during the first 
stage and treated with the AMG 820 plus pembrolizumab combination. If no subjects have 
an objective response per irRECIST then further enrollment may be discontinued; otherwise,
enrollment up to 29 subjects will occur.

Group 3 will enroll up to 55 advanced NSCLC subjects with low (< 50%) tumor 
PD-L1- expression who are naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R agents.  
Nineteen (19) subjects will be enrolled first during the first stage and treated with the 
AMG 820 plus pembrolizumab combination. If 3 or fewer subjects have an objective 
response per irRECIST then further enrollment may be discontinued; otherwise, enrollment 
up to 55 subjects will occur.

Group 4 will enroll up to 58 NSCLC subjects who have not responded to or have relapsed 
during monotherapy with anti-PD-1/PD-L1 agents, and are anti-CSF-1/CSF-1R naïve. These 
subjects will be further distributed equally between two sub-groups (4a and 4b) depending on 
the  PD-L1 expression in the tumor tissue: high (≥50%) and low (< 50%) expression. 
Ten (10) subjects per subgroup will be enrolled first, during the first stage. If no objective 
response per irRECIST is seen in either of the subgroups then further enrollment may be 
discontinued; otherwise, enrollment up to 58 subjects will occur.
Sample Size:  
It is anticipated that 67 to 197 subjects will be enrolled overall in this study. 
Part 1 will enroll 6 to 18 evaluable subjects. The sample size in Part 1 is based on practical 
consideration, and it is consistent with conventional oncology studies with the objective to 
evaluate the safety and tolerability of a treatment combination.  With 6 subjects in a cohort, there 
is a 47-91% probability of observing at least one DLT if the true DLT rate is 10-33%. 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 5 of 117
CONFIDENTIAL
Part 2 evaluation of efficacy will include at least 6 subjects from part 1 who have been treated 
with the recommended combination dose, and will enroll additional subjects with CRC, pancreatic 
cancer and NSCLC up to a maximum of 185 subjects overall. The sample size in each group 
evaluated in Part 2 is chosen to test whether AMG 820 can enhance the anti-tumor activity 
observed historically with pembrolizumab alone and/or overcome lack of response to 
pembrolizumab monotherapy. Other indications may be included dependent on emerging data.
Summary of Subject Eligibility Criteria:  
Subjects ≥ 18 years of age with pathologically documented, definitively diagnosed, advanced 
select solid tumors that are refractory to standard treatment, or the subjects have been intolerant 
to or refuse the standard treatment (certain prior therapies are restricted as per the study design) 
with no anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy,
investigational agent) within 28 days prior to start of treatment and no active autoimmune 
disease. Once consented to the study, subjects will undergo safety tests and provide a medical 
history to confirm they meet all requirements of the study.
For a full list of eligibility criteria, please refer to Section 4.1 through Section 4.2.
Investigational Product
Amgen Investigational Product Dosage and Administration:
AMG 820 will be manufactured and packaged by Amgen Inc. AMG 820 will be presented as a 
sterile, clear, colorless to slightly yellow frozen liquid in 20 mL glass vials.  Each glass vial will 
contain 3.0 mL of AMG 820 with a concentration of 70 mg/mL.
The starting dose for AMG 820 will be 1400mg administered via IV infusion Q3W (±3 days). 
AMG 820 will be administered in combination with pembrolizumab. AMG 820 will be administered 
on the same schedule as pembrolizumab and will be administered first. Further adjustments of 
the AMG 820 dose level will be evaluated as per the part 1 design based on the emerging safety
data.
Refer to Sections 6.2.1.1.
Non-Amgen Investigational Product Dosage and Administration:
Pembrolizumab will be manufactured by Merck. Pembrolizumab is supplied in 100 mg/4mL vials 
(25 mg/mL) solution for intravenous infusion.  Pembrolizumab will be administered at a dose of 
200 mg intravenously Q3W (±3 days).  Pembrolizumab will be administered on the same 
schedule as AMG 820 and will follow administration of AMG 820. Pembrolizumab infusion is to 
begin 15 minutes following the end of the AMG 820 infusion.
Both investigational products will be administered at the study center by a qualified staff member.  
A physician must be available at the time of administration of investigational product.
Refer to Section 6.2.1.1.
Procedures:  
After written informed consent has been obtained, all screening tests and procedures will be 
performed within 28 days prior to administration of the first dose of AMG 820 and/or 
pembrolizumab, unless otherwise noted.  The following procedures will occur per the Schedule of 
Assessments: medical, surgical and medication history, physical examination and vital signs, 
body weight, height, ECOG performance status, 12-lead electrocardiogram (ECG), recording of 
concomitant medications, review of adverse events, disease related events and serious adverse 
events. Blood will be collected for local laboratory testing including: chemistry, hematology, 
prothrombin time (PT) or international normalization ratio (INR) and partial thromboplastin time 
(PTT) or activated PTT (aPTT), endocrine function test, hepatitis B surface antigen, hepatitis B 
core antibody, hepatitis C virus antibody and human immunodeficiency virus (HIV).  Urine will be 
collected for urinalysis. In females of childbearing potential urine or serum pregnancy test will be 
performed locally. Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion. Central laboratory tests include: blood for biomarker analysis, 
anti-pembrolizumab antibodies, anti-AMG 820 antibodies and AMG 820 and pembrolizumab 
pharmacokinetics (PK). Formalin-fixed paraffin-embedded tumor tissue and fresh biopsied tumor 
tissue from either the primary tumor or a metastatic lesion and the associated pathology reports 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 6 of 117
CONFIDENTIAL
will be collected and submitted to the central laboratory. Radiographic (computed tomography 
[CT] or magnetic resonance imaging [MRI]) scans and tumor assessment will also be performed. 
AMG 820 and pembrolizumab will be administered at day 1 and Q3W (± 3 days) thereafter in 
combination.
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 5).  
Statistical Considerations:  
All subjects who are enrolled and receive at least one administration of AMG 820 will be included 
in the analysis, unless otherwise specified. 
During Part 1, safety data will be reviewed on an ongoing basis. Amgen, in consultation with the 
site investigators, will review in Dose Level Review Meetings (DLRMs) all available accumulating 
data, by cohort, prior to making dosing decisions.
The analysis of efficacy endpoints for Part 2 will be done and presented by group and sub-group, 
as appropriate. Efficacy data from Part 1 subjects may be combined with data from Part 2, as 
appropriate.  The proportion of subjects with objective response per irRECIST (irCR or irPR) and 
RECIST1.1 (CR or PR) criteria with corresponding 90% and 95% CI will be calculated. and 
tabulated for subjects treated at the recommended dose combination. Additional efficacy related 
endpoints (TTR, DOR, TTP, PFS at 6 and 12 months, and OS at 12 months) will be listed per 
patient. Kaplan Meier estimates may also be further presented, if data allows.
Descriptive statistics will be provided for selected demographics, safety, PK, PD and biomarker 
data by dose, group, sub-group and time as appropriate. Descriptive statistics on continuous 
data will include means, medians, standard deviations and ranges, while categorical data will be 
summarized using frequency counts and percentages.
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor:  
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Tel: 805-447-1000
Fax: 805-499-9495

Product:  AMG 820
Protocol Number:  20150195
Date:  10 May 2018
Page 7 of 117
CONFIDENTIAL
Study Design and Treatment Schema
EOT = End of Treatment
a AMG 820 1400 mg will be administered intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days).  AMG 820 will be dosed first.  
Pembrolizumab infusion will be started 15 min after completion of the AMG 820 infusion.
b Pre-specified de-escalation nominal dose levels shown above.  Intermiediate dose levels may be used based on review of cohort DLT period safety data by the DLRT
c Long-term follow-up every 12 weeks (± 28 days) until approximately 12 months after subject enrolled.
PART 1
Screening
CRC, Pancreatic Cancer, NSCLC
Enrollment (n = 6 – 18)
AMG 820 (1100 mg IV)b
+
Pembrolizumab (200 mg IV)b
End of Treatment and Safety Follow-up
Visit
Potential dose de-escalation 
cohorts may occur based on 
emerging safety data during 
study Part 1
AMG 820 (800 mg IV)b
+
Pembrolizumab (200 mg IV)b
AMG 820 (1400 mg IV) a
+
Pembrolizumab (200 mg IV) a
Treatment period
Long Term Follow-up
135 (+7) days 
after EOT
Every 12 
weeksc
28 Days

Product:  AMG 820
Protocol Number:  20150195
Date:  10 May 2018
Page 8 of 117
CONFIDENTIAL
EOT = End of Treatment
a AMG 820 dose level for part 2 will be determined during study Part 1
b AMG 820 will be administered intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days).  AMG 820 will be dosed first.  Pembrolizumab 
infusion will be started 15 min after completion of the AMG 820 infusion.
c Long-term follow-up every 12 weeks (± 28 days) until approximately 12 months after subject enrolled.
PART 2 – DOSE EXPANSION
Screening
CRC, Pancreatic, NSCLC
Enrollment
End of Treatment and Safety Follow-up
Visit
Naïve to 
anti-PD-1/PD-L1/CSF-1/CSF-1R 
treatment
Group 1: CRCMMR-proficient (n = 18)
Treatment period
Group 2: Pancreatic (n = 10)
Refractory/ relapsing on
anti-PD-1/PD-L1 + naïve to 
CSF-1/CSF-1R 
treatment
Group 4a: NSCLCPD-L1 low (n = 10)
Group 4b: NSCLCPD-L1 high (n = 10)
Group 1: CRCMMR-proficient (43 - n)
Group 2: Pancreatic (29 - n)
Long Term Follow-up
135 (+7) days 
after EOT
Every 12 
weeksc
28 Days
AMG 820 (Dose TBD)a
+
Pembrolizumab (200 mg IV)b
Group 3: NSCLCPD-L1 low (n = 19)
Group 2: NSCLCPD-L1 low (55 - n)
Group 4a: NSCLCPD-L1 low (29 - n)
Group 4b: NSCLCPD-L1 high (29 - n)

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 9 of 117
CONFIDENTIAL
Study Glossary
Abbreviation or Term
Definition/Explanation
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
CR
complete response
CRC
colorectal cancer
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CSF-1
Colony Stimulating Factor 1
CSF-1R
Colony Stimulating Factor 1 Receptor
DILI
drug-induced liver injury
DLRM
Dose Level Review Meeting
DLRT
Dose Level Review Team
DLT
dose limiting toxicity
dMMR
deficit in mismatch repair genes
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
End of Study for 
Individual Subject
defined as the last day that protocol-specified procedures are
conducted for an individual subject (ie, the date the subject 
withdraws full consent from the study, completes the safety follow-up 
visit or long-term follow-up [whichever is later] or death).
End of Study (primary 
completion)
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint(s).
End of Study (end of trial) defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes multiple 
parts (eg, safety follow-up or survival assessment), the end of study 
would include these additional parts
End of Treatment
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject
Heart rate
number of cardiac cycles per unit of time
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 10 of 117
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
IL
interleukin
ILD
interstitial lung disease
INR
international normalization ratio
IPIM
Investigational Product Instruction Manual
IRB/IEC
institutional review board/independent ethics committee
irCR
Immune-related complete response
irPR
Immune-related partial response
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors 
(RECIST) 
irSD
Immune-related stable disease
irPD
Immune-related progressive disease
IV
intravenous
LDH
lactate dehydrogenase
MRI
magnetic resonance imaging
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death-1
PD-L1
programmed death ligand 1
PET
positron emission tomography
PFS
progression free survival
PK
pharmacokinetics
PR
partial response
PR Interval
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG
PT
prothrombin time
PTT/aPTT
partial thromboplastin time/activated partial thromboplastin time
QW
every week
Q2W
every two weeks
Q3W
every three weeks
QRS interval
QRS interval the interval between the Q wave and the S wave in the 
heart's electrical cycle as measured by ECG; represents the time it 
takes for the depolarization of the ventricles

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 11 of 117
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
QT interval
QT interval is a measure of the time between the start of the Q wave 
and the end of the T wave in the heart's electrical cycle as measured 
by ECG
QTc interval
QT interval corrected for heart rate using accepted methodology
RECIST
Response Evaluation Criteria in Solid Tumor
SD
stable disease
Source Data
information from an original record or certified copy of the original 
record containing patient information for use in clinical 
research. The information may include, but is not limited to, clinical 
findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents (original records or certified copies). 
(ICH Guideline (E6)).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value.
Study Day 1
defined as the first day that protocol-specified investigational 
product(s)/protocol required therapies is/are administered to the 
subject
TAM
tumor associated macrophage
TIM
tumor infiltrating macrophage
TSH
thyroid stimulating hormone
TTP
time to progression
TTR
time to response
ULN
upper limit of normal

Product:  AMG 820 
Protocol Number:  20150195 
Date:  15 June  2018 
Page 12 of 117 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 7 
Study Glossary ................................................................................................................ 9 
1. 
OBJECTIVES ....................................................................................................... 17 
1.1 
Primary ..................................................................................................... 17 
1.2 
Secondary ................................................................................................. 17 
1.3 
Exploratory ................................................................................................ 17 
2. 
BACKGROUND AND RATIONALE ...................................................................... 17 
2.1 
Disease and Background .......................................................................... 17 
2.1.1 
c-fms PATHWAY, TUMOR ASSOCIATED 
MACROPHAGES (TAMs) and AMG 820 ................................... 17 
2.1.2 
PD-1 AND PD-L1 inhibitors ....................................................... 19 
2.1.3 
Metastatic Colorectal Cancer ..................................................... 19 
2.1.4 
Advanced Pancreatic Cancer .................................................... 21 
2.1.5 
Non-Small Lung Cancer (NSLC)................................................ 23 
2.2 
AMG 820 Background ............................................................................... 24 
2.2.1 
AMG 820 Clinical Experience .................................................... 25 
2.2.2 
AMG 820 Pharmacokinetics ...................................................... 25 
2.2.3 
AMG 820 Pharmacodynamics ................................................... 26 
2.2.4 
AMG 820 Dose Rationale .......................................................... 26 
2.3 
Risk Assessment ....................................................................................... 27 
2.4 
Non-Amgen Medicinal Product Background: Pembrolizumab .................... 27 
2.5 
Rationale ................................................................................................... 28 
2.6 
Clinical Hypotheses ................................................................................... 28 
3. 
EXPERIMENTAL PLAN ........................................................................................ 29 
3.1 
Study Design ............................................................................................. 29 
3.1.1 
Phase 1b Study Design (Part 1) ................................................ 30 
3.1.2 
Phase 2 Study Design ............................................................... 31 
3.2 
Number of Sites ........................................................................................ 32 
3.3 
Number of Subjects ................................................................................... 32 
3.4 
Replacement of Subjects .......................................................................... 33 
3.5 
Estimated Study Duration .......................................................................... 33 
3.5.1 
Study Duration for Subjects ....................................................... 33 
3.5.2 
End of Study .............................................................................. 33 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 33 
4.1 
Inclusion Criteria ....................................................................................... 34 
4.2 
Exclusion Criteria ...................................................................................... 35 
5. 
SUBJECT ENROLLMENT .................................................................................... 38 

Product:  AMG 820 
Protocol Number:  20150195 
Date:  15 June  2018 
Page 13 of 117 
CONFIDENTIAL 
 
 
5.1 
Treatment Assignment .............................................................................. 39 
6. 
TREATMENT PROCEDURES .............................................................................. 39 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 39 
6.2 
Investigational Product .............................................................................. 39 
6.2.1 
Amgen Investigational Product: AMG 820 ................................. 39 
6.2.1.1 
Dosage, Administration, and Schedule: 
AMG 820 ................................................................. 39 
6.2.1.2 
Dose-cohort Study Exploration and 
Stopping Rules ........................................................ 40 
6.2.1.3 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation: AMG 820 ....................................... 45 
6.2.2 
Non-Amgen Investigational Product: Pembrolizumab ................ 46 
6.2.2.1 
Dosage, Administration, and Schedule: 
Pembrolizumab ....................................................... 46 
6.2.2.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation: Pembrolizumab ............................. 47 
6.2.3 
Management of AMG 820 Related Periorbital or 
Conjunctival Swelling ................................................................ 49 
6.2.4 
Rescue Medications and Supportive Care Guidelines 
for Pembrolizumab .................................................................... 50 
6.2.4.1 
Pneumonitis and Interstitial Lung Disease 
(ILD) ........................................................................ 50 
6.2.4.2 
Diarrhea .................................................................. 52 
6.2.4.3 
Type 1 Diabetes Mellitus (if new Onset, 
Including Diabetic Ketoacidosis) or ≥ 
Grade 3 Hyperglycemia, if Associated 
With Ketosis (Ketonuria) or Metabolic 
Acidosis (Diabetic ketoacidosis) .............................. 52 
6.2.4.4 
Hypophysitis ............................................................ 52 
6.2.4.5 
Hyperthyroidism or Hypothyroidism ......................... 53 
6.2.4.6 
Hepatic Toxicity ....................................................... 53 
6.2.4.7 
Renal Failure or Nephritis ........................................ 53 
6.2.4.8 
Infusion Reactions ................................................... 53 
6.2.4.9 
Pembrolizumab Events of Clinical Interest .............. 54 
6.2.4.10 
Diet and Other Considerations While 
Taking AMG 820 and/or Pembrolizumab ................. 55 
6.3 
Other Protocol-required Therapies ............................................................ 56 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 56 
6.4.1 
Criteria for Permanent Discontinuation of AMG 820 
and Pembrolizumab Due to Potential Hepatotoxicity ................. 56 
6.4.2 
Criteria for Conditional Withholding of AMG 820 
and/or Pembrolizumab due to Potential Hepatotoxicity .............. 57 

Product:  AMG 820 
Protocol Number:  20150195 
Date:  15 June  2018 
Page 14 of 117 
CONFIDENTIAL 
 
 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 58 
6.5 
Concomitant Therapy ................................................................................ 58 
6.6 
Other Treatment Procedures ..................................................................... 58 
6.7 
Medical Devices ........................................................................................ 59 
6.8 
Product Complaints ................................................................................... 59 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 59 
7. 
STUDY PROCEDURES ....................................................................................... 60 
7.1 
Schedule of Assessments ......................................................................... 60 
7.2 
General Study Procedures ........................................................................ 64 
7.2.1 
Screening Enrollment ................................................................ 66 
7.2.2 
Treatment .................................................................................. 67 
7.2.3 
Safety Follow-up Visit(s) ............................................................ 69 
7.2.4 
Long-term Follow-up .................................................................. 70 
7.3 
Physical Examinations .............................................................................. 70 
7.4 
Radiological Imaging Assessment ............................................................. 71 
7.4.1 
Brain Magnetic Resonance Imaging Scans ............................... 72 
7.4.2 
Tumor Assessments .................................................................. 72 
7.5 
Antibody Testing Procedures .................................................................... 72 
7.6 
Biomarker Development ............................................................................ 72 
7.7 
Pharmacogenetic Studies ......................................................................... 74 
7.8 
Sample Storage and Destruction ............................................................... 74 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 75 
8.1 
Subjects’ Decision to Withdraw ................................................................. 75 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 76 
8.3 
Reasons for Removal From Treatment, or Study ...................................... 76 
8.3.1 
Reasons for Removal From Treatment ...................................... 76 
8.3.2 
Reasons for Removal From Study ............................................. 77 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 77 
9.1 
Definition of Safety Events ........................................................................ 77 
9.1.1 
Disease Related Events ............................................................ 77 
9.1.2 
Adverse Events ......................................................................... 77 
9.1.3 
Serious Adverse Events ............................................................ 78 
9.2 
Safety Event Reporting Procedures .......................................................... 79 
9.2.1 
Reporting Procedures for Disease Related Events .................... 79 
9.2.2 
Adverse Events ......................................................................... 79 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 79 

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9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 80 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 81 
9.3 
Pregnancy and Lactation Reporting .......................................................... 82 
9.4 
Pembrolizumab Events of Clinical Interest ................................................ 83 
9.5 
Definition of an Overdose of Pembrolizumab for This Protocol 
and Reporting of Pembrolizumab Overdose .............................................. 83 
9.6 
Definition and Reporting of Pembrolizumab Drug-induced Liver 
Injury ......................................................................................................... 84 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 84 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 84 
10.1.1 
Study Endpoints ........................................................................ 84 
10.1.1.1 
Primary Endpoints ................................................... 84 
10.1.1.2 
Secondary Endpoints .............................................. 85 
10.1.1.3 
Exploratory Endpoints ............................................. 85 
10.1.2 
Analysis Sets ............................................................................. 85 
10.1.3 
Covariates and Subgroups ........................................................ 85 
10.2 
Sample Size Considerations ..................................................................... 85 
10.3 
Planned Analyses ..................................................................................... 87 
10.3.1 
Interim Analyses ........................................................................ 87 
10.3.2 
Dose Level Review Team (DLRT) ............................................. 88 
10.3.3 
Primary Analysis ........................................................................ 89 
10.3.4 
Final Analysis ............................................................................ 89 
10.4 
Planned Methods of Analysis .................................................................... 89 
10.4.1 
General Considerations ............................................................. 89 
10.4.2 
Primary Efficacy Endpoint .......................................................... 89 
10.4.3 
Secondary Efficacy Endpoint(s) ................................................. 89 
10.4.4 
Safety Endpoints ....................................................................... 90 
10.4.4.1 
Adverse Events ....................................................... 90 
10.4.4.2 
Clinical Laboratory Tests ......................................... 90 
10.4.4.3 
Vital Signs ............................................................... 90 
10.4.4.4 
Pharmacokinetic Endpoints ..................................... 90 
10.4.4.5 
Relationship in Immune Infiltrate Status in 
Pre-treatment Biopsies vs. Clinical 
Response ................................................................ 91 
11. 
REGULATORY OBLIGATIONS ............................................................................ 91 
11.1 
Informed Consent ...................................................................................... 91 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 92 
11.3 
Subject Confidentiality ............................................................................... 92 
11.4 
Investigator Signatory Obligations ............................................................. 93 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 93 

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12.1 
Protocol Amendments and Study Termination .......................................... 93 
12.2 
Study Documentation and Archive ............................................................ 94 
12.3 
Study Monitoring and Data Collection ....................................................... 94 
12.4 
Investigator Responsibilities for Data Collection ........................................ 96 
12.5 
Language .................................................................................................. 96 
12.6 
Publication Policy ...................................................................................... 96 
12.7 
Compensation ........................................................................................... 97 
13. 
REFERENCES ..................................................................................................... 98 
14. 
APPENDICES .................................................................................................... 102 
List of Tables 
Table 1.  Study Part 2 Subject Groups........................................................................... 45 
Table 2.  Dose Modification Guidelines for Pembrolizumab Related Adverse 
Events .................................................................................................... 48 
Table 3.  Recommended Approach to Handling Pneumonitis and ILD ........................... 51 
Table 4.  Infusion Reaction Treatment Guidelines ......................................................... 54 
Table 5.  Schedule of Assessments ............................................................................... 61 
Table 6.  Laboratory Analytes ........................................................................................ 65 
List of Figures 
Figure 1.  Phase 1b/2 Simon Two-stage Study Design .................................................. 29 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 103 
Appendix B.  Sample Serious Adverse Event Report Form ......................................... 105 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 108 
Appendix D.  Modified Immune-Related Response Criteria in Solid Tumors 
(irRECIST) ............................................................................................ 110 
Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance 
Status ................................................................................................... 117 

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1.
OBJECTIVES
1.1
Primary

Evaluate the safety and tolerability of AMG 820 administered in combination with 
pembrolizumab in subjects with select advanced solid tumors

Evaluate the objective response rate (ORR) of AMG 820 and pembrolizumab 
combination as per irRECIST in subjects with select advanced solid tumors
1.2
Secondary

Evaluate the anti-tumor activity of AMG 820 and pembrolizumab combination in 
select advanced solid tumors by assessing
o
ORR per RECIST1.1
o
time to response (TTR), duration of response (DOR), and time to 
progression (TTP)
o
progression free survival (PFS) and overall survival (OS) at 6 and 
12 months

Characterize the pharmacokinetics (PK) of AMG 820 after intravenous (IV) 
infusion administration of AMG 820 in combination with pembrolizumab

Evaluate the relationship between the immune infiltrate status in pre-study tumor 
biopsies vs. clinical response
1.3
Exploratory

Evaluate the occurrence of anti-AMG 820 and anti-pembrolizumab antibody 
formation (immunogenicity)

Investigate treatment-associated biomarker changes, and relationship of 
biomarkers baseline status vs. clinical outcome in tumor tissue and blood

Evaluate pembrolizumab PK at end of pembrolizumab infusion administration.  
Blood samples collected for AMG 820 concentration measurement may also be 
used to measure the concentration profile of pembrolizumab, if deemed 
necessary
2.
BACKGROUND AND RATIONALE
2.1
Disease and Background
2.1.1
c-fms PATHWAY, TUMOR ASSOCIATED MACROPHAGES (TAMs) 
and AMG 820
The c-fms receptor (also known as M-CSF receptor [M-CSFR] or CSF-1 receptor 
[CSF-1R]), belongs to the class III receptor tyrosine kinase family that includes PDGFR 
α and β, VEGFR1, R2 and R3, Flt3 and c-kit (van der Geer et al, 1994; 
Blume-Jensen et al, 2001). Expression of c-fms is primarily restricted to cells of the 
myelomonocytic lineage (including monocytes, tissue macrophages, microglial cells and 
osteoclasts), hematopoietic precursors and trophoblasts (Dai et al, 2002; 
Pixley et al, 2004). The colony stimulating factor-1 (CSF-1, also known as macrophage 
stimulating factor [M-CSF]) seems to be the main ligand for CSF-1R 

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(Van Wesenbeeck et al, 2005; Wiktor-Jedrzejczak et al,1990), while the relevance of 
IL-34, a second possible ligand  (Lin et al, 2008), is yet to be fully elucidated. CSF-1 is 
expressed both as a membrane-bound and a soluble cytokine (Pixley et al, 2004). It 
influences the survival, proliferation, differentiation, chemotaxis and activation of 
macrophages and their precursors (Bourette et al, 2000; Cecchini et al, 1994, 
Hamilton, 1997).
All normal tissues are populated with macrophages, which are part of the innate immune 
system, recognizing, engulfing and destroying potential pathogens 
(Sasmono et al, 2004) through the release of reactive-oxygen species and 
reactive-nitrogen metabolites (Adams and Hamilton, 1984; Nathan et al, 1991). In 
addition, tissue macrophages contribute to both humoral and cell-mediated immune 
responses as antigen presenting cells. Conversion from a quiescent state to an 
immunologically active or microbicidal state can be induced by microbial products and 
pro-inflammatory cytokines including CSF-1,  IL-1, TNFα, IL-4, IL-12, IL-13, GM-CSF, 
IFNγ (Bingle et al, 2002; Pollard, 2004). At the tumor level, macrophages can represent 
a prominent component of the inflammatory infiltrate: tumor associated macrophages 
(TAMs) or tumor infiltrating macrophages (TIMs) (Noy and Pollard, 2014; 
Chanmee et al, 2014, Pollard, 2004; Chen et al, 2005).
Over the past decades, the mechanisms supporting the tumor promoting functions of 
TAMs have become increasingly clear (Noy and Pollard, 2014; Colegio et al, 2014; 
Chanmee et al, 2014; Ribatti et al, 2007; Sica et al, 2006; Condeelis et al, 2006; 
Leek et al, 2002) through their production of various pro-angiogenic factors 
(Bingle et al, 2002; Mantovani et al, 1992) such as proteases that degrade the tumor 
extracellular matrix thus aiding invasion and metastasis and mitogenic factors directly 
stimulatory to tumors (Leek et al, 2002). In addition, CSF-1 derived macrophages have 
been shown to be immunosuppressive via production of factors such as prostaglandins, 
indolamine 2,3 dioxygenase, nitric oxide, IL-10, and TGF-β (Bronte et al, 2001; 
MacMicking et al, 1997). CSF-1 serum levels as well as TAMs number have been 
associated in different ways with prognosis in cancer depending on various factors 
including tumor type and TAM content in the primary tumor vs metastases 
(Noy and Pollard, 2014; Chanmee et al, 2014; Lewis et al, 2006; Funada et al, 2003; 
Ohno et al, 2003; Caruso et al, 1999). However, in all preclinical tumor models tested to 
date (using both human tumor xenograft and syngeneic models) decrease of TAM 
number and/or their function/survival through targeting CSF-1R axis (Colegio et al, 2014; 

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Nowicki et al, 1996; Lin et al, 2001; Aharinejad et al, 2004, Zeisberger et al, 2006; 
Luo et al, 2006) resulted always in inhibition of tumor growth, never tumor progression. 
2.1.2
PD-1 AND PD-L1 inhibitors
Programmed cell death 1 (PD-1) is a negative costimulatory receptor expressed 
primarily on the surface of activated T cells. Binding of the ligands, PD-L1 and PD-L2, to 
the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. 
Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway 
can contribute to inhibition of active T cell immune surveillance of tumors
(Philips and Atkins, 2015; Swaika et al, 2015). 
To date, the two leading PD-1 inhibitors pembrolizumab and nivolumab, have been 
approved in advanced, previously treated melanoma and non-small cell lung cancer 
(NSCLC). Especially in the NSCLC setting, PD-L1 tumor expression seems to indicate 
an increase likelihood of responding to anti-PD-1 agents, and companion diagnostic kits 
for this biomarker have been developed 
(http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm466413.htm;
Keytruda® USPI, 2015).
2.1.3
Metastatic Colorectal Cancer
Colorectal cancer (CRC) is among the most common forms of cancer worldwide. CRC 
has the third highest cancer incidence and rate of death in the USA for men and women, 
although the related numbers have been steadily declining in the past decades
(Gill et al, 2014). Among patients already diagnosed with CRC, approximately one-fifth 
present with synchronous metastasis, and half of the remaining patients will develop 
subsequent metastases. In the treatment of metastatic CRC (mCRC) several cytotoxic 
agents have demonstrated efficacy, including 5-fluorouracil (5-FU), folinic acid, 
irinotecan, oxaliplatin and capecitabine. These drugs are commonly combined in 
various regimens, and can be further partnered with monoclonal antibodies targeting 
VEGF or EGFR signaling. Recently, two additional therapeutic options have gained 
approval. The clinical efficacy and safety of STIVARGA (regorafenib), a kinase inhibitor, 
were evaluated in an international, randomized (2:1), placebo-controlled trial in 
previously-treated 760 mCRC patients (Grothey et al, 2013). The major efficacy 
outcome measure was OS which showed significant, although modest, improvement 
(6.4 vs 5mo), and no effect on PFS nor ORR: 2mo vs 1.7mo, and 1% vs 4%, 
respectively (Stivarga USPI, 2012). LONSURF is a combination of trifluridine (a 
nucleoside metabolic inhibitor), and tipiracil (a thymidine phosphorylase inhibitor)

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(LONSURF USPI, 2015). Its clinical efficacy and safety were evaluated in a similar 
setting (800 patients with previously treated mCRC). A statistically significant 
improvement in overall survival (7.1 vs 5.3mo) and progression-free survival were 
demonstrated.  Evidently, for most patients with mCRC available treatment is palliative 
rather than curative, with an overall 5-year survival of approximately 10%. 
Subsequently, additional options are needed for patients who have disease progression 
despite available standard therapies, since many of them maintain good performance 
status and might be candidates for further treatments.
In the light of recent advances in the immunotherapeutics space, the potential 
significance of the immune system in tumor biology has been investigated for CRC as 
well (Kroemer et al, 2015; Markman and Shiao, 2015).  The presence of tumor infiltrating 
lymphocytes—especially CD8 + lymphocytes—in the tumor microenvironment, as well as 
regional lymph nodes, has been linked to better prognosis. Also, increased infiltration of 
specific regions of the CRC tumors by cytotoxic memory T lymphocytes 
(CD8+CD45RO+T cells) was highly correlated with reduced risk of recurrence of CRC 
and better survival. The prognostic significance of T cells—unlike other inflammatory 
cells—argues that cancer immunotherapies modulating T cell responses could lead to 
improved survival. Nonetheless, there was an almost complete lack of response to 
anti-PD-1/PD-L1 agents in CRC patients, except when administered in combination with 
bevacizumab +/-FOLFOX (a ph1b study with MPDL3280A), or in CRC patients with a 
deficit in mismatch repair genes (dMMR). A dMMR system is present in 10–20% of 
patients with sporadic CRC and is associated with a favorable prognosis in early-stage 
disease. In contrast, dMMR occurs in only 3–6% of patients with advanced CRC
(Llosa et al, 2015). Recent findings have suggested that checkpoint inhibitors may have 
increased activity in dMMR tumors, since dMMR have several times as many somatic 
mutations as proficient MMR tumors, and have prominent lymphocyte infiltrates, which 
are more likely to express PD-L1,  a hypothesis which was tested in a Phase II trial
(Le et al, 2015). This study showed that MMR status may be a predictive biomarker for 
clinical benefit from checkpoint inhibition. Although immunotherapy in dMMR tumors 
holds great promise, the complete absence of response in patients with proficient MMR 
CRC—who represent the vast majority—highlights the ongoing need to understand why 
patients with conventional CRC lack robust responses to immunotherapy.

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2.1.4
Advanced Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDA), representing 95% of pancreatic cancers, 
remains one of the most lethal cancer types with an overall 5-year survival rate of less 
than 5 %, and a median survival of less than 6 months. It is estimated that near 
40,000 people died of PDA in 2014, rendering it the fourth leading cause of 
cancer-related death in the USA (Cid-Aregui and Juarez, 2015). Early-stage PDA is 
asymptomatic, while patients with symptoms are often diagnosed as advanced and 
metastatic disease when less than 15 % are suitable for surgical resection. Hence, 
chemotherapy is the only option for most patients. For the last two decades, 
gemcitabine has been the standard first-line drug, however with only modest survival 
benefits. While different gemcitabine based combinations have been investigated in a 
number of randomized trials, only very few showed some beneficial effects, like for 
example gemcitabine plus erlotinib or gemcitabine plus S-1
(Cid-Aregui and Juarez, 2015). Recently,  gemcitabine plus albumin bound-paclitaxel 
(nab-paclitaxel) as well as a regimen combining fluorouracil, irinotecan, oxaliplatin, and 
leucovorin (FOLFIRINOX) have shown clear therapeutic advantage in advanced PDAC 
in phase III trials, over single agent gemcitabine. With the pending issue of their higher 
toxicities, these regimens now set the reference for ongoing and future clinical studies in 
advanced PDAC. FOLFIRINOX showed significant improvement in median overall 
survival (11.1 months vs. 6.8 months with gemcitabine) in patients with Eastern 
Cooperative Oncology Group (ECOG) performance status 0-1. Progression-free 
survival was also improved, from 3.4 to 6.4 months. Definitive deterioration in the quality 
of life at 6 mo was observed in 31% of patients in the FOLFIRINOX and in 66% in the 
gemcitabine group. However, the toxicity associated with FOLFIRINOX is important, in 
particular grade 3 and 4 myelosuppression and fatigue. For nab-paclitaxel combined 
with gemcitabine the median overall survival improved to 8.5 mo from 6.7 mo with 
gemcitabine alone (p < 0.001). The 1-year survival rate was 35% and 22%, respectively, 
and the 2-year survival was 9% and 4%, respectively. ORR was 23% and 7%, 
respectively. Adverse events of grade 3 or higher, such as myelosuppression and 
peripheral neuropathy were however increased in the combined nab-paclitaxel plus 
gemcitabine arm (Cid-Aregui and Juarez, 2015). In addition to chemotherapies, a 
number of agents targeting signaling pathways in tumor or stroma cells are being 
investigated. Likewise, immunotherapies that target PDAC in various ways are the 
subject of a number of clinical trials (Cid-Aregui and Juarez, 2015).

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A heavy infiltration of CD4 and CD8+ T cells expressing programmed cell death 1 (PD-1) 
and smaller numbers of myeloid cells and regulatory T cells seen in the PDA tissues 
provided rationale for the clinical evaluation of immune checkpoint inhibition as a 
pancreatic cancer therapeutic strategy (Komura et al, 2015; Brahmer et al, 2012). 
However, anti-PD-1 agents have been unsuccessful when tested in a small number of 
patients with advanced stage PDA, suggesting that it may be necessary to address the 
immunosuppressive effects of other PD-1 ligands or block additional co-inhibitory 
pathways (Brahmer et al, 2012). The PDA tissues appear also to be infiltrated by 
macrophages, especially M2 macrophages. In the recent years, line of evidence had 
tried to clarify how the monocytes were recruited and the mechanism by which they 
differentiate to macrophages. CSF/CSFR is a commonly accepted signaling pathway 
that associates with the process. Generally, the regional microenvironment, which is 
featured by dense stroma infiltration, plays a decisive role in recruiting monocytes and 
modulating macrophage phenotype. Since different areas of a solid tumor may exhibit 
distinct microenvironment, TAMs differ in phenotype as well as function from one region 
to another. Typically, TAMs in the hypoxia region polarize to M2, while those within the 
normoxic regions tend to be M1-like (Colegio et al, 2014).  Recent reports suggested 
that the macrophage phenotype is also stage dependent. For example, the 
anti-inflammation M1-like macrophages, which usually locate in chronic pancreatitis 
where tumor occurs, gradually converted to M2-like during tumor initiation and 
progression, reflecting the plasticity as well as heterogeneity of TAMs. As a support, 
pathological data revealed that M2-like macrophages were more abundant in PDA 
samples than those diagnosed as chronic pancreatitis (Komura et al , 2015). 
Consistently, further analysis showed that the M2-like macrophages associated with 
lymphatic metastasis, distant metastasis, chemoresistance, and hence the survival of 
the PDA patients. Additional evidence of inflammatory features of PDA form findings of 
the significantly elevated levels of interleukin (IL)-6, IL-7, IL-15, monocyte chemotactic 
protein-1, and interferon-c-inducible protein-1 in the sera of PDAC patients. The gene 
expression profile of CD14+ monocytes and CD4+ T cells was discernible between 
PDAC patients and healthy volunteers, and the differentially expressed genes were 
related to active inflammation. Intriguingly, PD-1 was significantly upregulated in the 
peripheral blood CD4+ T cells of PDAC patients. Correspondingly, the frequency of 
CD4+PD-1+ T cells was increased in the peripheral blood cells of PDAC patients, and 
this increase correlated to chemotherapy resistance. In conclusion, inflammatory 
conditions in both PDAC tissue and peripheral blood cells in PDAC patients appear to be 

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prominent, highlighting monocytes ⁄ macrophages as well as CD4+ T cells with influence 
of the clinical prognosis (Komura et al, 2015).
2.1.5
Non-Small Lung Cancer (NSLC)
Metastatic lung cancer is the leading cause of cancer death worldwide with a 5-year 
survival for advanced disease of less than 5% despite of a comprehensive therapeutic 
approach. In few tumor types with distinct molecular alterations, unprecedented benefits 
can be delivered by very specific molecular targeted therapies. For most patients with 
advanced NSCLC, platinum-based chemotherapy with or without maintenance therapy, 
and subsequently followed by second-line cytotoxic chemotherapy, is the standard 
treatment (median survival of approximately 1 year).  Second-line cytotoxic therapies (ie, 
docetaxel, pemetrexed and erlotinib) have only moderate efficacy and are associated
with significant toxicities. For this reason, strategies such as immunotherapy, which may 
have efficacy irrespective of histology or mutational status, are particularly attractive
(Minguet et al, 2015; Garon et al, 2015). Latest approvals (2015) of several 
immunotherapy agents reflect the scientific progress poised to shape further the patient 
outcomes in this indication (Garon et al, 2015; Romero, 2015). As such, anti–PD-1 and 
anti–PD-L1 antibodies have been shown to produce durable responses in clinical trials in 
approximately 20% of patients with advanced non–small-cell lung cancer, even without 
selecting for PD-L1 tumor expression.  Pembrolizumab has been recently approved for 
the treatment of subjects with advanced (metastatic) NSCLC whose disease has 
progressed after other treatments and have tumors that express PD-L1. In a phase 1 
study (KEYNOTE-001) 495 patients received pembrolizumab (at a dose of either 2 mg 
or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 
2 weeks) (Garon et al 2015). Among all the patients, the objective response rate was 
19.4%, and the median duration of response was 12.5 months. The median duration of 
progression-free survival was 3.7 months, and the median duration of overall survival 
was 12.0 months. Among all the patients with a PD-L1 tumor proportion score (TPS) of 
at least 50%, median progression-free survival was 6.3 months, and the median overall 
survival was not reached. In a subgroup of  these patients (73/313 patients in the 
validation group with TPS of at least 50%), the response rate was 45.2%. Among the 
1143 screened patients, 824 had samples that could be evaluated by the clinical-trial 
assay, with a prevalence of 23.2% of patients with a PD-L1 TPS of at least 50%, 37.6% 
with a score of 1 to 49%, and 39.2% with a score of less than 1% by the clinical-trial 
assay. The prevalence of a proportion score of at least 50% was 24.9% among 
previously untreated patients and 22.7% among previously treated patients. The ORR in 

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NSCLC patients with PD-L1 TPS between 1-49% and <1% was 16.5% and 10.7%, 
respectively (validation set). ORR values were similar in previously treated patients vs 
treatment naïve: 15.6% vs 19.2% (PD-L1 TPS between 1-49%), and 9.1% vs 16.7% 
(PD-L1 TPS <1%) (Garon et al, 2015).
A recent sensitivity analysis of nivolumab, and pembrolizumab activity according to the 
tumor expression of PD-L1 (Carbognin et al, 2015) suggests a significant differential 
effect in terms of activity according to PD-L1 expression on tumor cells status, which 
translated into a higher ORR for PD-L1 positive advanced tumors in comparison to 
PD-L1 negative tumors. With respect to disease setting, the analysis showed evidence 
of such effect for melanoma and NSCLC, and less for genitourinary cancers. 
Considering the PD-L1 expression cut-off, the difference in ORR between PD-L1 
positive and negative patients was significantly higher in studies adopting the cut-off of 
5%, with an absolute difference of 15.5% (95% CI 9.5–21.4). No significant difference 
was seen for trials where the cut-off was 1% (p=0.108) (Carbognin et al, 2015). In two 
randomized phIII studies in squamous NSCLC (CheckMate 017) (Brahmer et al, 2015) 
and non-squamous NSCLC (CheckMate 057) (Borghaei et al, 2015) OPDIVO was 
evaluated against docetaxel. Significant improvement was reported in both trials for OS 
(9.2 vs 6.2mo, and 12,2 vs 9.4mo, respectively). ORR in the CheckMate 057 study was 
19% in the OPDIVO arm vs 12% in the docetaxel arm. In the CheckMate 063 study , a 
phII, single arm study of OPDIVO in squamous NSCLC patients who had progressed 
after platinum based therapy and second line systemic chemotherapy, ORR was 15%, 
with 59% patients having responses of 6 months or longer (Rizvi et al, 2015).
2.2
AMG 820 Background
AMG 820 is a fully human IgG2 c-fms (CSF-1R) antagonistic antibody. This antibody 
binds to the first and second IgG regions of the extracellular domain of c-fms and 
blocked CSF-1 induced proliferation of primary human bone marrow-derived monocytic 
cells in vitro with an IC50 of 15.8 pM. AMG 820 had no detectable agonistic activity in the 
in vitro proliferation assays. AMG 820 cross-reacts with cynomolgus monkey c-fms as 
measured by binding to cynomolgus c-fms expressed on 2936E cells with a Kd of 
29.7 pM and inhibition of CSF-1-induced proliferation of primary bone marrow-derived 
monocytic cells from cynomolgus monkeys in vitro with an IC50 of 31.2 pM.  A maximal 
plateau level of CSF-1 elevation (500-1000 ng/mL) was observed in serum after a single 
IV dosing of 20 mg/kg AMG 820 in normal cynomolgus monkeys. The increase of serum 

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CSF-1 is presumably due to the ability of AMG 820 to block CSF-1 binding to c-fms and 
subsequent internalization and degradation of the ligand (Bartocci et al,1987).
Refer to the specific section of the AMG 820 Investigator’s Brochure (IB) for additional 
information related to the physical, chemical, and pharmaceutical properties and 
formulation(s).
2.2.1
AMG 820 Clinical Experience
In the first-in-human, open-label, dose-escalation study, 25 subjects with advanced solid 
tumors received AMG 820 at doses of 0.5 mg/kg every week (QW) and 1.5, 3, 6, 10, and 
20 mg/kg every 2 weeks (Q2W). The study was terminated after the dose-escalation 
part; the maximum administered dose was 20 mg/kg Q2W AMG 820, and the MTD was 
not determined. Key adverse events reported in the study included DLT of grade 3 
bilateral deafness in 1 subject, as well as commonly-reported adverse events of 
periorbital edema (without clinical sequelae) and AST increase (both noted in preclinical 
studies). Exposure to AMG 820 was increased with increasing AMG 820 dose, and no 
marked (> 2 fold) accumulation was observed after repeated-dose administrations. 
AMG 820 mediated pharmacodynamic effects included increase in CSF-1 levels, 
reduction of macrophages number in the skin, and decrease in TRAP5b levels. No 
subjects tested positive for anti-AMG 820 binding antibodies. Per central assessment, 
8 subjects (32%) had a best response of stable disease. Median of maximum 
percentage change from baseline in tumor volume was 19.32% (range: -24.0% 
to 104.8%).
Refer to the AMG 820 IB for additional clinical experience information. For non-clinical 
toxicology information, refer to Section 5.3 of the AMG 820 IB.
2.2.2
AMG 820 Pharmacokinetics
AMG 820 PK analysis was conducted for all 25 evaluable adult subjects with advanced 
solid tumors from the first-in-human study (20060347).  The initial study design was 
based on weekly IV infusions of AMG 820 at a starting dose of 0.5 mg/kg.  In 
subsequent higher dose cohorts, the dosing regimen was revised to IV infusion over a 
60-minute period Q2W.  Escalation of AMG 820 dose was advanced through the 1.5, 3, 
6, 10, and 20 mg/kg levels.  After single intravenous infusion dosing, mean AMG 820 
Cmax exposures were increased by approximately 13-fold and AUC exposures were 
increased by approximately 24-fold over a 13.3-fold range (1.5 to 20 mg/kg) of dose 
levels.  Over a narrower dose range from 3 to 20 mg/kg (6.7-fold), mean estimates of 
AUC increased by approximately 8-fold.  At the 20 mg/kg Q2W dose level, mean

Product:  AMG 820
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estimates of Cmax and AUC0-last were 619 µg/mL and 89200 µghr/mL, respectively, after 
the first dose.  AMG 820 accumulation in the systemic circulation was minimal (<2-fold) 
after repeated dose administration.
2.2.3
AMG 820 Pharmacodynamics
Serum CSF-1 levels were determined for several time points following each AMG 820 
dose for subjects in the 0.5-mg/kg QW and 1.5-mg/kg to 20-mg/kg Q2W cohorts.  At 
0.5 mg/kg QW AMG 820, CSF-1 levels were observed to rise from baseline over 3 to 
5 days following dosing before decreasing towards baseline.  At higher doses of 
AMG 820 (1.5 mg/kg to 20 mg/kg Q2W AMG 820), CSF-1 levels were similarly 
increased after dosing and elevated CSF-1 levels were sustained for the remainder of 
the dosing interval.  At 10 mg/kg Q2W AMG 820, CSF-1 levels appeared to reach a 
plateau after 3 weeks of exposure to AMG 820.  
Changes in serum IL-34 levels over time were assessed in all cohorts.  IL-34 levels did 
not demonstrate a dose-response relationship to AMG 820 administration.
2.2.4
AMG 820 Dose Rationale
In this study, AMG 820 will be administered at a fixed dose of 1400 mg in combination 
with 200 mg fixed dose of pembrolizumab as an intravenous infusion Q3W.
The AMG 820 dose of 1400 mg Q3W IV infusion is supported by AMG 820 PK and PD
(serum CSF-1 concentration) observed in the first-in-human FIH study (20060347).
Maximum concentrations (Cmax) are predicted to be within a range of observed Cmax 
exposures at AMG 820 dose levels that were safe and tolerated in the FIH study.  In 
addition, AMG 820 concentrations after IV infusion at 1400 mg are predicted to remain 
above concentrations associated with the observed maximum CSF-1 response in the 
FIH study.
In the FIH study, subjects received AMG 820 Q2W by IV infusion at doses that ranged 
from 1.5 to 20 mg/kg, with body weights ranging from 44.4 to 159 kg.  Among all 
subjects, AMG 820 was determined to be safe and tolerated. A maximum tolerated 
dose level was not identified in the FIH study. 
A transition from weight-based dosing (mg/kg) to fixed dosing (mg) is supported by 
AMG 820 PK in the FIH study.  In terms of clinical experience, the 1400 mg AMG 820 
dose is clearly bracketed by observed exposures in the FIH study.  After accounting for 
body weights of subjects in the FIH study, the resulting increases in IV dose were from 
102 mg to 2260 mg.  Linear increases in the corresponding AMG 820 exposures 

Product:  AMG 820
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(Cmax and C336h) were observed for all subjects.  Predictions of AMG 820 exposure at 
1400 mg include:

The range of Cmax (at 1 hour, end of infusion) values observed in FIH subjects on
day 1 were 44.9 to 744 μg/mL. At 1400 mg IV, a Cmax of approximately 550 μg/mL 
was predicted from interpolation of Cmax versus dose.

The range of trough concentration (at 336 hours), C336h, values observed in FIH 
subjects on day 1 were 1.23 to 231 μg/mL. At 1400 mg IV, a C336h of 
approximately 150 μg/mL was predicted from interpolation of C336h versus dose.
Importantly, a summary of Cmax and AUC exposures from the FIH study, normalized by 
dose, did not reveal an apparent trend over the range of body weights of subjects, 
providing support for a flat-based dose approach.
In addition, a population PK model developed from the FIH study was used to predict 
trough concentrations anticipated at the end of the proposed 3 week dosing interval.  
Based on population PK predictions, following Q3W dosing of 1400 mg AMG 820, trough 
concentrations are predicted to remain above concentrations associated with maximum 
CSF-1 response observed in the FIH study.
2.3
Risk Assessment
There are no important identified risks for AMG 820.
Important potential risks for AMG 820 include increased extracellular matrix, infection, 
growth plate changes and immunogenicity.  Refer to the AMG 820 IB for additional risk
information.
No significant risks or drug-drug interactions with pembrolizumab are anticipated at the 
AMG 820 starting dose of 1400 mg in the proposed study.   Explored AMG 820 dose 
levels ranging from 0.5 mg/kg QW and 1.5mg/kg to 20 mg/kg Q2W were generally 
well-tolerated in the FIH study. Approximately 25 subjects have received AMG 820.  
Treatment-related toxicities have been mild or moderate in most patients, and the most 
common toxicities are transient aspartate aminotransferase increase and periorbital 
edema.  No subjects have developed treatment emergent neutralizing antibodies.
2.4
Non-Amgen Medicinal Product Background: Pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, 
thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  

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Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number 
of indications.  For more details on specific indications refer to the 
Pembrolizumab Investigator’s Brochure.
2.5
Rationale
To date, anti-PD-1 antibodies have been approved for a number of indications However, 
the majority of patients do not show a response to monotherapy. A potential mechanism 
of resistance to anti-PD-1 therapy is the immunosuppressive activity of tumor 
infiltrating/associated macrophages, which may impair the T cells’ ability to enter the 
tumor itself or hamper the intra-tumoral T cell activation. CSF-1R mediates proliferation, 
survival, and differentiation of tissue resident macrophages. Inhibition and depletion of 
TAMs through CSF-1R blockade may therefore relieve immunosuppressive pathways 
that restrict productive anti-tumor T cell responses and result in enhanced T cell 
responses against tumors. CSF-1R blockade as monotherapy was shown to reduce 
TAMs frequency in human tumors and pre-clinical murine tumor models, and had mild 
efficacy in syngeneic murine tumor models. CSF-1R blockade combined with chemo 
and/or T cell-targeted therapies, such as anti-PD-1, has led to increased T cell 
recruitment into tumors and enhanced efficacy. AMG 820 is a fully human IgG2 
monoclonal antibody directed against human CSF-1R (c-fms) and represents a potential 
anti-tumor therapeutic approach by targeting macrophages in the tumor 
micro-environment. In a Phase 1 study, AMG 820 has shown a linear pharmacokinetic 
profile and promising pharmacodynamics effects (serum CSF-1 upregulation, depletion 
of macrophages in skin biopsies). AMG 820 dose options for Phase 2 were established 
without reaching a maximum-tolerated dose (MTD). Combination of a CSF-1R targeting 
antibody such as AMG 820, with an anti-PD-1 antibody like pembrolizumab may result in 
enhanced anti-tumor effect.
2.6
Clinical Hypotheses

AMG 820 in combination with pembrolizumab is safe and well tolerated when 
administered in subjects with select advanced solid tumors

AMG 820 can enhance the anti-tumor activity observed with pembrolizumab alone 
and/or overcome lack of response to pembrolizumab monotherapy in subjects with 
select advanced solid tumors

Product:  AMG 820
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3.
EXPERIMENTAL PLAN
3.1
Study Design
This is a multi-center Phase 1b/2 study testing the combination of AMG 820 and
pembrolizumab in subjects with select advanced solid tumors. Part 1 will evaluate safety 
of the selected starting dose for the combination. Part 2 will further evaluate safety and
test whether AMG 820 in combination with pembrolizumab can enhance the anti-tumor 
activity observed historically with pembrolizumab alone and/or overcome lack of 
response to pembrolizumab monotherapy.  Study part 2 will follow a Simon two-stage 
design to evaluate 4 groups as per the figure below:
Figure 1.  Phase 1b/2 Simon Two-stage Study Design
*PD-L1 low expression defined as <50% staining, high expression ≥50%
Eligible subjects enrolled in the study will receive AMG 820 1400 mg in combination with 
200 mg pembrolizumab as an intravenous infusion Q3W.  AMG 820 will initially be 
tested at a dose of 1400 mg Q3W based on the safety and tolerability demonstrated in 
the first-in-human study, which evaluated doses up to 20 mg/kg Q2W.  In addition, 
maximal sustained serum concentrations of CSF-1 were observed at AMG 820 doses of 
10 mg/kg Q2W and above.  Pembrolizumab will be administered Q3W at a dose of 
200 mg based on the dose currently being evaluated in pembrolizumab trials with 
registration intent in head and neck cancer.

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If the starting dose is not well tolerated, the lower pre-specified nominal AMG 820 dose
levels to be explored are 1100 mg and 800 mg Q3W.  The de-escalated doses of 
AMG 820 at 1100 mg and 800 mg are anticipated to result in lower serum AMG 820 
concentrations, based on inter-subject PK variability observed in the first-in-human 
study, while maintaining maximal sustained serum concentrations of CSF-1 observed at 
AMG 820 doses of 10 mg/kg Q2W and above.  The pembrolizumab dose level will 
remain at 200 mg Q3W.  While on study, subjects will undergo radiological MRI or 
CT assessment, and clinical measurement of their tumor lesions during week 
10 ± 1 week, and at 10 ± 2 week intervals thereafter. In accordance with the irRECIST 
criteria, in absence of clinical deterioration the subjects may continue on AMG 820 and 
pembrolizumab until progressive disease is confirmed by a  subsequent scan and/or 
clinical evaluation of tumor lesions 4 to 6 weeks after the first detection of tumor 
progression. Subjects will be treated with AMG 820 and pembrolizumab until confirmed 
disease progression per modified irRECIST (Appendix D), or intolerance of study 
treatment, or clinically significant deterioration of health status requiring discontinuation, 
whichever occurs first, or the subject withdrawal of consent.  Due to the mechanism of 
action of immune-enhancing therapies, subjects may experience enhanced T cell 
expansion and infiltration into tumors, leading to an apparent enlargement of existing 
lesions or the appearance of new lesions prior to maximal clinical benefit being 
observed.  A modified response criteria is necessary to allow the potential delayed 
clinical response to immune-enhancing therapies to be captured more accurately.
The overall study design is also described by a detailed study schema at the end of the 
protocol synopsis section.
The study endpoints are defined in Section 10.1.1.
3.1.1
Phase 1b Study Design (Part 1)
Part 1 of the study has a single-arm 6+3 design aimed at assessing the safety of the 
selected starting dose of AMG 820 in combination with pembrolizumab.  It will be 
conducted in subjects with select advanced solid tumors (CRC, pancreatic cancer, 
NSCLC and potentially other tumor types as per eligibility criteria).  If the selected 
starting dose is determined not tolerable following review of safety data, additional lower 
dose levels will be evaluated.  Up to 3 cohorts will be evaluated for safety and will 
include at least 6 subjects per cohort, and up to 18 subjects in total. The initial cohort will 
treat subjects at the selected starting dose of 1400 mg AMG 820 plus 200 mg 
pembrolizumab Q3W. The period for evaluation of a DLT in cycle 1 is 21 days.  A 

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Protocol Number:  20150195
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subject is not DLT-evaluable if he/she drops out before completion of cycle 1 for reasons 
other than an adverse event related to study drug.

If 0 or 1 of the initial 6 evaluable subjects experience a dose-limiting toxicity (DLT) 
then the dose combination will be determined to be tolerable and Part 2 initiated.

If 2 of the initial 6 evaluable subjects experience a DLT then 3 additional evaluable 
subjects will be enrolled. 

If 3 or more of the evaluable subjects experience a DLT (eg, 33% or higher with 
9 evaluable subjects) then the dose combination will be determined to be 
non-tolerable and a second Part 1 cohort will be enrolled to test a decreased dose of 
AMG 820 in combination with 200 mg pembrolizumab. Further degree of dose 
modification and/or schedule of administration will be decided based on analysis of 
emerging safety and PK data.
Prior to opening a subsequent cohort for enrollment, the Dose Level Review Team 
(DLRT) will evaluate data from subjects enrolled into prior cohorts (at least 21 days of 
safety follow-up) including events with a longer onset time or events following exposure 
to multiple doses.  If late onset events occur during a cohort, the DLRT may adaptively 
re-consider the doses evaluated within a cohort for subsequent dosing and/or possibly 
trigger a de-escalation or withholding of additional doses in subsequent cohorts.  
3.1.2
Phase 2 Study Design
The primary objective of study Part 2 is to further evaluate safety and efficacy of the
combination dose in the 4 selected CRC, pancreatic cancer and NSCLC subject groups.
Other tumor types may be explored based on emerging data.  The dose or doses to be 
evaluated in Part 2 will be based on results from Part 1.  Part 2 will begin after safety of 
the dose level(s) explored in Part 1 has been assessed and determined to be safe.  
Part 2 will include 6-9 subjects from Part 1 who have been treated with the 
recommended combination dose, and will enroll additional CRC, pancreatic cancer and 
NSCLC subjects following a Simon two-stage design: stage 1 will enroll up to 
67 subjects overall, stage 2 may add another 118 subjects as per the rules described 
below. The recommendations to enroll stage 2 are based on ORR (see rules described 
below); nonetheless, the DLRT (see Section 6.2.1.2.1) will make decisions after 
reviewing all available safety, efficacy, pharmacokinetic and pharmacodynamic data.  
Analysis of data in Part 2 will be done separately for each group (Group 1, 2, 3, 4a, 4b).

Group 1 will enroll up to 43 advanced MMR-proficient CRC subjects who are naïve to 
anti-PD-1/PD-L1/CSF-1/CSF-1R therapies. Eighteen (18) subjects will be enrolled 
during the first stage and treated with the AMG 820 plus pembrolizumab 
combination. If 2 or fewer subjects have an objective response per irRECIST then, 

Product:  AMG 820 
Protocol Number:  20150195 
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CONFIDENTIAL 
 
 
depending on the review of all available data, further enrollment may be 
discontinued; otherwise, enrollment up to 43 subjects will occur. 
• 
Group 2 will enroll up to 29 advanced pancreatic cancer subjects who are naïve to 
anti-PD-1/PD-L1/CSF-1/CSF-1R therapies.  Ten (10) subjects will be enrolled during 
the first stage and treated with the AMG 820 plus pembrolizumab combination.  If no 
subjects have an objective response per irRECIST then, depending on the review of 
all available data, further enrollment may be discontinued; otherwise, enrollment up 
to 29 subjects will occur. 
• 
Group 3 will enroll up to 55 advanced NSCLC subjects with low (< 50%) tumor 
PD-L1- expression who are naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R agents. 
Nineteen (19) subjects will be enrolled during the first stage and treated with the 
AMG 820 plus pembrolizumab combination.  If 3 or fewer subjects have an objective 
response per irRECIST then, depending on the review of all available data, further 
enrollment may be discontinued; otherwise, enrollment up to 55 subjects will occur. 
• 
Group 4 will enroll up to 58 NSCLC subjects who have not responded to or have 
relapsed during monotherapy with anti-PD-1/PD-L1 agents and are 
anti-CSF-1/CSF-1R naïve.  These subjects will be further distributed equally between 
two sub-groups (4a and 4b) depending on the PD-L1 expression in the tumor tissue: 
high (≥ 50%) and low (< 50%) expression (up to 29 in each sub-group).  For each 
sub-group, an initial set of 10 subjects will be enrolled during the first stage and 
treated with the AMG 820 plus pembrolizumab combination.  If no subjects have an 
objective response per irRECIST for either subgroup then, depending on the review 
of all available data, further enrollment may be discontinued; otherwise, enrollment 
up to 58 subjects will occur. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section and Figure 1 above. 
3.2 
Number of Sites 
The study will be conducted at approximately 15 sites in Australia, Canada, the United 
States, and Europe. Additional sites and countries may be added.  
Sites that do not enroll subjects within 4 months of site initiation may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Overall, this study may enroll between 67 and 197 subjects.  Six (6) to 
eighteen (18) subjects will be enrolled in part 1.  Once the safety of the recommended 
dose of the combination is established in Study Part 1, stage 1 of Study Part 2 will 
expand enrollment up to 67 subjects (including 6-9 subjects from Part 1 who have been 
treated with the recommended combination dose).  The subsequent  stage 2 of part 2 
may add another 118 subjects as per the study design rules.    
Refer to Section 10.2 for sample size considerations. 

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3.4
Replacement of Subjects
Subjects enrolled may be replaced if they are not evaluable for DLT (eg, a subject did 
not receive study treatment, or ended the study treatment before completion of DLT 
evaluation period for a reason other than experiencing a DLT).
3.5
Estimated Study Duration
3.5.1
Study Duration for Subjects
The duration of screening for each subject will be approximately 28 days.  The duration 
of treatment will vary for each subject.  Subjects enrolled in Part 1 and 2 of the study can 
be treated for up to 24 months if treatment is tolerable and clinical benefit is observed.  
All subjects will complete a safety follow-up visit approximately 135 (+7) days after the 
last dose of study treatment. After the safety follow-up visit, depending on the duration of 
their treatment on the study, some subjects will enter the long-term follow-up. The goal 
of the long-term follow-up is to obtain disease progression and survival information for a 
period of 12 months after the first combination dose.  The actual duration of the study for 
an individual subject is dependent upon the time required to assess PFS and OS at 
12 months.
For subjects who continue treatment past 12 months and up to 24 months (if tolerable 
and clinical benefit is observed), only Visit Date, IP Administration, and AE/SAE 
information will be collected in EDC.  Remaining follow-up to be performed per 
institutional standard of care.
3.5.2
End of Study
Primary Completion:  is anticipated to occur when all Study Part 1 and 2 subjects have 
been enrolled and treated for at least 12 months, been followed up for PFS and OS at 
12 months or discontinued from the study.
End of Trial:  is when the last subject is assessed or receives an intervention for 
evaluation in the study. This is anticipated to occur no sooner than when the last subject 
enrolled in the study has been followed for at least 12 months after the administration of 
the first combination dose of study treatment.
4.
SUBJECT ELIGIBILITY
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  

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Protocol Number:  20150195 
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Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).  All windows in Inclusion and Exclusion criteria 
below are relative to first day of study treatment.  
4.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures 
102 
Male or female age ≥ 18 years at the time of informed consent   
103 
Pathologically documented, definitively diagnosed, advanced CRC, pancreatic 
cancer or NSCLC that is refractory to standard treatment, or the subjects have 
been intolerant to or refuse standard treatment.  The select tumor types must 
also meet the following criteria: 
• 
Part 1 and Group 1: advanced MMR-proficient CRC subjects naïve to 
anti-PD-1/PD-L1/CSF-1/CSF-1R therapies 
• 
Part 1 and Group 2: advanced pancreatic cancer subjects with good 
performance status (defined as ECOG 0-1, good pain management and 
adequate nutritional intake) naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R 
therapies 
• 
Part 1 and Group 3: advanced NSCLC subjects with low (< 50%) tumor 
PD-L1- expression naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R therapies 
• 
Part 1 and Group 4a: NSCLC subjects with low (< 50%) tumor 
PD-L1-expression who are anti-CSF-1/CSF-1R naïve and have not 
responded to (disease progression or stable disease > 6 months) or have 
relapsed during monotherapy with anti-PD-1/PD-L1 therapies 
• 
Part 1 and Group 4b: NSCLC subjects with high (≥ 50%) tumor 
PD-L1-expression who are anti-CSF-1/CSF-1R naïve and have not 
responded to (disease progression or stable disease > 6 months) or have 
relapsed during monotherapy with anti-PD-1/PD-L1 therapies 
104 
Subject must have radiographically and/or clinically measurable disease per 
RECIST 1.1 (Eisenhauer et al, 2009).  Index lesions must not be chosen from a 
previously irradiated field unless there has been radiographic tumor progression 
in that lesion prior to enrollment.  See Note: Appendix D for index lesion and 
non-index lesion criteria. 
105 
ECOG performance status of 0 - 1 
106 
Adequate organ function determined prior to enrollment, defined as follows: 
• 
Hematological 
− 
ANC ≥ 1.5 x 109/L 
− 
platelet count ≥ 100 x 109/L 
− 
hemoglobin ≥ 9 g/dL (without need for hematopoietic growth factor or 
transfusion support) 
• 
Renal 
− 
serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR 24 hr creatinine 
clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. 

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(Note: Creatinine clearance need not be determined if the baseline serum 
creatinine is within normal limits. Creatinine clearance should be 
determined per institutional standard).

Hepatic

serum bilirubin 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with 
total bilirubin level > 1.5 x ULN

aspartate aminotransferase (AST) 2.5 x ULN OR 5 x ULN for subject 
with liver metastases

alanine aminotransferase (ALT) 2.5 x ULN OR 5 x ULN for subject 
with liver metastases

Coagulation

international normalization ratio (INR) or prothrombin time (PT) 
1.5 x ULN, unless the subject is receiving anticoagulant therapy, in 
which case PT and partial thromboplastin time (PTT)/activated PTT 
(aPTT) must be  within therapeutic range of intended use of 
anticoagulants

PTT or aPTT 1.5 x ULN unless the subject is receiving anticoagulant 
therapy as long as PT and PTT/aPTT is within therapeutic range of 
intended use of anticoagulants
107
Subjects with NSCLC: Available information regarding recently (within 3 months 
prior to day 1 and no systemic therapy given since the biopsy) evaluated PD-L1 
tumor expression status or willing to provide fresh tumor biopsy to determine 
eligibility. NSCLC subjects that failed to respond to or relapse during previous 
anti-PD-1/PD-L1 inhibitors immediately before considering enrolling into current 
study, may be accepted into the trial based on previously established PD-L1 
tumor expression, if discussed and agreed by the Sponsor.  
108
Subjects with CRC: Availability of a recent (within 3 months prior to day 1 and no 
systemic therapy given since the biopsy) and biomarker evaluable tumor tissue 
sample required at baseline.
109
Subjects with pancreatic cancer: Availability of a recent (within 3 months prior to 
day 1 and no systemic therapy given since the biopsy) and biomarker evaluable 
tumor tissue sample required at baseline, whenever feasible.
4.2
Exclusion Criteria
201
Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first study dose and neurologic symptoms 
should have returned to baseline), have no evidence of new or progressing brain 
lesions, and are not using steroids > 10 mg prednisone equivalent for at least 
7 days prior to trial treatment. This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability.
202
History of other malignancy within the past 2 years with the following exceptions:

malignancy treated with curative intent and with no known active disease 
present and has not received chemotherapy for ≤ 2 years before enrollment 
and felt to be at low risk for recurrence by the treating physician

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
adequately treated non-melanoma skin cancer, cervical carcinoma in situ,
superficial or in situ carcinoma of the bladder or breast ductal carcinoma in 
situ, without evidence of disease for any of these at the time of enrollment

prostatic intraepithelial neoplasia without evidence of prostate cancer at the 
time of enrollment
203
Subject has history of interstitial lung disease, (non-infectious) pneumonitis that 
required steroids, or current pneumonitis.
204
History or evidence of other active autoimmune diseases that has required 
prolonged systemic treatment in past 2 years (ie, with use of disease modifying 
agents such as corticosteroids or immunosuppressive drugs). 
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered 
a form of systemic treatment.
205
Evidence of clinically significant immunosuppression such as the following:

organ transplant or prior stem cell transplantation

any severe congenital or acquired cellular and/or humoral immune deficiency

other signs or symptoms of clinical immune system suppression or diagnosis 
of immunodeficiency

concurrent opportunistic infection
206
receiving systemic immunosuppressive therapy (> 2 weeks) within 7 days prior to
the first dose of study treatment, including oral steroid doses > 10 mg/day of 
prednisone or equivalent except for management of adverse events during the 
course of the study. Subjects that require intermittent use of bronchodilators or 
local steroid injection will not be excluded from the study.
207
receiving systemic immunostimulatory agents within 6 weeks or five half-lives, 
whichever is shorter, prior to first dose of study treatment (except 
anti PD-1/PD-L1 treatment if recruited into Group 4a or 4b).
208
Evidence of active infection within 2 weeks prior to first dose of study treatment.
209
Prior chemotherapy, radiotherapy, biological cancer therapy or major surgery
within 28 days prior to enrollment.  Note: patients may have received anti 
PD-1/PD-L1 treatment if recruited into group 4a and 4b (refractory/relapsed on 
anti-PD-1/PD-L1 + naïve to CSF-1/CSF-1R treatment).
210
Currently participating or has participated in a study (treatment period only) of an 
investigational agent or used an investigational device within 28 days of 
enrollment.
211
Adverse event due to cancer therapy administered more than 28 days prior to 
enrollment that has not recovered to CTCAE grade 1 or better. Note: Subjects 
with ≤ grade 2 neuropathy and alopecia are an exception to this criterion and
may qualify for the study.
212
Expected to require other cancer therapy while on study (eg, need of local 
palliative radiation treatment to the site of bone and other metastasis will be 
considered sign of clinical progression).
213
Other investigational procedures while participating in this study are excluded.
214
Positive for human immunodeficiency virus (HIV).

Product:  AMG 820
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215
Hepatitis B and C based on the following results:

Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B).

Negative HBsAg and positive for hepatitis B core antibody: hepatitis B virus 
DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis 
B virus DNA suggests occult hepatitis B.

Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is 
necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C
216
Received live vaccine within 28 days prior to enrollment.
217
Men of reproductive potential and women of childbearing potential who are 
unwilling to practice a highly effective method(s) of birth control while on study 
through 4 months after receiving the last dose of study drug.  Highly effective 
methods of birth control are defined as those which result in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly such as 
implants, injectables, combined oral contraceptives, intrauterine devices (IUDs), 
sexual abstinence or vasectomised partner.  
Note: Men and women who do not meet the definitions below are considered to 
be of reproductive potential or childbearing potential respectively. 

Men of non-reproductive potential are defined as having azoospermia, 
whether due to having had a vasectomy or due to an underlying medical 
condition.

Women not of childbearing potential are defined as: Any female who is 
postmenopausal defined as at least 12 months with no menses without 
an alternative medical cause; in women < 45 years of age, a high follicle 
stimulation hormone [FSH] level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy; in the absence of 
12 months of amenorrhea, a single FSH measurement is sufficient OR
have had a hysterectomy and/or bilateral oophorectomy, or bilateral
salpingectomy at least 6 weeks prior to screening, OR has a congenical 
or acquired condition that prevents childbearing.
218
Women who are lactating /breastfeeding or who plan to breastfeed while on 
study through 4 months after receiving the last dose of study drug.
219
Women with a positive pregnancy test.
220
Women planning to become pregnant while on study through 4 months after 
receiving the last dose of study drug.
221
Subject has known sensitivity to any of the products or components to be
administered during dosing.

Product:  AMG 820
Protocol Number:  20150195
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222
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge.
223
History or evidence of psychiatric, substance abuse, or any other clinically 
significant disorder, condition or disease (with the exception of those outlined 
above) that, in the opinion of the investigator or sponsor physician, if consulted, 
would pose a risk to subject safety or interfere with the study evaluation, 
procedures or completion.
5.
SUBJECT ENROLLMENT
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written IRB/IEC approval of the protocol, informed consent 
form, and all other subject information and/or recruitment material, if applicable (see 
Section 11.2).  All subjects must personally sign and date the IRB/IEC and Amgen 
approved informed consent form before commencement of study-specific 
activities/procedures.  
A subject is considered enrolled when the investigator decides that the subject has met
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF).
Each subject who enters into the screening period for the study (defined when the 
subject signs the informed consent) receives a unique subject identification number 
before any study-related activities/procedures are performed.  The subject identification 
number will be assigned manually.  This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject.  Subjects who do not meet all eligibility criteria may be rescreened at the 
discretion of the investigator.  If a subject is being rescreened, he or she may need to 
reconsent to the study to ensure that the IRB/IEC approved main informed consent form 
is signed within 28 days of enrollment.  Subjects who are determined not eligible after 
rescreen must be screen-failed and the reason for the screen-failure provided.  Subjects 
may only be enrolled once into this study.
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.

Product:  AMG 820
Protocol Number:  20150195
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5.1
Treatment Assignment
All subjects enrolled into the study will receive open-label AMG 820 in combination with 
pembrolizumab. The treatment assignment date is to be documented in the subject’s 
medical record.
6.
TREATMENT PROCEDURES
6.1
Classification of Product(s) and/or Medical Device(s)
The Amgen Investigational Product used in this study is AMG 820.  
The Non-Amgen Investigational product(s) used in this study is pembrolizumab. The 
Investigational Product Instruction Manual (IPIM), a document external to this protocol, 
contains detailed information regarding the storage, preparation, destruction, and 
administration of AMG 820 and pembrolizumab.
6.2
Investigational Product
AMG 820 and pembrolizumab will be administered intravenously Q3W on the same day 
in sequence. The recommended starting dose of AMG 820, 1400 mg, is guided by the 
AMG 820 First in Human study.  Pembrolizumab will be administered at 200 mg and will 
remain unchanged during the course of the study.  If the treatment combination is not 
well tolerated during Study Part 1, AMG 820 will be de-escalated to pre-specified 
nominal dose levels, 1100 mg and 800 mg. 
AMG 820 must be administered before pembrolizumab on the same treatment day. The 
pembrolizumab infusion is to begin 15 minutes following the end of the AMG 820 
infusion.
6.2.1
Amgen Investigational Product: AMG 820
AMG 820 will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.  AMG 820 will be presented as a 
sterile, clear, colorless to slightly yellow frozen liquid in 20 mL glass vials.  Each glass 
vial will contain 3.0 mL of AMG 820 with a concentration of 70 mg/mL.  
6.2.1.1
Dosage, Administration, and Schedule: AMG 820
AMG 820 must be prepared and administered by a qualified healthcare professional. 
Subjects should be assessed clinically for adverse events/toxicity prior to each dose 
using the CTCAE version 4 (Appendix A).  Complete blood count with differential and
chemistry panels including liver enzyme laboratory tests (ALT and AST) and total 
bilirubin should be obtained according to the Schedule of Assessments (Table 5) and the 
results should be checked within 2 days prior to each treatment. 

Product:  AMG 820 
Protocol Number:  20150195 
Date:  15 June  2018 
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Each cycle of AMG 820 will be 3 weeks.  The initial cohort will treat subjects with 
1400 mg AMG 820 plus 200 mg pembrolizumab Q3W.  All subsequent doses will be 
administered Q3W (± 3) days.  The treatment cycle interval may be increased due to 
toxicity as described in Section 6.  AMG 820 must be administered before 
pembrolizumab on treatment days.  Lower AMG 820 dose levels may be explored based 
on emerging safety data during study part 1.  If a subject requires corticosteroid dosing 
of > 10 mg prednisone daily (or equivalent) as supportive care, AMG 820 and 
pembrolizumab dosing must be withheld until the corticosteroid dose has decreased  
to ≤ 10 mg prednisone daily (or equivalent). 
AMG 820 will be diluted with the appropriate amount of 0.9% NaCl for a total volume of 
100 mL.  The final concentration of the AMG 820 will be 14 mg/mL (1400 mg total dose). 
AMG 820 preparations will be administered via intravenous (IV) infusion, through a 
0.22 µm, low protein binding filter, over a 60-minute period during the first dosing 
administration.  If the first administration is well-tolerated, the investigator may adopt a 
30-minute infusion period for subsequent infusions.  A physician or medical staff 
involved in study evaluation must be available during the administration of the 
investigational product to assess and treat adverse events that may arise during dosing.  
Subjects will be monitored in the clinic for at least 2 hours or longer if necessary, 
following dosing of drug combination for the first 3 cycles and as needed thereafter. 
The effects of overdose of this product are not known. 
Subjects will be treated with AMG 820 plus pembrolizumab until subjects experience 
confirmed PD as per irRECIST, intolerance to study treatment, or until the end of study, 
whichever occurs first.  The dose, start date, and lot number of AMG 820 are to be 
recorded on each subject’s CRF. 
6.2.1.2 
Dose-cohort Study Exploration and Stopping Rules 
6.2.1.2.1 
Dose Level Review Meetings 
A Dose Level Review Team (DLRT) will review the safety data to evaluate DLT.  The 
DLRT will be composed of the Investigator(s), Amgen Medical Monitor / Early 
Development Leader, Amgen Global Safety Officer or designee, Amgen Clinical 
Research Study Manager (CRSM) and Biostatistics representative or designee.  
Additional members may be added as needed (eg, clinical pharmacologist).  A quorum, 
defined as ≥ 50% of the participating investigators or their qualified designee (ie, sub-PI 
or research nurse or study coordinator possessing hard copy documentation [eg, e-mail] 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
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of the PI’s vote), must be in attendance for DLRM. The DLRM will be rescheduled if a 
quorum is not reached.
The DLRM members will recommend dosing decisions, which may include enrolling 
more subjects for DLT evaluation in part 1 of the study, de-escalation to a lower dose, 
delay or termination of dosing, or declare that the combination is tolerable based on DLT 
evaluation period data.  All DLRT decisions will be communicated to team members via 
formal correspondence.
The Dose Level Review Team (DLRT) will evaluate data from all subjects enrolled into 
all cohorts including events with a longer onset time or events following exposure to 
multiple doses.  If late onset events occur during a cohort, the DLRT may adaptively 
re-consider the doses evaluated within a cohort for subsequent dosing and/or possibly 
trigger a de-escalation or withholding of additional doses in subsequent cohorts.  For 
Part 2 of the study, DLRT safety reviews will only be held during stage 1. A total of 
3 DLRT safety reviews will occur: after the first 20 subjects (collectively from all
5 groups) have enrolled and completed 2 cycles of therapy, after an additional
20 subjects have enrolled and completed 2 cycles of therapy and after all subjects in 
stage 1 have enrolled completed 2 cycles of therapy.
The DLRT may request additional reviews or recommend modifying or suspending the 
study if safety concerns arise during the study. Refer to Section 10.3.2 for additional 
details regarding the DLRT.
All DLRM requirements are outlined in the protocol. A DLRM Charter will not be used.
6.2.1.2.2
Rules for DLT Evaluation in Part 1 of the study
The DLT evaluation period for a subject is 21 days from the initial administration of study 
treatment.  To be evaluable for a DLT, subjects must have had the opportunity to be on 
treatment for at least 21 days from the initial dosing of study treatment and have 
received at least 1 dose of AMG 820 and 1 dose of pembrolizumab in combination, or 
have a DLT during the DLT evaluation period after at least 1 dose of AMG 820 and 
pembrolizumab.  Subjects may be replaced if they are not evaluable for DLT to obtain at 
least 6 DLT-evaluable subjects in a cohort during Study Part 1 (eg, a subject did not 
receive study treatment, or ended the study treatment before completion of DLT 
evaluation period for a reason other than experiencing a DLT).

Product:  AMG 820
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Safety will be evaluated considering the incidence of DLTs among all DLT-evaluable 
subjects enrolled in part 1, which will include up to 3 cohorts. The initial cohort will treat 
subjects with 1400 mg AMG 820 plus 200 mg pembrolizumab Q3W using a 6+3 design.

If 0 or 1 of the initial 6 evaluable subjects experience a dose-limiting toxicity 
(DLT) then the dose combination will be determined to be tolerable and Study 
Part 2 will be initiated.

If 2 of the initial 6 evaluable subjects experience a DLT then 3 additional
evaluable subjects will be enrolled. 

If 33% or more of the evaluable subjects experience a DLT then the dose 
combination will be determined to be non-tolerable and a second Part 1 cohort 
will be enrolled to test a decreased dose of AMG 820 in combination with 200 mg 
pembrolizumab. Further degree of dose modification and/or schedule of 
administration will be decided based on analysis of emerging safety and PK data.
6.2.1.2.3
Dose-limiting Toxicity Definition
An adverse event will be considered related to study treatment (possibly, probably, or 
definitely related to the study treatment)  if there is a suspected “reasonable causal 
relationship” to the study treatment (ICH E2A), and not only a lack of an alternative 
explanation for the toxicity. All toxicities will be graded using the CTCAE version 4.0 
(Appendix A).
The occurrence of any of the following toxicities during DLT evaluation period (ie, 21 day
period from the initial administration of AMG 820 and pembrolizumab in combination) will 
be considered a DLT, if judged by the investigator to be related to the administration of 
AMG 820 and/or pembrolizumab:

Grade 4 non-hematologic toxicity

Grade 3 or higher pneumonitis 

Grade 3 non-hematologic toxicity lasting > 7 days despite appropriate treatment

Grade 3 fatigue will not be classified as DLT, irrespective of duration

Any grade 3 or higher non-hematologic laboratory value if:
-
medical intervention is required, or
-
the abnormality leads to hospitalization, or
-
the abnormality persists at grade 3 or higher for >1 week unless deemed not 
clinically important per both investigator and sponsor

Grade 3 or grade 4 febrile neutropenia

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
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
Grade 3 or higher thrombocytopenia with bleeding and Grade 4 or higher 
thrombocytopenia lasting > 48 hours or any thrombocytopenia requiring 
intervention

Delay in cycle 2 treatment for > 2 weeks due to study drug-related toxicity (unless 
clearly attributable to pembrolizumab only and delay is caused due to tapering of 
steroids)

Any other intolerable toxicity leading to permanent discontinuation of AMG 820 or 
pembrolizumab 
Lymphopenia of any grade is not considered a DLT 
Dose limiting toxicities do not include the following:

A transient (resolving to grade ≤  1 within 6 hours of onset) grade 3 
infusion-related adverse event

Any grade 3 endocrinopathy that is adequately controlled by hormonal 
replacement
Cumulative adverse events profile will be taken into consideration when making 
decisions on dose escalation or de-escalation. 
If an AE is clearly attributable to pembrolizumab (based on its known safety profile) and 
does not exceed the expected severity, this specific AE may be considered exempt from 
being a DLT.
Disease related events should not be considered a DLT.
Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver injury) 
will be considered a DLT.  A Hy’s Law case is defined as: AST or ALT values of 
≥3 x ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without signs of 
cholestasis and with no other clear alternative reason to explain the observed 
liver-related laboratory abnormalities (see Section 6.4 on hepatotoxicity management 
and Appendix A for further explanation of Hy’s law case and Management of Hepatic 
Function).
If a subject experiences a DLT during the DLT evaluation period, study treatment should
be discontinued for that subject.  Additionally, any treatment related toxicity meeting the 
DLT definition after day 21 should result in discontinuation of therapy.  In subjects with 
irPR, irCR or evidence of clinical benefit (as determined by the investigator), an option to 
continue at the same or at a reduced dose level can be considered once the toxicity 
returns to the subject’s baseline value or CTCAE grade ≤ 1 if deemed appropriate by the 
investigator and sponsor.

Product:  AMG 820
Protocol Number:  20150195
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6.2.1.2.4
Determination of Adverse Event Severity and Relatedness
Determination of the severity of adverse events will be consistent with CTCAE, 
version 4.0.  The relationship of an adverse event to investigational product will be 
determined by the investigator.  An adverse event will be considered related to study 
treatment (possibly, probably, or definitely related to the study treatment) if there is a 
suspected “reasonable causal relationship” to the study treatment (ICH E2A), and not 
only a lack of an alternative explanation for the toxicity (NCI Guidelines for 
Investigators - Adverse Event Reporting Requirements , Sept, 2013)
(see Section 9 – Safety Data Collection, Recording, and Reporting).
6.2.1.2.5
Cohort Dose Level Determination
Study Part 1
A Dose Level Review Team (DLRT) will convene before a decision is made to open 
study Part 2.  At the start of Part 1, enrollment of the first cohort of 6 to 9 evaluable 
patients will open for enrollment with a starting dose of AMG 820 1400 mg plus 
pembrolizumab 200 mg Q3W.  Following subject completion of the DLT period, the 
DLRT will review all available safety data for the first cohort.  If the data supports 
continued dosing at the selected starting dose, study Part 2 will be initiated at the same 
dose level. If it is determined that the starting dose is non-tolerable (if 33% or more of 
the evaluable subjects experience a DLT), dose de-escalation will occur and a second 
Part 1 cohort will be enrolled to test a decreased dose of AMG 820 in combination with 
200 mg pembrolizumab Q3W.  This will occur until identification of a well-tolerated dose 
for study Part 2. The AMG 820 (mg) pre-specified nominal cohort dose levels to be 
explored are 1100 mg and 800 mg Q3W.  The pembrolizumab dose level will remain at 
200 mg Q3W.

Product:  AMG 820
Protocol Number:  20150195
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Part 2
Part 2 will have 4 groups, which will be evaluated using a Simon two-stage design: 
Table 1.  Study Part 2 Subject Groups
Naïve to  anti-PD-1/PD-L1/CSF-1/CSF-1R  treatment
Group 1
CRCMMR-proficient
Group 2
Pancreatic Cancer
Group 3
NSCLCPD-L1 low
Refractory/ relapsing on anti-PD-1/PD-L1 + naïve to CSF-1/CSF-1R  treatment
Group 4a
NSCLCPD-L1 low
Group 4b
NSCLCPD-L1 high
The dose or doses (proposed recommended phase 2 dose, RP2D) to be evaluated in 
part 2 of the study will be based on results from part 1.  The DLRT may determine the 
RP2D, which is defined as a dose(s) that is/are safe and produces pharmacodynamic 
effects. Emerging safety data may be used to re-challenge the selected dose in Study 
Part 1.  If the initially selected dose is re-challenged, additional subjects may be enrolled 
in the corresponding cohort.  In addition, the study may be discontinued or modified at 
any time due to documented safety findings.
Enrollment into the second stage of the Simon two-stage design will be determined by 
results through Study Part 2 stage 1.
All dose level and enrollment decisions will be formally communicated to investigators 
via a memorandum. 
The dosing schedule is described by a schema in the protocol synopsis.
6.2.1.3
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation: AMG 820
A subject experiencing a DLT (days 1-21) will not receive additional AMG 820 plus
pembrolizumab treatment and will be followed until resolution of the event or toxicity. 
Subjects withdrawn from AMG 820 plus pembrolizumab therapy will be treated as 
deemed appropriate by the investigator. End of study procedures should be performed 
and the appropriate CRFs should be completed. Any treatment related toxicity meeting 
the DLT definition after day 21 may result in discontinuation of therapy. In subjects with 
irPR, irCR or evidence of clinical benefit (as determined by the investigator), an option to 
continue at the same dose level or a lower dose level can be considered. If deemed 
appropriate by the investigator and sponsor, AMG 820 can be re-initiated once the 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
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toxicity returns to the subject’s baseline value or CTCAE grade ≤ 1. For subjects with 
hepatotoxicity, refer to Section 6.4. For such subjects, there will be an increased 
frequency of monitoring at an interval deemed appropriate by the investigator and 
sponsor.  Subjects requiring more than 6 weeks from the last dose to recover from 
AMG 820 and/or pembrolizumab related grade 3 or 4 toxicities that meet the definition of 
a DLT will be permanently discontinued (please also see Table 2 for additional details).
If a subject experiences ≥ grade 3 toxicities or SAEs that are unrelated to AMG 820 
and/or pembrolizumab, then treatment will be postponed until the toxicity has resolved to 
grade 1 (as defined by the CTCAE, version 4) or returns to the subject’s baseline value. 
If the treatment break is longer than 6 weeks from the last dose the subject may resume 
treatment only after discussing the case with the Sponsor. If resuming treatment, 
AMG 820 may be administered at the same dose level or a lower dose level as per the 
Principal Investigator and Sponsor.
In the event one of the combination drugs is delayed or permanently discontinued for 
related toxicity, the subjects will have the option to continue on the other drug as long as 
the toxicity is clearly not related to the combination partner and the investigator and 
Sponsor assessment is that the patient may derive benefit from continuation with 
monotherapy.
6.2.2
Non-Amgen Investigational Product: Pembrolizumab
Non-Amgen investigational product pembrolizumab will also be used in this study. 
Pembrolizumab will be manufactured by Merck. Pembrolizumab will be labeled, 
packaged, and distributed by Amgen (or designee) using Amgen (or designee) clinical 
study drug distribution procedures. Pembrolizumab is supplied as pembrolizumab 
100 mg/4mL vials (25 mg/mL) solution for intravenous infusion. 
Additional details regarding the pembrolizumab product are provided in the IPIM.
6.2.2.1
Dosage, Administration, and Schedule: Pembrolizumab
Pembrolizumab must be prepared and administered by a qualified healthcare 
professional.  Subjects should be assessed clinically for adverse events/toxicity prior to 
each dose using the CTCAE version 4 (Appendix A).  Complete blood count with 
differential and chemistry panels including liver enzyme laboratory tests (ALT and AST)
and total bilirubin and thyroid function tests (triiodothyronine [T3] or free T3 [FT3] per 
local standard, free thyroxine [FT4], and thyroid stimulating hormone [TSH]) should be 
obtained according to the Schedule of Assessments (Table 5) and the results should be 

Product:  AMG 820
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checked within 2 days prior to each treatment.  Dosing will occur only if these test values 
are acceptable per Section 6.2.2.2.
Pembrolizumab at a dose of 200 mg will be administered intravenously Q3W (± 3 days).  
AMG 820 and pembrolizumab should be administered on the same day, with AMG 820 
administered first. The pembrolizumab infusion is to begin 15 minutes following the end 
of the AMG 820 infusion.  Pembrolizumab dosing will continue as long as there is 
derived clinical benefit, until confirmed PD per irRECIST, intolerance to treatment, 
24 months from the date of the first dose of pembrolizumab or end of study, whichever 
occurs first.  
Pembrolizumab infusion will be administered as a 30-minute intravenous infusion.  
Investigators should make every effort to target infusion timing to be as close to 
30 minutes as possible. However, given the variability of infusion pumps from site to site, 
a window of -5 and +10 minutes is permitted (ie, infusion time is 
30 minutes:-5 minutes/+ 10 minutes). A central catheter is not required for infusion; 
however if a subject has a central venous catheter in place, it is recommended that it be 
used for the infusion.  A 0.2 or 0.22 µm in-line filter made of polyethersulfone must be 
used during administration to remove any adventitious particles.  If the infusion set does 
not contain a 0.2 or 0.22 µm in-line filter, it is recommended to use an extension line 
containing the filter.  Details on the dose calculation, preparation, and administration are 
provided in the IPIM.
The dose, start date, and lot number of pembrolizumab are to be recorded on each 
subject’s CRF.
6.2.2.2
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation: Pembrolizumab
Pembrolizumab will be withheld for treatment-related adverse events as described in
Table 2. 

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Table 2.  Dose Modification Guidelines for Pembrolizumab Related Adverse 
Events
Toxicity
Hold 
Pembrolizumab 
Treatment For 
Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
Diarrhea/Colitis
2-3
Toxicity resolves to 
grade 0-1.
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
AST, ALT, or 
Increased 
Bilirubin3
2
Toxicity resolves to 
grade 0-1
Toxicity does not resolve within 
12 weeks of last dose.
3-4
Permanently discontinue
(see exception below)1
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
Type 1 diabetes 
mellitus or
3-4
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
grade 3-4 hyperglycemia 
associated with evidence 
of beta cell failure.
Resume pembrolizumab when 
subjects are clinically and 
metabolically stable.
Hypophysitis
2-4
Toxicity resolves to 
grade 0-1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
Hyperthyroidism 
3
Toxicity resolves to 
grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted.
Infusion 
Reaction
3-4
Permanently discontinue
Permanently discontinue
Pneumonitis
2
Toxicity resolves to 
grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
3-4 or Recurrent 
2
Permanently discontinue
Permanently discontinue
Page 1 of 2
Note: Permanently discontinue for any severe or grade 3 drug-related adverse event  that recurs or any 
life-threatening event.
AST = aspartate aminotransferase  ALT = alanine aminotransferase
1 For subjects with liver metastasis who begin treatment with grade 2 AST or ALT, if AST or ALT increases 
by greater than or equal to 50% relative to baseline and lasts for at least 1 week then subjects should be 
discontinued.
2 Subjects with intolerable or persistent grade 2 drug-related adverse event may hold study medication at 
physician   discretion.  Permanently discontinue study drug for persistent grade 2 adverse reactions for 
which treatment with study drug has been held, that do not recover to grade 0-1 within 12 weeks of the last 
dose
3 Subjects who have isolated elevated AST (with grade ≤1 ALT and normal bilirubin) attributed to AMG 820 
and are clinically asymptomatic may potentially continue with treatment upon discussion and agreement 
with Medical Monitor.

Product:  AMG 820 
Protocol Number:  20150195 
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Table 2.  Dose Modification Guidelines for Pembrolizumab Related Adverse 
Events 
Toxicity 
Hold 
Pembrolizumab 
Treatment For 
Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to 
grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other 
Drug-Related 
Toxicity2 
3 or Severe 
Toxicity resolves to 
grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Page 2 of 2 
Note: Permanently discontinue for any severe or grade 3 drug-related adverse event  that recurs or any 
life-threatening event. 
AST = aspartate aminotransferase  ALT = alanine aminotransferase 
1 For subjects with liver metastasis who begin treatment with grade 2 AST or ALT, if AST or ALT increases 
by greater than or equal to 50% relative to baseline and lasts for at least 1 week then subjects should be 
discontinued. 
2 Subjects with intolerable or persistent grade 2 drug-related adverse event may hold study medication at 
physician discretion.  Permanently discontinue study drug for persistent grade 2 adverse reactions for 
which treatment with study drug has been held, that do not recover to grade 0-1 within 12 weeks of the last 
dose. 
In case of related toxicity that does not resolve to grade 0 to 1 or baseline within 
12 weeks after the last infusion of pembrolizumab, pembrolizumab treatment should be 
discontinued after consultation with the Sponsor medical monitor.  With the investigator 
and Sponsor medical monitor agreement, subjects with laboratory adverse events still at 
grade 2 after 12 weeks may continue pembrolizumab treatment in the trial only if 
asymptomatic and controlled.   
Subjects enrolled in phase 1b, who develop a DLT during the DLT evaluation period will 
permanently discontinue pembrolizumab.  In subjects who develop a DLT clearly related 
to AMG 820 and have evidence of clinical benefit (as determined by the investigator), an 
option to continue at the same AMG 820 dose level or a lower dose level can be 
considered.  If deemed appropriate by the investigator and sponsor, treatment can be 
re-initiated once the toxicity returns to the subject’s baseline value or CTCAE grade ≤ 1. 
The reason for dose changes is to be recorded on each subject’s CRF. 
6.2.3 
Management of AMG 820 Related Periorbital or Conjunctival 
Swelling 
If a subject experiences grade 3 (severe) periorbital or conjunctival swelling, the study 
treatment should be withheld until the toxicity resolves or improves to grade 2 
(moderate).  If the event requires > 4 weeks to recover to grade 2 or lower (with or 

Product:  AMG 820 
Protocol Number:  20150195 
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without appropriate therapeutic intervention), the subject will be discontinued from the 
study and should be followed until the swelling  resolves to grade 2.  Appropriate 
therapeutic intervention (eg topical 1% hydrocortisone with 0.25% phenylephrine and/or 
diuretics) to resolve the swelling may be administered at the discretion of the 
Investigator to any subject experiencing periorbital edema or conjunctival swelling of any 
grade. 
6.2.4 
Rescue Medications and Supportive Care Guidelines for 
Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator including, but not limited, to the items outlined below. If a subject 
requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) as supportive 
care, AMG 820 and pembrolizumab dosing must be withheld until the corticosteroid dose 
has decreased to ≤10 mg prednisone daily (or equivalent) as detailed in Section 6.2.2.2. 
6.2.4.1 
Pneumonitis and Interstitial Lung Disease (ILD) 
Subjects with symptomatic pneumonitis, ILD, or acute interstitial pneumonitis (symptoms 
may include but are not limited to abnormal breath sounds, chest pain and/or tightness, 
dyspnea, dry cough, fatigue, fever, hemoptysis) should immediately stop receiving 
pembrolizumab and have an evaluation.  The evaluation may include bronchoscopy and 
pulmonary function tests to rule out other causes such as infection.  All attempts should 
be made to rule out other causes such as metastatic disease, bacterial or viral infection.  
It is important that subjects with a suspected diagnosis of pneumonitis be managed as 
per the guidance in Table 3. until treatment-related pneumonitis is excluded.  Treatment 
of both a potential infectious etiology and pneumonitis in parallel may be warranted.  
Management of the treatment of suspected pneumonitis with steroid treatment should 
not be delayed for a therapeutic trial of antibiotics.  If an alternative diagnosis is 
established, the subject does not require management as in Table 3; however, the 
adverse event should be reported regardless of etiology. 
If the subject is determined to have pembrolizumab associated pneumonitis, ILD, or 
acute interstitial pneumonitis, the suggested treatment is as follows (detailed plan in 
Table 3). 
• 
For grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks.  
• 
For grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed.  
• 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 

Product:  AMG 820 
Protocol Number:  20150195 
Date:  15 June  2018 
Page 51 of 117 
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Table 3.  Recommended Approach to Handling Pneumonitis and ILD 
Pembrolizumab 
Drug 
Associated 
Pneumonitis 
and ILD 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
(asymptomatic) 
No action 
Intervention not indicated. 
Grade 2 
Withhold 
pembrolizumab, may 
return to treatment if 
improves to grade 1 or 
resolves within 
12 weeks 
Consider pulmonary consultation with 
bronchoscopy and biopsy/ bronchoalveolar lavage 
(BAL) and infectious disease consultation if 
appropriate. 
Conduct an in person evaluation approximately 
twice per week until the subject is improving.  
Consider frequent Chest X-ray as part of 
monitoring. 
Treat with systemic corticosteroids at a dose of 
1 to 2 mg/kg/day prednisone or equivalent.  When 
symptoms improve to grade 1 or less, steroid 
taper should be started and continued over no 
less than 4 weeks.  Permanently discontinue for 
inability to reduce corticosteroid dose to 10 mg or 
less of prednisone or equivalent per day within 
12 weeks. 
Discontinue pembrolizumab if upon re-challenge 
the subject develops a second episode of grade 2 
or higher pneumonitis. 
Recurrent 
Grade 2 
Discontinue 
pembrolizumab 
Supportive care per instructions for Grade 2 
above. 
Grade 3 and 
Grade 4 
Discontinue 
pembrolizumab 
Hospitalize the subject and consider 
bronchoscopy with biopsy and/or BAL. 
Immediately treat with intravenous steroids 
(methylprednisolone 125 mg IV).  When 
symptoms improve to Grade 1 or less, a high dose 
oral steroid (prednisone 1 to 2 mg/kg once per day 
or dexamethasone 4 mg every 4 hours) taper 
should be started and continued over no less than 
4 weeks.  If IV steroids followed by high dose oral 
steroids does not reduce initial symptoms within 
48 to 72 hours, treat with additional 
anti-inflammatory measures.  Discontinue 
additional anti-inflammatory measures upon 
symptom relief and initiate a prolonged steroid 
taper over 45 to 60 days.  If symptoms worsen 
during steroid reduction, initiate a re-tapering of 
steroids starting at a higher dose of 80 or 100 mg 
followed by a more prolonged taper and 
administer additional anti-inflammatory measures, 
as needed.  In addition, prophylactic antibiotics for 
opportunistic infections should be considered. 
IV = intravenous 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 52 of 117
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6.2.4.2
Diarrhea

Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood and mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).

All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via intravenous infusion. For grade 2 or higher 
diarrhea, consider gastrointestinal (GI) consultation and endoscopy to confirm or rule
out colitis. 

For grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.

For grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 

When symptoms improve to grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
6.2.4.3
Type 1 Diabetes Mellitus (if new Onset, Including Diabetic 
Ketoacidosis) or ≥ Grade 3 Hyperglycemia, if Associated With 
Ketosis (Ketonuria) or Metabolic Acidosis (Diabetic ketoacidosis)
For type1 diabetes mellitus or grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type 1 diabetes mellitus and for 
grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 

Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
6.2.4.4
Hypophysitis

For grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 

For grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 53 of 117
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6.2.4.5
Hyperthyroidism or Hypothyroidism
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders.

Grade 2 hyperthyroidism events (and grade 2-4 hypothyroidism)

In hyperthyroidism, non-selective beta-blockers (eg, propranolol) 
are suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.

Grade 3-4 hyperthyroidism

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to grade 1 or less, 
steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required 
as the steroid dose is tapered.
6.2.4.6
Hepatic Toxicity

In case of hepatotoxicity, monitor liver function tests more frequently
(see Section 6.4.2 and Appendix A) until returned to baseline values or stabilized 
and subject is asymptomatic.

For grade 2 events, treat with IV or oral corticosteroids.

For grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  

Subjects who have isolated elevated AST (with grade ≤1 ALT and normal bilirubin) 
attributed to AMG 820 and are clinically asymptomatic may not require treatment 
with corticosteroids. These cases should be discussed with the medical monitor.

When symptoms improve to grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
6.2.4.7
Renal Failure or Nephritis

For grade 2 events, treat with IV or oral corticosteroids.

For grade 3-4 events, treat with IV corticosteroids.

When symptoms improve to grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
6.2.4.8
Infusion Reactions
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or 
anaphylaxis) are different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both adverse events.  Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 
24 hours of completion of infusion. 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 54 of 117
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Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab:
Table 4.  Infusion Reaction Treatment Guidelines
6.2.4.9
Pembrolizumab Events of Clinical Interest
Events of Clinical Interest that occur after the first dose of pembrolizumab through 
135 (+7) days after the last dose of pembrolizumab, or 135 (+7) days after initiation of a 
new anticancer therapy, whichever is earlier, must be reported to Amgen within 24 hours 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 55 of 117
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of the investigator’s knowledge of the event regardless of attribution to pembrolizumab.  
Information on how to identify and report Events of Clinical Interest can be referenced in 
Section 9.4.
6.2.4.10
Diet and Other Considerations While Taking AMG 820 and/or
Pembrolizumab
6.2.4.10.1
Diet During Treatment With AMG 820 and/or Pembrolizumab
Subjects should maintain a normal diet unless modifications are required to manage 
adverse events such as diarrhea, nausea or vomiting.
6.2.4.10.2
Contraception Requirements for AMG 820 and/or Pembrolizumab
AMG 820 and/or Pembrolizumab may have adverse effects on a fetus in utero.  
Furthermore, it is not known if AMG 820 or pembrolizumab has transient adverse effects 
on the composition of sperm.  Non-pregnant, non-breast-feeding women may be 
enrolled if they are willing to use acceptable method(s) of effective contraception or are 
considered of non-childbearing potential.  Refer to Section 4.2, exclusion criteria 214, for 
contraception requirements and definition of women of non-childbearing potential for this 
study.  Refer to the informed consent form for acceptable method(s) of effective 
contraception for subjects to use in this study.  Additional country-specific contraception 
requirements may be defined in a country-specific protocol supplement at the end of the 
Appendix Section of protocol as required by local laws and regulations.
Subjects should be informed that taking AMG 820 and/or pembrolizumab may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during the 
treatment and for 4 months after end of pembrolizumab.  In order to participate in the 
study they must adhere to the contraception requirements described above for the 
duration of the study treatment and during the follow-up period defined in Section 9.3
(Pregnancy and Lactation Reporting).  If there are any concerns that a subject will not 
reliably comply with the requirements for contraception, that subject should not be 
enrolled into the study.
6.2.4.10.3
Use of AMG 820 and/or Pembrolizumab in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study treatment. The outcome of the 
pregnancy will be reported to the sponsor and followed as described in Section 9.3
(Pregnancy and Lactation Reporting).  If a male subject impregnates his female partner, 
the investigator must be informed immediately and the pregnancy reported to the 
sponsor and followed as described in Section 9.3 (Pregnancy and Lactation Reporting).

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 56 of 117
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6.2.4.10.4
Use of AMG 820 and/or Pembrolizumab in Nursing Women
It is unknown whether AMG 820 and/or pembrolizumab are excreted in human milk.  
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, female subjects who are breast-feeding are not 
eligible for enrollment in this study.
6.3
Other Protocol-required Therapies
Systemic steroids for management of pembrolizumab immune related adverse events,
that are commercially available are not provided or reimbursed by Amgen (except if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these protocol-required therapies. 
6.4
Hepatotoxicity Stopping and Rechallenge Rules
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
AMG 820 and/or pembrolizumab as specified in the protocol and the United States Food 
And Drug Administration Guidance for Industry Drug-Induced Liver Injury: Premarketing
Clinical Evaluation, July 2009.
6.4.1
Criteria for Permanent Discontinuation of AMG 820 and 
Pembrolizumab Due to Potential Hepatotoxicity
AMG 820 and pembrolizumab should be discontinued permanently and the subject 
should be followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met: 

TBL ≥2x upper limit of normal (ULN) following baseline total bilirubin < ULN or 
INR > 1.5

AND increased AST or ALT from the relevant baseline value as specified below: 
Baseline AST or ALT value
AST or ALT elevation
< ULN
≥3x ULN

AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or
TBL values include, but are not limited to:

Hepatobiliary tract disease

Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus)

Product:  AMG 820
Protocol Number:  20150195
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
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia. 

Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms  

Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir)

Alpha-one antitrypsin deficiency

Alcoholic hepatitis

Autoimmune hepatitis 

Wilson’s disease and hemochromatosis

Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH) 

Non-hepatic causes (eg, rhabdomylosis, hemolysis)
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if AMG 820 and/or pembrolizumab should be 
withheld or permanently discontinued, as deemed appropriate for the safety of the 
subject.
6.4.2
Criteria for Conditional Withholding of AMG 820 and/or 
Pembrolizumab due to Potential Hepatotoxicity
For subjects who do not meet the criteria for permanent discontinuation of AMG 820 
and/or pembrolizumab outlined above and have no underlying liver disease, and 
eligibility criteria requiring normal transaminases and total bilirubin at baseline or 
subjects with underlying liver disease and baseline abnormal transaminases, the 
following rules are recommended for withholding of Amgen investigational product and 
other protocol-required therapies: 

Elevation of either AST or ALT according to the following schedule:
Baseline AST or ALT value
AST or ALT elevation 
Any
> 8x ULN at any time
Any
> 5x ULN but < 8x ULN for ≥2 weeks
Any
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule
Any
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).  

OR: TBL > 3x ULN at any time

OR: ALP > 8x ULN at any time

Product:  AMG 820
Protocol Number:  20150195
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Amgen investigational product should be withheld pending investigation into alternative 
causes of DILI.  If investigational product(s) is withheld, the subject is to be followed 
according to recommendations in Appendix A for possible DILI.  Rechallenge may be 
considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or 
elevated total bilirubin, is discovered and the laboratory abnormalities resolve to normal 
or baseline (Section 6.4.3).  
6.4.3
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen.
If signs or symptoms recur with rechallenge, then Amgen investigational product and 
other protocol-required therapies, as appropriate should be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Section 6.4.1) should never be rechallenged.
6.5
Concomitant Therapy
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9.
Concomitant therapies are to be collected in the CRF from informed consent through
135 (+7) days after the last dose of AMG 820 or pembrolizumab, whichever is later. In 
addition, any concomitant medications associated with serious adverse events that 
occur through 135 (+7) days after the cessation of all study treatment will be reported to 
Amgen and recorded in the CRF.
For concomitant therapies collect therapy name, indication, dose, unit, frequency, route, 
start date, and stop date.
6.6
Other Treatment Procedures
If a subject demonstrates evidence of new or worsening CNS metastases, all study 
treatments should be withheld and the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.  Subjects may be allowed to remain on 
study after discussion between the sponsor’s medical monitor and the investigator to 
determine the appropriateness of treatment resumption provided CNS lesions can be 
treated with stereotactic radiotherapy, Gamma Knife, or craniotomy.  After approval is 
obtained from the sponsor’s medical monitor, subjects may be allowed to reinitiate 

Product:  AMG 820
Protocol Number:  20150195
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AMG 820 and/or pembrolizumab treatment per Section 6.2.1.3 and 6.2.2.2, respectively, 
following stereotactic radiotherapy only when dosing of corticosteroid is ≤10 mg
prednisone daily or equivalent.  If higher doses of corticosteroid are used, AMG 820
and/or pembrolizumab must be held until that dose level is reached during the period of 
steroid tapering.
6.7
Medical Devices
Medical devices (eg, 0.2 or 0.22 μm in-line filter made of polyethersulfone, intravenous 
administration set, infusion pump syringes, sterile needles, alcohol prep pads) that are 
commercially available are not usually provided or reimbursed by the Sponsor (except, 
for example, if required by local regulation). The investigator will be responsible for 
obtaining supplies of these devices.
6.8
Product Complaints
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any drug(s) or device(s) provisioned and/or repackaged /modified by 
Amgen.  Drug(s) or device(s) includes investigational product.  
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported
according to the instructions provided in the IPIM.
6.9
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period
Subjects must not use any of the following therapies during screening or treatment 
period, unless indicated otherwise:

other investigational agents or procedures  

concurrent experimental or approved antitumor therapies other than study drugs and 
radiation therapy required for palliation.  

immunosuppressive agents with the exception of treatment for adverse events and 
CNS metastases 
o
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or 
equivalent) for related toxicities, AMG 820 and pembrolizumab dosing must be 
withheld until the corticosteroid dose has decreased to ≤10 mg prednisone daily 
(or equivalent)

Product:  AMG 820
Protocol Number:  20150195
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Page 60 of 117
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
any live vaccine therapies used for the prevention of infectious disease within 
28 days prior to enrollment and during treatment period. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, chicken pox, 
yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (eg, Flu - Mist®) are live attenuated vaccines, and are not allowed

any surgery or definitive radiotherapy (within 28 weeks prior to study day 1)
Subjects must not schedule any elective surgeries during the treatment period and for at 
least 30 days after the last administration of study drugs.  If a subject undergoes any 
unexpected surgery during the course of the study, all study treatments must be withheld 
and the investigator or designee should notify the sponsor’s medical monitor as soon as 
possible.  A subject may be allowed to resume study drugs if both the investigator and 
sponsor’s medical monitor agree to restart study therapy.
7.
STUDY PROCEDURES
7.1
Schedule of Assessments 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
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Table 5.  Schedule of Assessments
Sample Schedule of Assessments
Cycle
1
2
3
4
5
Weeks
1
2
3
4
5
6
7
9
10
12
13
Q
3
W
Q
6
W
Q
4
C
Safety
(b)
LT
F
U
Days
Screen
1
2
5
8
15
22
23
26
29
36
43
57
64
78
85
Hours (relative to EOI)
Pre
(m)
0
EOI
1
6
24
9
6
168
336
Pre
0
EOI
2
4
24
96
168
336
P
r
e
0
EOI
33
6
Pr
e
0
EOI
33
6
GENERAL & SAFETY ASSESSMENTS
Informed consent(a)
X
Medical History(a)
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
Physical exam(c)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG(d)
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
Height
X
Review of adverse 
events, disease related 
events and serious 
adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
Survival Assessment(e)
X
LABORATORY ASSESSMENTS
Serum/Urine Pregnancy 
Test(f)
X
X
X
X
X
X
X
X
X
PT or INR and PTT or 
aPTT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Lipase and Amylase
X
X
X
X
X
X
X
T3 (or FT3), FT4, TSH, 
Cortisol
X
X
X
X
X
X
X
X
HBsAg, HBcAb, HCV 
Ab, HIV
X
Tumor Specific Blood 
Testn
X
X
X
Page 1 of 2
Footnotes defined on the last page of the table

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 62 of 117
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Table 5.  Schedule of Assessments
Sample Schedule of Assessments
Cycle
1
2
3
4
5
Weeks
1
2
3
4
5
6
7
9
10
12
13
Q
3
W
Q
6
W
Q
4
C
Safety
(b)
LT
F
U
Days
Screen
1
2
5
8
15
22
23
26
29
36
43
57
64
78
85
Hours (relative to EOI)
Pre
(m)
0
EOI
1
6
24
9
6
168
336
Pre
0
EOI
2
4
24
96
168
336
P
r
e
0
EOI
33
6
Pr
e
0
EOI
33
6
Central Laboratory ASSESSMENTS
New Tumor tissue for 
PD-L1 testing(i)
X
RADIOLOGICAL ASSESSMENTS
Radiographic (CT or 
MRI,) Scans & Tumor 
Assessment(a)(j)
X
X
X
X
Xo
Dosing
AMG 820(g)
X
X
X
X
X
X
Pembrolizumab(g)
X
X
X
X
X
X
PK ASSESSMENTS
AMG 820 PK collection(k)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page 2 of 2
EOI = End of Infusion; LTFU = Long Term Follow-Up; Q3W = Every 3 Weeks; Q6W = Every 6 Weeks; Q4C = Every 4 Cycles
a Procedures to be performed ≤ 28 days prior to enrollment
b Safety follow-up will be performed  135 (+7) days after the last dose of AMG 820 or the last dose of pembrolizumab, whichever is later.  Suggested frequency of visits 
to follow any continuing events are approximately: every week for SAEs, Q2W for grade 3 or higher AEs (excluding AST elevation without drug-associated 
hepatotoxicity), and Q3W for other abnormalities until resolved to grade 1 or baseline.
c Physical exam including ECOG.  
d ECG performed at screening and safety follow-up visits and as clinically indicated during the study.
e Subjects will be followed for survival every 12 weeks (±28 days) from the date of the safety follow-up visit until up to approximately 12 months after date of enrollment.
Subsequent cancer treatments and disease status will be collected as part of the long-term follow-up survival assessment.
f Female subject of childbearing potential to have serum pregnancy test at screening; urine pregnancy test at all other time points. If urine pregnancy test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
g AMG 820 in combination with pembrolizumab will be administered every 3 weeks.
h Anti-AMG 820 and anti-pembrolizumab antibodies samples will be collected pre-dose and at indicated time points throughout the study.
i Tumor biopsy tissue is required per section 7.6. 

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j Radiographic imaging (CT or MRI) of the chest, abdomen and pelvis, and MRI of the brain if a subject has signs and symptoms suggestive of CNS metastases, are 
required at screening.  MRI of the brain is required for all NSCLC subjects at screening.  Tumor assessments must also include all other sites of disease.  The 
screening scans must be done within 28 days prior to enrollment.  During treatment, radiographic imaging (CT or MRI) of the chest, abdomen and pelvis, along with 
tumor assessments of all other sites of disease, (MRI of the brain if a subject has symptoms or signs suggestive of CNS metastases), will be performed independent 
of treatment cycle at week 10 (±1 week), and then every 10 weeks (±2 weeks) or more frequently if clinically indicated until confirmed PD per irRECIST or start of 
new anticancer treatment.  Imaging should not be adjusted for cycle initiation delays and performed according to the calendar.  The imaging modality selected (eg, 
CT or MRI) should remain constant for any individual subject.  Response or progression should be confirmed by repeated radiographic imaging ≥ 4 weeks after the 
first indication of response or progression.  Radiographic imaging is required at the safety follow-up visit if the subject ended treatment prior to confirmed PD and has 
not had radiographic tumor imaging performed within 6 weeks (+1 week) of the visit. The radiographic images will be submitted to a central imaging lab. 
k PK samples should be collected at the exact nominal time point as noted, where collection times are to be defined relative to the end of AMG 820 infusion. If unable to 
collect a PK sample at the specified nominal time point collect it as close as possible to the nominal time point and record the actual collection time. PK samples not 
collected at exact nominal time point will not be considered protocol deviations. 
m Safety labs should be performed and reviewed within 2 days prior to each dose. 
n CEA for CRC and CA 19-9 for pancreatic cancer every 6 weeks ± 2 weeks 
o For subjects who discontinued treatment for any reason other than confirmed PD, every effort should be made to perform radiographic imaging (CT or MRI) of the 
chest, abdomen and pelvis, along with tumor assessments of all other sites of disease every 12 weeks until documentation of confirmed PD per irRECIST, clinical 
progression, start of new anticancer therapy, or up to 12 months after subject’s enrollment for the study, whichever occurs first. 
 

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Refer to the applicable supplemental (eg, laboratory, imaging) manuals for detailed 
collection and handling procedures.  
7.2
General Study Procedures 
A signed and dated IRB/IEC-approved informed consent must be obtained before any
study-specific procedures are performed.
Procedures that are part of routine care are not considered study-specific procedures 
and may be used at screening to determine eligibility. All subjects will be screened for 
eligibility before enrollment. Only eligible subjects will be enrolled into the study. During 
treatment, assessments and procedures can be performed within 3 days of the planned 
visit. It is recommended that dosing occur on the same day of the week (eg, if first dose 
is administered on Monday, all subsequent doses should be administered on a Monday), 
however a ± 3-day dosing and study procedure window is allowed.
The following laboratory analytes in Table 6 will be assessed at various times throughout 
the study. 

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Table 6.  Laboratory Analytes
Chemistry
Coagulation
Endocrine
Function
Hematology
Other Labs
Sodium
Potassium
Chloride
Bicarbonate or 
CO2
Total protein
Albumin
Calcium
Magnesium
Phosphorus
Glucose
BUN or Urea
Creatinine
Uric acid
Total bilirubin
Direct bilirubin
Alkaline 
phosphatase
AST (SGOT)
ALT (SGPT)
Amylase
Lipase
PT or INR
PTT or aPTT
TSH
T3 (or FT3 per 
local standard)
FT4
Cortisol
RBC
Hemoglobin
Hematocrit
MCV
MCH
MCHC
RDW
Reticulocytes
Platelets
WBC
Differential
Total Neutrophils or 
Bands/stabs and 
Segmented 
Neutrophils^
Eosinophils^
Basophils^
Lymphocytes
Monocytes or Mid 
Cell Fraction
Nucleated RBC
Urine or serum 
pregnancy test
Urinalysis
Specific gravity
pH
Blood
Protein
Glucose
Bilirubin
Microscopic exam 
(performed at the 
discretion of the 
Principal Investigator)
Hep B surface 
antigen and Hep B 
total core antibody
Hep C antibody
HIV
CA 19-9 and CEA
Tumor PD-L1 testing
Anti-AMG 820 
antibody
AMG 820 PK
Anti-pembrolizumab 
antibody
Pembrolizumab PK
Biomarkers
development and 
immunophenotyping 
blood
Archived tumor 
tissue
Fresh tumor biopsy 
tissue
Serum IL34, IL10,  
VEGF, MCP-1, 
MMPs, CSF-1
^Local lab may report Granulocytes instead of Neutrophils, Eosinophils, and Basophils individually
AST = aspartate aminotransferase; ALT = alanine aminotransferase ; PT = prothrombin time; 
INR = international normalization ratio; PTT/aPTT = partial thromboplastin time/activated partial 
thromboplastin time; TSH = thyroid stimulating hormone; T3/FT3=free triiodothyronine ; FT4 = free 
thyroxine; PD-L1 = programmed cell death-1 ligand 1.

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7.2.1
Screening Enrollment
The following procedures are to be completed during the screening period within 
28 days of enrollment at time points designated in the Schedule of Assessments 
(Table 5):

Confirmation that the Informed Consent Form has been signed.

Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.
Additionally demographic data may be used to study the impact on biomarkers 
variability and pharmacokinetics of the protocol required therapies.

Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, 
temperature):  Subject should be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted. If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
as possible. The position selected and temperature location for a subject should be 
the same that is used throughout the study and documented on the vital sign CRF. 
Record all measurements on the vital signs CRF.

Complete medical and surgical history will be collected. Medical history will include 
information on the subject’s concurrent medical conditions. The current toxicity grade 
will be collected for each condition that has not resolved. Disease history must date 
back to the original diagnosis. Record all findings on the medical history CRF.

Medication History: Therapy name, indication, dose, unit, frequency, and start and 
stop date will be collected for prior therapies taken for current or prior malignancies.

Physical examination as per standard of care including ECOG performance status 
assessment. Physical examination findings should be recorded on the appropriate 
CRF (eg, medical history, event).

Body weight in kilograms should be measured without shoes.

Height in centimeters should be measured without shoes.

Documentation of concomitant medications (per Section 6.5). 

A 12-lead electrocardiogram (ECG) per standard of care:  The ECG must include the 
following measurements: heart rate, PR interval, QRS, QT and QTc intervals.  
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The 
investigator or designated site physician will review all ECGs.  Once signed, the 
original ECG tracing will be retained with the subject’s source documents.  At the 
request of the sponsor, a copy of the original ECG will be made available to the 
Sponsor.

Local Laboratory Assessments:

Within ≤ 28 days prior to enrollment:
o
hematology panel 
o
chemistry panel
o
lipase and amylase
o
hepatitis B surface antigen and Hepatitis B core antibody

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o
hepatitis C virus antibody
o
HIV
o
coagulation: PT or INR and PTT or aPTT
o
thyroid function tests: T3 (or FT3), FT4, TSH 
o
urinalysis
o
Serum or urine pregnancy test for female subjects of childbearing potential

Central Laboratory Assessment

Obtaining of tumor tissue for biomarker analyses is required as described below:
−
Submit a newly obtained or recent (tissue obtained within 3 months prior to 
day 1 and no systemic therapy given since the biopsy) formalin-fixed 
paraffin-embedded tumor biopsy tissue and associated pathology report from 
the primary or metastatic lesion for PD-L1 analysis and for biomarker analysis 
within 28 days prior to enrollment. Subjects with an inadequate or 
indeterminate samples may undergo re-biopsy, when feasible, as per the 
investigator assessment. PD-L1 testing will be performed at central 
laboratory. This tumor biopsy is required:

in all NSCLC subjects naïve to PD-1/PD-L1 inhibitors

whenever feasible in NSCLC subjects refractory/relapsing during 
treatment with PD-1/PD-L1 inhibitors, if enrolling immediately after 
into the current study and upon discussion with the Sponsor

in all CRC subjects

Whenever feasible in pancreatic cancer subjects
−
If available, submit also a formalin fixed paraffin embedded archival tumor 
tissue sample and associated pathology report.

Radiographic tumor imaging assessment must include CT or MRI scans of the chest, 
abdomen and pelvis.  MRI of the brain should be performed for all NSCLC subjects 
at screening, and in any subject if clinically indicated. See Section 7.4.

Recording of serious adverse events that occur after subject signs informed consent  

Review of inclusion and exclusion criteria
Subjects may be rescreened. If a subject is being rescreened, he or she may need to 
reconsent to the study to ensure that the IRB/IEC approved main informed consent form 
is signed within 28 days of enrollment or randomization.
7.2.2
Treatment 
Treatment begins when the first dose of protocol-required therapies is administered to a 
subject.
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 5).  Administration of 

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protocol-required therapies is to be performed after all other procedures are completed 
during each visit that it is required, unless otherwise stated.

Physical examination as per standard of care including ECOG performance status 
assessment. Physical examination findings should be recorded on the appropriate 
CRF (eg, medical history, adverse event) 

Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, 
temperature):  Subject should be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted. If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
possible.  The blood pressure position selected and temperature location for a 
subject should be the same that is used throughout the study and be documented on 
the vital signs CRF. 

Local laboratory assessments:  On treatment tests can be performed within 2 days of 
the planned visit.  Results should be reviewed prior to the administration of study 
treatment: 

hematology panel 

chemistry panel

lipase and amylase

coagulation: PT or INR and PTT or a PTT 

thyroid function tests: T3 (or FT3), FT4, TSH 

urinalysis

Serum or urine pregnancy test for female subjects of childbearing potential: 
Additional, on-treatment pregnancy testing may be performed at the 
investigator’s discretion.

Central laboratory assessments (refer to Schedule of Assessments as not all tests 
will be required after Amendment 2):
−
whole blood for biomarker analyses (Immunophenotyping)
−
serum for biomarker analyses of baseline circulating markers (IL34, IL10,  
VEGF MCP-1, MMPs, CSF-1)
−
Blood for immunogenicity (anti-AMG 820 antibody and anti-pembrolizumab
antibody). Note: All samples should be drawn within 24 hours before infusion 
of AMG 820 or pembrolizumab and at the same time as the pre-dose trough 
blood collection for the PK sample.
−
blood for PK of AMG 820 and pembrolizumab
−
biomarker development blood sample
−
tumor tissue biopsy for biomarker analyses is strongly encouraged in all 
subjects
o
Recommended collection of biopsies during the study at the time of the 
second CT scan at week 10 ± 2 weeks (formalin-fixed paraffin-embedded 
tumor biopsy tissue and associated pathology report, if available) or
whenever feasible. Subjects with an inadequate or indeterminate 
samples may undergo re-biopsy, when feasible, as per the investigator
assessment.  

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
Radiographic tumor imaging assessments must include CT scan or MRI scans of the 
chest, abdomen and pelvis.  In addition, MRI of the brain will be performed if signs or 
symptoms suggestive of CNS metastasis are present.  Imaging will be performed per 
the Schedule of Assessment (Table 5).

AMG 820 administration.  Note: AMG 820 must be administered before 
pembrolizumab

Pembrolizumab administration

Recording of adverse events, serious adverse events and disease related events

Documentation of concomitant medications (see Section 6.5)
7.2.3
Safety Follow-up Visit(s)
All subjects will complete a safety follow-up visit approximately 135 (+7) days after the
last dose of study treatment.
The following procedures will be performed:

Physical examination as per standard of care including ECOG performance status 
assessment. Physical examination findings should be recorded on the appropriate 
CRF (eg, medical history, event) 

Body weight in kilograms should be measured without shoes.

Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, 
temperature):  Subject should be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted. If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
as possible. The position selected and temperature location for a subject should be 
the same that is used throughout the study and documented on the vital sign CRF. 
Record all measurements on the vital signs CRF

A 12-lead ECG per standard of care:  The ECG must include the following 
measurements: heart rate, PR, QRS, QT and QTc intervals .  Subject must be in 
supine position in a rested and calm state for at least 5 minutes before ECG 
assessment is conducted.  If the subject is unable to be in the supine position, the 
subject should be in most recumbent position as possible.  The investigator or 
designated site physician will review all ECGs.  Once signed, the original ECG 
tracing will be retained with the subject’s source documents.  At the request of the 
sponsor, a copy of the original ECG will be made available to the Sponsor.

Local laboratory Assessments
-
hematology panel 
-
chemistry panel
-
lipase and amylase
-
coagulation: PT or INR and PTT or a PTT 
-
thyroid function tests: T3 (or FT3), FT4, TSH 
-
urinalysis
-
serum or urine pregnancy test for female subjects of childbearing potential

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
Central laboratory assessments (refer to Schedule of Assessments as not all tests 
will be required after Amendment 2):

All subjects
o
Blood for immunogenicity

Radiographic tumor imaging and tumor response assessments are to be performed if 
the subject ended study treatment prior to confirmed PD per irRECIST and has not 
had assessments performed within 6 weeks of the visit.

Radiographic tumor imaging assessments must include CT scan or MRI scans 
of the chest, abdomen and pelvis.  In addition MRI of the brain will be 
performed if signs or symptoms suggestive of CNS metastasis are present.  

Recording of adverse events

Recording of serious adverse events.  Note: Serious adverse events that occur  
through 135 (+7) days after the cessation of all study treatment are recorded in the 
subject’s medical record and are submitted to Amgen.

Recording of disease related events

Documentation of concomitant medications (see Section 6.5)
7.2.4
Long-term Follow-up
After the safety follow-up visit all subjects will enter the long-term follow-up. Subjects will 
be contacted by clinic visit or telephone to assess survival, disease status and initiation 
of first subsequent anti-tumor therapy following end of AMG 820 and pembrolizumab 
treatment.  
Contact for all subjects will be attempted every 12 weeks (± 28 days) following the safety 
follow-up visit, as applicable, until death, subject withdraws full consent, or up to 
12 months after subject’s enrollment for the study, whichever comes first.
For subjects who discontinued treatment for any reason other than confirmed PD, every 
effort should be made to perform radiographic imaging (CT or MRI) of the chest, 
abdomen and pelvis, along with tumor assessments of all other sites of disease every 
12 weeks until documentation of confirmed PD per irRECIST, clinical progression, start 
of new anticancer therapy, or up to 12 months after subject’s enrollment for the study, 
whichever occurs first.
7.3
Physical Examinations
A complete physical examination will be performed by the investigator or designee
according to local practices and at screening and time points specified in the Schedule
of Assessments (Section 7.1). At minimum, the examination should include
assessments of the head and neck, skin, neurological system, lungs, cardiovascular
system, abdomen (liver and spleen), thyroid, lymph nodes and extremities.

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7.4 
Radiological Imaging Assessment 
Radiological imaging to assess the extent of disease will be assessed by standardized 
contrast-enhanced MRI / CT and evaluated according to Immune-related Response 
Criteria in Solid tumor irRECIST (ref, Appendix D).  A contrast-enhanced MRI should be 
the preferred imaging method for tumor staging.  A CT should be done when MRI is not 
possible, is relatively contraindicated (eg, allergy to contrast) or for the evaluation of 
body sites where MRI is not the recommended adequate staging method.  In order to 
reduce radiation exposure for subjects, low dose CT techniques should be applied 
whenever possible.  Organ-specific imaging protocols or existing diagnostic guidelines 
should be followed whenever possible to evaluate the full extent of the disease 
appropriately.   
Radiographic imaging of the chest, abdomen and pelvis are required at screening.  
Tumor assessments must also include all other sites of disease.  The screening scans 
must be performed within 28 days prior to enrollment and will be used as baseline.  For 
NSCLC subjects, MRI of the brain is required at screening.  During treatment, follow-up 
radiographic imaging of the abdomen, pelvis and chest, along with tumor assessments 
of all other sites of disease, will be performed independent of treatment cycle at week 10 
(±1 week), and then every 10 weeks (±2 weeks) or more frequently if clinically indicated 
until confirmed PD per irRECIST or start of new anticancer treatment.  Response 
(immune-related Complete Response [irCR], immune-related Partial Response [irPR]) 
and progression (immune-related Progressive Disease [irPD]) require confirmation by a 
repeat, consecutive assessment no less than 4 to 6 weeks from the date of the first 
documented assessment.  For confirming response, the repeat scan may be performed 
any time after 4 weeks from the first suspected radiologic evidence of response and may 
be delayed, at the discretion of the managing physician, until the next scheduled scan to 
avoid unnecessary procedures.  Upon discussion with the Sponsor, subjects may 
continue to receive treatment after radiographic confirmation of progressive disease as 
long as they continue to derive clinical benefit  and until further increase in tumor burden. 
For analyses purpose, date of PD is the date of initial observed PD. 
Radiographic assessment at the end of the study or during the EOT visit should be 
performed if the last imaging assessment was performed  6 weeks before the EOT and 
the subject has not had evidence of confirmed disease progression. 
All radiological imaging scans will be done as indicated in the Imaging Manual provided 
by the core laboratory.  All subsequent scans will be performed in the same manner as 
at screening, preferably on the same scanner (unless a subject develops hypersensitivity 

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to MRI contrast during the study, in which case a switch to CT is acceptable after 
consultation with Amgen and the imaging core laboratory).
Determination of disease response for clinical management of subjects will be assessed 
at the clinical sites per irRECIST.  Scans will be submitted to the imaging core laboratory 
and may be used for response assessment including RECIST 1.1, irRECIST and 
exploratory analysis such as volumetric and viable tumor measurements.  Detailed 
information regarding the submission of images to the core laboratory is found in the 
Imaging Manual.
7.4.1
Brain Magnetic Resonance Imaging Scans
Brain MRI scans will be conducted at screening for all NSCLC subjects.  In subjects with 
known brain metastasis, brain MRI scans will be conducted at screening and at the 
same schedule as MRI/CT scans. Brain MRI scans may also be performed at any time, 
if in the judgment of the investigator, the subject displays signs or symptoms of central 
nervous system (CNS) disease progression.
7.4.2
Tumor Assessments
Tumor assessments will be performed at the sites based on modified irRECIST as 
outlined in Appendix D.
7.5
Antibody Testing Procedures
Blood sample(s) for Antibody testing are to be collected as indicated in the Schedule of 
Assessments, Table 5, for the potential measurement of anti-AMG 820 and 
anti-pembrolizumab binding antibodies.  Samples testing positive for anti-AMG 820 or 
anti-pembrolizumab binding antibodies may also be tested for neutralizing antibodies 
and may be further characterized for quantity/titer, isotype, affinity and presence of 
immune complexes.  Additional blood samples may be obtained to rule out 
anti-AMG 820 antibodies during the study.  
Refer to the Schedule of Assessments (Table 5), as applicable, for specific time points 
and the laboratory manual for detailed collection and handling instructions.
7.6
Biomarker Development
Fresh Pre-and Post-dose Tumor Tissues (and archival, if available)
All subjects enrolled into the study will be asked to provide fresh tumor tissue, whenever 
feasible, and archival tumor tissue, if available:

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Baseline:

The most recent (within 3 months) tumor biopsy (primary or metastatic lesion) 
obtained between last anti-cancer systemic treatment and day 1 of the current study 
(formalin-fixed paraffin-embedded tumor biopsy tissue and associated pathology 
report, if available)

Required in all NSCLC subjects naïve to PD-1/PD-L1 inhibitors

Whenever feasible in NSCLC subjects refractory/relapsing during 
treatment with PD-1/PD-L1 inhibitors, if enrolling immediately after into 
the current study and upon discussion with the Sponsor

Required in all CRC subjects

Whenever feasible in pancreatic cancer subjects

an archival formalin fixed paraffin embedded tumor tissue sample and the associated 
pathology report, if available.
During study treatment:

Collection of  at least one biopsy at the time of second CT scan (week 10 ± 2 weeks)
and additional sequential tumor biopsies strongly encouraged, whenever possible, in 
all subjects. Note: this biopsy will no longer be encouraged per the data of 
Amendment 2.
In order to satisfy inclusion criteria and secondary objective assessments, fresh and/or 
archival pre-treatment biopsies will be analyzed to evaluate PD-L1 expression by IHC 
and immune infiltrate (CD4, CD8 and CD68 cells) status.
In addition, within the exploratory analyses planned for the study all tumor material 
available may be analyzed to evaluate immune cell subsets and activation status 
through additional relevant protein and RNA biomarkers, including, but not limited to 
CD3, CD4, CD8, CD68, CD163, Ki67, PD-L1, FoxP3, GITR as well as transcriptome 
analysis using the NanoString Cancer ImmunePanel.  Further testing of biomarkers may 
be done dependent on emerging data.
Circulating Markers Blood Samples
Blood samples will be collected for evaluation of circulating markers that may include, 
and are not limited to CSF-1, IL-34, IL-10, VEGF, MCP-1, MMPs.
These samples will be used to help with understanding further subjects’ disease and 
their response to treatment.
Refer to the laboratory manual for detailed collection and handling procedures for all 
biomarker samples.

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Flow Cytometry Whole Blood Samples
Whole blood samples will be collected for immunophenotyping flow cytometry to identify 
changes in peripheral blood cell subsets and activation status.
Refer to the laboratory manual for detailed collection and handling procedures for all 
biomarker samples.
Refer to the Schedule of Assessments for specific time points and the laboratory manual 
for detailed collection and handling instructions. Note that not all samples will be 
required after Amendment 2.
7.7
Pharmacogenetic Studies
If the subject consents to the optional pharmacogenetic analysis of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  No additional samples are collected 
for this part of the study.  For subjects who consent to this/these analysis/analyses, DNA 
may be extracted from the available blood samples collected during the study.
7.8
Sample Storage and Destruction
Any blood or tissue sample collected according to the Schedule of Assessments 
(Table 5) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
disease, dose response and/or prediction of response to the combination of AMG 820 
and pembrolizumab, characterize antibody response, and other drug aspects 
(eg, mechanism of action/target, metabolites).  Results from these analyses are to be 
documented and maintained, but will not be necessarily reported as part of this study.  
Samples can be retained for up to 20 years.  

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Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent.
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or tumor tissue samples and any other components from the cells can be located 
and destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen.
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality.
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY
8.1
Subjects’ Decision to Withdraw
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution.
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study (eg, safety / long-term 
follow-up).  If this occurs, the investigator is to discuss with the subject the appropriate 
processes for discontinuation from investigational product or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule 
of Assessments (Table 5) and collection of data, including endpoints and adverse 
events.  The investigator must document the change to the Schedule of Assessments

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(Table 5) and the level of follow-up that is agreed to by the subject (eg, in person, by 
telephone/mail, through family/friends, in correspondence/communication with other 
physicians, from review of the medical records).  
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation, including any long-term follow up.  Subject 
data up to withdrawal of consent will be included in the analysis of the study, and where 
permitted, publically available data can be included after withdrawal of consent.  The 
investigator is to discuss with the subject appropriate procedures for withdrawal from the 
study.
8.2
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.   
Subjects may be eligible for continued treatment with Amgen investigational product(s)
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.
8.3
Reasons for Removal From Treatment, or Study
8.3.1
Reasons for Removal From Treatment
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following:

subject request 

safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy)

pregnancy

potential hepatotoxicity (as per Section 6.4.1)

other protocol-specified criteria (see Sections 6)

death

lost to follow-up

decision by Sponsor (other than subject request, safety concern, lost to follow-up)

disease progression

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8.3.2
Reasons for Removal From Study
Reasons for removal of a subject from the study are:

decision by sponsor 

withdrawal of consent from study

death

lost to follow-up
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING
9.1
Definition of Safety Events
9.1.1
Disease Related Events
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  These could include overall disease 
progression or pain or discomfort caused by growing tumors. Such events do not meet 
the definition of an Adverse Event unless assessed to be more severe than expected for 
the subject’s condition. 
Disease Related Events and/or Disease Related Outcomes that do not qualify as 
Serious Adverse Events: 

An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease Related Event. 

Death due to the disease under study is to be recorded on the Event CRF.
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the investigational product(s)/study treatment protocol required therapies and 
disease worsening, this must be reported as an Adverse Event or Serious Adverse 
Event.
9.1.2
Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.  
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 

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worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study,
is not considered an adverse event.  
For situations when an adverse event or serious adverse event is due to the primary 
tumor type being studied, report all known signs and symptoms.  Death due to disease 
progression in the absence of signs and symptoms should be reported as the primary 
tumor type (eg, metastatic pancreatic cancer).
Note:  The term “disease progression” should not be used to describe the disease 
related event or adverse event.
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.  
9.1.3
Serious Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event as 
defined in Section 9.1.1):

fatal

life threatening (places the subject at immediate risk of death)

requires in-patient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

congenital anomaly/birth defect

other medically important serious event
A disease related event (eg, disease progression or pain or discomfort caused by 
growing tumors) is to be reported as a serious adverse event if 

the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or

if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event, 

and the event meets at least 1 of the serious criteria above.

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An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention.
9.2
Safety Event Reporting Procedures 
9.2.1
Reporting Procedures for Disease Related Events
The investigator is responsible for ensuring that all Disease Related Events observed by 
the investigator or reported by the subject that occur after the first dose of AMG 820 or 
pembrolizumab through the safety follow-up visit (ie, 135 [+7] days after the last dose of 
AMG 820 or pembrolizumab, whichever is later) are reported using the Event CRF.  
Additionally, the investigator is required to report a fatal Disease Related Event on the 
Event CRF.  
Disease-Related Events assessed by the Investigator to be more severe than expected 
and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies, and determined to be serious, must be recorded 
on the Event CRF as Serious Adverse Events.
9.2.2
Adverse Events
9.2.2.1
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of AMG 820 or 
pembrolizumab through the safety follow-up visit (ie, 135 [+7] days after the last dose of 
AMG 820 or pembrolizumab, whichever is later) are reported using the Event CRF.
The investigator must assign the following adverse event attributes:

Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms),

Dates of onset and resolution (if resolved or improved to a lower grade),

Severity [and/or toxicity per protocol],

Assessment of relatedness to AMG 820 and/or pembrolizumab and

Action taken.

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The adverse event grading scale used will be the CTCAE version 4.0.  The grading 
scale used in this study is described in Appendix A.  The investigator must assess
whether the adverse event is possibly related to the AMG 820 and/or pembrolizumab.  
This relationship is indicated by a “yes” or “no” response to the question:  Is there a 
reasonable possibility that the event may have been caused by the investigational 
product(s)?  
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
procedure (including any screening procedure(s)).  This relationship is indicated by a 
“yes” or “no” response to the question:  “Is there a reasonable possibility that the event 
may have been caused by a study activity (eg, administration of investigational product,  
protocol-required procedure”? 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event.
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Event CRF.
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
9.2.2.2
Reporting Procedures for Serious Adverse Events
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the consent  
through 135 (+7) days after the cessation of all study treatment are recorded in the 
subject’s medical record and are submitted to Amgen.  Additionally, treatment related 
serious adverse events that occur after the safety follow-up visit through the end of the 
long-term follow-up will be reported.
All serious adverse events must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the Event CRF.

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If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet /electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the electronic Serious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available.
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 
The investigator is expected to follow reported serious adverse events until stabilization 
or resolution. 
All new information for serious adverse events must be sent to Amgen within 24 hours 
following knowledge of the new information.  The investigator may be asked to provide 
additional follow-up information, which may include a discharge summary or extracts 
from the medical record.  Information provided about the serious adverse event must be 
consistent with that recorded on the Event CRF.
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and GCP.
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes.
9.2.2.3
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period
There is no requirement to monitor study subjects for new serious adverse events 
following the protocol-required reporting period after the end of study.  However, these 
serious adverse events can be reported to Amgen.  In some countries (eg, European 
Union [EU] member states), investigators are required to report serious adverse events 

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that they become aware of after the protocol-required reporting period after the end of 
study.  If serious adverse events are reported, the investigator is to report them to 
Amgen within 24 hours following the investigator’s knowledge of the event.
Serious adverse events reported outside of the protocol-required reporting period will be
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.
9.3
Pregnancy and Lactation Reporting
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below.
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
through 7 months after the last dose of AMG 820 or 4 months after the last dose of 
pembrolizumab.
The pregnancy should be reported to Amgen’s Global Safety within 24 hours of the 
investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen’s Global Safety will seek to 
follow with the Investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the Investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.    
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
Investigator will report the event as a Serious Adverse Event.
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
Any lactation case should be reported to Amgen’s Global Safety within 24 hours of the 
investigator’s knowledge of event.  Report a lactation case on the Lactation Notification 
Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with the 
Investigator regarding additional information that may be requested.

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If a male subject's female partner becomes pregnant, the Investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner.
9.4
Pembrolizumab Events of Clinical Interest
Selected adverse events known as Pembrolizumab Events of Clinical Interest must be 
reported to Amgen within 24 hours of the investigator’s knowledge of the event 
regardless of attribution to pembrolizumab.
For the time period beginning at time of first dose of pembrolizumab through 
135 (+7) days following cessation of pembrolizumab treatment, or 135 (+7) days after 
initiation of a new anti-cancer therapy, any Pembrolizumab Events of Clinical Interest, or 
follow-up to a Pembrolizumab Events of Clinical Interest, whether or not related to the 
pembrolizumab, must be reported within 24 hours to Amgen.
Pembrolizumab Events of Clinical Interest for this trial include:

an overdose of pembrolizumab, as defined in Section 9.5

potential drug-induced liver injury (DILI) from pembrolizumab as defined in 
Section 9.6
Subjects should be assessed for possible Pembrolizumab Events of Clinical Interest 
prior to each dose.
9.5
Definition of an Overdose of Pembrolizumab for This Protocol and 
Reporting of Pembrolizumab Overdose
For the purpose of this trial, an overdose of pembrolizumab will be defined as any dose 
of pembrolizumab equal to or greater than 300 mg.  No specific information is available 
on the treatment of overdose of pembrolizumab.  In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for 
signs of toxicity.  Appropriate treatment should be provided if clinically indicated.
If an adverse event(s) or serious adverse event(s) is associated with (“result from”) the 
overdose of pembrolizumab, the adverse event(s) or serious adverse event is to be 
reported to Amgen as described in Section 9.2.2.  In addition, the adverse event(s) or 
serious adverse event(s) associated with (“result from”) the overdose of pembrolizumab
should be reported as Event of Clinical Interest as described in Section 9.4.

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9.6
Definition and Reporting of Pembrolizumab Drug-induced Liver 
Injury
For the purpose of this trial, potential DILI associated with (“resulting from”) 
pembrolizumab will be defined as:

elevated AST or ALT ≥3 x ULN and elevated total bilirubin ≥2 x ULN

AND ALP < than 2 x ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents.  The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow-up of these criteria will be provided in separate guidance 
document entitled, the pembrolizumab Event of Clinical Interest Guidance for Potential 
DILI in Clinical Trials.  
To facilitate appropriate monitoring for signals of DILI associated with pembrolizumab, 
cases of concurrent DILI according to the criteria specified above require the following:

The event is to be reported to Amgen as an adverse event of potential DILI within 
24 hours of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded)

The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed.

Workup to confirm DILI should be immediately initiated as described in the 
pembrolizumab Event of Clinical Interest Guidance for Potential DILI in Clinical Trials 
document.  Any confirmed event of DILI is to be reported as a serious adverse event 
within 24 hours after confirmation of the event.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3.
10.
STATISTICAL CONSIDERATIONS
10.1
Study Endpoints, Analysis Sets, and Covariates
10.1.1
Study Endpoints
10.1.1.1
Primary Endpoints

Dose limiting toxicities (DLT), treatment-emergent adverse events, treatment-related 
adverse events and clinically significant changes in vital signs, physical 
examinations, and clinical laboratory tests

Objective response rate (ORR) per irRECIST in subjects treated at the 
recommended combination dose

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10.1.1.2
Secondary Endpoints

OR per RECIST 1.1; TTR, DOR and TTP; OS and PFS at 6 and 12 months

PK parameters for AMG 820 including, but not limited to, maximum observed 
concentration (Cmax) and minimum observed concentration (Cmin).  In addition, area 
under the concentration-time curve (AUC) and, if feasible, half-life (t1/2) for AMG 820.

CD4, CD8 & CD68 cells number in fresh pre-treatment biopsies
10.1.1.3
Exploratory Endpoints

Anti-AMG 820 and anti-pembrolizumab antibodies levels

Biomarker readouts at baseline and treatment related changes

PK parameters for pembrolizumab include, but are not limited to, concentration at 
end of pembrolizumab infusion administration, maximum observed concentration 
(Cmax) and minimum observed concentration (Cmin).
10.1.2
Analysis Sets
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 820. The analysis of DLT will be restricted to DLT-evaluable subjects 
(see Section 6.2.1.2.2). The PK Analysis Set will contain all subjects who have received 
at least 1 dose of the investigational product and have at least 1 PK sample collected. 
These subjects will be evaluated for PK analysis unless the number of data points 
required for analysis is not enough, or significant protocol deviations have affected the 
data, or if key dosing or sampling information is missing.  
10.1.3
Covariates and Subgroups
The relationship of covariates to efficacy endpoints will be explored if appropriate.
Biomarker data (eg, PD-L1 expression) may be incorporated in additional exploratory 
subgroup or multivariate analyses. The exploratory analyses of biomarkers may be 
performed after collection of all samples during the conduct of the study and therefore 
may be reported after the primary analysis of the safety and efficacy endpoints.  
10.2
Sample Size Considerations
It is anticipated that 67 to 197 subjects will be enrolled overall in this study. 
Part 1 will enroll 6 to 18 evaluable subjects. The sample size in Part 1 is based on 
practical consideration, and it is consistent with conventional oncology studies with the 
objective to evaluate the safety and tolerability of a treatment combination.  With 
6 subjects in a cohort, there is a 47-91% probability of observing at least one DLT if the 
true DLT rate is 10-33%. 

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Part 2 evaluation of efficacy will include at least 6 subjects from part 1 who have been 
treated with the recommended combination dose, and will enroll additional CRC, 
pancreatic cancer and NSCLC subjects up to maximum 185 subjects overall. The 
sample size in each group evaluated in Part 2 is chosen to test whether AM820 can 
enhance the anti-tumor activity observed historically with pembrolizumab alone and/or 
overcome lack of response to pembrolizumab monotherapy. For each group and 
sub-group enrollment may stop early due to insufficient clinical activity. The pre-planned 
recommendation for early termination is based on ORR (evaluated when the subjects 
complete at least 6 months of treatment or earlier if already reaching the recommended 
number of responders), nonetheless the DLRT (see Section 6.2.1.2.1) will make the 
decision for early termination after reviewing all available safety, efficacy, 
pharmacokinetic and pharmacodynamic data.
Group 1 will consist of up to 43 subjects with MMR–proficient CRC (only 18 enrolled 
initially in the first stage) who are naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R treatment. In 
2015, Le et al reported a pembrolizumab objective response rate (ORR) per RECIST1.1 
and irRC of 0% (0 of 18 patients) for MMR–proficient colorectal cancers. It is anticipated 
that the combination treatment of AMG 820 and pembrolizumab will have an ORR of 
25% or higher in MMR–proficient CRC tumors; an ORR of 10% or less is considered to 
be insufficient anti-tumor activity to warrant future research. If 2 or fewer of the initial 
18 subjects have an objective response then the recommendation is for enrollment to 
Group 1 be stopped for futility. If 8 or more of the 43 subjects have an objective 
response then the true ORR is determined to be >10%.  This Simon Two-Stage design 
provides 80% power when the true ORR is 25% while maintaining a 1-sided, 
5% alpha error when the true ORR is 10% or lower. 
Group 2 will consist of up to 29 subjects with advanced pancreatic cancer (only 
10 enrolled initially in the first stage) who have not received prior treatment with a 
PD-1/PD-L1/CSF-1/CSF-1R inhibitor. In 2012, Brahmer et al reported a pembrolizumab
ORR of 0% (0 of 14 patients) for pancreatic cancer. It is anticipated that the combination 
treatment of AMG 820 and pembrolizumab will have an ORR of 20% or higher in 
pancreatic tumors; an ORR of 5% or less is considered to be insufficient anti-tumor 
activity to warrant future research. If none of the initial 10 subjects have an objective 
response then the recommendation is for enrollment to Group 2 be stopped for futility. If 
4 or more of the 29 subjects have an objective response then the true ORR is 
determined to be >5%.  This Simon Two-Stage design provides 80% power when the 

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true ORR is 20% while maintaining a 1-sided, 5% alpha error when the true ORR is 5% 
or lower. 
Group 3 will consist of up to 55 subjects (only 19 enrolled initially in the first stage) with 
NSCLC who have not received prior treatment with a PD-1/PD-L1/CSF-1/CSF-1R 
inhibitor, and who have tumor PD-L1 expression <50%. Garon et al in 2015 reported a 
pembrolizumab ORR per RECIST1.1 of 13.1% (28 of 214 patients) for NSCLC patients 
with tumor PD-L1 expression <50%, and an ORR of 14.4% (21 or 146 patients) for those 
with tumor PD-L1 expression from 1% to 49%. It is anticipated that the combination 
treatment of AMG 820 and pembrolizumab will have an ORR of 30% or higher in low 
PD-L1 expressing subjects; an ORR of 15% or less is considered to be insufficient 
anti-tumor activity to warrant future research. If 3 or fewer of the initial 19 subjects have 
an objective response then enrollment to Group 3 will be stopped for futility. If 13 or 
more of the 55 subjects have an objective response then the true ORR is determined to 
be >15%. This Simon Two-Stage design provides 80% power when the true ORR is 
30% while maintaining a 1-sided, 5% alpha error when the true ORR is 15% or lower. 
Group 4 will consist of up to 58 NSCLC who received prior treatment with a PD-1/PD-L1 
inhibitor, and failed to respond to or relapsed during therapy. These subjects must be 
also naive to anti-CSF-1/CSF-1R agents.  There will be two sub-groups. Sub-group 4a 
will enroll up to 29 (only 10 enrolled initially in the first stage)  subjects who have tumor 
PD-L1 expression <50% (see Garon et al., 2015) while sub-group 4b will enroll up to
29 subjects who have tumor PD-L1 expression ≥50% (only 10 enrolled initially in the first 
stage). It is anticipated that the combination treatment of AMG 820 and pembrolizumab 
will have an ORR of 20% or higher in these NSCLC subjects; an ORR of 5% or less is 
considered to be insufficient anti-tumor activity to warrant future research. If none of the 
initial 10 subjects in a sub-group have an objective response then the recommendation 
is for enrollment to the sub-group be stopped for futility. If 4 or more of the 29 subjects 
in the sub-group have an objective response then the true ORR is determined to be 
>5%. This Simon Two-Stage design provides 80% power when the true ORR is 20% 
while maintaining a 1-sided,5% alpha error when the true ORR is 5% or lower.
10.3
Planned Analyses
10.3.1
Interim Analyses
Safety and all clinical data will be monitored on an ongoing basis. All available 
cumulative data will be reviewed in Part 1 by cohort, prior to making dose escalation 
decisions, by the Dose Level Review Team (DLRT, see Section 6.2.1.2). In study Part 2 

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stage 1, similar assessments will be held after each set of 20 subjects have enrolled
through the end of Part 2 stage 1 enrollment. 
In Part 2, a Simon Two-Stage design is used for all groups (Group 1-3, 4a, 4b) with the 
first stage enrolling n=18, 10 19, 10 and 10 subjects, respectively (see design schema). 
Each group will enroll subjects to a first stage.  The second stage for each group will be 
enrolled depending on clinical activity from stage 1, evaluated when the subjects have 
been treated for at least 6 months or earlier if the required number of responders have 
been reached (see Section 10.2 for details). The pre-planned recommendations for 
enrollment to stage 2 are based on ORR per local irRECIST, however the DLRT will 
make the decisions for stage 2 enrollment after reviewing all available safety, efficacy, 
pharmacokinetic and pharmacodynamic data.
10.3.2
Dose Level Review Team (DLRT)
Dose Level Review Meetings (DLRMs) will be held to review data, monitor safety, and 
make decisions on dose escalation / change decisions. The DLRT will be composed of 
the investigators or designees, and the following Amgen representatives: medical 
monitor, early development leader, global safety officer or designee, clinical study 
manager, biostatistician and clinical pharmacologist.  Additional members may be added 
as needed. The following members are responsible for DLRT decisions: investigators, 
Amgen medical monitor, and global safety officer or designee. Study decisions by
DLRM participants must be unanimous.  All available study data, including data collected 
after the initial DLT window, and including demographics, IP administration, medical 
history, concomitant medications, adverse events, ECGs, vital signs, laboratory data, 
efficacy and PK/PD information will be reviewed. In addition to DLTs, all ≥ grade 3 
toxicities not meeting DLT criteria will be reviewed and may be considered in DLRT 
decisions.  The study may be discontinued or modified at any time due to documented 
safety findings.
All DLRM requirements are outlined in the protocol.  A DLRM Charter will not be used.

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10.3.3
Primary Analysis
The primary analysis (primary and secondary endpoints) may be done separately for 
each group (eg, if the pancreatic cancer group completes target enrollment months 
ahead of the other cancer groups, analysis for Group 2 would be executed):
1. At 6 months: once the target enrollment is complete and each subject has been 
treated for at least 6 months or responded or withdrawn from the study, the 
analysis of the primary endpoints will occur.
2. At 12 months: once the target enrollment is complete and each subject has been 
treated for at least 12 months or has been followed up for PFS and OS for
12 months or withdrawn from the study, the analysis of primary and secondary 
endpoints (safety endpoints, ORR, PFS and OS at 6 and 12 months) will occur
10.3.4
Final Analysis
A final analysis is planned after all subjects from Part 1 and Part 2 have ended the study.
10.4
Planned Methods of Analysis 
10.4.1
General Considerations
Descriptive statistics will be provided for selected demographics, safety, PK, PD and
biomarker data by dose, dose schedule, and time as appropriate. Descriptive statistics
on continuous data will include means, medians, standard deviations and ranges, while
categorical data will be summarized using frequency counts and percentages. Graphical
summaries of the data may also be presented. Analysis of data in Part 2 will be done 
separately for each group (Group 1, 2, 3, 4a, 4b).
10.4.2
Primary Efficacy Endpoint
For subjects treated at the maximum tolerated combination (combining subjects from 
Part 1 and Part 2), the proportion of subjects with OR (a complete or partial response to 
treatment) per irRECIST with corresponding 90% and 95% CI will be calculated and 
tabulated.
10.4.3
Secondary Efficacy Endpoint(s)
The following analyses will be done using secondary efficacy endpoint data for all 
subjects treated at the maximum tolerated combination (combining subjects from Part 1 
and Part 2). The proportion of subjects with OR per RECIST 1.1 and corresponding 
90% and 95% CI will be calculated and tabulated. Using the Kaplan Meier estimate, the 
PFS at 6 and 12 months and the OS at 6 and 12 months with corresponding 90% CI will 
be tabulated. Listings will be produced for all subjects indicating the OS, PFS, TTR, 
DOR and TTP. Kaplan Meier curve will be presented for OS, PFS, TTR, DOR and TTP 
with estimates for rates and 80% CI at selected weeks.

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10.4.4
Safety Endpoints
Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the Safety Analysis Set, which includes subjects that are enrolled and 
received at least 1 dose of AMG 820.
10.4.4.1
Adverse Events
Subject incidence of all treatment-emergent adverse events will be tabulated by system
organ class and preferred term. The number and percentage of subjects reporting
adverse events will be evaluated overall and by AMG 820 dose level and will also be 
tabulated by relationship to AMG 820. Tables of dose limiting toxicities, fatal adverse 
events, serious adverse events, adverse events leading to withdrawal from 
investigational product or other protocol-required therapies, and significant 
treatment-emergent adverse events will also be provided.
10.4.4.2
Clinical Laboratory Tests
Clinical chemistry, hematology, and urinalysis data will be listed and reviewed for each 
subject. Values outside the normal laboratory reference ranges will be flagged as high
or low on the listings. Depending on the size and scope of changes in laboratory data,
summaries of laboratory data over time and/or changes from baseline over time may be
provided. Tables of maximum shifts from baseline for selected laboratory values may
also be provided.
10.4.4.3
Vital Signs
Vital signs data will be listed and reviewed for each subject. Depending on the size and 
scope of changes, summaries of vital signs data over time and/or changes from baseline
over time may be provided.
10.4.4.4
Pharmacokinetic Endpoints
The analysis of pharmacokinetic endpoints will include data from all subjects who have 
received at least 1 dose of the investigational product and have at least 
1 pharmacokinetic sample collected.
The PK parameters for AMG 820  and pembrolizumab will be estimated using standard 
non-compartmental PK methods and summarized by treatment groups using means, 
standard deviations, medians, minimums and maximums for intensive and peak/trough 
determinations. PK parameters for AMG 820 and pembrolizumab will include, but not be 
limited to, maximum observed concentration (Cmax) and minimum observed 
concentration (Cmin).  In addition, area under the concentration-time curve (AUC) and, if 

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feasible, half-life (t1/2) will be determined for AMG 820.  Serum concentrations at each 
time point along with PK parameter values may be listed for each subject.  Individual 
AMG 820  concentration/time profiles will be plotted by treatment group.  Summary 
statistics will be computed for each sampling time and parameter as appropriate.  
Analyses to explore relationship between exposure and safety and exposure and 
efficacy may also be performed.
10.4.4.5
Relationship in Immune Infiltrate Status in Pre-treatment Biopsies 
vs. Clinical Response
Logistic regression will be used to model immune infiltrate status vs. clinical response. 
Immune infiltrate will be measured by CD4, CD8 and CD68 T cell numbers in fresh 
pre-treatment biopsies.  Clinical response will be measured by OR per irRECIST and 
RECIST 1.1. The logistic regression models will be done separately for each tumor type 
and sub-type, as appropriate.
11.
REGULATORY OBLIGATIONS
11.1
Informed Consent
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population.
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject  after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered.  
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 

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records, and the informed consent form  is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject.
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  
11.2
Institutional Review Board/Independent Ethics Committee
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product.
The investigator must submit and, where necessary, obtain approval from the IRB/IEC
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures.
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen.
11.3
Subject Confidentiality
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.  

Subjects are to be identified by a unique subject identification number.  

Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.  

On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.  

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
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations).

Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below.
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information.
11.4
Investigator Signatory Obligations
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator.  
The coordinating investigator, identified by Amgen, will be any or all of the following:

a recognized expert in the therapeutic area

an Investigator who provided significant contributions to either the design or 
interpretation of the study

an Investigator contributing a high number of eligible subjects
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
12.1
Protocol Amendments and Study Termination
The IRB/IEC must be informed of all amendments and give approval.  The investigator 
must send a copy of the approval letter from the IRB/IEC to Amgen.
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.
Subjects may be eligible for continued treatment with Amgen investigational product(s)
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 

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whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially.
12.2
Study Documentation and Archive
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form.
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  
Elements to include:

Subject files containing completed CRFs, informed consent forms, and subject 
identification list

Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC
and Amgen

Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable.

Non-investigational product(s) and or medical device(s) documentation, as 
applicable.
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available.
Retention of study documents will be governed by the Clinical Trial Agreement.
12.3
Study Monitoring and Data Collection
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected.

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The Amgen Clinical Monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs.
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.
Data capture for this study is planned to be electronic:

All source documentation supporting entries into the CRFs must be maintained and 
readily available.

Updates to CRFs will be automatically documented through the software’s “audit 
trail”.

To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer.

The investigator signs only the Investigator Verification Form for this electronic data 
capture study or the investigator applies an electronic signature in the EDC system if 
the study is set up to accept an electronic signature.  This signature indicates that 
investigator inspected or reviewed the data on the CRF, the data queries, and 
agrees with the content.
Amgen (or designee) will perform self-evident corrections (SECs) to obvious data errors 
in the clinical trial database. SECs will be documented in the Standard Self Evident 
Corrections document and the eCRF Specific Instructions, both of these will be available 
through the EDC system. Examples of obvious data errors that may be corrected by 
Amgen (or designee) include deletion of obvious duplicate data (ie, the same results 
sent twice with the same date but different visits eg, week 4 and early termination) and 

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updating a specific response if the confirming datum is provided in the "other, specify" 
field (eg, for race, reason for ending study).  
12.4
Investigator Responsibilities for Data Collection
The investigator is responsible for complying with the requirements for all assessments
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 5), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.  
12.5
Language
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  CRFs must be 
completed in English.  TRADENAMES® (if used) for concomitant medications may be 
entered in the local language.  
12.6
Publication Policy
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states:

Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work 
are appropriately investigated and resolved.  Authors should meet 
conditions 1, 2, and 3.

When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above.

Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship.

All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed.

Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 

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Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications.
12.7
Compensation
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document.

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13.
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14.
APPENDICES

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Appendix A.  Additional Safety Assessment Information
Adverse Event Grading Scale
The Common Terminology Criteria for Adverse Events (CTCAE) is available at the 
following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Drug-induced Liver Injury Reporting & Additional Assessments 
Reporting
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.4 require 
the following:

The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded)

The appropriate CRF (eg, Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to the Amgen. 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3.
Additional Clinical Assessments and Observation
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Sections 6.4.1 and 6.4.2 or who experience AST or ALT elevations ≥3 x ULN are to
undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include: 

Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours 

In cases of TBL ≥2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic.

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
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL:

Obtain complete blood count (CBC) with differential to assess for eosinophilia

Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis

Obtain serum acetaminophen (paracetamol) levels

Obtain a more detailed history of: 

Prior and/or concurrent diseases or illness

Exposure to environmental and/or industrial chemical agents 

Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever

Prior and/or concurrent use of alcohol, recreational drugs and special diets

Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms

Obtain viral serologies

Obtain CPK, haptoglobin, LDH, and peripheral blood smear

Perform appropriate liver imaging if clinically indicated

Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected 

Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist)

Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to
continue for a minimum of 4 weeks after discontinuation of all investigational 
product(s) and protocol-required therapies.
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs.

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Appendix B.  Sample Serious Adverse Event Report Form

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Appendix C.  Pregnancy and Lactation Notification Worksheets

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Appendix D.  Modified Immune-Related Response Criteria in Solid Tumors 
(irRECIST)
The Immune-related Response Criteria (irRC) based on bidimensional measurements 
were derived from WHO/RECIST to serve as guidelines to systematically characterize 
additional patterns of response in patients with advanced melanoma receiving 
ipilimumab therapy and to allow the potential delayed clinical response to 
immune-enhancing therapies to be captured more accurately (Wolchok JD et al., 2009).  
Recent evaluation showed that irRC using unidimensional measurements provided 
highly concordant tumor response assessment and less measurement variability 
compared with bidimensional measurements (Nishino M et al., 2013). This study will 
utilize a modified criteria (irRECIST), adapting the immune-related response criteria to 
conventional RECIST 1.1 (Eisenhauer et al, 2009) as outlined below.
Antitumor response based on total measurable tumor burden

For irRECIST, only index and measurable new lesions are taken into account (in 
contrast to conventional RECIST 1.1, which does not require the measurement of 
new lesions, nor do they include new lesion measurements in the characterization of 
evolving tumor burden).
Tumor burden assessment:

All measurable and non-measurable lesions should be assessed at screening and at 
the defined tumor assessment time points.
o
At baseline tumor assessment: tumor burden is the sum of the longest 
diameters (SLD) of all index lesions (5 lesions per organ, up to 10 total 
lesions). 
o
At each subsequent tumor assessment: tumor burden is the SLD of the index 
lesions and of new, measurable lesions (> 10 mm in the longest diameter; up 
to 5 new lesions per organ and up to 10 total lesions) added together

Tumor burden = SLDindex lesions + SLDnew, measurable lesions
Time point response assessment using modified irRECIST
Percentage changes in tumor burden per assessment time point describe the size and 
growth kinetics of both conventional and new lesions as they appear.  At each tumor 
assessment, the response in index and new measurable lesions is defined based on the 
change in tumor burden (after ruling out irPD).  Decreases in tumor burden must be 
assessed relative to baseline measurements (ie, the SLD of all index lesions at 
screening).  

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Definitions: 

Methods of measurement:
o
The same imaging modality, method of assessment, and technique must be 
used throughout the study to characterize each identified and reported lesion.
o
MRI or CT scans should be performed with contiguous slice thickness of 
5 mm or less according to the Imaging Manual. Subjects should be evaluated 
at screening for tolerance to MRI/CT IV contrast.  Subjects intolerant of CT IV 
contrast ie, allergy or renal insufficiency should be imaged using non-contrast 
CT for the chest and MRI (with or without contrast) for the abdomen and 
pelvis to enable the best detection of disease throughout the study starting at 
baseline.  If a subject develops a medical contradiction to the MRI/CT IV 
contrast while on study, preapproval of the sponsor is needed to switch from 
contrast enhanced MRI to non-contrast MRI or to CT (and vice versa).
o
If a combined PET/CT scan is performed at the discretion of the investigator
at baseline and subsequent timepoints, the CT portion of that exam should 
not be substituted for the dedicated diagnostic CT exams required by this 
protocol unless the investigator or the site radiologist can document that the 
CT performed as part of a PET/CT is of identical diagnostic quality to the
diagnostic CT as described in the Imaging Manual, then the CT portion of the 
PET/CT can be used for tumor measurements.
o
Pathological lymph nodes (short axis >10 mm) should be assessed by 
MRI/CT.  Only nodes with short axis > 15 mm are to be included as 
measurable lesions.
o
Patients with suspected brain metastases will also undergo MRI of the brain.
o
All baseline evaluations should be performed as closely as possible to the 
beginning of treatment, and not more than 28 days before the beginning of 
the treatment (cycle 1 day 1).

Measurable disease: Subject must have radiographically measurable disease per 
RECIST 1.1 (Eisenhauer et al, 2009).  
o
Measurable lesions:

Lesions with clear borders that can be measured accurately in 
one dimension (longest diameter > 10 mm as measured by MRI/CT 
with scan slice thickness < 5 mm).

Pathologic lymph nodes are measurable when the longest diameter 
perpendicular to the long axis (short axis) is > 15 mm on MRI/CT. 

Must exclude cystic lesions, pleural/pericardial effusions and ascites.
o
Non-Measurable lesions: 

All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 mm but < 15 mm short axis) and 
other truly non-measurable lesions are considered non-measurable 
and characterized as non-index lesions. 

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
Only cancerous lesions should be selected as non-measurable 
lesions and not indeterminate lesions and lesions that could be 
cancer. Other examples of non-measurable lesions include some 
bone lesions*, leptomeningeal disease, inflammatory breast disease, 
lymphangitic involvement of the skin or (lymphangitis cutis/pulmonis), 
and groups of lesions that are small and numerous.

Fluid collections
o
Ascites, pleural effusion, or pericardial effusion, should not be 
selected as non-measurable disease at baseline or, if new or 
increased, as evidence of progressive disease. These 
collections may occur with both benign and malignant 
conditions, and their etiology is often not clear. These 
collections may often be removed via interventional 
procedures, which can lead to a false interpretation of disease 
response. Thus, these fluid collections should not be used as 
a baseline non-index or as evidence of disease response.

Bone Lesions
o
Bone scans, PET scans or plain films are not considered 
adequate imaging techniques to measures bone lesions. 
However, these techniques can be used to confirm the 
presence or absence of bone lesions.
o
Osteolytic (lytic) bone lesions or mixed lytic-blastic lesions, 
with identifiable soft tissue components, that can be evaluated 
by cross-sectional imaging technique such as CT or MRI can 
be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described 
above. Only the soft tissue component of the bone lesion 
should be measured.
o
Many osteoblastic (blastic) bone abnormalities can be benign 
and should not be selected as baseline lesions. An isolated 
new small blastic lesion should not be selected as a new 
lesion unless there is demonstrated growth on subsequent 
scans. Multiple new blastic lesions that are clearly cancerous 
may be considered for new lesions.

Cystic lesions:
o
Lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable or non-measurable) since they are, by 
definition, simple cysts.
o
Cystic lesions thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition 
of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred 
for selection as index lesions. If a cystic lesion is clearly 
cancerous and has both cystic and solid components, then the 
complete lesion should be measured including both 
components without excluding the cystic portion of a cystic 
tumor lesion when measuring.

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
Lesions with prior local treatment:
o
Tumor lesions situated in a previously irradiated area, or an 
area subject to other loco-regional therapy, should not be 
considered measurable unless there has been demonstrated 
progression in the lesion.
o
Index lesions: all measurable lesions up to a maximum of 5 lesions per organ 
and 10 lesions in total, representative of all involved organs, are to be 
identified as Index lesions, recorded and measured.  Index lesions are to be 
selected on the basis of their size and their suitability for accurate repeated 
measurements by imaging, and most representative of the subject’s tumor 
burden and overall disease status.
o
New lesions: New measureable lesions (ie, accurately and serially 
measureable in at least 1 dimension > 10 mm for non-nodal lesions or the 
short axis is ≥15 mm for nodal lesions).  The new measurable lesions should 
be selected on the basis of their size and suitability for accurate repeated 
measurements by CT or MRI.  If there are more than 10 measureable new 
lesions detected at an imaging time point for a subject, lesions not selected 
for measurements would be considered non-Index lesions.
o
Non-Index lesions: measurable lesions, other than index lesions, and all sites 
of non-measurable disease, will be identified as non-index lesions.  
Non-index lesions will be evaluated at the same assessment time points as 
the index lesions.  In subsequent assessments, changes in non-index lesions 
will contribute only in the assessment of complete response.

Pathologic lymph nodes with short axis ≥10 mm but < 15 mm at 
baseline should be considered as non-index lesions 
o
Unable to evaluate (UE):  Any lesion present at baseline which was not 
assessed or was unable to be evaluated leading to an inability to determine 
the status of that particular tumor for that time point
o
Not Available (NA): Scan not available
o
Not Done (ND):  Radiographic imaging were not performed at this time point 
to evaluate the index lesions
o
Merging lesions:

When two or more index lesions merge, the smaller lesion should 
have 0 mm recorded for the current and all future assessments, and 
the larger lesion should have the longest diameter of the merged 
lesion recorded for the current assessment and be followed for future 
assessments.  
o
Separating lesions:

When an index lesion splits into 2 or more lesions, the largest 
measurable part of the split lesion should be considered to be the 
previously recorded index lesion with measurements provided for the 
current assessment and followed for future assessments.  The 
remaining lesions would be non-index lesions. Any new lesions that 
result from separating should be documented as non-index lesions 
that were generated by separating and not truly new lesions.

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
Index lesion response
o
Immune-related Complete Response (irCR) – complete disappearance of all 
index lesions in two consecutive observations at least 4 weeks apart

Pathologic lymph nodes must have reduction in short axis to < 10 mm 
o
Immune-related Partial Response (irPR) – decrease of 30% or greater in 
tumor burden compared with baseline in two consecutive observations at 
least 4 weeks apart 
o
Immune-related Stable Disease (irSD) -  not meeting the criteria for irCR or 
irPR, in the absence of immune-related progressive disease
o
Immune-related Progressive Disease (irPD) – at least a 20% increase in 
tumor burden compared with nadir (at any single time point) in two 
consecutive observations at least 4 weeks apart
o
When the size of the tumor lesion is considered ‘too small to measure’ 
(eg, less than 5 mm), a default value of 5 mm should be assigned for index 
lesions.  If this is nadir, irPD will be judged from the tumor burden calculated 
using the default value.  

Non-Index Lesion Response
o
irCR – complete disappearance of all non-index lesions.  

Pathologic lymph nodes must have reduction in short axis to < 10 mm 
o
irPR and irSD – non-Index lesions are not considered in the definition of irPR
or irSD.  Measurements of non-index lesions are not required, but they are 
evaluated at each timepoint as ‘present’, ‘absent’ or ‘unequivocal 
progression’.  If a significant partial response is observed in a non-index 
lesion, it should be described as a comment.
o
irPD – increases in number or size of non-index lesion(s) does not constitute 
progressive disease.  New lesions that are measurable up to 5 new lesions 
per organ and 10 total) are included in the calculation of tumor burden in 
response assessments

Overall response
o
irCR – complete disappearance of all lesions (whether measurable or not, 
and no new lesions) 

Confirmation by a repeat, consecutive assessment no less than 
4 weeks from the date of the first documented response
o
irPR – decrease in tumor burden > 30% relative to baseline. 

Confirmation by a repeat, consecutive assessment no less than
4 weeks after the first documentation
o
irSD – not meeting criteria for irCR or irPR, in the absence of irPD
o
irPD – increase in tumor burden ≥20% relative to nadir (minimum recorded 
tumor burden) and at least 5 mm absolute increase compared to nadir.   

Confirmation by a repeat, consecutive assessment no less than 
4 weeks from the date of the first documented assessment.  

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Response confirmation:

irCR and irPR:
o
the repeat confirmation scan may be performed any time after 4 weeks from 
the first suspected radiologic evidence of response and may be delayed until 
the next scheduled scan to avoid necessary procedures

irPD:
o
In subjects who have initial evidence of radiological PD by irRECIST (irPD on 
one scan), it is at the discretion of the PI whether to continue a subject on 
study treatment until repeat imaging is obtained based on their assessment of 
clinical stability.  Subjects may receive study treatment and tumor 
assessment should be repeated ≥ 4 weeks later in order to confirm irPD per 
site assessment.  
o
In determining whether or not the tumor burden has increased or decreased 
per irRECIST, the local site investigator should consider all index as well as 
any incremental new measureable lesion(s).
o
irPD is confirmed at repeat imaging (irPD on two consecutive scans at least 
4 weeks apart) if tumor burden remains ≥ 20% and at least 5 mm absolute 
increase compared to nadir
o
Subjects with a global deterioration of health status requiring discontinuation 
of treatment without radiographic confirmation of disease progression
(confirmed irPD) at the time should have the reason for treatment 
discontinuation classified as ‘ clinical disease progression’.  In this case, irPD 
cannot be assigned at the time as the overall objective tumor response.  
Every effort should be made to radiographically confirm irPD even after 
discontinuation of treatment.

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Measurement and Tumor Response Assessment Based on modified irRECIST
Measurable lesions

≥ 10 mm (unidirectional measure) 

Pathologic lymph nodes: short axis ≥15 mm
Measurement of each lesion
The longest diameter (mm)
The sum of the measurements 
(SLD)

The sum of the longest diameters (SLD) of all index 
lesions and new measurable lesions, if any

Up to 5 lesions per organ, up to 10 total 
Response assessment

irPD: ≥ 20% increase from nadir and at least 5 mm 
absolute increase compared to nadir (requires 
confirmation)

irSD: < 30% decrease from baseline and < 20% increase 
from nadir

irPR: ≥30% decrease from baseline (requires 
confirmation)

irCR: Disappearance of all lesions (requires 
confirmation)
New Lesions
The presence of new lesion(s) does not define progression.  
Measurable new lesions (>10 mm): The measurements of 
the new lesions(s) are included in the SLD
Confirmation
Confirmation by 2 consecutive observations at least 4 weeks 
apart required for irCR, irPR and irPD.
Modified irRECIST Overall Response Assessment
Measurable Response
Non-measurable Response
Overall Response
Index and new 
measurable lesions 
(tumor burden)a, %
Non-Index lesions
New non-measurable 
lesions
Using irRECIST
↓ 100%
Absent
Absent
irCRb
↓ 100%
Stable/NA 
Any
irPRb
↓ 100%
Unequivocal 
progression
Any
irPRb
↓ >30%
Absent/Stable/NA
Any
irPRb
↓ >30%
Unequivocal 
progression
Any
irPRb
↓ <30% to ↑ <20%
Absent/Stable/NA
Any
irSD
↓ <30% to ↑ <20%
Unequivocal 
progression
Any
irSD
↑ >20%
Any
Any
irPDb
UE
Any
Any
UE
ND
Any
Any
UE
NA
Any
Any
UE
NA = not available; ND = not done; UE = unable to evaluate
a Decrease assessed relative to baseline, including new measurable lesions (> 10 mm)
b Response (irCR, irPR) and progression (irPD) are confirmed by a second, consecutive assessment at least 
4 weeks apart.

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Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, 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 a bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead

Product:  AMG 820 
Protocol Number:  20150195 
Date:  15 June 2018 
Page 1 of 14 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of 
AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors 
Amgen Protocol Number: AMG 820 20150195 
Eudra CT Number: 2016-001080-36 
 
Amendment Date:  
 
15 June 2018 
Rationale: 
The following updates were made to the protocol dated 03 October 2016 to incorporate 
requested changes from Merck as well as clarifying language and administrative 
updates: 
 
Updated language for Section 2.4 and Section 2.5 with Merck-provided 
language for pembrolizumab product background. 
 
Updated language in Section 3.4 to clarify that all subjects who are not DLT 
evaluable can be replaced. 
 
Updated language in Section 3.5.1 to clarify the data collected for subjects who 
continue past 12 months and up to 24 months on treatment. 
 
Updated language in Section 4 to clarify that all windows in Inclusion and 
Exclusion criteria are relative to first day of study treatment. 
 
Modified Exclusion Criterion to exclude subjects with history of or active 
pneumonitis. 
 
Updated relevant sections to require safety labs to be reviewed within 2 days 
prior to dosing. 
 
Updated Table 2 to indicate that pembrolizumab should be permanently 
discontinued for Recurrent Grade 2 pneumonitis. 
 
Updated Table 2 with footnote to indicate that treatment may possibly continue 
under certain circumstances of isolated elevated AST attributed to AMG 820 
with agreement from Medical Monitor. 
 
Updated Table 3 to indicate that pembrolizumab should be permanently 
discontinued for Recurrent Grade 2 pneumonitis or ILD. 
 
Provided language for corticosteroid treatment of Hepatic Toxicity 
(Section 6.2.4.6) or Renal Failure or Nephritis (Section 6.2.4.7): Grade 2 events 
should be treated with IV or oral corticosteroids while grade 3-4 events should 
be treated with IV corticosteroids. 
 
Updated the reporting period of Pembrolizumab Events of Clinical Interest 
(Section 6.2.4.9) to be after the first dose of pembrolizumab through  
135 (+7) days after the last dose of pembrolizumab, or 135 (+7) days after 
initiation of a new cancer therapy. 

Product:  AMG 820
Protocol Number:  20150195
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Page 2 of 14
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
Updated Section 6.2.4.10 through Section 6.2.4.10.4 to include AMG 820 as well 
as pembrolizumab in diet and other considerations while taking treatment.

Removed anticoagulation therapy from Excluded Treatments (Section 6.9) as 
the statement conflicted with Inclusion/Exclusion criteria.

Provided language in relevant sections of protocol for suggested follow up 
frequency of AEs after EOS (Q3W for SAEs, Q2W for grade 3 or higher AEs, 
Q3W for other abnormalities) until return to baseline.

Per Merck, removed all pembrolizumab PK testing from Schedule of 
Assessments.

As Amgen has decided to discontinue investigating the combination of AMG 820 
and pembrolizumab, removed non-essential biomarker and tissue sample 
collection from Schedule of Assessments.

Corrected Schedule of Assessments footnotes to align with text in body of 
protocol.

Removed Myeloblasts, Promyelocytes, Myelocytes, Metamyelocytes, Atypical 
lymphocytes from required routine hematology laboratory analytes.

Updated Section 9.3 with new template language for pregnancy and lactation 
reporting.

Clarified guidance for use of PET/CT scans in Appendix D by removing vague 
language.

Provided clarifying language in Section 9.2.1 for when disease-related events 
should be considered serious adverse events.

Corrected typo in Section 3.5.1 updating the safety follow-up visit to occur 
135 days after last dose of study treatment.

Updated Sponsor Contact information.

Updated protocol amendment date throughout document.

Corrected grammar errors throughout document.

Updated Page numbers in Table of Contents.

Product:  AMG 820
Protocol Number:  20150195
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Page 3 of 14
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Description of Changes:
Section:  Headers
Replace:  03 October 2016
With (changes are bolded): 15 June 2018
Section: Title Page
Replace:  
 MD, 
With:
 MD MS, 
Section: Title Page
Replace:  
With:
Section: Title Page
Add: Amendment 2 Date: 15 June 2018
Section: Investigator’s Agreement, Paragraph 1:
Replace: 03 October 2016
With: 15 June 2018
Section: 2.4 Non-Amgen Medicinal Product Background: Pembrolizumab:
Replace entire section: In the United States, pembrolizumab is approved for patients 
with unresectable or metastatic melanoma and disease progression following ipilimumab 
and a BRAF inhibitor (if BRAF V600 mutation positive) and patients with metastatic 
NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who 
have disease progression on or after platinum-containing chemotherapy or 
FDA-approved therapy for EGFR or ALK genomic tumor aberrations 
(Keytruda® USPI, 2014).
Pembrolizumab is a humanized monoclonal antibody (IgG4 kappa immunoglobulin with
an approximate molecular weight of 149 kDa) that blocks the interaction between PD-1
and its ligands, PD-L1 and PD-L2 (Keytruda® USPI, 2014). Consequently, the PD-1
pathway-mediated inhibition of the immune response is released, including the
anti-tumor immune response, with resultant tumor recognition by the cytotoxic T cells.

Product:  AMG 820
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Page 4 of 14
CONFIDENTIAL
(Hamid el al, 2013).
For additional information, refer to the Pembrolizumab Investigator’s Brochure.
With: 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal 
antibody (mAb) with high specificity of binding to the programmed cell death 1 
(PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 
(PD-L1) and programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro 
data, pembrolizumab has high affinity and potent receptor blocking activity for 
PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a 
number of indications.  For more details on specific indications refer to the 
Pembrolizumab Investigator’s Brochure.
Section: 2.5 Rationale, Paragraph 1:
Replace: To date, anti-PD-1 antibodies have been approved for melanoma 
(unresectable or metastatic that progressed following ipilimumab and, if BRAF V600 
mutation positive, a BRAF inhibitor), and for squamous NSCLC (metastatic disease that 
progressed on or after platinum-based chemotherapy).  They have also shown, and are 
further investigated, for promising single agent activity in other selected solid and 
hematological malignancies.  Most patients still, however, do not show a response to the 
monotherapy.
With: To date, anti-PD-1 antibodies have been approved for a number of 
indications. However, the majority of patients do not show a response to 
monotherapy.
Section: 3.4 Replacement of Subjects:
Delete: Subjects enrolled in Study Part 1 may be replaced if they are not evaluable for 
DLT (eg, a subject did not receive study treatment, or ended the study treatment before 
completion of DLT evaluation period for a reason other than experiencing a DLT).
Subjects enrolled in phase 2 who withdraw or are removed form treatment or from 
the study will not be replaced.

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Section: 3.5.1 Study Duration for Subjects, Line 4:
Replace: 30
With: 135 
Section: 3.5.1 Study Duration for Subjects, End of Section:
Add: For subjects who continue treatment past 12 months and up to 24 months (if 
tolerable and clinical benefit is observed), only Visit Date, IP Administration, and 
AE/SAE information will be collected in EDC.  Remaining follow-up to be 
performed per institutional standard of care.
Section:  4 Subject Eligibility, End of Sentence 2:
Add: All windows in Inclusion and Exclusion criteria below are relative to first day 
of study treatment.
Section:  4.2 Exclusion Criteria, Criterion 203:
Replace:
203   Evidence of active or radiological sequelae of non-infectious pneumonitis/  
interstitial lung disease.
With:
203   Subject has history Evidence of active or radiological sequelae of interstitial 
lung disease, (non-infectious) pneumonitis that required steroids, or current 
pneumonitis. /interstitial lung disease.
Section:  4.2 Exclusion Criteria, Criterion 204:
Add: 
204
History or evidence of other active autoimmune diseases that has required 
prolonged systemic treatment in past 2 years (ie, with use of disease modifying 
agents, such as corticosteroids or immunosuppressive drugs). 
Section:  6.1 Classification of Product(s) and/or medical Devices(s), Line 1:
Delete: The Amgen Investigational Product (except if required by local regulation) 
use in this study is AMG 820.

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 6 of 14
CONFIDENTIAL
Section:  6.2.1.1 Dosage, Administration, and Schedule: AMG 820, Line 6:
Replace: 48hrs
With: 2 days
Section:  6.2.2.1 Dosage, Administration, and Schedule: Pembrolizumab, Paragraph 1, 
Lines 8:
Replace: 48hrs
With: 2 days
Section:  6.2.2.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation: Pembrolizumab, Table 2, AST, ALT, or Increased Bilirubin 
Toxicity:
Add Footnote 3: Subjects who have isolated elevated AST (with grade ≤1 ALT and 
normal bilirubin) attributed to AMG 820 and are clinically asymptomatic may 
potentially continue with treatment upon discussion and agreement with Medical 
Monitor.
Section:  6.2.2.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation: Pembrolizumab, Table 2, Pneumonitis Toxicity, Grade 3-4:
Add: or Recurrent 2
Section:  6.2.4.1 Pneumonitis and Interstitial Lung Disease (ILD), Table 3:
Add: Recurrent Grade 2, Discontinue pembrolizumab, Supportive care per 
instruction for Grade 2 above.
Section:  6.2.4.1 Pneumonitis and Interstitial Lung Disease (ILD), After Table 3:
Delete: For grade 2 pneumonitis or ILD that improves to ≤grade 1 within 12 weeks, 
the following rules should apply:

Second episodes of pneumonitis ir ILD: Permanently discontinue 
pembrolizumab if upon rechallenge subjects develops pneumonitis ≥grade 2
Section:  6.2.4.6 Hepatic, Section Title:
Add: Hepatic Toxicity

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 7 of 14
CONFIDENTIAL
Section:  6.2.4.6 Hepatic, 1st Bullet:
Replace: For grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
With: In case of hepatotoxicity For grade 2 events, monitor liver function tests more 
frequently (see Section 6.4.2 and Appendix A) until returned to baseline values or 
stabilized and subject is asymptomatic (consider weekly).
Section:  6.2.4.6 Hepatic, 2nd Bullet:
Add: For grade 2 events, tTreat with IV or oral corticosteroids.
Section:  6.2.4.6 Hepatic, 3rd Bullet:
Add: Subjects who have isolated elevated AST (with grade ≤1 ALT and normal 
bilirubin) attributed to AMG 820 and are clinically asymptomatic may not require 
treatment with corticosteroids. These cases should be discussed with the medical 
monitor.
Section:  6.2.4.7 Renal Failure or Nephritis, 1st Bullet:
Add: For grade 2 events, treat with IV or oral corticosteroids.
Section:  6.2.4.7 Renal Failure or Nephritis, 2nd Bullet:
Replace: For grade 3-4 events, treat with IV systemic corticosteroids.
Section:  6.2.4.9 Pembrolizumab Events of Clinical Interest, Line 2-3:
Replace: …90 (+7) days after the last dose of pembrolizumab, or 30 (+7) days after 
initiation of a new anticancer therapy…
With: …135 90 (+7) days after the last dose of pembrolizumab, or 135 30 (+7) days after 
initiation of a new anticancer therapy…
Section:  6.2.4.10  Diet and Other Considerations While Taking Pembrolizumab, Section 
Title:
Add: Diet and Other Considerations While Taking AMG 820 and Pembrolizumab
Section:  6.2.4.10.1  Diet During Treatment With Pembrolizumab, Section Title:
Add: Diet During Treatment With AMG 820 and Pembrolizumab
Section:  6.2.4.10.2  Contraception Requirements for Pembrolizumab, Section Title:
Add: Contraception Requirements for AMG 820 and Pembrolizumab

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 8 of 14
CONFIDENTIAL
Section:  6.2.4.10.2  Contraception Requirements for Pembrolizumab, Paragraph 1, 
Lines 1-2:
Add: AMG 820 and Pembrolizumab may have adverse effects on a fetus in utero.  
Furthermore, it is not known if AMG 820 or pembrolizumab has transient adverse 
effects…
Section:  6.2.4.10.2  Contraception Requirements for Pembrolizumab, Paragraph 2, 
Lines 1:
Add: Subjects should be informed that taking AMG 820 and pembrolizumab may 
involve…
Section:  6.2.4.10.3  Use of Pembrolizumab in Pregnancy, Section Title:
Add: Use of AMG 820 and Pembrolizumab in Pregnancy
Section:  6.2.4.10.3  Use of Pembrolizumab in Pregnancy, Line 2:
Add: … subject will immediately be removed from the study treatment.  
Section:  6.2.4.10.4  Use of Pembrolizumab in Nursing Women, Section Title:
Add: Use of AMG 820 and Pembrolizumab in Nursing Women
Section:  6.4.2 Criteria for Conditional Withholding of AMG 820 and/or Pembrolizumab 
due to Potential hepatotoxicity, Paragraph 1, 4th Bullet:
Delete: OR: ALP > 8x ULN at any time>>
Section:  6.9 excluded Treatments, Medical Devices, and/or Procedures During Study 
Period, 3rd Bullet, 1st Sub-Bullet:
Add: 
o
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or 
equivalent) for related toxicities, AMG 820 and pembrolizumab dosing must be 
withheld until the corticosteroid dose has decreased to ≤10 mg prednisone daily 
(or equivalent)
Section:  6.9 excluded Treatments, Medical Devices, and/or Procedures During Study 
Period, 5th Bullet:
Delete: anticoagulation therapy (low dose warfarin [<2 mg/day] or low molecular 
weight heparing for prophylaxis against central venous catheter thrombosis is 
allowed)

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 9 of 14
CONFIDENTIAL
Section: Table 5. Schedule of Assessments:
Delete: 

All Whole Blood for Biomarker Analyses (Immunophenotyping)

All Serum for Biomarker Analyses of baseline circulating markers (IL34, IL10, 
VEGF, MCP-1, MMPs, CSF-1)

All Archive tumor tissue

All New Tumor tissue for biomarker analyses

All Anti-AMG 820 antibody collection

All Anti-pembrolizumab antibody collection

All Biomarker Development Blood sample

All pembrolizumab PK testing.
Section: Table 5. Schedule of Assessments, Footnote b:
Replace: Safety follow-up will be performed approximately 135 (+7) days after the last 
dose of AMG 820 or the last dose of pembrolizumab, whichever is later.
With: Safety follow-up will be performed approximately 135 (+7) days after the last dose 
of AMG 820 or the last dose of pembrolizumab, whichever is later.  Suggested 
frequency of visits to follow any continuing events are approximately: every week 
for SAEs, Q2W for grade 3 or higher AEs (excluding AST elevation without drug-
associated hepatotoxicity), and Q3W for other abnormalities until resolved to 
grade 1 or baseline.
Section: Table 5. Schedule of Assessments, Footnote i:
Delete: Obtaining of tumor biopsies during study (week 10 +/- 2 weeks) are 
strongly encouraged.
Section: Table 5. Schedule of Assessments, Footnote j, Second to Last Sentence:
Replace: …prior to confirmed PD and has not had radiographic tumor imaging 
performed within 4 weeks (+1 week) of the visit.
With: …prior to confirmed PD and has not had radiographic tumor imaging performed 
within 4 6 weeks (+1 week) of the visit.
Section: Table 5. Schedule of Assessments, Footnote m:
Replace: 48hrs
With: 2 days

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 10 of 14
CONFIDENTIAL
Section: Table 5. Schedule of Assessments, Footnote l:
Delete:
l PK samples indicated in table should be collected at the end of pembrolizumab 
infusion.  AMG 820 pre-dose samples may also be assayed for pembrolizumab 
concentrations.
Section: Table 6. Laboratory Analytes, Hematology:
Delete: 

Myeloblasts

Promyelocytes

Myelocytes

Metamyelocytes

Atypical lymphocytes
Section: 7.2.2 Treatment, Central Laboratory Assessments:
Add: Central laboratory assessments (refer to Schedule of Assessments as not all 
tests will be required after Amendment 2):
Section: 7.2.3 Safety Follow-up Visit(s), Central Laboratory Assessments:
Add: Central laboratory assessments (refer to Schedule of Assessments as not all 
tests will be required after Amendment 2):
Section: 7.4 Radiological Imaging Assessment, Paragraph 1, Line 2:
Replace: …contrast-enhanced MRI or CT and evaluated according...
With: …contrast-enhanced MRI /or CT and evaluated according...
Section: 7.4 Radiological Imaging Assessment, Paragraph 2, Line 16:
Add: … continue to receive treatment after radiographic confirmation of progressive 
disease…
Section: 7.6 Biomarker Development, During Study Treatment:
Add: Collection of  at least one biopsy at the time of second CT scan 
(week 10 ± 2 weeks) and additional sequential tumor biopsies strongly encouraged, 
whenever possible, in all subjects. Note: this biopsy will no longer be encouraged 
per the data of Amendment 2.

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 11 of 14
CONFIDENTIAL
Section: 7.6 Biomarker Development, Flow Cytometry Whole Blood Samples:
Add: Refer to the Schedule of Assessments for specific time points and the laboratory 
manual for detailed collection and handling instructions. Note that not all samples will 
be required after Amendment 2.
Section: 9.2.1 Reporting Procedures for Disease Related Events, Paragraph 2:
Delete: Events assessed by the investigator to be related to the investigational 
medicinal product(s)/study treatment/protocol-required therapies, and determined 
to be serious, require reporting of the event on the Event CRF.
Section: 9.2.1 Reporting Procedures for Disease Related Events, Paragraph 2:
Add: Disease-Related Events assessed by the Investigator to be more severe than 
expected and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies, and determined to be serious, must be 
recorded on the Event CRF as Serious Adverse Events.
Section: 9.3 Pregnancy and Lactation Reporting, Paragraph 3:
Replace: Amgen’s Global Safety will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth.
With: Amgen’s Global Safety will seek to follow with the Investigator regarding 
additional information that may be requested. pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth.
If a female subject becomes pregnant during the study, the Investigator should 
attempt to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
Investigator will report the event as a Serious Adverse Event.
Section: 9.3 Pregnancy and Lactation Reporting, Paragraph 4+5:
Replace: If a lactation case occurs while the female subject is taking protocol-required 
therapies report the lactation case to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 12 of 14
CONFIDENTIAL
1 week after the last dose of AMG 820 or 4 months after the last dose of 
pembrolizumab.  
With: If a female breastfeeds while lactation case occurs while the female subject 
is taking protocol-required therapies report the lactation case to Amgen as specified 
below. 
In addition to reporting a lactation case during the study, investigators should 
monitor for lactation cases that occur after the last dose of protocol-required 
therapies through 1 week after the last dose of AMG 820 or 4 months after the last 
dose of pembrolizumab.  
Section: 9.3 Pregnancy and Lactation Reporting, End of Paragraph 6:
Add: Amgen Global Patient Safety will follow-up with the Investigator regarding 
additional information that may be requested.
If a male subject's female partner becomes pregnant, the Investigator should 
discuss obtaining information regarding the birth outcome and health of the infant 
from the pregnant partner.
Section: 9.4 Pembrolizumab Events of Clinical Interest, Paragraph 2, Lines 2-3:
Replace: …90 (+7) days following cessation of pembrolizumab treatment, or 30 (+7) 
days after initiation of a new anti-cancer therapy…
With: …135 90 (+7) days following cessation of pembrolizumab treatment, or 
135 30 (+7) days after initiation of a new anti-cancer therapy…
Section: 10.3.1 Interim Analyses, End of Section:
Delete: The study may be discontinued or modified at any time due to documented
safety findings.
Section: 10.3.2 Dose Level Review Team (DLRT), End of Paragraph 1:
Add: The study may be discontinued or modified at any time due to documented 
safety findings.
Section: Appendix D. Modified Immune-Related Response Criteria in Solid Tumors 
(irRECIST), Time point response assessment using modified irRECIST, Definitions, 
1st Bullet, Methods of Measurement, 3rd Sub-Bullet:
Replace: If a combined PET/CT scan is performed at the discretion of the investigator at 
baseline and subsequent timepoints. The CT portion of that exam should not be 

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 13 of 14
CONFIDENTIAL
substituted for the dedicated diagnostic CT exams required by this protocol.  The PET 
portion of the CT may introduce additional data which may bias the investigator’s 
assessment of response if it is not routinely or serially performed.  However, if the 
investigator or the site radiologist…
With: If a combined PET/CT scan is performed at the discretion of the investigator at 
baseline and subsequent timepoints, the CT portion of that exam should not be 
substituted for the dedicated diagnostic CT exams required by this protocol unless.  The 
PET portion of the CT may introduce additional data which may bias the 
investigator’s assessment of response if it is not routinely or serially performed.  
However, if the investigator the Investigator or the site radiologist…
Section: Appendix D. Modified Immune-Related Response Criteria in Solid Tumors 
(irRECIST), Time point response assessment using modified irRECIST, Definitions, 
2nd Bullet, Mesureable disease, 4th Sub-Bullet:
Replace: New lesions: New measured lesions (ie, accurately and serially measureable in 
at least 1 dimension > 10 mm for non-nodal lesions or the short axis is ≥15 mm for 
nodal lesions).
With: New lesions: New measureable measured lesions (ie, accurately and serially 
measureable in at least 1 dimension > 10 mm for non-nodal lesions or the short axis is 
≥15 mm for nodal lesions).
Section: Appendix D. Modified Immune-Related Response Criteria in Solid Tumors 
(irRECIST), Time point response assessment using modified irRECIST, Response 
confirmation, 2nd Bullet, irPD, 2nd Sub-Bullet:
Replace: In determining whether or not the tumor burden has increased or decreased 
per irRECIST, the local site investigator should consider all index and non-index lesions 
as well as any incremental new lesion(s).
With: In determining whether or not the tumor burden has increased or decreased per 
irRECIST, the local site Investigator investigator should consider all index and non-
index lesions as well as any incremental new measureable lesion(s).

Product:  AMG 820
Protocol Number:  20150195
Date:  15 June 2018
Page 14 of 14
CONFIDENTIAL
Section: Appendix D. Modified Immune-Related Response Criteria in Solid Tumors 
(irRECIST), Time point response assessment using modified irRECIST, Response 
confirmation, 2nd Bullet, irPD, 4th Sub-Bullet:
Replace: Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at the time should have the 
reason for treatment discontinuation classified as ‘non-confirmed disease progression’.  
In this case, irPD cannot be assigned at the time as the overall objective tumor 
response.  Every effort should be made to document the objective progression even 
after discontinuation of treatment.
With: Subjects with a global deterioration of health status requiring discontinuation of 
treatment without radiographic confirmation objective evidence of disease 
progression (confirmed irPD) at the time should have the reason for treatment 
discontinuation classified as ‘clinical non-confirmed disease progression’.  In this case, 
irPD cannot be assigned at the time as the overall objective tumor response.  Every 
effort should be made to radiographically confirm irPD document the objective 
progression even after discontinuation of treatment.

Product:  AMG 820 
Protocol Number:  20150195 
Date:  03 October 2016 
Page 1 of 9 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of 
AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors 
Amgen Protocol Number: AMG 820 20150195 
Eudra CT Number: 2016-001080-36 
 
Amendment Date:  
 
03 October 2016 
Rationale: 
The following updates were made to the protocol dated 11 December 2015 to 
incorporate requested changes from EU VHP review: 
• 
Updated Safety Follow Up period from 30 days to 135 days after last study 
treatment throughout the protocol. 
• 
Added a Dose Rationale section for AMG 820 (Section 2.2.4) and corresponding 
Table of Contents entry. 
• 
Clarified important identified risks, important potential risks, and referred to most 
current IB for AMG 820 in Risk Assessment Section 2.3. 
• 
Added new exclusion criterion to exclude subjects with active infection within 
2 weeks prior to study enrollment. 
• 
Added new exclusion criterion to exclude subjects who have received systemic 
immunostimulatory agents within 6 weeks or five half-lives, whichever is shorter, 
prior to first dose of study treatment (except anti PD-1/PD-L1 treatment if 
recruited into Group 4a or 4b). 
• 
Modified existing exclusion criteria to also exclude subjects with prior stem cell 
transplantation. 
• 
Modified existing exclusion criteria to also exclude subjects who have other 
signs or symptoms of clinical immune system suppression. 
• 
Part of an existing exclusion criterion was updated to be a stand-alone criterion 
(previously part of Exclusion 205, the following is now Exclusion 206: receiving 
systemic immunosuppressive therapy (> 2 weeks) within 7 days prior to the first 
dose of study treatment, including oral steroid doses > 10 mg/day of prednisone 
or equivalent except for management of adverse events during the course of the 
study. Subjects that require intermittent use of bronchodilators or local steroid 
injection will not be excluded from the study). 
• 
Updated exclusion criteria to include only highly effective methods of birth 
control which are in accordance with CTFG’s recommendations (removed 
statements regarding barrier methods of contraception as being acceptable). 
• 
Updated exclusion criteria to define women and men of reproductive potential or 
childbearing potential, respectively. 

Product:  AMG 820 
Protocol Number:  20150195 
Date:  03 October 2016 
Page 2 of 9 
CONFIDENTIAL 
 
 
• 
Updated Dose Limiting Toxicity Definition for thrombocytopenia to indicate that 
any Grade 3 or higher thrombocytopenia with bleeding, and Grade 4 or higher 
thrombocytopenia lasting >48 hours or any thrombocytopenia requiring 
intervention is considered a DLT. 
• 
Updated Schedule of Assessments to require urine pregnancy test prior to each 
infusion for women of childbearing potential. 
• 
Updated Schedule of Assessments and relevant areas of protocol to require MRI 
of brain for subjects with NSCLC at screening. 
• 
Updated Reasons for Removal from Treatment to include “pregnancy” and 
“potential hepatotoxicity” (in accordance with section 6.4.1). 
• 
Removed reference not cited in protocol. 
• 
Corrected spelling and grammatical errors throughout protocol. 
• 
Table of Contents page numbers updated at page 26 and beyond to reflect 
addition of Section 2.2.4 AMG 820 Dose Rationale.