A Randomized, Double Blind Placebo Controlled, First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Subcutaneous Doses of AMG 570 in Healthy Subjects
Phase: PHASE1
Conditions: Systemic Lupus Erythematosus
Sponsor: Amgen

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 1 of 79 
CONFIDENTIAL 
Title:  A Randomized, Double Blind Placebo Controlled, First in Human Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 
Single Ascending Subcutaneous Doses of AMG 570 in Healthy Subjects 
Amgen Protocol Number (AMG 570) 20140322 
Clinical Study Sponsor: 
Amgen Inc. One Amgen Center Drive 
Thousand Oaks, CA 91320-1799  
Phone: +1 805-447-1000  
Key Sponsor 
Contact(s): 
, MD, PhD 
Medical Science Medical Director 
Telephone: 
 
Email: 
 
 
Clinical Research Study Manager 
Telephone: 
  
Email: 
  
Original Date: 
 18 August 2015 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
 27 October 2015 
 08 January 2016 
 04 May 2017 
 24 January 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, Amgen’s general 
number in the US (1-805-447-1000). 
Approved
NCT Number: NCT02618967
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 2 of 79 
CONFIDENTIAL 
Investigator’s Agreement 
I have read the attached protocol entitled “A Randomized, Double Blind Placebo 
Controlled, First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of Single Ascending Subcutaneous Doses of AMG 570 in 
Healthy Subjects”, dated 24 January 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 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) 
Approved

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 3 of 79 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title: A Randomized, Double Blind Placebo Controlled, First in Human Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending 
Subcutaneous Doses of AMG 570 in Healthy Subjects 
Study Phase:  1   
Indication:  Systemic Lupus Erythematosus 
Primary Objective:  To assess the safety and tolerability of single subcutaneous (SC) doses of 
AMG 570 in healthy subjects. 
Secondary Objective(s):   
• 
To characterize the PK of single subcutaneous (SC) doses of AMG 570 in healthy 
subjects. 
• 
To evaluate the PD effects (B7RP-1 occupancy and inhibition of B cell survival) of single 
subcutaneous (SC) doses of AMG 570 in healthy subjects. 
• 
To evaluate the immunogenicity of AMG 570.  
 Exploratory Objective(s):   
• 
To evaluate the relationship between PK, B7RP-1 occupancy, 
 and changes 
in percentage and absolute counts of naïve and memory B cells following single 
subcutaneous (SC) doses of AMG 570 in healthy subjects. 
• 
To evaluate the PD effect of single subcutaneous (SC) doses of AMG 570 in healthy 
subjects on serum IgG and IgM. 
Hypotheses:  A single SC dose administration of AMG 570 will achieve an acceptable safety and 
tolerability profile in healthy subjects within the proposed dose ranges  
(SC: 7 to 700 mg AMG 570). 
Primary Endpoint: Subject incidences of treatment-emergent adverse events, including clinically 
significant changes in physical examinations, vital signs, laboratory safety tests, and 
electrocardiograms (ECGs). 
Secondary Endpoint(s):  
• 
AMG 570 PK parameters (eg, maximum observed concentration [Cmax], time at 
Cmax [tmax,], and area under the concentration-time curve [AUC]). 
• 
Anti-AMG 570 binding antibodies. 
• 
Peripheral blood B7RP-1 receptor occupancy. 
• 
Peripheral blood changes in percentage and absolute counts of naïve and memory 
CD19+ B cells (naïve = IgD+CD27-, memory = IgD-CD27+). 
Exploratory Endpoint(s): Exploratory biomarkers may include but are not limited to the 
following:  
• 
.  
• 
Serum IgG and IgM.  
Study Design:   This is a randomized, placebo-controlled, double-blind, single ascending dose 
(SAD) study in healthy subjects.  The study consists of 7 SC cohorts.  Subjects will be 
randomized in a 3:1 ratio to receive AMG 570 or placebo accordingly.  
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 4 of 79 
CONFIDENTIAL 
 
 
Dose Levels 
Cohort # 
Planned Dose (mg) 
Route 
N (active:placebo) 
1 
7 
SC 
8 (6:2) 
2 
21 
SC 
8 (6:2) 
3 
70 
SC 
8 (6:2) 
4 
140 
SC 
8 (6:2) 
5 
210 
SC 
8 (6:2) 
6 
420 
SC 
8 (6:2) 
7 
700 
SC 
8 (6:2) 
The actual dose to be administered may be adjusted based on safety, tolerability, and preliminary 
PK and PD data of previous dose levels.  Dose adjustments may involve either an increase or a 
decrease in the planned dose, but will not exceed pharmacokinetic criteria defined in the rationale 
for dose selection Section 2.4.5. 
Sample Size:   Approximately 56 healthy subjects will be enrolled into 7 cohorts (6 active: 
2 placebo in each cohort). 
Summary of Subject Eligibility Criteria:  Subjects in this study will be males and females 
between ages of 18 and 65 years, and the females must be of non-reproductive potential.  
Subjects should have a body mass index of ≥ 18.0 and ≤ 30.0 kg/m2.  For a full list of eligibility 
criteria, please refer to Section 4.1 and Section 4.2. 
Investigational Product   
Amgen Investigational Product Dosage and Administration:   
This first in human study will utilize sentinel dosing for the first two subjects of each cohort.  The 
sentinel pair (the first 2 subjects in each cohort) will be dosed with one subject receiving a single 
dose of AMG 570 and the other receiving placebo.  The remaining subjects of each cohort may 
be dosed 24 hours after the sentinel pair.  
For subcutaneous dosing in Cohorts 1 & 2, diluent will be used.  For subcutaneous dosing in 
Cohorts 3 to 5, doses will be administered in a 1.0 mL per injection format (up to 3 x 1 mL 
injections depending on treatment arm).  For subcutaneous dosing in Cohort 6, doses will be 
administered in a 1.5 mL per injection format (4 x 1.5 mL injections).  For subcutaneous dosing in 
Cohort 7, doses will be administered in a 2 mL per injection format (5 x 2.0 mL injections). 
Dosage and IP Administration 
Product Name 
AMG 570 
Placebo 
Diluent 
Formulation 
Description 
10 mM acetate, 9.0% 
(w/v) sucrose, 0.01% 
(w/v) polysorbate 80 
10 mM acetate, 9.0% 
(w/v) sucrose, 0.004% 
(w/v) polysorbate 20 
10 mM acetate, 9.0% 
(w/v) sucrose, 0.004% 
(w/v) polysorbate 20 
Dosage Form 
Solution 
Solution 
Solution 
Unit dose 
Strength 
70 mg/ml 
NA 
NA 
Procedures:   After signing the informed consent, subjects will be screened to determine 
eligibility.  The screening period is 42 days.  Prior to enrollment, baseline assessments will be 
performed.  Subjects who meet the inclusion and exclusion criteria after completion of all 
screening and baseline procedures will be enrolled in the study.  
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 5 of 79 
CONFIDENTIAL 
 
 
Subjects will be confined to the research facility from day -1 to day 3, where critical clinical safety 
and study evaluations will be performed including physical examination, vital signs, clinical 
laboratory tests, ECGs, PK, and biomarker sample collections.  
On study day 1, subjects will complete pre-dose assessments and receive a single SC dose of 
AMG 570 or placebo.  Subjects may check out of the research facility on Day 3 after all 
assessments have been completed.  If needed to facilitate study evaluation at specified time 
points subjects may also stay at the research facility up to Day 11.    After discharge from the 
research facility, subjects must return to the research facility on an outpatient basis at specified 
time points for collection of blood samples for PK and PD measurements and completion of 
safety assessments (including blood samples for antibody analysis).  All adverse events, 
including serious adverse events, and use of concomitant medication will be collected for the 
duration of the study.  
Subjects’ participation in the study will conclude with the completion of the end of study 
procedures.  However, if an end of study test result demonstrates a significant clinical or 
laboratory abnormality, the subject will be followed until resolution of the abnormality or until it is 
considered clinically stable by the Principal Investigator.  If a subject’s CD3-CD19+ B cell counts 
are < 107 cells/µL (the lower limit of normal for healthy volunteers), the subject will return for 
further testing of B cell counts every 3 months until the subject has B cell counts ≥ 107 cells/µL.  
Such follow-up visit(s) for B cell counts will continue every 3 months, up to 12 months after the 
end of study. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 8).   
Statistical Considerations:  Descriptive statistics will be provided for selected demographics, 
safety, immunogenicity, PK, PD, and biomarker end points.  Descriptive statistics on continuous 
measurements will include means, medians, standard deviations, and ranges, while categorical 
data will be summarized using frequency counts and percentages.  Data will be presented and 
summarized by treatment and may also be presented by time as appropriate. 
The number and percent of subjects reporting any adverse events will be tabulated by system 
organ class and preferred term and may be further classified by severity and relationship to 
treatment.  Subject incidence of clinically significant changes in vital signs, physical examinations, 
clinical laboratory safety tests, ECGs, and the development of AMG 570 binding antibodies will be 
noted.  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 
 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 6 of 79 
CONFIDENTIAL 
 
Study Design and Treatment Schema 
 
  
 
 
   
 
 
 
 
 
 
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DLRM 
DLRM 
DLRM 
n = 8 
(6 active: 2 Placebo per cohort) 
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Screening (-42 to -1)
End of Study 
DLRM 
DLRM 
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DLRM 
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DLRM 
 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 7 of 79 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADA 
Anti-drug antibodies 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BAFF 
B cell activating factor 
B7RP-1 
B7-related protein-1 (also known as ICOSL) 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CRF 
case report form 
DLRM 
dose level review meeting 
DLT 
dose limiting toxicity 
DCs 
dendritic cells 
DILI 
drug-induced liver injury 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
EMEA 
European Medicines Agency 
end of study for individual 
subject  
defined as the last date that protocol-specified procedures are 
conducted for an individual subject 
end of treatment 
defined as the date of final assessment for the protocol specified 
treatment phase of the study for an individual subject 
end of study (primary 
completion) 
defined as the date 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 trial 
defined as the date 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), the end of study  would include these 
additional parts 
FIH 
First in Human 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GSO 
Global Safety Officer 
HBcAb 
hepatitis B core antibody 
HepBsAg 
hepatitis B surface antigen 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 8 of 79 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
HepCAb 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
Ig 
Immunoglobulin 
IC50 
inhibitory concentration at 50% 
IC90 
inhibitory concentration at 90% 
IC99 
inhibitory concentration at 99% 
ICF 
informed consent form 
ICOS 
ICOSL 
inducible co-stimulator 
inducible co-stimulator ligand 
ICH 
IV  
International Conference On Harmonisation 
intravenous 
IP 
Investigational Product 
IPIM 
Investigational Product Instruction Manual 
IPRO 
Immunophenotyping and Receptor Occupancy 
IRB 
Institutional Review Board 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MABEL 
Minimum Anticipated Biological Effect Level 
MRSD 
maximum recommended starting dose 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PR 
the interval measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart’s electrical cycle as 
measured by electrocardiogram 
QRS 
the interval between the Q wave and the S wave in the heart’s 
electrical cycle as measured by electrocardiogram; represents the 
time it takes for depolarization of the ventricles 
QT 
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 
electrocardiogram 
QTc 
QT interval corrected for heart rate using accepted methodology 
RO 
receptor occupancy 
RNA 
ribonucleic acid 
SRBC 
sheep red blood cells 
SC 
Subcutaneous 
SLE 
Systemic Lupus Erythematosus 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 9 of 79 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
study day 1 
defined as the first day that protocol specified investigational product 
is administered to the subject 
Th1 
T helper type 1 
Th2 
T helper type 2 
 tmax 
time to maximum concentration 
ULN 
upper limit of normal 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 10 of 79 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 15 
1.1 
Primary ..................................................................................................... 15 
1.2 
Secondary ................................................................................................. 15 
1.3 
Exploratory ................................................................................................ 15 
2. 
BACKGROUND AND RATIONALE ...................................................................... 15 
2.1 
Disease ..................................................................................................... 15 
2.2 
Amgen Investigational Product Background .............................................. 16 
2.2.1 
Pharmacology ........................................................................... 16 
2.2.2 
Pharmacokinetics ...................................................................... 17 
2.2.3 
Toxicology ................................................................................. 18 
2.3 
Risk Assessment ....................................................................................... 18 
2.4 
Rationale ................................................................................................... 19 
2.4.1 
AMG 570, AMG 557 and Blisibimod Molecular 
Structure Information ................................................................. 22 
2.4.2 
AMG 557 Clinical Background ................................................... 22 
2.4.3 
Blisibimod Clinical Background .................................................. 22 
2.4.4 
AMG 570 Clinical Background ................................................... 23 
2.4.5 
Rationale for Dose Selection ..................................................... 23 
2.4.6 
Rationale for Key Aspects of Study Design ............................... 25 
2.5 
Clinical Hypotheses ................................................................................... 26 
3. 
EXPERIMENTAL PLAN ........................................................................................ 26 
3.1 
Study Design ............................................................................................. 26 
3.2 
Number of Sites ........................................................................................ 26 
3.3 
Number of Subjects ................................................................................... 26 
3.4 
Replacement of Subjects .......................................................................... 26 
3.5 
Estimated Study Duration .......................................................................... 27 
3.5.1 
Study Duration for Subjects ....................................................... 27 
3.5.2 
End of Study .............................................................................. 27 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 27 
4.1 
Inclusion Criteria ....................................................................................... 28 
4.2 
Exclusion Criteria ...................................................................................... 29 
5. 
SUBJECT ENROLLMENT .................................................................................... 30 
5.1 
Randomization/Treatment Assignment ...................................................... 31 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 31 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 11 of 79 
CONFIDENTIAL 
 
 
6. 
TREATMENT PROCEDURES .............................................................................. 32 
6.1 
Classification of Product(s) ........................................................................ 32 
6.2 
Investigational Product .............................................................................. 32 
6.2.1 
Amgen Investigational Product AMG 570 .................................. 32 
6.2.1.1 
Dosage, Administration, and Schedule .................... 32 
6.2.1.2 
Dose Level Review Meeting (DLRM) 
Membership ............................................................ 33 
6.2.1.3 
Dose-Cohort Study Escalation and 
Stopping Rules ........................................................ 33 
6.2.1.4 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 37 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 38 
6.3.1 
Criteria for Permanent Withholding of AMG 570 due to 
Potential Hepatotoxicity ............................................................. 38 
6.4 
Concomitant Therapy ................................................................................ 39 
6.5 
Alcohol, Tobacco Restrictions and Exercise Restriction ............................ 39 
7. 
STUDY PROCEDURES ....................................................................................... 39 
7.1 
Schedule of Assessments ......................................................................... 39 
7.2 
General Study Procedures ........................................................................ 42 
7.2.1 
Informed Consent ...................................................................... 42 
7.2.2 
Screening .................................................................................. 42 
7.2.3 
Day -1, Day 1 and Day 2 and Other Treatment .......................... 43 
7.2.4 
End of Study Visit/ Early Termination ........................................ 44 
7.2.5 
Medical History .......................................................................... 44 
7.2.6 
Adverse Event ........................................................................... 44 
7.2.7 
Concomitant Medications .......................................................... 45 
7.2.8 
Physical Examination ................................................................ 45 
7.2.9 
Vital Signs ................................................................................. 45 
7.2.10 
Height, Weight, and Body Mass Index ....................................... 46 
7.2.11 
Electrocardiograms.................................................................... 46 
7.2.12 
Estimated Glomerular Filtration Rate (eGFR) ............................ 46 
7.2.13 
Clinical Chemistry ...................................................................... 46 
7.2.14 
Hematology ............................................................................... 47 
7.2.15 
Urinalysis ................................................................................... 48 
7.2.16 
Drug, Alcohol, and Cotinine Screen ........................................... 48 
7.2.17 
Hepatitis B, Hepatitis C and HIV Status ..................................... 49 
7.2.18 
Serum Follicle-stimulating Hormone and Estradiol..................... 49 
7.2.19 
Pregnancy Test ......................................................................... 49 
7.2.20 
Pharmacokinetic Blood Sample Collection for 
AMG 570 Serum Concentrations ............................................... 49 
7.2.21 
Immunophenotyping and Receptor Occupancy (IPRO) 
Assay Blood Collections ............................................................ 49 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 12 of 79 
CONFIDENTIAL 
 
 
.............................................................. 50 
7.2.23 
IgG and IgM Blood Collection .................................................... 50 
7.2.24 
Anti-Drug Antibody Testing (ADA) ............................................. 50 
7.3 
Exploratory Biomarker Samples for Future Use......................................... 50 
7.4 
Pharmacogenetic Sample of Blood for Cell Pellets .................................... 51 
7.5 
Sample Storage and Destruction ............................................................... 51 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 52 
8.1 
Subjects’ Decision to Withdraw ................................................................. 52 
8.1.1 
Investigator or Sponsor Decision to Withdraw or 
Terminate Subjects’ Participation Prior to Study 
Completion ................................................................................ 52 
8.1.2 
Reasons for Removal From Treatment ...................................... 53 
8.1.3 
Reasons for Removal From Study ............................................. 53 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 53 
9.1 
Definition of Safety Events ........................................................................ 53 
9.1.1 
Adverse Events ......................................................................... 53 
9.1.2 
Serious Adverse Events ............................................................ 54 
9.2 
Safety Event Reporting Procedures .......................................................... 54 
9.2.1 
Adverse Events ......................................................................... 54 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 54 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 55 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 56 
9.3 
Pregnancy Reporting ................................................................................ 57 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 57 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 57 
10.1.1 
Study Endpoints ........................................................................ 57 
10.1.1.1 
Primary Endpoints ................................................... 57 
10.1.1.2 
Secondary Endpoints .............................................. 57 
10.1.1.3 
Exploratory Endpoints ............................................. 57 
10.1.2 
Analysis Sets ............................................................................. 57 
10.1.2.1 
Safety Analysis Set ................................................. 57 
10.1.2.2 
Pharmacokinetic (PK) Concentration 
Analysis Set ............................................................ 58 
10.1.2.3 
Pharmacokinetic (PK) Parameter Analysis 
Set .......................................................................... 58 
10.1.2.4 
Pharmacodynamic (PD) Analysis Set ...................... 58 
10.1.3 
Covariates and Subgroups ........................................................ 58 
10.2 
Sample Size Considerations ..................................................................... 58 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 13 of 79 
CONFIDENTIAL 
 
 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 58 
10.4 
Planned Analyses ..................................................................................... 59 
10.4.1 
Data Monitoring Committee (DMC), Data Review 
Team (DRT) or Dose Level Review Team (DLRT) .................... 59 
10.4.2 
Primary Analysis ........................................................................ 59 
10.5 
Planned Methods of Analysis .................................................................... 59 
10.5.1 
General Considerations ............................................................. 59 
10.5.2 
Primary Endpoint ....................................................................... 59 
10.5.2.1 
Adverse Event ......................................................... 59 
10.5.2.2 
Clinical Laboratory Tests ......................................... 60 
10.5.2.3 
Vital Signs ............................................................... 60 
10.5.2.4 
Electrocardiograms ................................................. 60 
10.5.2.5 
Study Disposition and Demographic Data ............... 60 
10.5.3 
Secondary Endpoint(s) .............................................................. 60 
10.5.3.1 
PK Analysis ............................................................. 60 
10.5.3.2 
Antibody Analysis .................................................... 61 
10.5.3.3 
PD Analysis ............................................................. 61 
10.5.4 
Exploratory Endpoints ............................................................... 61 
11. 
REGULATORY OBLIGATIONS ............................................................................ 61 
11.1 
Informed Consent ...................................................................................... 61 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 62 
11.3 
Subject Confidentiality ............................................................................... 62 
11.4 
Investigator Signatory Obligations ............................................................. 63 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 63 
12.1 
Protocol Amendments and Study Termination .......................................... 63 
12.2 
Study Documentation and Archive ............................................................ 64 
12.3 
Study Monitoring and Data Collection ....................................................... 64 
12.4 
Investigator Responsibilities for Data Collection ........................................ 66 
12.5 
Language .................................................................................................. 66 
12.6 
Publication Policy ...................................................................................... 66 
12.7 
Compensation ........................................................................................... 67 
13. 
REFERENCES ..................................................................................................... 68 
14. 
APPENDICES ...................................................................................................... 71 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 14 of 79 
CONFIDENTIAL 
 
 
List of Tables 
Table 1.  Comparison of AMG 570 and AMG 557 Mean ± SD 
Pharmacokinetic Parameters in Cynomolgus Monkey ............................ 17 
Table 2.  Observed or Predicted AMG 570 Pharmacokinetic Parameters and 
Exposure Margins ................................................................................... 24 
Table 3.  Dose Levels .................................................................................................... 33 
Table 4.  Dose Cohort Stopping Rules........................................................................... 35 
Table 5.  Dose Stopping Values for Vital Signs .............................................................. 36 
Table 6.  Dose Stopping Values for ECG ....................................................................... 36 
Table 7.  Dose Stopping Values for Clinical Laboratory Results .................................... 37 
Table 8.  AMG 570 Schedule of Assessments ............................................................... 40 
Table 9.  Clinical Chemistry ........................................................................................... 47 
Table 10.  Hematology .................................................................................................. 48 
Table 11.  Urinalysis ...................................................................................................... 48 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 72 
Appendix B.  Sample Serious Adverse Event Form ....................................................... 74 
Appendix C.  Pregnancy Notification Worksheet (Pregnancy in Partner of a 
Male Subject).......................................................................................... 79 
 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 15 of 79 
CONFIDENTIAL 
 
 
1. 
OBJECTIVES 
1.1 
Primary 
To assess the safety and tolerability of single subcutaneous (SC) doses of AMG 570 in 
healthy subjects. 
1.2 
Secondary 
• 
To characterize the PK profile of single subcutaneous (SC) doses of AMG 570 in 
healthy subjects. 
• 
To evaluate the PD effects (B7RP-1 occupancy and inhibition of B cell survival) of 
single subcutaneous (SC) doses of AMG 570 in healthy subjects. 
• 
To evaluate the immunogenicity of AMG 570. 
1.3 
Exploratory 
• 
To evaluate the relationship between PK, B7RP-1 occupancy, 
 and 
changes in percentage and absolute counts of naïve and memory B cells following 
single subcutaneous (SC) doses of AMG 570 in healthy subjects.   
• 
To evaluate the PD effect of single subcutaneous (SC) doses of AMG 570 in healthy 
subjects on serum IgG and IgM.   
2. 
BACKGROUND AND RATIONALE  
2.1 
Disease 
Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease of unknown 
cause with diverse clinical manifestations that disproportionately affects minorities (in 
particular, blacks and Hispanics) and women of childbearing potential (Tsokos, 2011; 
Rahman and Isenberg, 2008; Kotzin, 1996).  The prevalence of SLE in the United States 
varies widely in different studies but is generally thought to be underestimated due to the 
difficulty in diagnosis of the disease and obtaining reliable data to estimate the true 
numbers of subjects with this disease.  The prevalence of SLE in the population varies 
from 20 to 150 cases per 100,000 (Pons-Estel, 2010; Helmick, 2008; Lawrence, 2008; 
Chakravarty, 2007).  There are significant racial differences in prevalence rates with 
164 (white) to 406 (African American) per 100,000 (Chakravarty, 2007).  In the US, 
one-third of patients diagnosed with lupus have moderate to severe SLE.  
SLE is a heterogeneous disease that is characterized by periods of remission and flares 
that range from mild to severe.  It is associated with highly variable inter-individual 
symptoms and can be fatal.  SLE can affect the skin (rash), musculoskeletal system 
(arthritis, bone tissue death), nervous system (seizures, psychosis), lungs (pleuritis, 
pneumonitis), and the blood (venous or arterial clots, anemia).  In addition, 
approximately 65% of patients will develop lupus nephritis, which is an inflammatory 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
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condition of the kidney that can range from mild focal to severe diffuse proliferative 
glomerulonephritis (Adams et al, 2006).  Lupus nephritis can also lead to kidney failure 
and is a serious complication of SLE.   
The treatment options and duration of SLE are highly individualized and depend on 
symptoms, organ involvement, and disease severity.  Antimalarial and nonsteroidal 
anti-inflammatory drugs (NSAIDs) are useful in the treatment of mild symptoms such as 
arthralgia and cutaneous manifestations.  Oral corticosteroids and cytotoxic agents are 
used in more severe disease.  Other medications (cyclophosphamide, 
immunosuppressive agents, and tacrolimus) may be used depending on the severity and 
organ systems involved.  Belimumab (anti-BAFF) is a newer agent that is approved for 
patients with mild to moderate disease currently taking standard therapy. 
Although the clinical heterogeneity of SLE presents diagnostic challenges, antibodies to 
nuclear components represent a common manifestation of the disease.  The presence of 
class-switched immunoglobulin G (IgG) autoantibodies implicate immune dysregulation 
as a driving force for disease pathogenesis, with T cells appearing to play a role in the 
development of autoantibody production by B cells.  T cells are believed to be drivers of 
many different autoimmune diseases including SLE and rheumatoid arthritis (RA) due to 
their central role in the control of immune system function.  Simultaneous blockade of 
the B7-related protein-1 (B7RP-1)/ inducible co-stimulator (ICOS) pathway and 
B cell-activating factor (BAFF) with AMG 570 is hypothesized to result in blockade of 
T-cell activation, B-cell maturation, and antibody production. 
2.2 
Amgen Investigational Product Background 
2.2.1 
Pharmacology 
AMG 570 is a bispecific molecule inhibiting both BAFF and B7RP-1.  AMG 570 contains 
two tandem copies of BAFF-binding peptides identical to the BAFF binding peptides of 
blisibimod (also known as AMG 623) fused to the C-terminus of AMG 557, a fully human 
IgG2 against B7RP-1 currently in clinical development for SLE.  In terms of anti-BAFF 
effect, AMG 570 has similar binding affinity and cellular potency to blisibimod.  AMG 570 
has 29 pM KD BAFF binding affinity and 0.86 nM IC50 in a BAFF cellular assay.  
Blisibimod was reported to have an IC50 of 0.2 nM.  For anti-B7RP-1 effect, AMG 570 
has similar binding affinity and inhibitory activity to AMG 557.  AMG 570 has 28 pM KD  
B7RP-1 binding affinity and 1.36 nM IC50 in a B7RP-1 cellular assay.  AMG 557 has 
17 pM KD  B7RP-1 binding affinity and AMG 557 parental antibody 16H has 1.35 nM  
IC50 in a B7RP-1 cellular assay.  AMG 570 binds and inhibits cynomolgus monkey  
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Product:  AMG 570 
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BAFF and B7RP-1, but not rodent B7RP-1.  A mouse surrogate BAFF/B7RP-1 bispecific 
molecule showed dual-target inhibition in vivo and was more efficacious than the single 
B7RP-1 or BAFF inhibitors in the mouse NZB/NZW lupus model.  We hypothesize that 
targeting both BAFF and B7RP-1 by AMG 570 will achieve a large effect size in the 
treatment of SLE.   
2.2.2 
Pharmacokinetics 
The pharmacokinetics (PK) of AMG 570 after a single IV or SC administration was 
characterized in male cynomolgus monkeys.  
PK profiles of AMG 570 and AMG 557 were similar in cynomolgus monkeys (Table 1). 
Table 1.  Comparison of AMG 570 and AMG 557 Mean ± SD Pharmacokinetic 
Parameters in Cynomolgus Monkey 
Molecule 
10 mg/kg SC  
10 mg/kg IV 
Cmax 
(µg/mL) 
AUC 
(µg•day/ 
mL) 
CL or CL/F 
(mL/day/kg) 
C0 
(µg/mL) 
AUC 
(µg•day/ 
mL) 
CL or CL/F 
(mL/day/ 
kg) 
AMG 570 
90.0 ± 8.54 
693 ± 102 
13.9 ± 2.63 
323 ± 30.6 
1140 ± 219 
9.03 ± 1.80 
AMG 557 
112 ± 9.50 
991.6 ± 144 
10.3 ± 1.5 
264 ± 23.3 
1087.5 a 
9.31a 
a n=2 
C0 = extrapolated initial concentration after IV administration; Cmax = Maximum observed drug concentration 
during a dosing interval; AUC= area under the concentration-time curve from zero to end of dosing interval; 
CL = clearance after IV administration; CL/F = apparent drug clearance after SC administration; 
F = Bioavailability of drug 
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Serum AMG 557 exposures in the FIH study (Cmax and AUC) increased more than dose 
proportionally at lower doses after either single or multiple SC doses.  However, an 
approximately dose-proportional increase in exposure was observed at higher doses 
(≥ 140 mg for SAD; ≥ 70 mg for MAD).  Maximum concentration of AMG 557 was 
reached in 3-7 days (tmax) after SC administration.  Bioavailability after SC dosing was 
estimated to be ~57%. 
2.2.3 
Toxicology 
2.3 
Risk Assessment 
This is the first single dose study proposed in human subjects with AMG 570. 
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The assessment of potential side effects of AMG 570 is based on the pre-clinical studies 
conducted to date (Section 2.2.3) and by observations of safety and tolerability of 
AMG 557 and blisibimod clinical studies.  Summaries of findings from the pre-clinical 
studies with AMG 570 can be found in the AMG 570 Investigator’s Brochure (IB).  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
  
 
 
  
The proposed risk assessment and management plan for the study has been developed 
in accordance with the requirements of regulatory guidelines and strategies to identify 
and mitigate risks for FIH clinical trials with investigational medicinal products.  
Please refer to the AMG 570 IB, Section 7 for a description of these potential side 
effects. 
 
 
 
 
2.4 
Rationale 
The interaction of ICOS on T cells with its sole ligand, B7RP-1 on antigen presenting 
cells, including B cells, plays a role in T cell effector functions including cytokine 
production, T cell differentiation, T cell-dependent help for B cell differentiation and 
immunoglobulin (Ig) isotype switching (Moore et al, 2011; Paulos et al, 2010; Dong and 
Nurieva, 2003; McAdam et al, 2001; Coyle et al, 2000).  ICOS is elevated on T cells in 
patients with SLE, RA and Sjögren’s syndrome (Ma et al, 2012; Simpson et al, 2010; 
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Hu et al, 2009; Hutloff et al, 2004).  B7RP-1 is expressed on B cells, dendritic cells 
(DCs), monocytes and macrophages, and to a lesser degree on T cells and 
non-lymphoid cells like endothelial cells, where it is up-regulated by inflammatory stimuli 
(Kroczek  et al, 2004; Groom et al, 2002; Khayyamian et al, 2002; Yoshinaga  et al, 
1999). 
BAFF is mainly expressed by monocytes, neutrophils and DCs (Chu et al, 2007; 
Rickert et al, 2011).  BAFF supports naïve and transitional B cell survival through binding 
to the BAFF receptor expressed on B cells (Mackay and Browing, 2002).  Increased 
levels of BAFF have been observed in patients with SLE, RA, and Sjögren’s syndrome 
(Mariette et al, 2003; Groom et al, 2002; Cheema et al, 2001, Zhang et al, 2001).  
Elevated levels of BAFF may cause excessive survival signals to autoreactive B cells, 
possibly as they pass through critical tolerance checkpoints while maturing in the spleen 
and lymphoid tissues.  Indeed, increased dependence on BAFF for autoantigen binding 
B cells was demonstrated in a monoclonal Ig-transgenic model (Lesley et al, 2004).  At 
target-saturating doses, belimumab has modest efficacy, validating the BAFF pathway 
yet also demonstrating a strong need for therapies with better efficacy.   
The combination of a T cell modulator, AMG 557 (Amgen’s anti-B7RP-1 mAb), and 
BAFF binding peptides as in the B7RP-1-BAFF bispecific, AMG 570, has the potential 
for better efficacy than belimumab.  
Dual BAFF and B7RP-1 inhibition is likely to be well-tolerated.  Separate inhibition of 
BAFF or B7RP-1 has moderate impact on the immune system.  BAFF inhibitors 
(belimumab and blisibimod) are well-tolerated in the clinic.  AMG 557 is in early clinical 
development and has an acceptable safety profile to date. 
For proof-of-concept, a mouse surrogate bispecific molecule was generated by fusion of 
two tandem copies of BAFF-binding peptides from AMG 523 to the C-terminus of 
anti-mouse B7RP-1 blocking antibody 1B7 (described by Hu et al, 2009).  AMG 523 has 
structure similar to blisibimod with two additional amino acids (Leu, Pro) at the 
N-terminus.  AMG 523 has binding specificity, affinity and cellular potency similar to 
blisibimod.  The surrogate bispecific inhibits mouse BAFF induced B cell proliferation 
with potency similar to the BAFF peptibody AMG 523.  The surrogate also inhibited 
mouse B7RP-1-Fc binding to ICOS on mouse T cells with potency similar to anti-mouse 
B7RP-1 antibody 1B7.  The surrogate bispecific PK property was evaluated in mouse.  
Male CD-1 mice were given single dose intravenous (IV) administration via lateral tail 
vein of surrogate bispecific (5mg/kg), anti-B7RP-1 mAb 1B7 (4.68mg/kg), or anti-BAFF 
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Product:  AMG 570 
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peptibody AMG 523 (1.88mg/kg).  Doses of the bispecific and single parental inhibitors 
were adjusted based on MW to be molar equivalents.  The surrogate bispecific has PK 
properties similar to 1B7 in mouse with no detectable clipping of the BAFF-binding 
peptides.   
To investigate the dual PD effects of the surrogate bispecific, we evaluated the surrogate 
bispecific effect on B cells, memory T cells and antibody responses in the sheep red 
blood cell (SRBC) challenge model.  BALB/c mice (n=5) were immunized with sheep red 
blood cell (SRBC) on day 0 and boosted on day 28.  Mice were treated with 
mIgG1 isotype control (5mpk), anti-mouse B7RP-1 antibody 1B7 (5mpk), anti-BAFF 
peptibody AMG 523 (5mpk), combination of 1B7 (5mpk) and AMG 523 (5mpk), or 
surrogate bispecific (1, 5 or 10 mpk) twice per week for 5 weeks starting on day 0.  
Spleen cells were collected on day 35 for FACS analysis and B cell numbers were 
measured as a PD marker to monitor BAFF inhibition.  AMG 523 treatment led to more 
than 50% reduction of splenic B cells, whereas no significant B cell reduction was 
observed with anti-B7RP-1 mAb 1B7 treatment or isotype control.  To monitor the 
B7RP-1 inhibitory PD effect, memory T cells (CD4+CD44hiCD62Lo) in spleen were 
measured by FACS analysis.  Splenic memory T cells were significantly reduced in the 
1B7 treated group, but not in the AMG 523 treatment or isotype treatment groups.  
Unlike single agent treatment, surrogate bispecific treatment resulted in reduction of both 
B cells and memory T cells, suggesting dual BAFF and B7RP-1 inhibition.  The dual PD 
effect of the surrogate bispecific was comparable to the combination of anti-BAFF and 
anti-B7RP-1 treatment group.  In addition, and importantly for a bispecific approach, the 
effective doses for B cell vs. memory T cell reduction were in a similar range. 
The surrogate bispecific was compared with single agent treatment in the NZB/NZW 
lupus model, a mouse model of spontaneous disease, in both prophylactic and 
therapeutic mode.  Surrogate bispecific treatment resulted in B cell reduction similar to 
that observed with combination or AMG 523 treatment and B7RP-1 occupancy similar to 
combination or 1B7 treatment groups.  Altogether, prophylactic treatment with surrogate 
bispecific was comparable to combination therapy and more efficacious than single 
agents in the NZB/NZW lupus model. 
The surrogate bispecific was also compared with single agents in NZB/NZW mice with 
delayed initiation of treatment starting at 7.5 months of age when mice had developed 
anti-dsDNA IgG.  Similarly, surrogate bispecific treatment had a modest yet significant 
effect in improving survival, with p=0.0029 compared with isotype control (Kaplan Meier 
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Product:  AMG 570 
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Plot).  Combination treatment also had modest yet significant effect in improving 
survival, with p=0.0239 vs isotype control.  No significant difference between other 
groups was observed.  
2.4.1 
AMG 570, AMG 557 and Blisibimod Molecular Structure Information 
The bispecific AMG 570 antibody has a peptide-linker-peptide-linker construct fused to 
the C-terminus of each heavy chain of AMG 557.  AMG 557 is a human IgG2.  
Blisibimod has a peptide-linker-peptide-linker construct fused to the N-terminus of each 
chain of a human Fc.  The peptides in AMG 570 are BAFF-binding peptides identical to 
those in blisibimod.  Molecular weights of AMG 570, AMG 557 and blisibimod are 
approximately 161, 148, and 64 kDa, respectively. 
2.4.2 
AMG 557 Clinical Background 
Single dose administration of AMG 557 to subjects with mild, stable SLE with 
subcutaneous (SC) doses of 1.8, 6, 18, 60, 140, and IV dosing of 210 mg and 18 mg 
demonstrated an acceptable safety profile with no observed neutralizing antibodies 
(study 20060132).  AMG 557 demonstrated nonlinear pharmacokinetic properties, as 
expected for a therapeutic targeting a cell surface receptor.  The degree of target 
occupancy was dose/concentration-related, reversible, and achieving maximal levels in 
the 140 mg SC group.  Consistent pharmacodynamic effects on immunophenotype or 
KLH responses were not observed following single doses of AMG 557.   
The estimated mean AMG 557 target occupancy IC50 was 0.0888 μg/mL (0.60 nM), IC90 
of 0.8 μg/mL (5.4 nM), and IC99 of 8.8 μg/mL (59.5 nM). 
2.4.3 
Blisibimod Clinical Background 
Subjects with mild to moderate SLE were treated with blisibimod single SC doses of 0.1, 
0.3, 1.0, or 3.0 mg/kg or IV doses of 1.0, 3.0, or 6.0 mg/kg in a first-in-human study 
(study 20040147) and multiple dose 0.3, 1.0, 3.0 (SC) or 6.0 (IV) mg/kg in phase1b 
(study 20040250).  Blisibimod treatment led to a significant decrease in naïve B cells 
(IgD+CD27-) and an increase in class-switched memory B cells (IgD-CD27+) (Stohl et al, 
2015).  This significant reduction in naïve B-cells was observed when blisibimod 
concentration was 3 μg/mL (47 nM) or higher.  No consistent effects on T cells, NK cells, 
plasmablasts, or plasma cells were evident.  The Phase 2 study of blisibimod in subjects 
with moderate-to-severe SLE (Furie, 2014) demonstrated significantly higher SLE 
Responder Index (SRI-5) responses in subjects randomized to the highest dose of 
blisibimod 200 mg once-weekly (QW at Week 20 (p=0.02)).  
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2.4.4 
AMG 570 Clinical Background 
AMG 570 is currently being evaluated in this ongoing FIH study in healthy subjects. As 
of 1 January 2018, 48 subjects have received a single SC dose of AMG 570 or placebo 
at the following doses: 7, 21, 70, 140, 210, or 420 mg.  All dose levels have 
demonstrated acceptable safety and tolerability with no severe, life-threatening, or fatal 
events reported.  A multiple ascending dose study in patients with rheumatoid arthritis 
(study 20150196) has also been initiated with 9 subjects receiving 6 doses of AMG 570 
at 70 mg SC q 2 weeks.  Subjects at this dose level have demonstrated acceptable 
safety and tolerability with no severe, life-threatening, or fatal events reported.  
Preliminary safety, pharmacokinetics, and pharmacodynamics results from the cohorts 
receiving 7-140 mg of study 20140322, are described in Sections 6.1 and 6.2. of the 
Investigator’s Brochure.   
2.4.5 
Rationale for Dose Selection 
The proposed doses for AMG 570 first-in-human (FIH) clinical study were selected 
based on predicted human exposures utilizing clinical PK and pharmacodynamics (PD) 
human data from AMG 557,as well as PK, pharmacology, and toxicology data from 
AMG 570, and data from blisibimod clinical studies. 
The exposure margins were computed from serum AMG 570 exposures at the NOAEL 
of 200 mg/kg in cynomolgus monkeys determined in a 3 month Good Laboratory 
Practice (GLP) toxicology study, and from the projected human PK exposures for the 
proposed doses.  AMG 570 and AMG 557 PK in cynomologus monkeys were 
comparable based on PK studies for AMG 570 and AMG 557, as shown in Table 1.  The 
projected AMG 570 human PK simulations were initially conducted using mean PK/PD 
parameters derived from modeling AMG 557 phase-1 data in SLE patients. The PK 
predictions have since been updated based on emerging data from this study (Table 2). 
Given the safety and tolerability of AMG 557 and blisibimod, the established PK/PD 
relationships, and the NOAEL of 200 mg/kg, the first dose level of this study will be 
7 mg SC, derived from the US FDA guidance on the maximum recommended starting 
dose (MRSD)(CDER, 2005).  This dose is expected to demonstrate intermediate 
B7RP-1 occupancy in peripheral blood based on simulated relationship between 
predicted AMG 570 exposure and effective concentration but no reduction in naïve B 
cells or any other biologic effect based on predicted AMG 570 serum level and 
blisibimod PD data.  Subsequent dose levels are 21, 70, 140, 210, 420, and 700 mg SC.  
Planned clinical dose levels are also supported by adequate margin based on NOAEL 
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from the 3-month AMG 570 GLP toxicology study in the cynomolgus monkey (Table 2).  
Observed and/or predicted exposure margins are shown in Table 2 below. 
Table 2.  Observed or Predicted AMG 570 Pharmacokinetic Parameters and 
Exposure Margins 
Using the US FDA MRSD guidance for starting doses in healthy volunteers, a safety 
factor of 10, and a NOAEL of 200 mg/kg (2400 mg/m2), the human equivalent dose 
would be 4500 mg (2400 mg/m2 = 65 mg/kg for a 70 kg individual) and MRSD of 
AMG 570 would be 450 mg or 65-times the proposed starting dose of 7 mg.  
 
 
 
 (Table 2).   
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As outlined in Section 6.1 of the Investigator’s Brochure, preliminary assessment of data 
from this study indicates dose-related and reversible receptor occupancy of B7RP-1 
(now referred to as ICOSL in the Investigator’s Brochure).  Preliminary assessment on 
total circulating B cells indicates a significant reduction in B cell relative to baseline at 
day 57 in cohorts 2 (21 mg) and 3 (70 mg) compared to the accumulated placebo.  
Preliminary assessment of IgM and IgG levels indicate that relative to baseline, 
AMG 570 has demonstrated no dose-related changes compared to the accumulated 
placebo group. 
Based on the 3-month GLP toxicology study in cynomolgus monkeys and interim 
pharmacokinetics data from this ongoing FIH study, it is anticipated that a 700 mg SC 
dose of AMG 570 in humans would not exceed the exposure associated with the 
AMG 570 NOAEL in cynomolgus monkeys.  At this highest planned SC dose, the 
exposure margins are 44- and 10-fold below the Cmax and AUC at the NOAEL in 
monkeys.  Based on interim pharmacokinetics and pharmacodynamics data from this 
ongoing study, it is also anticipated that a 700 mg SC dose of AMG 570 is expected to 
result in 90% or more B7RP-1 RO at day 8 and B cell depletion of up to 40% compared 
to baseline by day 57.  Significant changes to circulating IgG and IgM levels are not 
anticipated based on interim data. 
In summary, the dose range of 7 mg to 700 mg SC is projected to result in human 
exposures less than the exposures tested in the cynomolgus monkey 3-month GLP 
toxicology study.  This dose range is expected to be well tolerated and to result in 
pharmacological activity useful for dose selection in subsequent clinical trials. 
2.4.6 
Rationale for Key Aspects of Study Design 
Healthy volunteers are to be enrolled in this single ascending dose (SAD) study.  The 
understanding of both targets of AMG 570, B7RP-1 and BAFF, and previous experience 
with AMG 557 and blisibimod with their acceptable safety and tolerability profiles justifies 
testing in healthy volunteers.  Further, a single dose of AMG 570 is not expected to 
provide great benefit in subjects with autoimmune disease.   
The single ascending dose design requires thorough evaluation of the safety profile for 
dose escalation.  Subjects will be carefully monitored for adverse events and safety 
laboratory results, including peripheral blood B cell numbers and serum IgG.  Testing in 
this population will provide initial information on the PK of AMG 570, which is expected 
to be similar to AMG 557.   
Approved 
 
 

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Biomarkers include B7RP-1 target occupancy on peripheral blood B cells and 
.  The percentage and absolute counts of 
total lymphocytes, monocytes, granulocytes and lymphocyte populations including 
CD3+ T cells, CD16/56+ NK cells and naïve and memory CD19+ B cells 
(naïve = IgD+CD27-; memory = IgD-CD27+)  will be determined.  The levels of serum IgG 
and IgM immunoglobulins and 
 will also be measured. 
2.5 
Clinical Hypotheses 
A single SC dose administration of AMG 570 will achieve acceptable safety and 
tolerability profiles in healthy subjects within the proposed dose ranges (7 to 700 mg SC 
AMG 570). 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a randomized, placebo-controlled, double-blind, SAD study in healthy subjects. 
The study consists of 7 SC cohorts.  Subjects will be randomized in a 3:1 ratio to receive 
AMG 570 or placebo according to Table 3.  The overall study design is described by a 
study schema at the end of the protocol synopsis section.  The study endpoints are 
defined in Section 10.1.1. 
3.2 
Number of Sites 
Three sites in the US will be utilized in this study.  Additional sites may be added at the 
discretion of the medical monitor.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  Approximately 
56 healthy subjects will be enrolled into 7 cohorts (6 active: 2 placebo in each cohort). 
See Section 10.2 for the sample size rationale. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study prior to receiving 
AMG 570 will be replaced at the discretion of the Amgen Medical Monitor and Principal 
Investigator by notifying the unblinded study pharmacist or designee.  The new subject 
will receive the identical treatment as the replaced subject, but will be assigned a 
replacement number associated with this new record.  The unblinded study pharmacist 
or designee will retain the randomization list. 
Approved 
 
 

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3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The planned length of participation in the study will be approximately 5 months (13 visits) 
which includes up to 6 weeks for screening, 1 day for drug dosing, 15 weeks for 
evaluation of drug distribution, followed by end of study (EOS) visit. 
Subject’s participation in the study will conclude at the completion of the end of study 
procedures.  Once complete, this will conclude the subject’s participation in the study. 
However, if an end of study test result demonstrates a significant clinical or laboratory 
abnormality, the subject will be followed until resolution of the abnormality or until it is 
considered clinically stable by the Principal Investigator.  If a subject’s CD3-CD19+ B cell 
counts are < 107 cells/µL (the lower limit of normal for healthy volunteers 
(Becton, Dickinson , 2015)), the subject will return for further testing of B cell counts 
every 3 months until the subject has B cell counts ≥ 107 cells/µL.  Follow-up visits for 
B cell counts will continue every 3 months, for up to 12 months after the end of study.   
Subject participation may be adjusted based on treatment-emergent data.  All 
adjustments or modifications to the schedule outline above will be agreed upon by the 
Investigator in consultation with the Sponsor.  The Institutional Review Board (IRB) will 
be informed via written correspondence. 
3.5.2 
End of Study 
Primary Completion:  the time when the last subject has completed the EOS visit as 
outlined in the Schedule of Assessments (Table 8). 
End of Trial:  the time when the last subject has completed either the EOS visit or the 
last safety follow-up visit.  See Section 3.5.1 for details.  
As noted previously, the EOS for each cohort may be prolonged pending 
treatment- emergent data. 
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). 
Approved 
 
 

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4.1 
Inclusion Criteria 
A subject that has provided written informed consent may be eligible for inclusion in this 
study only if the following criteria are met:  
101 
Male and female subjects ≥ 18 to ≤ 65 years of age, at the time of signing the 
informed consent  
102 
Healthy as determined by the investigator or medically qualified designee based 
on a medical evaluation including medical history, physical examination, 
neurological examination, laboratory tests and cardiac assessment 
103 
Body weight ≥ 50 kg and a body mass index (BMI) within the range of 
18-30 kg/m2 (inclusive) 
104 
Normal or clinically acceptable ECG (12-lead reporting ventricular rate and PR, 
QRS, QT, QTc) at screening  and prior to dosing (QTc < 450 msec based on 
3 measures taken approximately 60  seconds apart ) as deemed acceptable by 
the site investigator 
105 
Female subjects must be of documented non-reproductive potential (ie, 
postmenopausal [see definition below]; OR history of hysterectomy; OR history of 
bilateral salpingectomy; OR history of bilateral oophorectomy) 
• 
Female subjects will be considered postmenopausal if no vaginal 
bleeding or spotting for at least 12 months and:  
• 
If less than 55 years of age, follicle stimulating hormone (FSH) and 
estradiol must be within the laboratory’s reference range for 
postmenopausal females.  (FSH >40MIU/ml and estradiol < 40pg/ml 
(<147 pmol/L)) 
• 
If 55 to 59 years of age and there is uncertainty regarding menopausal 
status, FSH must be within the laboratory’s reference range for 
postmenopausal females  
• 
 If 60 years of age or older, evaluation of FSH is not needed to confirm 
postmenopausal status  
106 
Male subjects must agree to practice a highly effective method of birth control for 
the duration of the study and continuing for 20 weeks after the last dose of study 
drug.  Highly effective methods of birth control include sexual abstinence, 
vasectomy, a partner who is of non-childbearing potential (surgically sterile or 
postmenopausal), or a condom with spermicide (men) in combination with the 
following methods used by the female partner: hormonal birth control or 
intrauterine device or use of a barrier method. 
107 
Male subjects must agree to not donate sperm for the duration of the study and 
continuing for 20 weeks after the last dose of study drug  
108 
Subjects must be current for all vaccinations recommended by the CDC within a 
year of and at least 30 days prior to enrollment.  Seasonal influenza vaccine 
need only be administered during influenza season (October through May). 
109 
Capable of giving signed informed consent which includes compliance with the 
requirement and restriction listed in the consent form and in the protocol 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 29 of 79 
CONFIDENTIAL 
 
 
4.2 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
201 
Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert’s syndrome or asymptomatic 
gallstones) 
202 
History of active infections (viral, bacterial, or fungal) within 21 days of receiving 
the study medication.  
203 
History or diagnosis of obstructive sleep apnea  
204 
History of significant respiratory disorder 
205 
History or current evidence of febrile seizures, epilepsy, convulsions or significant 
head injury 
206 
Positive serology for HIV antibodies, Hepatitis B surface Antigen (HepBsAg), 
Hepatitis B core antibody(HBcAb) or Hepatitis C Antibodies (HepCAb) (confirmed 
by Polymerase Chain Reaction (PCR) or RIBA) at screening 
207 
Where participation in the study would result in donation of blood or blood 
products in excess of 500mL within a 56-day period 
208 
History of regular alcohol consumption exceeding 7 units weekly for female 
subjects and 14 units weekly for male subjects within 6 months of screening.  
This is equivalent to a half-pint (240 mL) of beer, 1 glass (125 mL) of wine, or a 
(25 mL) measure of spirits daily for women and one pint (480 mL) of beer, 
2 glasses (250 mL) of wine, or 2 measures (50 mL) of spirits daily for men.  
209 
History of tobacco or nicotine-containing product use within 6 months of 
screening. 
210 
The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigation product (whichever is longer) 
211 
History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that in the opinion of the investigator or medical 
monitor (if appropriate), contraindicates their participation 
212 
Subject received a vaccine (either live attenuated or non-live) within 30 days of 
randomization or plan to receive live attenuated vaccine within 30 days and 
5 half-lives of the last dose of study medication 
213 
Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day 
214 
Evidence of renal disease, defined as: 
Calculated glomerular filtration rate < 80 mL/min using the Cockcroft-Gault 
equation: 
[(140-age) x Body Weight (kg)]*  
72 x  serum creatinine (mg/dL) 
*(For female subjects multiply by 0.85) 
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215 
Evidence of liver disease (eg, serum ALT or AST > 2x upper limit of normal) 
216 
Total WBC < 4 x 109/L or Platelet count < 140  x 109/L 
217 
Circulating IgG or IgM levels < LLN at screening 
218 
CD3-CD19+ B cell counts < 107 cells/µL at screening 
219 
Underlying condition that predisposes the subject to infections (eg, uncontrolled 
diabetes - HbA1c ≥ 7%, history of splenectomy) 
220 
Known sensitivity to mammalian derived products 
221 
Positive serum βhCG at screening or positive serum βhCG or urine hCG prior to 
dosing 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board (IRB) approval of the 
protocol, informed consent form (ICF), and all other subject information and/or 
recruitment material, if applicable (Section 11.2).  All subjects must personally sign and 
date the ICF before commencement of study-specific procedures.  A subject is 
considered enrolled when the investigator decides that the subject has met all eligibility 
criteria.  
The Investigator is to document the enrollment decision and date, in the subject’s 
medical record and in/on the enrollment eCRF. 
Each subject who enters into the screening period for the study, which is the first time 
that a subject undergoes detailed assessments to determine their potential for eligibility 
into the study, receives a unique subject identification number before any study 
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.  A screen failed subject may be 
rescreened up to two times at the discretion of the PI with the agreement of the Amgen 
Medical Monitor. 
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.  The identification number will be 11 digits: the first 3 are the protocol 
identifier (322), the next 5 digits represent the site number which consists of the 2-digit 
country code (66) and 3-digit study-specific site number (001), and the last 3 digits are 
assigned in sequential order as subjects are screened (eg, 001, 002, 003, etc.).  Thus, 
the first subject screened at site 66002 would be 32266002001, and the second subject 
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would be 32266002002, and so forth.  This number will not be the same as the 
randomization number assigned for the study.  
5.1 
Randomization/Treatment Assignment 
Randomization to AMG 570 or placebo will be based on a randomization schedule 
prepared by Amgen before the start of the study and retained by the unblinded study 
pharmacist or designee.  On Day 1, once eligibility for study participation has been 
confirmed (based on data collected during screening visits and on Day -1), eligible 
subjects will be randomized to receive either AMG 570 or placebo.  The randomization 
date is to be documented in the subject’s medical record and on the enrollment eCRF. 
Unique randomization numbers will be assigned in sequential order according to when 
each subject met the eligibility criteria.  At no time will the same randomization number 
be assigned to more than one subject. 
In the event a subject is randomized, but withdraws before receiving study medication, 
or during the study for reasons other than adverse events (Section 9.1), a replacement  
subject may be enrolled at the discretion of the Amgen Medical Monitor and Principal 
Investigator.  The unblinded study pharmacist or designee will be notified.  The new 
subject will receive the identical treatment as the replaced subject but will be assigned a 
replacement number per the randomization list. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study or may 
potentially impact the safety of subjects currently enrolled or subjects in subsequent 
cohorts.  Unblinding at the study site for any other reason will be considered a protocol 
deviation.  The investigator is strongly encouraged to contact the Amgen Clinical Study 
Manager before unblinding any subject’s treatment assignment, but must do so within 
1 working day after the event.   
Treatment assignments will be unblinded after the initial database lock at the end of the 
trial.  After initial database lock and receipt of written authorization from Amgen to 
unblind, the unblinded pharmacist will release the specified unblinded pharmacy records 
to site staff designated to enter the subject treatment into each subject’s Investigational 
Product Administration Electronic Case Report Form (eCRF).  
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6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) 
The Amgen Investigational Product and/or placebo used in this study include: 
AMG 570 and placebo.  The Investigational Product Instruction Manual (IPIM), a 
document external to this protocol, contains detailed information regarding the storage, 
preparation, destruction, and administration of AMG 570 and placebo. 
6.2 
Investigational Product 
All investigational products will be administered at the research facility by a qualified staff 
member.  A physician must be present at the time of investigational product 
administration.  
6.2.1 
Amgen Investigational Product AMG 570 
AMG 570 will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.  AMG 570, which is a clear colorless 
sterile solution, will be packaged in open label 5mL glass vials containing 70 mg/ml of 
AMG 570 formulated with 10mM acetate, 9.0%(w/v) sucrose, 0.01%(w/v) polysorbate 80 
at pH 5.2.  Placebo will be presented in identical containers and stored/packaged the 
same as AMG 570, but will not contain AMG 570 protein.  Diluent for lower doses will 
also be supplied as a clear colorless sterile solution in 10mL glass vials.  All AMG 570, 
placebo and diluent supplies will be shipped to the study site and should be stored at 
2°C to 8°C with limited exposure to light. 
For more information regarding investigational product handling and preparation please 
see the study specific IPIM which is provided as a separate document.  
6.2.1.1 
Dosage, Administration, and Schedule 
All study drug will be administered (Table 3) at the research facility by a qualified staff 
member.  A physician must be available during each administration of investigational 
product.  The date, time, lot number and volume of investigational product administered 
will be recorded on the individual subject’s electronic case report form (eCRF).  Subject 
will be randomized only once to one of 7 Cohorts starting with Cohort 1 and continuing in 
a sequential manner to Cohort 7.  Within each cohort, subjects will be randomized to 
receive a single SC of AMG 570 or placebo in a ratio of 3:1.  Once a dose is selected for 
a cohort, no dose adjustments will be made for an individual subject within the cohort.  
Each subject will only receive one dose of the investigation product. 
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A sentinel dosing strategy will be used.  The first 2 subjects in each cohort will be 
randomized such that 1 subject receives AMG 570 and 1 subject receives placebo.  This 
sentinel pair will be dosed first and will be observed for at least 24 hours before study 
drug is administered to the remainder of the cohort.  An informal safety review will be 
held after the sentinel subjects of each cohort are dosed and prior to dosing the 
subsequent 6 subjects.  The decision to continue with the cohort as planned will be 
based on available data for vital signs and adverse events occurring in the prior 
24 hours, and will be reviewed by the PI, medical monitor, and GSO or designee. 
Table 3.  Dose Levels 
Cohort # 
Planned Dose (mg) 
Route 
N(active:placebo) 
1 
7 
SC 
8 (6:2) 
2 
21 
SC 
8 (6:2) 
3 
70 
SC 
8 (6:2) 
4 
140 
SC 
8 (6:2) 
5 
210 
SC 
8 (6:2) 
6 
420 
SC 
8 (6:2) 
7 
700 
SC 
8 (6:2) 
6.2.1.2 
Dose Level Review Meeting (DLRM) Membership 
The DLRM members will be composed of the investigator(s), Amgen Medical Monitor, 
Amgen Global Safety Officer (GSO) or designee, Early Development Leader or 
designee, Clinical Study Manager or designee, and Biostatistics representative or 
designee.  Additional members may be added as needed (eg, PK Scientist).  The DLRM 
voting members will include the investigator(s), Amgen Medical Monitor and Amgen 
GSO or designee. 
6.2.1.3 
Dose-Cohort Study Escalation and Stopping Rules 
Dose-Cohort Study Escalation 
The decision to dose escalate will be based on the review of safety data during the dose 
level review meeting.  Within each cohort, the safety data will be assessed after all 
8 subjects have been enrolled and at least 6 subjects have completed the day 57 visit.  
Emerging PK and PD data will be reviewed in a blinded fashion at the DLRM as these 
data become available.  Peripheral blood B cell number and serum IgG levels through 
day 57 post-dose for individual cohorts will be incorporated into each DLRM 
assessment. 
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The DLRM voting members will be responsible for dosing decisions, which may include:  
1) escalation to the next planned dose 
2) escalation to an intermediate dose (a dose lower than the next planned dose) 
3) de-escalation to a lower dose 
4) continuation, delay, or termination of dosing  
5) repetition or expansion of a cohort. 
Dose adjustments (if any) will be made on a treatment cohort basis and not on an 
individual basis, and will be agreed upon by Amgen after reviewing emerging safety, PK, 
and/or PD data. 
Dose Stopping and Review 
Further dosing of AMG 570 will be either stopped or modified to a lower dose if 
suspected adverse drug reactions and/or changes in safety data (including but not 
limited to vital signs, ECGs, clinical laboratory results, or laboratory parameters reflecting 
humoral immune status) are observed and these changes pose a health risk.  A DLRM 
is held when a dose limiting toxicity (DLT) has occurred.  A DLT is defined as any 
treatment-related fatal, life threatening or disabling serious adverse event (SAE).  In 
addition, any adverse event or change in vital signs, clinical laboratory test value, or 
ECG which is considered drug related, and poses a significant health risk, as determined 
by the Investigators and Sponsor, would also constitute a DLT and form the basis for 
stopping dose escalation in the study.  If a decision is made not to proceed following 
dosing of sentinel subjects, a Dose Level Review Meeting (DLRM) will be held.  In 
addition, dosing will be stopped or modified if any of the scenarios shown in Table 4 are 
met. 
Dose Cohort Stopping Rules 
This section addresses how subject safety will be monitored through adherence to rules 
for stopping dosing within a dose cohort (which precludes any further dose escalation). 
Table 4 describes the dose stopping rules to be used for stopping dosing within a cohort. 
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Table 4.  Dose Cohort Stopping Rules 
Scenario 
Action 
Any occurrence of a CTCAE Grade 2 adverse 
event of the same system class (eg, 
hepatobiliary, cardiovascular) observed in 2 or 
more subjects in the same cohort 
Stop dosing additional subjects in the cohort 
and convene DLRM.  
Review AE and all relevant safety data for 
evidence of relationship to treatment and 
clinical significance.  Consider unblinding to 
determine relatedness to investigational 
product.*  
Upon unanimous decision of the review team, 
one of the following decisions may be made:  
• 
Enrollment of the cohort may resume, 
• 
The cohort may be expanded at the same 
dose, 
• 
A lower dose cohort may be added to the 
study,  
• 
Escalation to the next planned dose may 
occur,  
• 
Escalation to an intermediate dose (a 
dose lower than the next planned dose) 
may take place. 
Any occurrence of a CTCAE Grade 3 or 
greater adverse event in a dose cohort 
Stop dosing additional subjects in the cohort 
and convene DLRM.  
Review AE and all relevant safety data for 
evidence of relationship to treatment and 
clinical significance.  Consider unblinding to 
determine relatedness to investigational 
product.*  
If Grade 3 adverse event is determined to be 
related to study drug, and clinically significant 
by the DLRM, no further dose escalation to 
proceed.  
Otherwise, upon unanimous decision of the 
review team, one of the following decisions 
may be made:  
• 
Enrollment of the cohort may resume, 
• 
The cohort may be expanded at the same 
dose,   
• 
A lower dose cohort may be added to the 
study. 
* A subject’s treatment assignment should only be unblinded when knowledge of the treatment is essential 
for the further management of the subject, or may impact the safety of subjects currently enrolled, or 
subjects in subsequent cohorts 
Vital Signs Stopping Rules 
If 2 subjects within the same cohort develop persistent out of range vital sign 
assessments (3 repeated measurements) as specified in Table 5 below in the first 
3 days following dose administration, additional subjects within the cohort (if applicable) 
will not be dosed and a DLRM will be convened. 
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Table 5.  Dose Stopping Values for Vital Signs 
Vital Sign Assessments 
Temperature > 38.5° C 
Heart rate < 42 or > 120 bpm 
Blood Pressure (supine, sustained): 
• 
Systolic < 80 or > 160 mm Hg; 
• 
Diastolic > 105 mm Hg 
ECG Stopping Rules 
Should a subject in a dose cohort present with an ECG result (in triplicate readings) 
greater than the values provided in Table 6 below after dosing, the ECG will be repeated 
in triplicate and the etiology of the ECG abnormality will be evaluated.  If the increased 
interval is thought to be drug-related, the patient should be monitored closely until the 
abnormality resolves.  If 2 subjects within the same cohort develop treatment-related 
ECG abnormalities as specified in Table 6 below, additional subjects within the cohort (if 
applicable) will not be dosed and a DLRM will be convened. 
Table 6.  Dose Stopping Values for ECG  
ECG assessments 
PR interval > 220 msec 
QRS interval > 125 msec 
QTc > 500 msec 
Clinical Laboratory Value Stopping Rules 
Should a subject in a dose cohort have a laboratory value or assessment that meets the 
criteria in Table 7 below, the laboratory assessment(s) will be repeated within 5 days.  If 
the out-of-range laboratory assessment result persists after the repeated assessment(s) 
in 2 or more subjects, additional subjects within the cohort (if applicable) will not be 
dosed and a DLRM will be convened.  
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Table 7.  Dose Stopping Values for Clinical Laboratory Results 
Chemistry Laboratory Findings 
Sodium  
   < 130 or > 150 mmol/L 
Potassium  
   < 3.1 or > 5.4 mmol/L 
Glucose 
   < 50 or fasting > 125 mg/dL 
Creatinine 
   > 50% increase above subject’s baseline 
Calcium 
   < 8.0 or >12 mg/dL 
CPK 
                > 5 x ULN without known alternative etiology 
Magnesium          < 1.0 mg/dL 
AST 
 
   > 2.5 x ULN 
ALT 
 
   > 2.5 x ULN 
Bilirubin  
   > 2 x ULN 
Hematology Laboratory Findings 
Hemoglobin          < 10 gm/dL 
WBC                     < 2000 or >15,000/mm3 
Platelets                < 100,000/mm3 
Neutrophils            < 1,000/mm3 
Lymphocytes         < 500/mm3 
Humoral Immune Status Stopping Rules 
Humoral immune status will be monitored by peripheral blood B cell counts and total 
serum IgG.  Values of these parameters will affect dosing of AMG 570 by the following 
two conditions: 
1) If any subject exhibits a peripheral blood B cell count < 107 cells/µl accompanied 
by a serum IgG level < 639 mg/dl (Agarwal, 2007) at any time during the study, 
further dose escalation will be postponed until B cell counts and IgG levels 
recover without development of infectious complications in these subjects.   
2) If any subject in a dose cohort has a peripheral blood B cell count < 107 cells/µl 
and a serum IgG level < 639 mg/dl at day 57 post-dose (Agarwal, 2007), patients 
rather than healthy subjects will be enrolled in subsequent cohorts. 
Infections will be monitored and classified per CTCAE guidelines with stopping rules 
delineated in Table 4. 
6.2.1.4 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
This protocol allows for some alterations from the currently outlined dosing schedule, but 
the maximum dose will not exceed 700 mg. 
The actual dose to be administered may be adjusted by the DLRM voting members 
based on safety, tolerability, and preliminary PK data of previous dose levels.  Dose 
adjustments may involve either an increase or a decrease in the planned dose, but will 
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not exceed pharmacokinetic criteria defined in the Rationale for Dose Selection 
(Section 2.4.5). 
If consistent adverse events of moderate or severe intensity occur in the group, or if 
unacceptable pharmacological effects, reasonably attributable in the opinion of the 
investigator to dosing with AMG 570, are observed in more than 2 subjects in a group, 
the dose escalation will be temporarily halted and no additional subjects will be dosed 
until a full safety review by DLRM of the study has taken place.  Relevant data will be 
reviewed and discussed with the investigator, appropriate Amgen personnel, and IRB 
prior to resumption of dosing. 
Clinically or medically significant suspected adverse drug reactions, and serious adverse 
events considered to be related to study procedures will be followed until resolved or 
considered stable.  The study may be terminated at any point in time at the discretion of 
the sponsor.  
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
6.3.1 
Criteria for Permanent Withholding of AMG 570 due to Potential 
Hepatotoxicity 
Following the single-dose administration of study drug, subjects 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) 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 
elevated TBL values include, but are not limited to: 
o Hepatobiliary tract disease 
o Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, 
and parvovirus) 
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o Right sided heart failure, hypotension, or any cause of hypoxia to 
the liver causing ischemia 
o Exposure to hepatotoxic agents/drugs or hepatotoxins including 
herbal and dietary supplements, plants, and mushrooms 
o Heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir) 
o Alpha-one antitrypsin deficiency 
o Alcoholic hepatitis 
o Autoimmune hepatitis 
o Wilson’s disease and hemochromatosis 
o Nonalcoholic fatty liver disease including steatohepatitis 
o Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
6.4 
Concomitant Therapy 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care. 
Concomitant therapies are to be collected from informed consent through the EOS.  
Acetaminophen (up to 2 g per day) for analgesia will be allowed.  Other concomitant 
medication may be allowed on a case by case basis by the investigator in consultation 
with the Amgen Medical Monitor if required.  Details (name, indication, dose, frequency, 
and dates) of all concomitant medications will be recorded in the subject’s source 
documents and on the eCRF. 
Concomitant medications will not be collected after the EOS visit for subjects returning 
for additional IPRO monitoring.  
6.5 
Alcohol, Tobacco Restrictions and Exercise Restriction 
• 
Prior to admission to the clinic of each clinic visit, subject will abstain from alcohol 
consumption for 24 hours. 
• 
Use of tobacco, nicotine or nicotine-containing product is not allowed from 
6-months prior to screening until after the final follow-up visit.  
• 
Subjects are required to refrain from strenuous exercise 48 hours prior to each 
blood collection for clinical laboratory testing.  Subjects may participate in light 
recreational activities during the study. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
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Table 8.  AMG 570 Schedule of Assessments 
Activity 
Screen 
Treatment and Evaluation  (each dosing session) 
EOS1 
Month 
 
 
~1m 
 
 
~2m 
3.5m 
Study Day 
Screening8 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
62 
Day 
8 
Day 
112 
Day 
15 
Day 
222 
Day 29 
Day 
43 
Day 
57 
Day 
71 
Day 105 
Window 
-42 to  
-1 
 
 
 
10m 
(+/-) 
15m 
(+/-) 
30m 
(+/-) 
30m 
(+/-) 
60m 
(+/-) 
6h 
(+/-) 
1d 
(+/-) 
1d 
(+/-) 
1d 
(+/-) 
1d 
(+/-) 
2d 
(+/-) 
2d 
(+/-) 
4d 
(+/-) 
4d 
(+/-) 
4d 
(+/-) 
4d 
(+/-) 
Relative to Dosing(h) 
 
 
Pre 
0 
0.5 
6 
12 
24 
48 
72 
120 
168 
240 
336 
504 
672 
1008 
1344 
1680 
2496 
General Assessment  
ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Med/Drug/Alcohol 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI (Ht & Wt) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Safety Assessments  
Physical Exam 2 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
ECG3 
X 
X 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
AEs & Con. Meds 
 
 
 
SAE 
 
 
Lab Assessments  
Drug/ Alcohol/Cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HepC, HepB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem/Chem/Urinalysis4 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
FSH/Estradiol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing    
Treatment Assignment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 570 or Placebo 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on the last page of this table. 
 
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Table 8.  AMG 570 Schedule of Assessments 
Activity 
Screen 
Treatment and Evaluation  (each dosing session) 
EOS1 
Month 
 
 
~1m 
 
 
~2m 
3.5m 
 Study Day 
Screening 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
6 
Day 
8 
Day 
11 
Day 
15 
Day 
22 
Day 29 
Day 
43 
Day 
57 
Day 
71 
Day 105 
Window 
-42 to  
-1 
  
 
 
10m 
(+/-) 
15m 
(+/-) 
30m 
(+/-) 
30m 
(+/-) 
60m 
(+/-) 
6h 
(+/-) 
1d 
(+/-) 
1d 
(+/-) 
1d 
(+/-) 
1d 
(+/-) 
2d 
(+/-) 
2d 
(+/-) 
4d 
(+/-) 
4d 
(+/-) 
4d 
(+/-) 
4d 
(+/-) 
Relative to Dosing(h) 
 
 
Pre 
0 
0.5 
6 
12 
24 
48 
72 
120 
168 
240 
336 
504 
672 
1008 
1344 
1680 
2496 
PK Assessments of AMG 570 
Cohort 1 to 6 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker & Immunological Assessments 
Immunophenotyping and 
Receptor Occupancy (IP & 
RO) assays5 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
ADA 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
IgG and IgM serum 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Exploratory Biomarkers6 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Pharmacogenetic 
Blood for cell pellets7 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
1 If a subject’s CD3-CD19+ B cell counts are < 107 cells/uL (the lower limit of normal for healthy volunteers, the subject will return for further testing of B cell counts every 3 months until the 
subject has B cell counts ≥ 107 cells/uL.  Follow-up visits for B cell counts will continue every 3 months, for up to 12 months after the end of study.    
2 A complete physical will be performed at screening and EOS.  A brief physical will be performed at all other timepoints unless required for evaluation of AEs. 
3 On day -1 baseline, three sets of triplicate baseline ECGs will be collected ≥ 30 minutes apart and at other time-points single triplicate ECGs will be collected, (ie, <30 seconds between 
subsequent ECGs) 
4 All Subjects must fast from all food and drink (except water) for at least 8 hours prior to any clinical lab evaluation. 
5 The AMG 570 IPRO assay will measure absolute counts for CD3+ T cells, CD16/56+ NK cells, CD19+ B cells as well as: 1) naïve B cell % of B cells and counts; 2)   memory B cell % of 
B cells and counts; 3) free B7RP-1 MFI (or MESF) on memory B cells and: 4) total B7RP-1 MFI (or MESF) on memory B cells.  Receptor occupancy will be calculated from the 
measurements of free and total B7RP-1. 
6.Exploratory biomarkers will include collection of serum, plasma and PAX gene RNA for future use.  
7 Blood for cell pellet sample will be obtained from the exploratory biomarker sample 
8 Subjects who require vaccination must receive vaccination(s) at least 30 days prior to receiving IP (tetanus booster and flu vaccinations may be administered by the investigator site during 
the screening window).  Seasonal influenze vaccine need only be administered during influenza season (October through May). 
 
 
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7.2 
General Study Procedures 
Adherence to the study design requirements, including those specified in the Schedule 
of Assessments (Table 8) are essential and required for study conduct. 
This section lists the procedure and parameters of each planned study assessment.  
The exact timing of each assessment is listed in the Schedule of Assessments 
(Section 7).  
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same 
nominal time, the assessment should occur in the following order: ECGs, vital signs, 
blood draws.  The timing of the assessment should allow the blood draw to occur at the 
exact nominal time. 
The timing and number of planned study assessments, including: Safety, PK, PD and 
Immunogenicity assessment may be altered during the course of the study based on 
newly available data (eg, to obtain data closer to the time of peak plasma concentration) 
to ensure appropriate monitoring. 
The IRB will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form. 
No more than 500 mL of blood, including from any extra assessments that may be 
required, will be collected over the duration of the study. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
7.2.1 
Informed Consent 
Before any study-related screening or baseline procedure can be completed, a subject 
must sign and date the IRB approved ICF.  
7.2.2 
Screening 
After informed consent, all screening procedures will be performed between Day -42 and 
Day -1.  Study eligibility must be met per inclusion/exclusion criteria prior to enrollment.  
The following procedures will be completed during the screening period at time points 
designated in the Schedule of Assessments (Table 8). 
• 
Informed Consent (confirmation that the ICF has been signed) 
• 
Medical, Medication, Drug and Alcohol History 
• 
Demographic data including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety 
• 
BMI calculated using height and weight  
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• 
Compete Physical Examination 
• 
Electrocardiogram (triplicate) 
• 
Vital Signs  
• 
Drug, Alcohol, and Cotinine Screen 
• 
HIV (human immunodeficiency virus), HBcAb (hepatitis B core antibody), 
HepBsAg (hepatitis B surface antigen),HepCAb (Hepatitis C antibody)  
• 
Laboratory Assessments (including creatinine clearance, chemistry, hematology, 
and urinalysis) 
• 
Follicle-Stimulating Hormone and estradiol (postmenopausal females only) and 
Pregnancy Test (females only) 
• 
IPRO assay, IgG and IgM 
• 
subjects may be rescreened only with permission of the Amgen medical monitor 
(Section 5) 
Given the potential of AMG 570 to modulate IgG levels and possible safety risks to 
healthy subjects with low IgG levels, all subjects with a screening IgG level of below 
800 mg/dl (8 g/L) will be discussed with the Amgen Medical Monitor prior to 
enrollment in the study.  Such subjects will have the entirety of their screening 
immune status parameters reviewed prior to approval of suitability for the study.  
7.2.3 
Day -1, Day 1 and Day 2 and Other Treatment 
Subjects will be admitted to the clinical unit on Day -1 at which time the following 
assessments will be obtained: 
• 
Brief Physical Examination 
• 
ECG (triplicate sets) 
• 
Vital Signs  
• 
Drug, Alcohol, and Cotinine Screen 
• 
Laboratory Assessments (chemistry, hematology, and urinalysis)  
• 
Pregnancy Testing (females only) 
• 
Treatment Assignment (can occur any time prior to dosing) 
Subject will stay overnight and then undergo Day 1 assessments as follows: 
• 
ECG (triplicate) 
• 
Vitals 
• 
IPRO, ADA, IgG, IgM, 
 Exploratory Biomarkers, blood for cell pellets 
• 
PK 
• 
Dosing 
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Prior to the subject being discharged, the following assessments will be completed or 
samples obtained: 
• 
Brief Physical Examination 
• 
ECG (triplicate) 
• 
Vitals 
• 
Laboratory Assessments (chemistry, hematology, and urinalysis) 
• 
PK 
If subject stays in house up to Day 11, then subject does not have to be discharged from 
research facility on Day 3.  After discharge, subject will return to clinical unit on an 
outpatient basis for scheduled study procedures including blood draws for PK 
assessment, safety, immunogenicity, and other assessment as per Schedule of 
Assessments (Table 8).   
7.2.4 
End of Study Visit/ Early Termination 
The following procedures will be completed at the EOS visits as per Schedule of 
Assessments (Table 8): 
• 
Complete Physical Examination 
• 
ECG (triplicate) 
• 
Vitals  
• 
Laboratory Assessments (chemistry, hematology, and urinalysis) 
• 
Pregnancy Testing (females only) 
• 
PK 
• 
IPRO, ADA, IgG, IgM, 
 Exploratory Biomarkers  
As noted previously, the EOS for each cohort may be prolonged pending treatment 
emergent data. 
7.2.5 
Medical History 
The Investigator or designee will collect a complete medical history.  Medical history will 
include information on the subject’s concurrent medical conditions.  Record all findings 
on the medical history eCRF. 
7.2.6 
Adverse Event 
Adverse event and serious adverse event assessments will be made throughout the 
study and will be evaluated and recorded in the source documents and on the eCRF for 
the duration of the study.  Determination of the severity of all adverse events will be 
consistent with CTCAE Version 4.0 unless specified otherwise. 
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7.2.7 
Concomitant Medications 
Concomitant medication(s) will be recorded throughout the study in the source 
documents and eCRF.  Sites will collect therapy name, indication, dose, unit, frequency, 
route, and start and stop dates for all concomitant medications. 
7.2.8 
Physical Examination 
A physical examination will be performed by the investigator or designated physician or 
nurse practitioner at time points specified in the Schedule of Assessments (Table 8).  
Pre-Dose abnormal findings will be reported on the medical history eCRF.  Abnormal 
findings found after the subject has received study medication will be reported on the 
Event eCRF.  A complete physical examination will include, at a minimum, assessment 
of cardiovascular, respiratory, gastrointestinal and neurological systems.  A brief 
physical examination will include assessment of the skin, lungs, cardiovascular system, 
and abdomen (liver and spleen). 
7.2.9 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Record all measurements on the vital signs 
eCRF.  The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs eCRF.  Vital signs (blood 
pressure, heart rate, respiratory rate, and temperature) will be recorded by the principal 
investigator or designee at time points specified in the Schedule of Assessments 
(Table 8).  
Blood pressure will be measured in the following manner: 
• 
Subjects should be lying in a semi-supine or supine position quietly and comfortably 
for at least 5 minutes.  The upper arm should be bare without constrictive clothing 
and supported at heart level. 
• 
Exercise should be avoided for at least 30 minutes prior to measurement. 
• 
An appropriately sized cuff (cuff bladder encircling at least 80 percent of the arm) 
should be used to ensure accuracy.  At least 2 measurements should be made and 
the average recorded. 
• 
Neither the subject nor the observer (measurer) should talk during measurement. 
Subjects should be lying in a semi-supine or supine position quietly and comfortably for 
at least 5 minutes for respiratory and heart rate assessments.  Abnormal measurements 
may be repeated upon investigator discretion.  Record all measurements on the vital 
signs eCRF. 
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7.2.10 
Height, Weight, and Body Mass Index 
Height in centimeters will be measured without shoes at screening. 
Weight in kilograms will be measured without shoes at time point specified in the 
Schedule of Assessments (Table 8). 
Subject BMI will be calculated using height and weight measurements taken at 
screening according to the following formula: 
BMI (kg/m2) = weight (kg) / (height [cm]/100)2 
7.2.11 
Electrocardiograms 
During the study, 12-lead electrocardiograms (ECG) will be performed at the time points 
indicated in the Schedule of Assessments (Table 8). 
The subject must be in supine position in a rested and calm state for at least 5 minutes 
before the ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in the most recumbent position possible. 
ECGs should be performed in a standardized method, in triplicate, and run consecutively 
(ie, <30 seconds apart), prior to blood draws or other invasive procedures.  Each ECG 
must include the following measurements: QRS, QT, QTc, RR, and PR intervals. 
• 
3 sets of triplicate baseline ECGs collected ≥ 30 minutes apart between each set 
and within each baseline set ECG in triplicate will be run consecutively 
(ie, <30 seconds between subsequent ECGs) [ie, total ≥ 9 ECGs] 
• 
1 set of triplicate ECGs at all other time points, single triplicate ECGs run 
consecutively (ie, <30 seconds between subsequent ECGs) 
The Principal Investigator or designated site physician or nurse practitioner  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 Amgen.  Standard ECG machines should be used for all study-related 
ECG requirements. 
7.2.12 
Estimated Glomerular Filtration Rate (eGFR) 
For determining eligibility, estimated glomerular filtration rate (eGFR) will be calculated 
using the Cockcroft-Gault formula based on serum creatinine, age, sex and weight at 
time point indicated in the Schedule of Assessments (Table 8). 
7.2.13 
Clinical Chemistry 
All laboratory tests must be reviewed and signed by the principal investigator or qualified 
designee.  Additional safety laboratory assessments may be performed for subject 
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safety.  Blood samples for clinical chemistry will be collected at time points specified in 
the Schedule of Assessments (Table 8). 
The tests listed below will be conducted and analyzed by standard laboratory 
procedures: 
Table 9.  Clinical Chemistry 
Albumin 
Blood urea nitrogen or Urea 
Calcium 
Chloride 
Glucose 
Phosphorus 
Potassium  
Creatinine 
Magnesium  
Sodium 
Carbon Dioxide or Bicarbonate 
Uric acid 
Aspartate aminotransferase (AST)  
Alanine aminotransferase (ALT) 
Cholesterol  
Total bilirubin (TBIL) 
Alkaline phosphatase (ALP) 
Direct bilirubin 
Total protein  
Triglycerides 
High-density lipoprotein 
Creatine Phosphokinase (CPK) 
Hemoglobin A1C** 
 * All Subjects must fast from all food and drink (except water) for at least 8 hours prior to any clinical lab 
evaluation. 
 **Hemoglobin A1C will be collected only at screening. 
7.2.14 
Hematology 
All laboratory tests must be reviewed and signed by the principal investigator or qualified 
designee.  Additional safety laboratory assessments may be performed for subject 
safety.  Blood samples for hematology tests will be collected at time points specified in 
the Schedule of Assessments (Table 8). 
The tests listed below will be conducted and analyzed by standard laboratory 
procedures: 
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Table 10.  Hematology 
Red blood cells 
White blood cells with differential count: 
• 
Total neutrophils (OR segmented 
neutrophils and band cells) 
• 
Eosinophils 
• 
Lymphocytes 
• 
Basophils 
• 
Monocytes 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Platelet count 
Mean corpuscular hemoglobin concentration 
* All Subjects must fast from all food and drink (except water) for at least 8 hours prior to any clinical lab 
evaluation. 
7.2.15 
Urinalysis 
All laboratory tests must be reviewed and signed by the principal investigator or qualified 
designee.  Additional safety laboratory assessments may be performed for subject 
safety.  Urine samples will be collected at time points specified in the Schedule of 
Assessments (Table 8). 
The tests listed below will be conducted and analyzed by standard laboratory 
procedures: 
Table 11.  Urinalysis 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Microscopic exam (performed at the discretion of the principal investigator or qualified 
designee): 
White blood cells 
Red blood cells 
Epithelial Cells 
Bacteria 
Casts 
Crystals 
* All Subjects must fast from all food and drink (except water) for at least 8 hours prior to any clinical lab 
evaluation. 
7.2.16 
Drug, Alcohol, and Cotinine Screen 
The drug and alcohol tests will include at minimum testing for drugs with a high potential 
for abuse, including amphetamines, barbiturates, benzodiazepines, cocaine, ethanol, 
opiates, and cannabinoids. 
Subjects who test positive for drug, alcohol, and cotinine will not qualify for 
investigational product administration.  The intention is to detect drugs of abuse and not 
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those prescribed therapeutically.  Subjects with a positive drug test may be retested 
once at the discretion of the investigator.  Drug, alcohol, and cotinine assessments are 
to be completed at time points indicated in the Schedule of Assessments (Table 8).   
7.2.17 
Hepatitis B, Hepatitis C and HIV Status 
Hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HBcAb), hepatitis C 
antibody (HepCAb), and HIV status will be assessed.  If the results show a negative 
HepBsAg and positive for HBcAb:  a hepatitis B virus DNA by polymerase chain reaction 
(PCR) is necessary.  If the results show a positive HepCAb:  hepatitis C virus ribonucleic 
acid (RNA) by PCR is necessary.  The test must be confirmed negative at screening for 
the subject to be eligible for this study.   
7.2.18 
Serum Follicle-stimulating Hormone and Estradiol 
Additional serum will be collected for an FSH and estradiol for females who are at least 
1 year postmenopausal at screening unless 60 years or older.  Results must be 
consistent with postmenopausal status per local laboratory ranges to be eligible for this 
study.  Postmenopausal status will be recorded on the medical history eCRF. 
7.2.19 
Pregnancy Test 
A serum pregnancy test must be completed for all females at screening.  A serum or 
highly sensitive urine pregnancy test will be collected at Day -1 and EOS as specified in 
the Schedule of Assessments (Table 8).  The screening (serum) and Day -1 (serum or 
urine) pregnancy test must be confirmed negative for the subject to be eligible for this 
study. 
7.2.20 
Pharmacokinetic Blood Sample Collection for AMG 570 Serum 
Concentrations 
Blood samples will be collected for determination of AMG 570 serum concentrations at 
time points indicated in the Schedule of Assessments (Table 8).  Instructions for 
collecting, processing, and shipping samples are provided in a separate document from 
Amgen. 
7.2.21 
Immunophenotyping and Receptor Occupancy (IPRO) Assay Blood 
Collections  
Whole blood samples for Immunophenotyping and Receptor Occupancy (IPRO) will be 
collected at timepoints indicated in the Schedule of Assessments (Table 8).  The 
Immunophenotyping assay will measure B cells and B cell subsets.  The Receptor 
Occupancy assay will measure B7RP-1 receptor occupancy.  Instructions for collecting, 
processing, and shipping the IPRO samples will be provided in a separate document 
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from Amgen.  Immunophenotyping blood collection instructions for collecting, 
processing, and shipping samples are provided in a separate document from Amgen. 
 
7.2.23 
IgG and IgM Blood Collection 
Blood samples will be collected for determination of serum Immunoglobulin IgG and IgM 
levels at time points indicated in the Schedule of Assessments (Table 8).  Instructions for 
collecting, processing, and shipping samples will be provided in a separate document 
from Amgen. 
7.2.24 
Anti-Drug Antibody Testing (ADA) 
Blood samples for antibody testing are to be collected at day 1, 29, 57, and the EOS 
time point (Schedule of Assessments, Table 8) for the measurement of anti-AMG 570 
binding antibodies.  Samples testing positive for binding antibodies 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 570 antibodies during 
the study.  In the event of safety-related concerns, more frequent testing (eg, every 
month) or testing for a longer period of time may be requested.  Follow-up testing is not 
required where it is established that the subject did not receive AMG 570.  
Subjects who test positive for binding antibodies, and have clinical sequelae that are 
considered potentially related to an anti-AMG 570 antibody response may also be asked 
to return for additional follow-up testing.  Refer to the Schedule of Assessments 
(Table 8), as applicable, for specific time points and the laboratory manual for detailed 
collection and handling instructions. 
7.3 
Exploratory Biomarker Samples for Future Use 
Exploratory biomarker blood samples will be collected for serum, plasma and Paxgene 
RNA at the time points indicated in the Schedule of Assessments (Table 8).  Biomarkers 
are objectively measured and evaluated indicators of normal biologic processes, 
pathogenic processes, or pharmacologic responses to a therapeutic intervention.  
Biomarker development samples can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity. 
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Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to AMG 570. 
7.4 
Pharmacogenetic Sample of Blood for Cell Pellets 
A blood sample will be analyzed for pharmacogenetic analyses at the time point 
indicated in the Schedule of Assessments (Table 8).  Pharmacogenetic analyses focus 
on inherited genetic variations to evaluate their possible correlation to the disease 
activity and/or responsiveness to AMG 570.  The goals include the use of genetic 
markers to help in the investigation to identify subjects who may have positive or 
negative response to AMG 570.  No additional samples will be collected for this part of 
the study; however for those subjects who consent to these studies, DNA will be 
extracted from samples already collected from the exploratory biomarker sample.   
7.5 
Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessment (Table 8) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.   
This analysis includes testing to ensure analytical methods produce reliable and valid 
data throughout the course of the study.  The analysis 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 
dose response and/or prediction of response to AMG 570, characterize antibody 
response, and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites).  Results from this analysis are to be documented and maintained but are 
not necessarily reported as part of this study.  Samples can be retained for up to 
20 years.   
Since the evaluations are not expected to benefit the subject directly nor 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 
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made available to the subject, members of the family, the personal physician, nor 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 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. 
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.  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.   
8.1.1 
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.    
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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.  
8.1.2 
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, protocol deviation, non-compliance, 
pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
8.1.3 
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 
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, and gout) has increased in severity, frequency, and/or 
duration more than expected by the investigator’s assessment.  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.   
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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 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.   
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria.  
• 
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 
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, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Adverse Events 
9.2.1.1 
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 enrollment through the end of 
study 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), 
• 
Severity   
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• 
Assessment of relatedness to investigational product 
• 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  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 investigational product.  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. 
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 as a single event with the worst severity on the Event CRF.  The 
investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
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 informed 
consent through EOS are recorded in the subject’s medical record and are submitted to 
Amgen.  All serious adverse events must be submitted to Amgen within 24 hours 
following the investigator’s knowledge of the event via fax. 
See Appendix B for a sample of the Serious Adverse Event Worksheet.   
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 reversibility.   
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New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  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.  
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
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 good 
clinical practice.  
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.  
9.2.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after 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 that they 
become aware of after 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.  
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9.3 
Pregnancy Reporting 
If a pregnancy occurs in a 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 20 weeks for the female partner of a male subject. 
The pregnancy should be reported to Amgen’s Global Patient 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).   
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints 
Subject incidences of treatment-emergent adverse events, including clinically 
significant changes in physical examinations, vital signs, laboratory safety tests, 
and electrocardiograms (ECGs). 
10.1.1.2 
Secondary Endpoints 
• 
To characterize the PK profile of single subcutaneous (SC) doses of AMG 570 in 
healthy subjects 
• 
To determine the PD effects (B7RP-1 occupancy and inhibition of B cell survival) 
of single subcutaneous (SC) doses of AMG 570 in healthy subjects 
• 
To determine the immunogenicity of AMG 570 
10.1.1.3 
Exploratory Endpoints 
Exploratory biomarkers may include but are not limited to the following:  
• 
.  
• 
Serum IgG and IgM.  
10.1.2 
Analysis Sets 
For safety, pharmacokinetic concentration, pharmacokinetic parameter and 
pharmacodynamic analyses, subjects will be analyzed according to the treatment they 
received, not the treatment to which they are randomized. 
10.1.2.1 
Safety Analysis Set 
The safety set will consist of all subjects who have received AMG 570/placebo. 
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10.1.2.2 
Pharmacokinetic (PK) Concentration Analysis Set 
The PK concentration analysis set will contain all subjects who have received AMG 570 
and have at least one quantifiable PK sample collected.  
10.1.2.3 
Pharmacokinetic (PK) Parameter Analysis Set  
The PK parameter analysis set will consist of all subjects who have received AMG 570 
and for whom at least one PK parameter can be adequately estimated. 
10.1.2.4 
Pharmacodynamic (PD) Analysis Set  
The PD analysis set will consist of all subjects who have received AMG 570/placebo and 
for whom at least one PD parameters have quantifiable baseline sample (not needed for 
B7RP-1 occupancy) and at least one quantifiable post-baseline PD sample collected.  
10.1.3 
Covariates and Subgroups 
No subgroup analysis is planned. 
10.2 
Sample Size Considerations 
Approximately 56 healthy subjects will be enrolled into 7 cohorts (6 active: 2 placebo in 
each cohort).  This sample size is based on practical considerations and is typical for 
this type of study.  For safety considerations, for a cohort, with 6 subjects receiving 
AMG 570, there is an 82% chance of at least one subject experiencing an adverse event 
with a true incidence rate of 25% and a 74% chance of at least one subject experiencing 
an adverse event with 20% true incidence rate.  With a total of 42 subjects expected to 
receive AMG 570 across all 7 cohorts, there is a 34% chance of at least 1 subject 
experiencing an adverse event with a true incidence rate of 1% and the chance of at 
least 1 subject experiencing an adverse event increases to 88% and 99% with a true 
incidence rate of 5% and 10%, respectively.  
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Amgen staff and their designees involved in the study will not be blinded, but will only be 
given treatment assignments when there is a need to use the information for analysis, 
discussion and internal decision making.  
Access to treatment assignments and other restricted data will be managed as 
described in the Managing Access to Restricted Study Data Document.  Unblinded 
individuals are to ensure unblinding and potentially unblinding information not be 
distributed to the investigators or subjects prior to the study being formally unblinded at 
the end of the trial. 
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10.4 
Planned Analyses 
10.4.1 
Data Monitoring Committee (DMC), Data Review Team (DRT) or Dose 
Level Review Team (DLRT) 
A Dose Level Review Team (DLRT) will be used to oversee progress of the study and 
make recommendations relating to early closure/extension or alteration of the study 
based on ongoing monitoring of the study data.  The DLRT members will consist of the 
principal investigator or designee, Amgen Medical Monitor, Amgen Global Safety Officer 
or designee, Amgen Clinical Research Study Manager or designee, and biostatistics 
representative or designee.  Additional members may be added as needed (eg, PK 
scientist).  The key objectives of the DLRT are to review data, monitor safety, and make 
dose change decisions. 
10.4.2 
Primary Analysis 
The primary analysis will occur after all subjects have completed the study. 
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, immunogenicity, 
PK, PD, and biomarker data.  Descriptive statistics on continuous measurements will 
include means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages.  Data will be presented and 
summarized by treatment and by time as appropriate. 
The number and percent of subjects reporting any adverse events and each adverse 
event will be tabulated by system organ class and preferred term and may be further 
classified by severity and relationship to treatment.  Subject incidence of clinically 
significant changes in vital signs, physical examinations, clinical laboratory safety tests, 
ECGs, and the development of AMG 570 binding antibodies will be noted.  
10.5.2 
Primary Endpoint 
10.5.2.1 
Adverse Event 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities.  The number and percentage of subjects reporting 
adverse events will be evaluated for each treatment group and will be tabulated by 
relationship to the study drug.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies will also be provided. 
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10.5.2.2 
Clinical Laboratory Tests 
Clinical chemistry, hematology, and urinalysis data will be reviewed for each subject. 
Values outside the normal laboratory reference ranges will be flagged as high or low. 
The analyses of safety laboratory endpoints may include summary statistics over time 
and/or changes from baseline by treatment.  Shifts in grades of safety laboratory values 
between the baseline and the worst on-study value may be tabulated by treatment 
group.  Clinically significant changes in clinical laboratory test values will be noted. 
10.5.2.3 
Vital Signs 
Vital signs data will be reviewed for each subject.  Depending on the size and scope of 
the changes, the analyses of vital signs may include summary statistics over time and/or 
changes from baseline over time by treatment.  Clinically significant changes in vital 
signs will be noted. 
10.5.2.4 
Electrocardiograms 
Descriptive summary statistics of ECG values over time and/or changes from baseline to 
post-baseline maximum and post-baseline minimum may be provided for each ECG 
parameters. 
Subjects’ maximum change from baseline in QTcF will be categorized and the number 
and percentage of subjects in each group will be summarized. 
Subjects’ maximum post baseline values will also be categorized and the number and 
percentage of subjects in each group will be summarized. 
10.5.2.5 
Study Disposition and Demographic Data 
The number of subjects who are randomized, have received investigational product and 
have completed the study will be tabulated.  Demographic characteristics will be 
summarized using descriptive statistics. 
10.5.3 
Secondary Endpoint(s) 
10.5.3.1 
PK Analysis 
Serum AMG 570 concentrations will be determined using a validated assay.  Individual 
serum concentration-time plots for AMG 570 will be presented for each subject as well 
as mean concentration-time plots for each treatment. 
The following pharmacokinetic parameters will be calculated but not limited to maximum 
observed concentration [Cmax], time at Cmax [tmax], and area under the concentration-time 
curve [AUC] using non-compartmental methods.  Actual dosing and sampling times will 
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be used for calculation of individual PK parameters.  Summary statistics will be 
generated for each PK parameter for each treatment. 
Additional analyses using compartmental methods or population PK analysis may be 
performed. 
10.5.3.2 
Antibody Analysis 
Anti-AMG 570 binding antibody will be assessed using a validated assay.  The number 
and percentage of subjects who have developed anti- AMG 570 antibodies at any time, 
at baseline and during post-baseline visits will be summarized by treatment group. 
10.5.3.3 
PD Analysis 
PD end points (including but not limited to peripheral blood B7RP-1 receptor occupancy, 
peripheral blood changes in percentage and absolute counts of naive and memory 
CD19+B cells) will be summarized by treatment using descriptive statistics at each visit 
and may be listed by subject if deemed necessary.  
10.5.4 
Exploratory Endpoints 
Biomarker end points (including but not limited to 
 and serum IgG and 
IgM immunoglobulins levels) will be summarized by treatment using descriptive statistics 
at each visit and may be listed by subject if deemed necessary.  
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 subject 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 
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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 records, and the informed consent form is to 
be signed and personally dated by the subject 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.  Refer to ICH GCP guideline, 
Section 4.8.9.   
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 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 for all 
subsequent protocol amendments and changes to the informed consent document.  The 
investigator is to notify the IRB 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 approval/renewal throughout the 
duration of the study.  Copies of the investigator’s reports and the IRB continuance of 
approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
• 
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 demographics page, in addition to the unique subject identification number, 
include the age at the 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 strict 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 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 named 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 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  The 
IRB/ must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB 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 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 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 it is 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.  
Elements to include: 
• 
Subject files containing completed CRF, 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 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. 
The 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. 
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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 electronic CRFs must be 
maintained and readily available. 
• 
Updates to electronic 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.  This signature indicates that the investigator inspected or reviewed 
the data on the CRF, the data queries, and agrees with the content. 
Additional information on the current guidelines for publications can be found at the 
following location: http://www.icmje.org/. 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database. SECs will be documented in the CRF Standard Instructions 
and the CRF 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 with different visit, [eg, week 4 and early termination]) and updating a specific 
response if the confirming datum is provided in the “other, specify” field (eg, for race, 
reason for ending study). 
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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 8), 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.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, the investigator will solicit input and 
assistance from Amgen staff as appropriate. 
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.  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 corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
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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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Rickert RC, Jellusova J, Miletic AV.  Signaling by the TNFR superfamily in B-cell biology 
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TJ, Roncador G, Huttley GA, Goodnow CC, Vinuesa CG, Cook MC. Expansion of 
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Stohl W Joan TM, R. John L et al. Treatment of systemic lupus erythematosus patients 
with the BAFF antagonist “peptibody” blisibimod (AMG 623): Results from randomized, 
double-blind phase 1a and phase 1b trials, Submitted (under review). 2015.  
Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365:2110-2121. 
Yoshinaga SK, Whoriskey JS, Khare SD, et al.  T-cell co-stimulation through B7RP-1 
and ICOS. Nature. 1999;402:827–832. 
Zhang J, Roschke V, Baker KP et al. Cutting edge: a role for B lymphocyte stimulator in 
systemic lupus erythematosus. J Immunol 2001;166:610. 
US Department of Health and Human Services, Center for Drug Evaluation and 
Research (CDER).  Guidance for Industry:  Estimating the maximum safe starting dose 
in initial clinical trials for therapeutics in adult healthy volunteers.  July 2005. 
US Department of Health and Human Services, Center for Drug Evaluation and 
Research (CDER).  Guidance for Industry:  Immunogenicity assessment for therapeutic 
protein products. August 2014. 
Approved 
 
 

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14. 
APPENDICES 
Approved 
 
 

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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used 
and is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronicapplications/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 6.3 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, 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 9.1.2. 
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 
Section 6.3.1 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. 
• 
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 
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− 
Obtain serum acetaminophen (paracetamol) levels 
− 
Obtain a more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o 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. 
Approved 
 
 

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Appendix B.  Sample Serious Adverse Event Form 
 
 
Approved 
 
 

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Approved 
 
 

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Approved 
 
 

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Approved 
 
 

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Appendix C.  Pregnancy Notification Worksheet (Pregnancy in Partner of a Male 
Subject) 
 
 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 1 of 5 
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Amendment 4 
Protocol Title:  A Randomized, Double Blind Placebo Controlled, First in Human 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single Ascending Subcutaneous Doses of AMG 570 in 
Healthy Subjects 
 
Amgen Protocol Number AMG 570 20140322 
Amendment Date: 
24 January 2018 
 
Rationale: 
The protocol has been amended to include an additional cohort – Cohort 7.  Enrollees in 
cohort 7 will receive a single subcutaneous (SC) dose of 700 mg AMG 570 or placebo 
(6 active and 2 placebo).  The addition of this cohort will increase enrollment to a total of 
approximately 56 subjects and will provide high dose safety, pharmacokinetic, and 
pharmacodynamic data that will inform multiple dose paradigms in future studies.  
Available data for Cohorts 1-6 have been used to support updates to dose selection, 
study design, safety and biostatistical information throughout the protocol.   Where 
available, observed data have replaced predicted values for increased accuracy.   
Administrative, typographical and formatting changes have been made throughout the 
protocol where applicable.   
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 2 of 5 
CONFIDENTIAL 
 
 
Description of Changes: 
Section:  Global 
Change:  Minor corrections have been made throughout the protocol (eg, administrative 
updates, typographical and formatting errors). 
Section:  Global 
Change:  Addition of Cohort 7 with planned dose 700 mg SC,  
N (active:placebo) = 8(6:2) 
Section:  Protocol Synopsis, Sample Size (global change) 
Replace:   
Approximately 48 healthy subjects will be enrolled into 6 cohorts (6 active: 2 placebo in 
each cohort). 
With:   
Approximately 56 healthy subjects will be enrolled into 7 cohorts (6 active: 2 placebo 
in each cohort). 
Section:  Protocol Synopsis, Study Design, Dose Levels (global change) 
Replace:   
The study consists of 6 SC cohorts.   
With:  
The study consists of 7 SC cohorts.   
Section:  Synopsis, Investigational Product Dosage and Administration 
Add:   
For subcutaneous dosing in Cohort 7, doses will be administered in a 2 mL per 
injection format (5 x 2.0 mL injections). 
Section:  Section 2.3 Risk Assessment 
Add:   
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
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Section:  2.4.4 AMG 570 Clinical Background 
Replace: 
As of 15 January 2017, 32 subjects have received a single SC dose of AMG 570 or 
placebo at the following doses: 7, 21, 70, or 140 mg. Preliminary safety, 
pharmacokinetics, and pharmacodynamics results from study, are described in 
Sections 6.1 and 6.2. of the Investigator’s Brochure. 
With: 
As of 1 January 2018, 48 subjects have received a single SC dose of AMG 570 or 
placebo at the following doses: 7, 21, 70, 140 mg, 210 mg, or 420 mg.  Preliminary 
safety, pharmacokinetic, and pharmacodynamic results from the cohorts receiving 
7-140 mg of AMG 570 are described in Sections 6.1 and 6.2 of the Investigator’s 
Brochure.  All dose levels have demonstrated acceptable safety and tolerability 
with no severe, life-threatening, or fatal events reported.  A multiple ascending 
dose study in patients with rheumatoid arthritis (study 20150196) has also been 
initiated with 9 subjects receiving 6 doses of 70 mg AMG 570 or placebo  
SC q 2 weeks.  Subjects at this dose level have demonstrated acceptable safety 
and tolerability with no severe, life-threatening, or fatal events reported.   
Section:  2.4.5 Rationale for Dose Selection (Table 2) 
Add: 
• 
Observed AMG 570 Pharmacokinetic Parameters and Exposure Margins for 
210 mg and 420 mg doses 
• 
Predicted AMG 570 Pharmacokinetic Parameters and Exposure Margins for 
700 mg dose 
Section:  2.4.5 Rationale for Dose Selection  
Replace: 
Based on the 3-month GLP toxicology study in cynomolgus monkeys and interim 
pharmacokinetics data from this ongoing FIH study, it is anticipated that a 420 mg SC 
dose of AMG 570 in humans would not exceed the exposure associated with the 
AMG 570 NOAEL in cynomolgus monkeys. At this highest planned SC dose, the 
exposure margins are 160- and 48-fold below the Cmax and AUC at the NOAEL in 
monkeys. Based on interim pharmacokinetics and pharmacodynamics data from this 
ongoing study, it is also anticipated that a 420 mg SC dose of AMG 570 is expected to 
Approved 
 
 

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Date:  24 January 2018 
Page 4 of 5 
CONFIDENTIAL 
 
 
result in 90% or more B7RP-1 RO at day 8 and B cell depletion of at least 40% 
compared to baseline. Significant changes to circulating IgG and IgM levels are not 
anticipated based on interim data. 
With: 
Based on the 3-month GLP toxicology study in cynomolgus monkeys and interim 
pharmacokinetics data from this ongoing FIH study, it is anticipated that a 700 mg SC 
dose of AMG 570 in humans would not exceed the exposure associated with the 
AMG 570 NOAEL in cynomolgus monkeys.  At this highest planned SC dose, the 
exposure margins are 44- and 10-fold below the Cmax and AUC at the NOAEL in 
monkeys.  Based on interim pharmacokinetics and pharmacodynamics data from this 
ongoing study, it is also anticipated that a 700 mg SC dose of AMG 570 is expected to 
result in 90% or more B7RP-1 RO at day 8 and B cell depletion of up to 40% compared 
to baseline by day 57.  Significant changes to circulating IgG and IgM levels are not 
anticipated based on interim data. 
Section:  Section 3.3, Number of Subjects 
Replace: 
Approximately 48 healthy subjects will be enrolled into 6 cohorts. 
With: 
Approximately 56 healthy subjects will be enrolled in 7 cohorts. 
Section:  10.2 Sample Size Considerations 
Replace: 
With a total of 36 subjects expected to receive AMG 570 across all 6 cohorts, there is a 
30% chance of at least 1 subject experiencing an adverse event with a true incidence 
rate of 1% and the chance of at least 1 subject experiencing an adverse event increases 
to 84% and 98% with a true incidence rate of 5% and 10%, respectively. 
With: 
With a total of 42 subjects expected to receive AMG 570 across all 7 cohorts, there is a 
34% chance of at least 1 subject experiencing an adverse event with a true incidence 
rate of 1% and the chance of at least 1 subject experiencing an adverse event increases 
to 88% and 99% with a true incidence rate of 5% and 10%, respectively. 
Approved 
 
 

Product:  AMG 570 
Protocol Number:  20140322 
Date:  24 January 2018 
Page 5 of 5 
CONFIDENTIAL 
 
 
Section:  10.5.2.1 Adverse Event 
Delete: 
or from study, and significant treatment-emergent adverse events 
Section 10.5.2.4 Electrocardiograms 
Replace: 
Descriptive summary statistics of ECG values over time and/or changes from baseline 
over time may be provided for each ECG parameters. 
With: 
Descriptive summary statistics of ECG values over time and/or changes from baseline to 
post-baseline maximum and post-baseline minimum may be provided for each ECG 
parameters. 
Section:  10.5.3.2 Antibody Analysis 
Delete: 
The incidence of anti-AMG 570 antibodies will be listed for each subject 
Approved 
 
 

Superseded 
 
 
Product:  AMG 570 
Protocol Number:  20140322 
Date:  04 May 2017 
Page 1 of 11 
Amendment 3 
Protocol Title:  A Randomized, Double Blind Placebo Controlled, First in Human 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single Ascending Subcutaneous Doses of AMG 570 in 
Healthy Subjects 
 
Amgen Protocol Number AMG 570 20140322 
Amendment Date: 
04 May 2017 
Rationale: 
The protocol has been amended to include an additional cohort – Cohort 6.  Enrollees in 
cohort 6 will receive a single subcutaneous (SC) dose of 420 mg AMG 570.  The 
addition of this cohort will extend enrollment to an additional 8 subjects for a total of 
48 subjects.  The addition of this cohort will provide additional safety, pharmacokinetics, 
and pharmacodynamics data that will facilitate the understanding of the 
exposure-response relationship to inform future studies with AMG 570.  Available data 
for Cohorts 1-4 have been used to support updates to dose selection, study design, 
safety and biostatistical information throughout the protocol.   Where available, observed 
data have replaced predicted values for increased accuracy. 
Additional updates have been made to incorporate clarification and guidance previously 
released to sites regarding the following: 
• 
Length of in-house stay – up to 11 days allowed for in-house residence 
• 
CDC vaccine recommendation – flu season (October-May) 
• 
Renal disease exclusion criteria – removal of additional criteria does not pose 
safety risk, does not interfere with ability to assess safety of subject, and does 
not affect scientific integrity of study. 
• 
Screening IgG below 800 mg/dl – review with Amgen Medical Monitor prior to 
enrollment 
• 
Delegation of responsibilities to designated physician or nurse practitioner 
• 
Timing of consecutively run ECGs –  ECGs should be run in as short a time as 
possible 
• 
Self-evident corrections – updated template language has been incorporated into 
protocol 
Administrative, typographical and formatting changes have been made throughout the 
protocol where applicable.   
Confidential 
 
 

Superseded 
 
 
Product:  AMG 570 
Protocol Number:  20140322 
Date:  08 January 2016 
Page 1 of 12 
CONFIDENTIAL 
 
Amendment 2 
Protocol Title:  A Randomized, Double Blind Placebo Controlled, First in Human 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single Ascending Subcutaneous Doses of AMG 570 in 
Healthy Subjects 
 
Amgen Protocol Number AMG 570 20140322 
 
Change Summary  Date: 
08 January 2016 
Rationale: 
The AMG 570 20140322 protocol is being amended to allow for longer screening period 
so subjects are up to date on their vaccinations prior to screening for the study 
Specifically, the following major changes are being made: 
• 
Increase of screening window from 28 days to 42 days to allow required 
vaccination 
• 
Increase timing for taking triplicate ECG from 30 sec to 60 sec 
• 
Clarification of contraception language 
Minor typographical errors were corrected and clarifications were made. 

Superseded 
 
 
Product:  AMG 570 
Protocol Number:  20140322 
Date:  27 October 2015                                                                                              Page 1 of 20 
Confidential 
 
 
Amendment 1 
Protocol Title:  A Randomized, Double Blind Placebo Controlled, First in Human 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single Ascending Subcutaneous Doses of AMG 570 in 
Healthy Subjects 
 
Amgen Protocol Number AMG 570 20140322 
 
Change Summary  Date: 
27 October 2015 
 
Rationale: 
The AMG 570 20140322 protocol is being amended in response to FDA concerns for the 
potential of prolonged immune suppression in healthy subjects based on decreases in B 
cells and serum IgG levels observed in the 3-month repeat dose toxicology study in 
cynomolgus monkeys   and inadequate  nonclinical  toxicology studies to support the IV 
route of administration. 
Specifically, the following major changes are being made: 
• 
Removal of all language pertaining to 210 mg and 420 mg intravenous (IV) 
administration  
• 
Update to the Serum AMG 570 concentration-time profile  
• 
Changes to Section 6.2.1.3 to include increasing length of DLRM interval from 28 to 
57 days and addition of Humoral Immune Status Stopping Rules 
• 
Update to Schedule of Assessments (SOA) pertaining to language about IV dosing 
• 
Alignment of Endpoints listed in Section 10.1.1 with other sections of the protocol 
 
Minor typographical errors were corrected and clarifications were made.