Conditions: Advanced Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 171
Healthy volunteers: no

Brief summary:
To evaluate the safety and tolerability of AMG 404, a monoclonal antibody that binds to PD-1 and inhibits its engagement with ligands, in patients with advanced solid tumors.

Detailed description:

Arms:
arm 1: Cohort 1 arm 2: Cohort 2 arm 3: Cohort 3 arm 4: Cohort 4 arm 5: Cohort 6 arm 6: Cohort 7 arm 7: Cohort 8 arm 8: Cohort 9

Interventions: intervention 1: AMG 404
Intervention descriptions: intervention 1: AMG 404 will be examined for safety, tolerability, PK, and PD of AMG 404 in subjects with advanced solid tumors.

Protocol document:
Prot_000.pdf: 
Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 1 of 176 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
A Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of 
AMG 404, a Programmed Death-1 (PD-1) 
Antibody,
 
, in Patients With 
Advanced Solid Tumors 
Short Protocol Title: 
AMG 404 in Patients with Advanced Solid 
Tumors 
Protocol Number: 
20180143 
Investigational Product: 
AMG 404 
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen Inc.  
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
USA 
Telephone Number: 
+1 (805) 447-1000 
Key 
Sponsor 
Contact 
Name: 
, MD 
, Vet Dr 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
USA 
Telephone Number: 
Email Address: 
EudraCT Number: 
2018-004268-80 
NCT Number: 
NCT03853109 
Protocol Date: 
Document Version 
Date 
Original 
Amendment 1 
Amendment 2 
Amendment 3 
23 October 2018 
02 January 2019 
15 July 2019 
31 January 2020 
Amendment 4 
24 November 2020 
Amendment 5 
16 July 2021 
Amendment 6 
20 May 2022 
Version/Date: 
Data Element Standards Version 
6.1 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 2 of 176 
CONFIDENTIAL 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; [for all other countries, insert the local toll-free Medical Information 
number]; Amgen’s general number in the US, 1-805-447-1000. 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 3 of 176 
CONFIDENTIAL 
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1 Study to Evaluate Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 404, a Programmed 
Death-1 (PD-1) Antibody, 
, in 
Patients With Advanced Solid Tumors, dated 20 May 2022, and agree to abide by all 
provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse and dependent children) and my sub-investigators 
(including, if applicable, their spouses and dependent children) at the start of the study 
and for up to 1 year after the study is completed, if there are changes that affect my 
financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator 
Date (DD Month YYYY) 
 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 4 of 176 
CONFIDENTIAL 
 
 
1. 
Table of Contents 
1. 
Table of Contents ................................................................................................... 4 
2. 
Protocol Synopsis ................................................................................................. 11 
3. 
Study Schema and Schedule of Activities ............................................................. 20 
3.1 
Study Schema ........................................................................................... 20 
3.2 
Schedule of Activities ................................................................................ 24 
4. 
Background and Rationale .................................................................................... 39 
4.1 
Disease and Target Background ............................................................... 39 
4.1.1 
PD-1/PD-L1 Inhibitors and Treatment of NSCLC ....................... 40 
4.2 
Amgen Investigational Product Background:  AMG 404 ............................ 41 
4.2.1 
Nonclinical Pharmacology ......................................................... 41 
4.2.2 
Toxicology ................................................................................. 41 
4.2.3 
Nonclinical Pharmacokinetics .................................................... 42 
4.2.4 
Rationale for Development AMG 404 ........................................ 43 
4.5 
Benefit/Risk Assessment ........................................................................... 45 
4.5.1 
Therapeutic Context .................................................................. 46 
4.5.2 
Benefits ..................................................................................... 46 
4.5.3 
Risks ......................................................................................... 46 
5. 
Objectives, Endpoints and Hypotheses ................................................................. 50 
5.1 
Objectives and Endpoints .......................................................................... 50 
5.2 
Hypotheses ............................................................................................... 51 
6. 
Study Design ........................................................................................................ 51 
6.1 
Overall Design .......................................................................................... 51 
6.2 
Number of Subjects ................................................................................... 59 
6.2.1 
Replacement of Subjects ........................................................... 59 
6.2.2 
Number of Sites ......................................................................... 59 
6.3 
End of Study ............................................................................................. 60 
6.3.1 
End of Study Definition .............................................................. 60 
6.3.2 
Study Duration for Subjects ....................................................... 60 
6.4 
Dose Rationale ......................................................................................... 60 
6.4.1 
First in Human Starting Dose Selection Rationale ..................... 60 
6.4.2 
Recommended Phase 2 Dose Selection ................................... 62 


Product:  AMG 404  
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Page 5 of 176 
CONFIDENTIAL 
 
 
6.5 
Patient Input on Study Design ................................................................... 66 
7. 
Study Population .................................................................................................. 66 
7.1 
Inclusion Criteria ....................................................................................... 66 
7.2 
Exclusion Criteria ...................................................................................... 68 
7.3 
Subject Enrollment .................................................................................... 72 
7.4 
Screen Failures ......................................................................................... 72 
8. 
Treatment Procedures .......................................................................................... 73 
8.1 
Investigational and Non-investigational Products ...................................... 73 
8.1.1 
Investigational Product:  AMG 404 ............................................ 73 
8.1.2 
Cohorts 1-9 Investigational Product ........................................... 75 
8.1.7 
Medical Devices ........................................................................ 81 
8.1.9 
Other Treatment Procedures ..................................................... 82 
8.1.10 
Product Complaints ................................................................... 82 
8.1.11 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 83 
8.2 
Method of Treatment Assignment ............................................................. 84 
8.3 
Blinding ..................................................................................................... 84 
8.4 
Dose Modification ...................................................................................... 84 
8.4.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 84 
8.4.2 
DLT Definition ............................................................................ 85 
8.4.3 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 87 
8.4.3.1 
Amgen Investigational Product:  AMG 404 .............. 87 
8.4.3.4 
Immune-related Adverse Reactions ........................ 89 
8.4.3.5 
Infusion-related Reactions ....................................... 89 
8.4.3.6 
Embryo-fetal Toxicity ............................................... 89 
8.4.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 90 


Product:  AMG 404  
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Page 6 of 176 
CONFIDENTIAL 
 
 
8.4.5 
Dose Modification Guidelines for SARS-COV2 
Infection .................................................................................... 90 
8.4.6 
Dose Modification Due to Surgery During Study 
Treatment .................................................................................. 91 
8.5 
Preparation/Handling/Storage/Accountability ............................................ 91 
8.6 
Treatment Compliance .............................................................................. 91 
8.7 
Treatment of Overdose ............................................................................. 91 
8.8 
Prior and Concomitant Treatment ............................................................. 92 
8.8.1 
Prior Treatment ......................................................................... 92 
8.8.2 
Concomitant Treatment ............................................................. 92 
8.8.2.1 
SARS-COV2-Vaccination ........................................ 92 
9. 
Discontinuation Criteria ......................................................................................... 93 
9.1 
Discontinuation of Study Treatment........................................................... 93 
9.2 
Discontinuation From the Study ................................................................ 94 
9.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 94 
9.2.2 
Reasons for Removal From Study ............................................. 94 
9.3 
Lost to Follow-up ....................................................................................... 94 
10. 
Study Assessments and Procedures .................................................................... 95 
10.1 
General Study Periods .............................................................................. 95 
10.1.1 
Screening, Enrollment and/or Randomization ............................ 95 
10.1.2 
Treatment Period ....................................................................... 96 
10.1.3 
Extended Treatment Period ....................................................... 96 
10.1.4 
Safety Follow-up ........................................................................ 96 
10.1.5 
Long-term Follow-up .................................................................. 96 
10.1.6 
End of Study for a Particular Study Subject ............................... 96 
10.2 
Description of General Study Assessments and Procedures ..................... 96 
10.2.1 
General Assessments ............................................................... 97 
10.2.1.1 
Informed Consent .................................................... 97 
10.2.1.2 
Demographics ......................................................... 97 
10.2.1.3 
Medical History ........................................................ 97 
10.2.1.4 
Physical Examination .............................................. 97 
10.2.1.5 
Physical Measurements .......................................... 97 
10.2.1.6 
Performance Status................................................. 98 
10.2.2 
Efficacy Assessments ................................................................ 98 
10.2.3 
Safety Assessments .................................................................. 99 
10.2.3.1 
Adverse Events and Serious Adverse 
Events ..................................................................... 99 
10.2.3.2 
Vital Signs ............................................................. 103 
10.2.3.3 
Electrocardiograms (ECGs) ................................... 103 
10.2.4 
Clinical Laboratory Assessments ............................................. 104 
10.2.4.1 
Pregnancy Testing ................................................ 104 


Product:  AMG 404  
Protocol Number:  20180143 
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Page 7 of 176 
CONFIDENTIAL 
 
 
10.2.5 
Pharmacokinetic Assessments ................................................ 105 
10.2.7 
Antibody Testing Procedures ................................................... 106 
11. 
Statistical Considerations .................................................................................... 111 
11.1 
Sample Size Determination ..................................................................... 111 
11.2 
Analysis Sets, 
 and Covariates .............................................. 112 
11.2.1 
Analysis Sets ........................................................................... 112 
11.2.2 
Covariates ............................................................................... 112 
11.3 
Adaptive Design ...................................................................................... 113 
11.4 
Statistical Analyses ................................................................................. 113 
11.4.1 
Planned Analyses .................................................................... 114 
11.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................. 114 
11.4.1.2 
Primary Analysis ................................................... 118 
11.4.1.3 
Final Analysis ........................................................ 118 
11.4.2 
Methods of Analyses ............................................................... 118 
11.4.2.1 
General Considerations ......................................... 118 
11.4.2.2 
Efficacy Analyses .................................................. 118 
11.4.2.3 
Safety Analyses .................................................... 119 
11.4.2.4 
Other Analyses ...................................................... 120 
12. 
References ......................................................................................................... 121 
13. 
Appendices ......................................................................................................... 124 
13.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 125 
13.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 128 
13.3 
Appendix 3.  Study Governance Considerations ..................................... 129 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 8 of 176 
CONFIDENTIAL 
 
 
Committee(s) .......................................................................................... 129 
Regulatory and Ethical Considerations .................................................... 129 
Recruitment Procedures .......................................................................... 130 
Informed Consent Process ...................................................................... 130 
Data Protection/Subject Confidentiality ................................................... 132 
Publication Policy .................................................................................... 132 
Investigator Signatory Obligations ........................................................... 133 
Data Quality Assurance ........................................................................... 134 
Source Documents .................................................................................. 135 
Study and Site Closure............................................................................ 136 
Compensation ......................................................................................... 136 
13.4 
Appendix 4.  Toxicity Management Guidelines ........................................ 137 
13.5 
Appendix 5.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 148 
Definition of Adverse Event ..................................................................... 148 
Definition of Serious Adverse Event ........................................................ 149 
Recording Adverse Events and Serious Adverse Events ........................ 150 
Evaluating Adverse Events and Serious Adverse Events ........................ 150 
Reporting of Serious Adverse Event ........................................................ 152 
13.6 
Appendix 6.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 158 
Definition of Females of Childbearing Potential ....................................... 158 
Collection of Pregnancy Information ........................................................ 160 
Collection of Lactation Information .......................................................... 161 
13.7 
Appendix 7.  Sample Storage and Destruction ........................................ 164 
13.8 
Appendix 8.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 166 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 167 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 168 
13.9 
Appendix 9.  ECOG Performance Status and NYHA 
Classification ........................................................................................... 170 
13.10 Appendix 10.  Modified Response Evaluation Criteria in Solid 
Tumors Version 1.1 (Modified RECIST 1.1) ............................................ 171 
 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 9 of 176 
CONFIDENTIAL 
 
 
List of Tables 
Table 2-1.  Guideline for Dose Level Decisions ............................................................. 15 
Table 3-1.  Schedule of Activities for Cohorts 1-9 .......................................................... 24 
Table 4-1.  Key Safety Risks of AMG 404 ...................................................................... 47 
Table 4-2.  Potential Safety Concerns Based on Drug Class Effects, 
Biological Mechanism of Action, and Nonclinical Studies ........................ 48 
Table 6-1.  Guideline for Dose Level Decisions for Cohort 2 (480 mg) and 
Cohort 4 (1050 mg) ................................................................................ 54 
Table 8-1.  Cohorts 1-9 Investigational Product:  AMG 404 ........................................... 75 
Table 8-8. Dose Modification Guidelines for SARS-COV2 Infection ............................... 91 
Table 11-1.  Stopping Boundary Overall for Combined Monotherapy Data of 
Cohorts 3, 6, 7, 8, and 9 with Posterior Probability of 80% and 
Grade 4 or Higher Treatment-Related Adverse Event Limit of 
20% ...................................................................................................... 116 
Table 11-2.  Stopping Boundary for Enrollment within Cohorts 3, 6-
 
Individually with Posterior Probability of 80% and Subject 
Incidence of Grade 4 or Higher Treatment-Related Adverse 
Event Limit of 20% ................................................................................ 117 
Table 11-3.  Operating Characteristics with Batch Size of 10 Subjects 
(Combining All Monotherapy Data of Expansion Cohorts 3, 6, 
7, 8 and 9) ............................................................................................ 117 
Table 11-4.  Operating Characteristics With Batch Size of 10 Subjects 
(Cohort-Specific Enrollment with Maximum Cohort Sample 
Size of n=40 Subjects) .......................................................................... 117 
Table 13-1.  Analyte Listing ......................................................................................... 128 
Table 13-2.  Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Reactions Associated With 
AMG 404* ............................................................................................. 137 
Table 13-3.  Dose Modification Guidelines for Chemotherapy Hematological 
Toxicity ................................................................................................. 145 


Product:  AMG 404  
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CONFIDENTIAL 
 
 
Table 13-4.  Dose Modification Guidelines for Chemotherapy 
Nonhematological Toxicity .................................................................... 145 
Table 13-5.  Management of Infusion-Related Reactions With AMG 404 .................... 146 
Table 13-6.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 167 
List of Figures 
Figure 3-1.  Study Schema ............................................................................................ 20 
Figure 3-2.  Study Schema ............................................................................................ 21 
Figure 3-3.  Study Schema ............................................................................................ 22 
Figure 3-4.  Study Schema ............................................................................................ 23 
Figure 13-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form (Paper-Based Form) .................................................................... 153 
Figure 13-3.  Pregnancy and Lactation Notification Forms ........................................... 162 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 11 of 176 
CONFIDENTIAL 
 
 
2. 
Protocol Synopsis 
Protocol Title:  A Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, 
 
, in Patients With Advanced Solid 
Tumors 
Short Protocol Title:  AMG 404 in Patients with Advanced Solid Tumors 
Study Phase:  1 
Indication:  Advanced solid tumors 
Rationale 
The programmed cell death-1 (PD-1) receptor-ligand interaction is a major pathway that 
tumors use to suppress immune control. PD-1, part of the immunoglobulin (Ig) 
superfamily and related to CD28 and cytotoxic T-lymphocyte-associated protein-4 
(CTLA-4), has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2).  
Enhancement of anti-tumor immunity through inhibition of PD-1 has been effective in 
treatment of many malignancies when given as a single agent and when given as part of 
combination therapies. AMG 404, the investigational product under study, is a 
monoclonal antibody that binds to PD-1 and blocks its ability to interact with ligands 
PD-L1 and PD-L2.  
This first in human AMG 404 study is designed to assess safety and tolerability of 
AMG 404 monotherapy, 
 in patients with 
solid tumor malignancies.  
 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 12 of 176 
CONFIDENTIAL 
 
 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability 
and determine the recommended 
phase 2 dose (RP2D) of AMG 404 in 
patients with advanced solid tumors  
 
Dose limiting toxicities (DLTs), 
treatment-emergent adverse events, 
treatment-related adverse events, and 
changes in vital signs, and clinical 
laboratory tests 
Secondary 
 
To evaluate the pharmacokinetics 
(PK) of AMG 404 as a monotherapy 
 
 
 
PK parameters of AMG 404 including, 
but not limited to, maximum observed 
serum concentration (Cmax), time to 
achieve Cmax (tmax), and area under 
the serum concentration-time curve 
(AUC) 
 
To assess the immunogenicity of  
AMG 404 as a monotherapy 
 
 
 
Subject incidence of anti-AMG 404 
antibodies 
 
To evaluate the preliminary antitumor 
activity of AMG 404 as a 
monotherapy
 
 
Objective tumor response, duration of 
overall response, progression-free 
survival, disease control rate (DCR), 
and duration of stable disease 
measured by CT/MRI and assessed 
per modified RECIST 1.1 
 
Hypotheses 
AMG 404 is safe and well tolerated in patients with advanced solid tumors.  
Overall Design 
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study to 
evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of AMG 404 
as a monotherapy 
, in subjects with 
advanced solid tumors.  The study may be conducted in Australia, United States, 
France, Poland, Spain, Turkey, United Kingdom, Belgium, South Korea, Taiwan, Japan, 
China, Singapore, Canada, Brazil, and Mexico.  Other countries or regions may 
participate.  
.  Cohorts 1-9 will evaluate the 
safety, tolerability, PK and pharmacodynamics of AMG 404 with the following Q4W 
doses:  Cohort 1 – 240 mg, Cohort 2 – 480 mg, Cohort 3 – Expansion at the dose of 
480 mg (subjects enrolled outside of China), Cohort 4 – Exploratory Dose of 1050 mg, 
Cohort 5 – China and National Medical Products Administration (NMPA) certified sites in 
Taiwan and/or Hong Kong Specific Expansion at the recommended phase 2 dose 
(RP2D) with a safety lead-in 
 
Cohort 6 – Expansion at the RP2D , Cohort 7 – Expansion at the RP2D in specific 
indications as specified in Section 3.1, Cohort 8 – Expansion at the RP2D in subjects 
with tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient 


Product:  AMG 404  
Protocol Number:  20180143 
Date:  20 May 2022 
Page 13 of 176 
CONFIDENTIAL 
 
 
(dMMR), and Cohort 9 – Expansion at the RP2D in subjects with non-small cell lung 
cancer (NSCLC) that is PD-L1 positive, Tumor Proportion Score (TPS)  50% 
(Cohorts 6-9 will enroll subjects outside of China).  
In Cohorts 1-9, AMG 404 will be administered intravenously (IV) over approximately 
30 minutes, every 4 weeks in subjects with advanced solid tumors.  Cohorts 3 and 4 can 
be opened once Cohort 2 has been completed and determined to be tolerable.  Cohorts 
5-9 can be opened once the first 6-9 subjects in Cohort 4 have completed the DLT 
evaluation period and data have been reviewed to determine the RP2D.  The DLT 
evaluation period will be 28 days.  The Dose Level Review Meeting (DLRM) may 
recommend escalation to the next planned dose, escalation to an intermediate dose (a 
dose lower than the next planned dose), continuation or delay in dosing, repetition or 
expansion of a cohort, de-escalation to a lower dose, or termination of the study. 
Administration of AMG 404 (in all cohorts) may continue until evidence of disease 
progression, intolerance to study medication, withdrawal of consent, or in the absence of 
the above up to 12 months if subject achieves a complete response, and up to 
24 months if partial response or stable disease.  Subjects with complete response may 
be permitted to continue treatment beyond 12 months, up to a maximum of 24 months 
of total therapy, upon discussion with the medical monitor.  Subjects with complete 
response, partial response, stable disease or continued clinical benefit at 
24 months of treatment, may continue treatment for up to an additional 24 months 
(up to 48 months of treatment in total), upon discussion with the medical monitor.  
If a subject completes or discontinues treatment for reasons other than progression, 
tumor evaluations should continue according to the Schedule of Activities (Table 3-1) 
until progression or start of a new treatment regimen. 
Cohorts 1, 2 and Cohort 4 
The doses of 240 mg, 480 mg and 1050 mg will be examined for safety, tolerability, PK, 
and pharmacodynamics of AMG 404 in subjects with advanced solid tumors.  Rules for 
dose determination, and dose expansion are derived using a modified Toxicity 


Product:  AMG 404  
Protocol Number:  20180143 
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Page 14 of 176 
CONFIDENTIAL 
 
 
Probability Interval (mTPI) model (Ji et al. 2010) with a target toxicity probability interval 
(TPI) of 0.20 to 0.33 with a TPI  0.33 defined as excessive toxicity.   
 
Subjects will not be dosed at a level above the dose level indicated by the mTPI 
model.  In particular, subjects will not be dosed at the current dose level or higher 
when the mTPI model indicates stopping enrollment at the current dose level and 
patients will not be dosed at an escalated dose level when the mTPI indicates 
staying at the current dose level. 
 
After reviewing a broad range of safety information including vital signs, 
laboratory values and detailed adverse events profiles, the team may choose to 
dose subjects below the dose level indicated by the mTPI model.  For example, 
the team may choose to stop enrollment at the current dose level even if the 
mTPI model indicates staying at the current dose level.  
The Dose Level Review Team (DLRT) will review data, monitor safety, and make 
recommendations on dose modifications based on all subjects that have been enrolled.  
A Dose Level Review Meeting will be conducted after Cohorts 1, 2 and 4 and may 
convene ad hoc to review safety data if deemed necessary.  
Three dose levels are planned to be tested: 
 
Cohort 1:  240 mg every 4 weeks (N  2-4) 
 
Cohorts 2 and 3:  480 mg every 4 weeks (Cohort 2:  N  6-9; Cohort 3: N  20) 
 
Cohort 4:  1050 mg every 4 weeks (N  20) 
Dose escalation will begin with a run-in dose level of 240 mg (Cohort 1).  If no DLTs are 
observed in Cohort 1, dose escalation will continue to the next planned dose level in 
Cohort 2.  If DLTs are observed in Cohort 1, subsequent dosing will be determined by 
Amgen after consulting with the Dose Level Review Team (DLRT) and constrained by 
the mTPI model.  
The table below shows rules for dose determination and dose expansion per the mTPI 
model.  


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CONFIDENTIAL 
 
 
Table 2-1.  Guideline for Dose Level Decisions 
No. of Subjects 
Number of DLT observed at current dose 
ESCALATEa 
STAY AT CURRENT 
DOSE 
STOP ENROLLMENT 
AT CURRENT DOSE 
3 
N/A 
≤ 1 
≥ 2 
4 
N/A 
≤ 1 
≥ 2 
5 
N/A 
≤ 2 
≥ 3 
6 
0 
1 – 2 
≥ 3 
7 
≤ 1 
2 – 3 
≥ 4 
8 
≤ 1 
2 – 3 
≥ 4 
9 
≤ 1 
Maximum sample size 
reached 
Maximum sample size 
reached  
a For Cohort 4 (1050 mg), if the rules for dose escalation are met, enrollment may be stopped as there is 
sufficient evidence that 1050 mg dose is safe and tolerable; and this is the highest planned dose level 
being investigated on study. 
Cohort 3 
Upon completion of Cohort 2 of the study and depending on data obtained, dose 
expansion may proceed with the planned dose of 480 mg in Cohort 3 (N  20) outside of 
China.  
Cohorts 5-9  
Upon completion of the first 6-9 subjects in Cohort 4 of the study and depending on data 
obtained, dose expansion may proceed with the RP2D in Cohort 5 with a safety lead-in 
(from China or NMPA certified sites in Taiwan and/or Hong Kong only) and Cohorts 6-9 
(from all countries participating on the study, excluding China).  The RP2D will be 
determined following review of available data obtained in Cohorts 1 through 4 including 
safety, tolerability, PK and PD data.  
. 
Cohort 5 was a China/Taiwan/Hong Kong-specific expansion cohort with a safety 
lead-in at one dose below the RP2D followed by evaluation at RP2D, as appropriate.    
Up to 12 subjects would be enrolled in China, and/or in Taiwan, and/or Hong Kong (if 
Taiwan or Hong Kong, only NMPA certified sites will participate).  
 
Intrasubject dose escalation for Cohorts 1-9 
Intra-Subject dose escalations are allowed on this study for subjects enrolled, where 
applicable.  Subjects enrolled to Cohort 1 who complete the DLT period may proceed to 
480 mg once Cohort 2 has been deemed safe by the DLRT; subjects receiving 480 mg 


Product:  AMG 404  
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Page 16 of 176 
CONFIDENTIAL 
 
 
(in Cohorts 1-3) who complete the DLT period may proceed to the RP2D once 
determined if a dose higher than 480 mg is selected as the RP2D.  Subjects enrolled to 
the safety lead-in dose in Cohort 5, may escalate to the RP2D dose level once the RP2D 
is determined safe following the China/Taiwan/Hong Kong specific DLRT 
recommendation.  
. 
All intra-subject dose escalations may occur after consultation with the sponsor if:  
 
No DLT has been reported for this subject during or after completion of the DLT 
period 
Subjects who do not proceed to the higher dose may receive additional cycles at the 
original dose. 


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Number of Subjects 
Cohort 1: Up to 4 evaluable subjects may be enrolled to this cohort. 
Cohort 2:  Up to 9 evaluable subjects may be enrolled to this cohort. 
Cohort 3:  An additional 20 evaluable subjects will be enrolled in the dose expansion part 
of the study outside of China. 
Cohort 4:  Up to 20 evaluable subjects may be enrolled to this cohort. 
Cohort 5:  Approximately 12 evaluable subjects will be enrolled from China, or from 
National Medical Products Administration (NMPA) certified sites in Taiwan and/or Hong 
Kong 
  
Cohort 6:  Approximately 20 evaluable subjects will be enrolled in the dose expansion at 
the RP2D outside of China.  
Cohort 7:  Up to 40 evaluable subjects  
Cohort 8:  Up to 40 evaluable subjects 
Cohort 9:  Up to 40 evaluable subjects 
Summary of Subject Eligibility Criteria 
Adult subjects ( 18 years old) with histologically or cytologically proven metastatic or 
locally advanced solid tumors who are checkpoint inhibitor naïve.  Subjects enrolled to 


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Cohort 9 may not have received prior systemic treatment for their metastatic or recurrent 
disease (prior neoadjuvant, adjuvant, and/or chemotherapy given concurrently with 
definitive radiation is allowed).  
Once consented to the study, subjects will provide a medical history and undergo 
screening safety tests to confirm all eligibility requirements of the study have been met.  
For a full list of eligibility criteria, 
, please 
refer to Section 7.1 and Section 7.2. 
Treatments 
In Cohorts 1-9, AMG 404 will be administered intravenously (IV) over approximately 
30 minutes, every 4 weeks in subjects with advanced solid tumors. 
Three dose levels are planned to be tested:  
 
Cohort 1:  240 mg every 4 weeks (N  2-4) 
 
Cohorts 2 and 3:  480 mg every 4 weeks (Cohort 2:  N  6-9; Cohort 3: N  20) 
 
Cohort 4:  1050 mg every 4 weeks (N  20)  
Upon completing Cohort 2 of the study and depending on data obtained, the dose 
expansion may proceed with the planned dose of 480 mg in Cohort 3 (N  20) outside of 
China. 
After the first 6-9 subjects have completed the DLT evaluation period in Cohort 4 of the 
study and depending on data obtained, the dose expansion may proceed with the RP2D 
in Cohorts 5-9, 
    
Procedures 
After written informed consent has been obtained, all screening tests and procedures will 
be performed within 28 days of administration of the first dose (cycle 1, day 1) of 
AMG 404, unless otherwise noted.  Subjects will be seen in clinic where critical clinical 
safety and study evaluations will be performed including physical examination, vital 
signs, clinical laboratory tests, electrocardiograms (ECGs), PK, and 
 sample 
collections. 
For a full list of study procedures, including the timing of each procedure, please refer to 
General Assessments (Section 10.2) and the Schedule of Activities (for Cohorts 1-9, 


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refer to Table 3-1
 
 
Statistical Considerations 
The primary analysis will occur when target enrollment is complete and each subject 
either completes 6 months on study or withdraws from the study.  
The DLRT will review data, monitor safety, and make recommendations on dose 
modifications based on all subjects that have been enrolled.  Rules for dose 
determination and dose expansion are derived using a modified Toxicity Probability 
Interval (mTPI) model.  
Descriptive statistics will be provided for selected demographics, safety, PK, efficacy 
 
 by cohort, or time as appropriate.  Descriptive statistics on continuous 
data will include means, medians, standard deviations and ranges, while categorical 
data will be summarized using frequency counts and percentages.  
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected.  These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing. 
The proportion of subjects with an objective tumor response (partial and complete 
response) and disease control rate (DCR) (partial or complete control) with 
corresponding exact 80% CI will be calculated and tabulated.  Similarly, the proportion of 
subjects and 80% CI will be tabulated for 1-year duration of overall response, 1-year 
PFS, 1-year duration of stable disease and 1-year OS.  Kaplan-Meier curves will be 
presented for duration of overall response, PFS, OS, and duration of stable disease with 
estimates for rate and 80% CI at selected weeks if data allows.  
For a full description of statistical analysis methods, please refer to Section 11. 
Sponsor Name: Amgen Inc.  


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3. 
Study Schema and Schedule of Activities 
3.1 
Study Schema 
Figure 3-1.  Study Schema 
Cohort 1
(Dose Escalation)
Cohort 2
(Dose Escalation)
Cohort 3
(Dose Expansion)
Cohort 4
(Safety Exploratory Dose)
Cohort 5
(China/Taiwan/Hong Kong
RP2D* Expansion)
Cohort 6
(RP2D Expansion)
Cohort 8
(Tumor Specific Efficacy)
Cohort 9
(Tumor Specific Efficacy)
Cohort 7
(Tumor Specific Efficacy)
RP2D = Recommended Phase 2 Dose; Q3W = every 3 weeks; and Q6W = every 6 weeks
* With safety lead-in
Refer to the schematics for each cohort below and Section 6.1 for further details
 
Page 1 of 4 


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Figure 3-2.  Study Schema 
Amgen Proprietary - Confidential
End of Treatment
AMG 404 240 mg IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
Cohort 1: 240 mg Dose Escalation (N=2-4)
Cohort 2: 480 mg Dose Escalation (N=6-9)
End of Treatment
AMG 404 480 mg IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
Cohort 3: 480 mg Dose Expansion (N=20)
End of Treatment
AMG 404 480 mg IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
Cohort 4: 1050 mg Safety Exploratory Dose (N=20)
End of Treatment
AMG 404 1050 mg IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
End of Treatment
AMG 404 RP2D* IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
Cohort 5: RP2D* China/Taiwan/Hong Kong Specific Expansion (N=12)
Cohort 6: RP2D Expansion (N=20)
End of Treatment
AMG 404 RP2D IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
RP2D = Recommended Phase 2 Dose; and IV = intravenous
*
With safety lead-in
 
Page 2 of 4 


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Figure 3-3.  Study Schema 
Amgen Proprietary - Confidential
Cohort 7 (N40)

Melanoma

Small Cell Lung Cancer

NSCLC, PD-L1 positive

Head and Neck Squamous Cell Cancer, PD-L1 positive

Urothelial, PD-L1 positive

Gastric or GEJ adenocarcinoma, PD-L1 positive

Esophageal, squamous, PD-L1 positive

Cervical, PD-L1 positive

Hepatocellular Carcinoma

Merkel Cell Carcinoma

Squamous Cell Carcinoma of the skin

Renal Cell Carcinoma, clear cell

Subtypes of sarcoma
o
Undifferentiated pleiomorphic / malignant 
fibrous histiocytoma
o
Poorly differentiated and/or dedifferentiated 
liposarcoma
o
Alveolar Soft Tissue Sarcoma
o
Angiosarcoma

Thymic carcinoma

Nasopharyngeal carcinoma (
)

Mesothelioma
RP2D = Recommended Phase 2 Dose; PD-L1 = programmed death-ligand 1; 
GEJ = esophagogastric junction adenocarcinoma; 
; IV = intravenous; 
TPS = tumor proportion score; NSCLC = non-small cell lung cancer; 
MSI-high = microsatellite instability; and dMMR = mismatch repair deficient
End of Treatment
AMG 404 RP2D IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
Cohort 7: RP2D Tumor Specific Efficacy (N=40)
Cohort 8: RP2D Tumor Specific Efficacy (N=40)
End of Treatment
AMG 404 RP2D IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
Cohort 9: RP2D Tumor Specific Efficacy (N=40)
End of Treatment
AMG 404 RP2D IV
every 4 weeks
Screening
Safety Follow up
Long Term Follow 
up
Cohort 8  (N = 40)

MSI- high or dMMR subjects
-
20 metastatic colorectal cancer
Cohort 9  (N = 40)

Non-small cell lung cancer, PD-L1 positive, 
TPS 50
 
Page 3 of 4 


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3.2 
Schedule of Activities 
Table 3-1.  Schedule of Activities for Cohorts 1-9 
CYCLES 
Screening  
(up to 
28 days 
before 
Day 1) 
Treatment Period 
Follow-up 
1* 
2* 
3* and 
beyond 
Extended 
Treatment 
 
 
 
DAYS 
1* 
2 
4 
8 
(1d) 
15 
(1d) 
1* 
2 
4 
8 
(1d) 
15 
(1d) 
1* 
1* 
EOT12 Safety 
F/U10, 12 LTFU10 
Hours  
(relative to end of infusion) 
 
Pre 
dose 
0 
EOI 
2 
4 
24 
72 
168 
336 
Pre 
dose 
0 
EOI 
2 
4 
24 
72 
168 
336 
Pre 
dose 
0 
EOI 
Pre 
dose 
0 
EOI 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, ECOG 
PS, wt, (Ht at screening only)  
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate measurement1 
X 
X1 
X1 
 
X1 
 
 
 
 
 
X1 
 
 
 
 
 
 
 
X1 
 
X1 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Adverse events review 
 
 
 
Serious Adverse Events17 
X 
 
Concomitant medication review 
X 
 
LABORATORY ASSESSMENTS 
Pregnancy test (females of 
childbearing potential only)2 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Chemistry3 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
HIV, Hepatitis B and C 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
ACTH, ANA, ANCA4 
X 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
 
X4 
 
X4 
X4 
 
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Table 3-1.  Schedule of Activities for Cohorts 1-9 
CYCLES 
Screening  
(up to 
28 days 
before 
Day 1) 
Treatment Period 
Follow-up 
1* 
2* 
3* and 
beyond 
Extended 
Treatment 
 
 
 
DAYS 
1* 
2 
4 
8 
(1d) 
15 
(1d) 
1* 
2 
4 
8 
15 
1* 
1* 
EOT12 
Safety 
F/U10, 12 LTFU10 
Hours (relative to end of 
infusion) 
 
Pre 
dose 
0 
EOI 
2 
4 
24 
72 
168 
336 
Pre 
dose 
0 
EOI 
2 
4 
24 
72 
168 
336 
Pre 
dose 
0 
EOI 
Pre 
dose 
0 
EOI 
 
 
 
RADIOLOGICAL ASSESSMENTS 
Tumor Evaluation/staging  
(CT, MRI, as appropriate)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
 
X5 
 
X 
 
 
Brain MRI or CT with contrast5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
 
X5 
 
 
 
 
PHARMACOKINETIC ASSESSMENTS6 
Cohorts 1–6 (all subjects), 
Cohorts 7–9 (at least 
10 subjects of each cohort) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Cohorts 7–9 (remaining 
subjects) 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
 
RESEARCH LABS, ALL SITES 
ADA/Immunogenicity 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X9 
 
 
 
X 
X 
 
Whole Blood for Cytometry13 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X8 
 
 
 
 
 
 
LTFU 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 2 of 2 
Footnotes defined on next page of this table 


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* A Cycle is defined as 28 (3) days; Day 1 assessments must be done within 48 hours of AMG 404 infusion; screening assessments if done within 48 hours do not have to be repeated on 
day 1 of treatment; AMG 404 will be infused on Day 1 after all safety assessments have been completed. 
CT  computed tomography;
 ECG  electrocardiogram; ECOG PS  Eastern Cooperative Oncology Group Performance Status; EOT  end of 
treatment; HIV  human immunodeficiency virus; LTFU  long-term follow-up; MRI  magnetic resonance imaging; PK  pharmacokinetic; SFU  safety follow-up. 
1 A set of triplicate ECGs must be performed at screening; all ECGs will be triplicates with each tracing approximately 30 seconds apart and run consecutively.  ECGs will only be collected 
for subjects enrolled to Cohorts 1, 2 and 4 at the following time points:  Screening, C1D1 predose and end of infusion, C1 D1 (4 hours post dose), C2D1 end of infusion, C3D1 end of 
infusion, C4D1 end of infusion, and C5D1 end of infusion.  Beginning with Cycle 6 and beyond for subjects enrolled to Cohorts 1, 2 and 4 will have ECGs performed if clinically indicated.  
Subjects enrolled to Cohort 3 and Cohorts 5-9 will have an ECG performed at screening and then as clinically indicated. 
2 Pregnancy testing is required for all female subjects of childbearing potential.  Serum pregnancy test at screening and 48 hours prior first dose of AMG 404.  Beginning with cycle 2 and 
beyond, a urine or serum pregnancy test is required within 48 hours prior to AMG 404 infusion.  
3 Chemistry to include:  Albumin, Alkaline Phosphatase, ALT, AST, BUN/Total urea, Bicarbonate or CO2, Calcium, Calcium Corrected, Chloride, Creatinine, Glucose, Potassium, Sodium, 
Total Bilirubin, Total protein, TSH, Free T4 
4 ACTH to be done at screening, prior to C1D1, and then every 8 weeks (prior to cycles 1, 3, etc). ANA and ANCA (cytoplasmic and perinuclear) to be done at screening and then if clinically 
indicated. 
5 
tumor evaluation scans every 8 ( 1) weeks, same modality should be used throughout study. MRI or CT of brain required for all 
subjects during screening and required on study only if subject has history of CNS disease; otherwise as clinically indicated.  If a subject discontinues treatment for reasons other than 
progression, tumor assessments should continue in follow up every 8 (1) weeks until progression or start of a new treatment regimen.  Subjects with extended treatment will undergo 
tumor evaluation scans every 12 ( 2) weeks, and MRI or CT of brain as clinically indicated. 
6 PK blood samples should be collected at the exact nominal time point as noted above (see hour postdose column).  If unable to collect a blood sample at the specified nominal time point, 
collect it as close as possible to the nominal time point and record the actual collection time.  PK samples not collected at exact nominal time point will not be considered protocol 
deviations. 
9 Beginning with cycle 3, ADA/Immunogenicity sample collected every cycle, predose (ie, cycle 3, cycle 4, cycle 5, etc).  
10 Safety follow-up visit is to take place 30 ( 3) days and 140 days (7 days) after last dose.  Long-term follow-up phone call at 6 months (1 week) after last dose to collect information on 
survival, start of new therapies, and disease status. 
12 The EOT and SFU may be combined if the visit occurs 30 ( 3) days after the last dose of AMG 404.  In addition, for subjects that continue treatment of AMG 404 in the extended 
treatment period only, assessments for ADA/immunogenicity and PK will not be collected at EOT and SFU visits.  
13 Whole blood cytometry collections are required for Cohorts 1-6 only for receptor occupancy immunophenotyping.  Last sample is collected cycle 3 predose (not required cycle 4 and 
beyond). 
14 Whole blood immunophenotyping collections are required for Cohorts 7-9 only for analysis of lymphocyte activation and exhaustion.  Last sample is collected cycle 3 predose (not 
required cycle 4 and beyond). 
During the long-term follow-up phase serious adverse events suspected to be related to investigational products that the investigator becomes aware of 
will be reported to Amgen.  After end of study, serious adverse events suspected to be related to investigational products will be reported to Amgen.  Please refer to 
Section 10.2.3.1.1.3 for additional details. 
  


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4. 
Background and Rationale 
4.1 
Disease and Target Background 
Anti-tumor surveillance by the immune system is a well-known mechanism to prevent 
growth and spread of malignancies.  This natural defense mechanism is, however, 
susceptible to fatigue.  T cells can lose their efficacy through increased expression of the 
programmed cell death-1 (PD-1) proteins and their ligands, PD-L1. (Riley et al, 2009).  
The programmed cell death-1 (PD-1) receptor-ligand interaction is a major pathway 
hijacked by tumors to suppress immune control (Pedoeem et al, 2014).  The normal 
function of PD-1, expressed on the cell surface of activated T cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4), which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2). 
Enhancement of anti-tumor immunity through inhibition of PD-1/PD-L1 has been 
effective in treatment of many malignancies (Pembrolizumab US Prescribing 
Information, Nivolumab US Prescribing Information and Cemiplimab US Prescribing 
Information).  For example, use of PD-1/PD-L1 monoclonal antibodies have resulted in 
objective tumor response and/or improved survival in lung cancer, melanoma, urothelial 
carcinoma, head and neck squamous cell carcinoma, and cutaneous squamous cell 
carcinoma (Gong et al, 2018). 
While objective responses have been achieved in many patients, some do not benefit 
from anti-PD-1 monotherapy.  Optimal therapy will likely require combining anti-PD-1 
monoclonal antibody treatment with conventional therapies and novel targeted or 
immunotherapy approaches.  
The use of combinations of chemotherapy, targeted therapy, and other checkpoint 
inhibitors and immune modulating agents along with PD-L1 inhibitors is being 
investigated in multiple disease states and has been shown to improve efficacy over 
some of the former standard therapies (for example, in non-small cell lung cancer in 
combination with chemotherapy or in combination with chemotherapy and 
antiangiogenic therapy [Socinski et al, 2018], and in melanoma in combination with 
CTLA-4 inhibitors [Wolchok et al, 2017]). 


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4.1.1 
PD-1/PD-L1 Inhibitors and Treatment of NSCLC 
Programmed cell death-1 checkpoint blockade has transformed the treatment of 
NSCLC.  Programmed cell death-1, and then PD-L1 inhibitors were first approved for 
NSCLC in the second line or later setting based on studies showing significant 
anti-tumor activity and improved overall survival in both squamous and non-squamous 
NSCLC when compared to docetaxel alone.  Nivolumab, pembrolizumab, and 
atezolizumab are approved by the United States Food and Drug Administration (US 
FDA) for treatment of second line or later advanced or metastatic NSCLC (Doroshow et 
al, 2019).   
In the front-line setting, clinical trials with PD-1/ PD-L1 inhibitors have demonstrated 
improved overall survival when given as monotherapy in PD-L1 expressing tumors and 
in combination with chemotherapy.  Pembrolizumab is US FDA approved for first line 
monotherapy in advanced NSCLC expressing PD-L1 with tumor proportion score 
(TPS)  1% (Keytruda USPI).  Cemiplimab is approved for the first-line treatment of 
NSCLC with high PD-L1 TPS  50% (Libtayo USPI).  Atezolizumab is also approved for 
first-line treatment of tumors with high PD-L1 expression (Tecentriq USPI).  The addition 
of PD-1/PD-L1 inhibitors to first line chemotherapy demonstrated improvement in overall 
survival in metastatic NSCLC regardless of PD-L1 expression. (Chiang et al, 2020).  The 
Keynote-189 study compared pembrolizumab, platinum-based drug, and pemetrexed to 
placebo, carboplatin, and pemetrexed in subjects with non-squamous NSCLC and 
reported a 12 month overall survival of 69.2% versus 49.4% 
(HR  0.49; 95% CI: 0.38 to 0.64; P  0.001), and led to the FDA approval of 
pembrolizumab, platinum-based drug, and pemetrexed for first line treatment of 
metastatic nonsquamous NSCLC regardless of PD-L1 expression (Gandhi et al, 2018). 


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4.2 
Amgen Investigational Product Background:  AMG 404 
4.2.1 
Nonclinical Pharmacology 
AMG 404 is a fully human antibody that binds human and cynomolgus monkey PD-1 
with high affinity and blocks the ability of these receptors to interact with human ligands, 
PD-L1 and PD-L2.  The ligand blocking activity of AMG 404 was evaluated in three 
different assays using three different readouts and both cell-expressed, as well as 
recombinant, soluble ligands.  In each assay, AMG 404 demonstrated the expected 
dose-dependent activity, indicating it is a potent inhibitor of human and cynomolgus 
monkey PD-1 binding.   
AMG 404 blocks the interaction between cynomolgus monkey PD-1 and human PD-L1 
with a similar IC50 as human PD-1 and human PD-L1, suggesting that cynomolgus 
monkey is an appropriate species for nonclinical safety evaluation.   
AMG 404 is an IgG1 antibody; however, the Fc region has been modified to eliminate 
undesired interactions with Fc gamma receptors.  The absence of Fc-binding to Fc 
gamma receptors was demonstrated in a functional assay where the ability of AMG 404 
to induce ADCC activity was compared to a positive control anti-CD38 antibody and 
negative control antibodies.  In this assay, AMG 404 activity was comparable to the 
negative control antibodies and was much less than the positive control.  These results 
demonstrate that the Fc region of AMG 404 does not interact with Fc gamma receptors. 
4.2.2 
Toxicology 
The potential for AMG 404 to cause acute release of cytokines from human peripheral 
blood leukocytes (PBL) in the presence of human endothelial cells (HUVECs) was 
evaluated in vitro.  Human PBL were cultured in autologous Platelet Poor Plasma (PPP) 
in the presence of HUVECs with AMG 404 (0.0112 – 35 µg/mL) for 24 hours, and 
supernatants from the cultures were subsequently assessed for the presence of 
cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, and TNFα).  Under the 


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conditions tested in this assay, AMG 404 did not induce cytokine release above 
background levels. 
AMG 404 was evaluated in a 28-day GLP toxicology study in cynomolgus monkeys.  
Doses of 0, 10 or 100 mg/kg were administered by slow IV bolus, and doses of 0 or 
100 mg/kg were administered SC (3 animals/sex/group).  Animals were dosed once 
weekly (4 total doses).  There were no AMG 404-related clinical signs or effects on body 
weight, food consumption, respiratory rate, body temperature, organ weights, or 
urinalysis parameters and no AMG 404-related ocular, electrocardiographic, neurologic, 
or macroscopic findings.  AMG 404-related clinical pathology changes were limited to 
mild decreases in lymphocytes for females at all dose levels on Day 2 that were 
generally similar to control and/or baseline values on Day 9 and throughout the 
remainder of the study, and mildly increased C-reactive protein in some animals.  
AMG 404-related microscopic findings included an increased incidence and/or severity 
of mononuclear cell infiltration in the brain (minimal to mild) and/or spinal cord (minimal) 
of animals given  10 mg/kg IV or 100 mg/kg SC and at the administration site (minimal 
to mild) of males given 100 mg/kg SC.  The increased incidence and/or severity of 
mononuclear cell infiltration in the brain and/or spinal cord observed in this study may 
represent an exacerbation of this background finding in cynomolgus monkeys, while the 
mononuclear cell infiltration at the administration site was considered an expected 
reaction to the administration of an exogenous protein.  In conclusion, administration of 
AMG 404 by once weekly IV bolus or SC injection was well tolerated in cynomolgus 
monkeys at levels of 10 mg/kg IV and 100 mg/KG IV and SC. 
4.2.3 
Nonclinical Pharmacokinetics 
The PK of AMG 404 was characterized after single intravenous (IV) bolus injection at 0.5 
and 5 mg/kg and single subcutaneous (SC) injection at 5 mg/kg to male cynomolgus 
monkeys.  Serum concentrations of AMG 404 declined in a biphasic manner for the first 
168 hours post dose followed by a more rapid decrease, most likely because of the 
formation of anti-AMG 404 antibodies (ADA) which were observed in all animals at 
336 hours post dose.   
The toxicokinetics (TK) of AMG 404 were characterized in a Good Laboratory Practice 
(GLP) study after weekly IV administration of 10 or 100 mg/kg or SC administration of 
100 mg/kg for four consecutive weeks.  Following repeat dose administration, AMG 404 
exposure increased approximately dose-proportionally from 10 to 100 mg/kg as 


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measured by Cmax and AUC over 6 days.  AMG 404 exposures were similar between 
male and female animals.   
4.2.4 
Rationale for Development AMG 404 
Blockade of the PD-1/PD-L1 T-cell checkpoint pathway is an effective and generally well 
tolerated approach to stimulating immune response to tumor cells.  While objective 
responses have been achieved in many patients, some do not benefit from PD-1 
monotherapy. Optimal therapy will likely require combining anti-PD-1 monoclonal 
antibody treatment with conventional therapies and novel targeted or immunotherapy 
approaches.  Amgen is developing a large oncology portfolio and to maximize this 
portfolio for patient benefit, Amgen is developing AMG 404.  Access to AMG 404 allows 
Amgen to develop a deeper understanding of target engagement and pharmacodynamic 
profile in combination with our portfolio and facilitates more rapid dosing and dose 
frequency adaptations while studying across multiple malignancies (solid tumors and 
hematologic malignancies).   
This study will evaluate AMG 404 as a monotherapy 
 
 to determine safety and tolerability.  
 


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4.5 
Benefit/Risk Assessment 
AMG 404  
This is a first-in-human study with AMG 404.  Based on nonclinical toxicity studies of 
AMG 404, clinical experience with AMG 404, and clinical experience with other 
anti-PD(L) -1 therapies, the overall benefit/risk profile favors clinical development of 
AMG 404 for patients with advanced solid tumors.   
Clinical signs and symptoms, along with other safety laboratory parameters, will be 
monitored during the study and at the appropriate time points to ensure subjects’ safety.   
The following benefit/risk assessment supports the conduct of this clinical trial.  Refer to 
the AMG 404 Investigator’s Brochure for further information. 


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4.5.1 
Therapeutic Context 
AMG 404 
AMG 404 will be investigated in subjects with advanced solid tumors as monotherapy 
 
4.5.2 
Benefits 
AMG 404 
As AMG 404 is in early development and clinical experience is limited, key benefits are 
being investigated and will be described when the data become available. 
4.5.3 
Risks 
AMG 404 
AMG 404 is being evaluated as an ongoing monotherapy in the current study.  
Based on the available clinical data with AMG 404, hypothyroidism, colitis, 
pneumonitis, and myasthenia gravis are identified risks of AMG 404 (see 
Table 4-1). 


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Table 4-1.  Key Safety Risks of AMG 404 
Safety Risk  
Description  
Hypothyroidism  
Administration of AMG 404 has been associated with 
hypothyroidism or blood thyroid stimulating hormone increased.  
Signs and symptoms that may be associated with 
hypothyroidism include fatigue, increased sensitivity to cold, 
constipation, dry skin, weight gain, hoarseness, muscle 
weakness, myalgia, arthralgia, menstrual disturbance, alopecia, 
bradycardia, hypercholesterolemia, depression, impaired 
memory, and enlarged thyroid gland (goiter).  
Hypothyroidism or blood thyroid stimulating hormone increased 
reported events did not lead to AMG 404 discontinuation or 
AMG 404 treatment interruption.  Subjects should be monitored 
for laboratory values of thyroid stimulating hormone and Free T4, 
and signs and symptoms of hypothyroidism during AMG 404 
treatment.  Subjects should continue to be monitored after 
discontinuation of AMG 404 due to the risk of late onset 
hypothyroidism.  Requirements for monitoring and management 
of hypothyroidism are provided in the clinical study protocol. 
Colitis  
Administration of AMG 404 has been associated with colitis.  
Signs and symptoms that may be associated with colitis include 
diarrhea, abdominal pain, abdominal cramping, and blood or 
mucus in the stool.  
Colitis events have led to AMG 404 discontinuation.  Subjects 
should be monitored for signs and symptoms of colitis during 
AMG 404 treatment.  Subjects should continue to be monitored 
after discontinuation of AMG 404 due to the risk of late onset 
colitis.  Requirements for monitoring and management of colitis 
are provided in the clinical study protocol(s). 
Pneumonitis 
Administration of AMG 404 has been associated with 
pneumonitis.  Signs and symptoms that may be associated with 
pneumonitis include cough, shortness of breath, chest pain and 
fatigue.  Pneumonitis events have led to discontinuation of 
AMG 404.  Subjects should be monitored for signs and symptoms 
of pneumonitis during AMG 404 treatment.  Subjects should 
continue to be monitored after discontinuation of AMG 404 due to 
the risk of late onset pneumonitis.  Requirements for monitoring 
and management are provided in the clinical study protocol(s). 
Myasthenia Gravis  
Administration of AMG 404 has been associated with the serious 
myasthenia gravis in one subject in a combination study of 
AMG 404 and AMG 160 for prostate cancer. 
Signs and symptoms that may be associated with myasthenia 
gravis include diplopia, ptosis, muscle weakness and fatigability, 
difficulty with speech, swallowing, and/or breathing.  Myasthenia 
gravis event led to permanent discontinuation of the study drugs.  
Subjects should be monitored for signs and symptoms of 
myasthenia gravis during AMG 404 treatment. 
 


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Additional key safety information, which are based on the mechanism of action, 
the nonclinical safety pharmacology and toxicology studies for AMG 404, 
available data from the ongoing clinical study, and class effects of approved 
PD-1/PD-L1 checkpoint inhibitors, but for which a causal association with 
AMG 404 has not been established, are summarized below (see Table 4-2). 
Table 4-2.  Potential Safety Concerns Based on Drug Class Effects, Biological 
Mechanism of Action, and Nonclinical Studies 
Safety Risk 
Description 
Immune-related toxicities 
Immune-related adverse effects associated with PD-1 blocking 
agents include pneumonitis, colitis, hepatitis, endocrinopathies, 
nephritis and renal dysfunction, skin reactions, encephalitis, and 
other immune-related adverse reactions (including the 
identified risks of hypothyroidism, colitis, pneumonitis, and 
myasthenia gravis).  
Infusion-related reactions 
Severe and life-threatening infusion-related reactions have 
been observed with other anti-PD-1 therapies and may occur 
with the administration of AMG 404.  Signs and symptoms may 
include pyrexia, chills, rigors, flushing, urticaria, hypotension, 
dyspnea, wheezing, headache, back pain, and abdominal pain.  
Embryofetal toxicity 
Based on its mechanism of action, AMG 404 may cause fetal 
harm if administered during pregnancy.  Animal studies 
published in the literatures have demonstrated that 
inhibition of the PD-1/PD-L1 pathway can lead to increased 
risk of immune-mediated rejection of the developing fetus 
resulting in fetal death.  However, the risk to a fetus 
following conception by an AMG 404 exposed male, or the 
risk to a fetus from an AMG 404 exposed male sexual partner 
of a pregnant woman, is uncharacterized. 
PD-1  programmed cell death 1; PD-L1  programmed death ligand 1 
Clinical signs and symptoms of immune-related toxicities and infusion-related reactions, 
along with safety laboratory parameters, will be monitored during the study to ensure 
subjects’ safety.  To mitigate embryofetal toxicity risk, study subject contraception will be 
required, and pregnancy status will be monitored.  Refer to Section 8.4.3 for specific 
recommendations regarding the mitigation and management of immune-related 
toxicities, infusion-related reactions, and embryofetal toxicity. 
For additional key safety information, refer to the AMG 404 Investigator’s 
Brochure.


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Refer to the AMG 404 Investigator’s Brochure,
 for further description of key 
safety information. 
5. 
Objectives, Endpoints and Hypotheses 
5.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability 
and determine the recommended 
phase 2 dose (RP2D) of AMG 404 in 
patients with advanced solid tumors  
 
Dose limiting toxicities (DLTs), 
treatment-emergent adverse events, 
treatment-related adverse events, and 
changes in vital signs, and clinical 
laboratory tests 
Secondary 
 
To evaluate the pharmacokinetics 
(PK) of AMG 404 as a monotherapy 
 
 
 
PK parameters of AMG 404 including, 
but not limited to, maximum observed 
serum concentration (Cmax), time to 
achieve Cmax (tmax), and area under 
the serum concentration-time curve 
(AUC) 
 
To assess the immunogenicity of  
AMG 404 as a monotherapy 
 
 
 
Subject incidence of anti-AMG 404 
antibodies 
 
To evaluate the preliminary antitumor 
activity of AMG 404 as a 
monotherapy
 
 
Objective tumor response, duration of 
overall response, progression-free 
survival, disease control rate (DCR), 
and duration of stable disease 
measured by CT/MRI and assessed 
per modified RECIST 1.1 
 


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Exploratory 
 
5.2 
Hypotheses 
AMG 404, as a monotherapy 
 is safe and 
well tolerated in patients with advanced solid tumors. 
6. 
Study Design 
6.1 
Overall Design 
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study to 
evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of 
AMG 404 in subjects with advanced solid tumors.  The study may be conducted in 
Australia, United States, France, Poland, United Kingdom, Belgium, Spain, Turkey, 
South Korea, Taiwan, Japan, Singapore, China, Canada, Brazil and Mexico. Other 
countries or regions may participate.  The study will consist of up to 9 cohorts to 
evaluate the safety, tolerability, PK and PD of AMG 404 administered every 4 weeks 
(Q4W) with the following doses:  Cohort 1 – 240 mg, Cohort 2 – 480 mg, 
Cohort 3 – Expansion at the dose of 480 mg (subjects enrolled outside of China), 
Cohort 4 – Exploratory Dose of 1050 mg, Cohort 5 – China/Taiwan/Hong Kong Specific 
Expansion at the recommended phase 2 dose (RP2D) with a safety lead-in (
 
), Cohort 6 – Expansion at the RP2D, 
Cohort 7 – Expansion at the RP2D in specific indications as specified in Section 2.1, 
Cohort 8 – Expansion at the RP2D in subjects with tumors that are microsatellite 


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instability-high (MSI-H) or mismatch repair deficient (dMMR), and Cohort 9 – Expansion 
at the RP2D in subjects with non-small cell lung cancer (NSCLC) that is PD-L1 positive, 
TPS  50% (Cohorts 6-9 will enroll subjects outside of China).   
In Cohorts 1-9, AMG 404 will be administered intravenously (IV) over approximately total 
30 minutes, every 4 weeks in subjects with advanced solid tumors.  Cohorts 3 and 4 can 
be opened once Cohort 2 has been completed and determined to be tolerable. Cohorts 
5-9 can be opened once the first 6-9 subjects in Cohort 4 have completed the DLT 
evaluation period and data have been reviewed to determine the RP2D.  The DLT 


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evaluation period will be 28 days.  The Dose Level Review Meeting (DLRM) may 
recommend escalation to the next planned dose, escalation to an intermediate dose (a 
dose lower than the next planned dose), continuation or delay in dosing, repetition or 
expansion of a cohort, de-escalation to a lower dose, or termination of the study. 
Administration of AMG 404 may continue until evidence of disease progression, 
intolerance to study medication, withdrawal of consent, or in the absence of the above 
up to 12 months if subject achieves a complete response, and up to 24 months if partial 
response or stable disease.  For subjects with complete response, treatment beyond 
12 months may be permitted upon discussion with the medical monitor.  After 
discussion with the medical monitor, subjects with complete response, partial 
response, stable disease or continued clinical benefit at 24 months of treatment, 
may continue treatment for up to an additional 24 months (up to 48 months of 
treatment in total).  If a subject completes or discontinues treatment for reasons other 
than progression, tumor evaluations should continue according to the Schedule of 
Activities (for Cohorts 1-9, refer to Table 3-1, 
 
 
 until progression or start of a new treatment regimen. 
Cohort 1, 2 and Cohort 4 
The doses of 240 mg, 480 mg and 1050 mg will be examined for safety, tolerability, PK, 
and PD of AMG 404 in subjects with advanced solid tumors.  Rules for dose 
determination, and dose expansion are derived using a modified Toxicity Probability 
Interval (mTPI) model (Ji et al. 2010) with a target toxicity probability interval (TPI) of 
0.20 to 0.33 with a TPI  0.33 defined as excessive toxicity.   
 
Subjects will not be dosed at a level above the dose level indicated by the mTPI 
model.  In particular, subjects will not be dosed at the current dose level or higher 
when the mTPI model indicates stopping enrollment at the current dose level and 
patients will not be dosed at an escalated dose level when the mTPI indicates 
staying at the current dose level. 
 
After reviewing a broad range of safety information including vital signs, 
laboratory values and detailed adverse events profiles, the team may choose to 
dose subjects below the dose level indicated by the mTPI model.  For example, 
the team may choose to stop enrollment at the current dose level even if the 
mTPI model indicates staying at the current dose level.  
The Dose Level Review Team (DLRT) will review data, monitor safety, and make 
recommendations on dose modifications based on all subjects that have been enrolled.  
A Dose Level Review Meeting will be conducted after Cohorts 1, 2 and 4 and may 
convene ad hoc to review safety data if deemed necessary.  


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Three dose levels are planned to be tested: 
 
Cohort 1:  240 mg every 4 weeks (N  2-4) 
 
Cohorts 2 and 3:  480 mg every 4 weeks (Cohort 2:  N  6-9; Cohort 3: N  20) 
 
Cohort 4:  1050 mg every 4 weeks (N  20) 
Dose escalation will begin with a run-in dose level of 240 mg (Cohort 1).  If no DLTs are 
observed in Cohort 1, dose escalation will continue to the next planned dose level in 
Cohort 2.  If DLTs are observed in Cohort 1 subsequent will be determined by Amgen 
after consulting with the Dose Level Review Team (DLRT) and constrained by the mTPI 
model.  
The table below shows rules for dose determination and dose expansion per the mTPI 
model.  
Table 6-1.  Guideline for Dose Level Decisions for Cohort 2 (480 mg) and Cohort 4 
(1050 mg) 
No. of Subjects 
Number of DLT observed at current dose 
ESCALATEa 
STAY AT CURRENT 
DOSE 
STOP ENROLLMENT 
AT CURRENT DOSE 
3 
N/A 
≤ 1 
≥ 2 
4 
N/A 
≤ 1 
≥ 2 
5 
N/A 
≤ 2 
≥ 3 
6 
0 
1 – 2 
≥ 3 
7 
≤ 1 
2 – 3 
≥ 4 
8 
≤ 1 
2 – 3 
≥ 4 
9 
≤ 1 
Maximum sample size 
reached 
Maximum sample size 
reached  
a For Cohort 4 (1050 mg), if the rules for dose escalation are met, enrollment may be stopped as there is 
sufficient evidence that 1050 mg dose is safe and tolerable; and this is the highest planned dose level 
being investigated on study. 
Cohort 3 
Upon completion of Cohort 2 of the study and depending on data obtained, dose 
expansion may proceed with the planned dose of 480 mg in Cohort 3 (N  20) outside of 
China. 
Cohorts 5-9 
Upon completion of the first 6-9 subjects in Cohort 4 of the study and depending on data 
obtained, dose expansion may proceed with the RP2D in Cohort 5 with a safety lead-in 


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(from China, and from National Medical Products Administration (NMPA) certified sites in 
Taiwan and Hong Kong) and Cohorts 6-9 (from all countries participating on the study, 
excluding China).  The RP2D will be determined following review of available data 
obtained in Cohorts 1 through 4 including safety, tolerability, PK and PD data.  
 
   
Cohort 5 was a China/Taiwan/Hong Kong-specific expansion cohort with a safety lead-in 
at one dose below the RP2D followed by evaluation at RP2D, as appropriate.  Up to 
12 subjects would be enrolled in China and NMPA certified sites in Taiwan, and/or Hong 
Kong.  
 
The overall study design is described by a study schema in Figure 3-1.  The endpoints 
are defined in Section 5.1. 
Intra-subject dose escalation for Cohorts 1-9 
Intra-subject dose escalations are allowed on this study for subjects enrolled, where 
applicable.  Subjects enrolled to Cohort 1 who complete the DLT period may proceed to 
480 mg once Cohort 2 has been deemed safe by the DLRT; subjects receiving 480 mg 
(in Cohorts 1-3) who complete the DLT period may proceed to the RP2D once 
determined if a dose higher than 480 mg is selected as the RP2D.  Subjects enrolled to 
the safety lead-in dose in Cohort 5, may escalate to the RP2D dose level once the RP2D 
is determined safe following the China/Taiwan/Hong Kong specific DLRT 
recommendation.  
. 
All intra-subject dose escalations may occur after consultation with the sponsor if:  
 
No DLT has been reported for this subject during or after completion of the DLT 
period 


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Subjects who do not proceed to the higher dose may receive additional cycles at the 
original dose. 


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6.2 
Number of Subjects 
Up to 275 evaluable subjects with advanced solid tumors will be enrolled in the study. 
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 11.1. 
6.2.1 
Replacement of Subjects 
Subjects that are not DLT-evaluable may be replaced.  A DLT-evaluable subject is 
defined as:  
 
Subject who has received at least 90% of the planned dose of investigational 
product(s) and is followed for at least 1 cycle, or  
 
Subject who has experienced a DLT; 
In addition, for subjects enrolled to Cohorts 7-
 subjects must complete an on-study 
radiographic assessment. 
6.2.2 
Number of Sites 
Approximately 35 investigative sites in Australia, United States, France, Poland, Turkey, 
Spain, United Kingdom, Belgium, South Korea, Taiwan, Japan, China, Singapore, 
Canada, Brazil, Mexico, and other countries or regions may participate in the study.  


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Sites that do not enroll subjects within 3 months (provided slots are available) of site 
initiation may be closed. 
6.3 
End of Study 
6.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up), as 
applicable. 
6.3.2 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for up to 
approximately 2.5 years.  This includes, the screening period lasting up to 28 days, a 
treatment period up to 2 years, and a follow up period of 6 months after end of 
treatment.  Subjects with continued clinical benefit may have their study duration 
extended for up to 2 additional years of treatment (refer to Section 10.1.3). 
The actual duration for individual subjects will vary depending upon tolerability of study 
treatment(s), evidence of clinical progression, and willingness to participate in the study. 
6.4 
Dose Rationale 
6.4.1 
First in Human Starting Dose Selection Rationale 
The PK of AMG 404 was based on allometric scaling of clearance and volume 
parameters obtained from studies in cynomolgus monkeys.  The AMG 404 human PK 
parameter estimates were comparable to those derived from human population PK 
models for pembrolizumab and nivolumab (Ahamadi, 2017; Bajaj, 2017).  The predicted 
terminal elimination half-life (t1/2,z) is estimated to be consistent with other therapeutic 
anti-PD1 mAbs. The planned doses of AMG 404 in this study are 240, 480 and 1050 mg 
administered as short-term IV infusions (approximately 0.5 hours) every four weeks 
(Q4W) in patients with advanced malignancies.  Dose escalation decisions will be 
guided primarily by observed safety and tolerability of AMG 404, 
Dose selection was informed by the clinical experience with other therapeutic anti-PD1 
mAbs.  Pembrolizumab and nivolumab have been shown to be generally well-tolerated 


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at and above exposures of their approved doses in patients, which are 200 mg Q3W and 
240 mg Q2W, respectively, where flat exposure-response relationships for safety were 
observed (Chatterjee, 2016; Feng, 2017; Wang, 2017; CDER Clin Pharm Biopharm 
Review for nivolumab; CDER Clin Pharm Biopharm Review for pembrolizumab).  
AMG 404 is a human IgG1 anti-PD1 mAb analogue that targets the human PD-1.  The 
fraction crystallizable (Fc) region of AMG 404 has been engineered to eliminate 
undesired interactions with Fc gamma receptors and complement.  In studies with Hut78 
T cells and human peripheral blood mononuclear cells, AMG 404 did not have residual 
antibody-dependent cellular cytotoxicity (ADCC) activity.  Taken together, the projected 
AMG 404 efficacious dose is expected to be well-tolerated.  Implementing precautionary 
measures for AMG 404 as a new molecular entity, a 2-fold safety factor was added to 
the projected efficacious dose estimate for the starting dose.  
To determine the starting dose, efficacious exposure targets for AMG 404 were first 
computed by scaling clinically efficacious exposures (as assessed by the time-averaged 
concentration over a dosing interval at steady state [Cavg,ss]) for approved dosing 
regimens of anti-PD-1 mAbs, pembrolizumab (200 mg Q3W) and nivolumab (240 mg 
Q2W) (Freshwater, 2017; Zhao, 2017) by the corrections for molecular weight ratios and 
the ratios of in vitro pharmacological activity for inhibition of human PD-1 binding to 
PD-L1.  In combination with human PK predictions, the efficacious doses of AMG 404 
that achieve the predicted Cavg,ss exposures were determined to be between 350 and 
720 mg Q4W IV using the results of the 2 studies with a mean estimate of 535 mg 
Q4W IV.  
The starting dose of 240 mg Q4W IV was selected using the efficacious dose estimate of 
480 mg based on both approximately the mean efficacious dose estimate (535 mg Q4W 
IV) and evaluation of in vitro pharmacological activities of AMG 404 and nivolumab, 
which is also approved for dosing at 480 mg Q4W IV (Prescribing information for 
Opdivo®) and addition of the 2-fold safety factor.  By starting one dose level below the 
predicted efficacious dose, exposure of subjects to doses that are not expected to be 
efficacious is limited.  Receptor occupancy (RO) data were not utilized for FIH dose 
selection given that saturated receptor occupancy of other therapeutic anti-PD1 mAbs 
was observed at subtherapeutic doses in patients. 
The starting dose is also supported by the 28-day GLP nonclinical toxicology study in 
cynomolgus monkeys.  AMG 404 has been well-tolerated at doses up to 100 mg/kg QW.  
At the predicted human exposures of proposed starting dose, exposure multiples for 


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AUC and Cmax are calculated to be 24- and 23-fold, respectively when compared to the 
AUC and Cmax at the highest non-severely toxic dose (HNSTD) of 100 mg/kg QW in 
monkeys. 
The highest planned dose is 1050 mg Q4W IV.  At this dose, exposure multiples for both 
AUC and Cmax are calculated to be 5-fold when compared to the AUC and Cmax at the 
HNSTD in monkeys. 
A fixed dose regimen was selected for the FIH study given that, for mAb-based 
therapies, body weight may or may not be a determinant of PK variability (Wang, 2009; 
Bai, 2012).  Use of fixed dosing for AMG 404 is further supported by the flat 
exposure-response relationships for efficacy and safety of other therapeutic anti-PD1 
mAbs, indicating that fixed dosing of AMG 404 is not expected to have a clinically 
meaningful effect on safety and efficacy.  In addition, fixed dosing has logistical 
advantages including ease of administration, reduced risk of dosing errors, minimal 
preparation by hospital staff, and reduced patient waiting time.  
6.4.2 
Recommended Phase 2 Dose Selection 
Predicted efficacious exposure targets for AMG 404 monotherapy in subjects were 
computed by scaling clinically efficacious exposures, as assessed by time-averaged 
concentration over a dosing interval at steady state (Cavg,ss), for approved dosing 
regimens of anti-PD-1 mAbs as described above in Section 6.4.1.  Using preliminary 
human PK parameter estimates from population PK modeling of observed data from the 
study, the efficacious monotherapy dose of AMG 404 that achieves the computed 
exposure target is predicted to be within range of 480 mg IV Q4W, which is the 
cohort-2 dose. 
Safety, tolerability, PK, and PD of AMG 404 at dose levels of 240, 480, and 1050 mg are 
being investigated in subjects with advanced solid tumors.  As of 08-October-2019 data 
cut-off date, AMG 404 was safe and well tolerated across the 240- and 1050-mg dose 
range with no dose-related increases in frequency or severity of adverse events in 
subjects and no DLTs.  Preliminary PK results were consistent with those for other 
therapeutic anti-PD-1 mAbs. Maximum observed drug concentrations (Cmax) of AMG 404 
occurred at or near the end of infusion with a median tmax of 0.5 to 2.5 hours, as 
expected with 0.5-hour IV infusion administration.  An approximately dose-proportional 
increase was observed over the dose range of 240 to 1050 mg IV Q4W with ~5-fold 
increases in exposure for both Cmax and AUC for a 4.4-fold increase in AMG 404 
dose.  Peripheral RO data were not expected to provide meaningful information to 


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assess efficacy of AMG 404, given that saturating peripheral RO has been observed 
clinically at exposures lower than therapeutic doses of other anti-PD-1 mAbs.  However, 
preliminary PD results at the 240-mg and 1050-mg dose levels were consistent with the 
expected saturation of RO for these doses given the potent inhibition of PD-1/PD-L1 
interactions in vitro with low nanomolar IC50 values and preliminary observed AMG 404 
exposures in human subjects.  As of the data cutoff date, 6/36 (16.7%) subjects with 
postbaseline results are positive for binding ADAs. Of the 6 binding ADA-positive 
subjects, 5 were in the 480 mg cohort and 1 was in the 1050 mg cohort.  Of the 
5 binding ADA-positive subjects in the 480 mg cohort, 1 subject had pre-existing binding 
ADAs and the rest were treatment-emergent.  3/5 of the binding ADA-positive subjects in 
the 480 mg cohort had an ADA response that was transient.  The 1 binding ADA-positive 
subject in the 1050 mg cohort had treatment-emergent ADA that was sustained at SFU.  
All of the binding ADAs observed in this study as of the data cutoff date were of low 
magnitude, with no impact on exposure and have no association with clinical sequelae. 
Taking into consideration cumulative preliminary safety data PK, PD, and ADA data, the 
AMG 404 recommended phase 2 dose for monotherapy is 480 mg IV Q4W in subjects 
with advanced solid tumors.  The efficacious monotherapy dose of AMG 404 is predicted 
to be within range of this dose.   


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6.5 
Patient Input on Study Design 
No patient input was obtained for the design of this study. 
7. 
Study Population 
Eligibility criteria will be evaluated during screening.  Subjects must meet eligibility 
criteria on Cycle 1, Day 1 of treatment.   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 13.3).  
7.1 
Inclusion Criteria 
Subjects are eligible to participate in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures.  
102 
Age  18 years old at the time of signing informed consent 
103 
Life expectancy of  3 months, in the opinion of the investigator 
104 
Subject must have histologically or cytologically confirmed metastatic or locally 
advanced solid tumors not amenable to curative treatment with surgery or 
radiation. Additionally, for: 
 
Cohort 7:  subject must have a tumor as specified in the Study Schema 
(Section 3.1)  
 
Cohort 8, 
:  subject must be MSI-H or MMR-deficient 


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 
Cohort 9:  subject must have NSCLC, PD-L1 positive, TPS  50%; not have 
EGFR or ALK or ROS1 genomic tumor aberrations and may not have 
received prior systemic treatment for the advanced disease (prior 
neoadjuvant, adjuvant, or concurrent chemoradiation is allowed).  
105 
At least 1 measurable lesion as defined by modified RECIST 1.1 which has not 
undergone biopsy within 3 months of the screening scan.  This lesion cannot be 
biopsied at any time during the study. Note:  If there is only one lesion available 
for biopsy and radiographic assessment, it may be permitted to be biopsied after 
discussion with sponsor. 
106 
Subjects with treated brain metastases are eligible provided they meet the 
following criteria: 
 
Definitive therapy was completed at least 2 weeks prior to enrollment. 
 
No evidence of radiographic CNS progression or CNS disease following 
definitive therapy and by the time of study screening.  Patients manifesting 
progression in lesions previously treated with stereotactic radiosurgery may 
still be eligible if pseudoprogression can be demonstrated by appropriate 
means and after discussion with the medical monitor. 
 
Any CNS disease is asymptomatic, any neurologic symptoms due to CNS 
disease have returned to baseline or are deemed irreversible, the patient is 
off steroids for at least 7 days (physiologic doses of steroids are permitted), 
and the patient is off or on stable doses of anti-epileptic drugs for malignant 
CNS disease. 
107 
Eastern Cooperative Oncology Group (ECOG) Performance Status of  2. 
108 
Hematologic function, as follows without growth factor support within 2 weeks 
prior to study day 1:   
 
Absolute neutrophil count (ANC)  1.0 x 109/L 
 
Platelet count  75 x 109/L  
 
Hemoglobin  9 g/dL (90 g/L) 
109 
Adequate renal laboratory assessments, as follows:  
Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal 
Disease) calculation  60 ml/min/1.73 m2 for Cohorts 1, 2, 4, 5, and 
.  
Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal 
Disease) calculation  45 ml/min/1.73 m2 for Cohorts 3, 6, 7, 8, 9, 
.  
110 
Hepatic function, as follows:  
 
Total bilirubin  1.5 x ULN or  3 x ULN for subjects with liver metastasis 


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 
AST  3 x ULN or  5 x ULN for subjects with liver metastasis 
 
ALT  3 x ULN or  5 x ULN for subjects with liver metastasis 
 
Alkaline phosphatase  2.5 x ULN or  5 x ULN for subjects with liver 
metastasis (Note:  elevated alkaline phosphatase is acceptable if it is due to 
non-hepatic associated pathology [eg, bone disease]).  
111 
Cohort 5 only:  Subject is a resident in China, Taiwan, or Hong Kong. 
7.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 


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201 
Primary brain tumor, untreated or symptomatic brain metastases and 
leptomeningeal disease (exception: benign asymptomatic tumors are permitted).  
Other Medical Conditions 
202 
History of other malignancy within the past 2 years, with the following  
exception[s]: 
 
Malignancy treated with curative intent and with no known active disease 
present for  2 years before enrollment and felt to be at low risk for 
recurrence by the treating physician. 
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
 
Adequately treated cervical carcinoma in situ without evidence of disease. 
 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer. 
 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ. 
 
Other malignancies which do not require systemic therapy, may be 
considered upon discussion with the medical monitor. 
203 
History of solid organ transplantation.  
204 
Major surgery within 28 days of study day 1.  
Prior/Concomitant Therapy 
205 
Prior treatment with anti-programmed death 1 (PD-1), anti-PD-L1, CTLA-4 or 
other checkpoint inhibitor drugs (
).  
206 
Anti-tumor therapy (radiotherapy, chemotherapy, antibody therapy, molecular 
targeted therapy, or investigational agent) within 21 days prior to study day 1. 
Note:  Palliative radiotherapy is permitted.  
207 
Live vaccine therapy within 4 weeks prior to study drug administration. 
208 
Current treatment or within 14 days of day 1 with immunosuppressive 
corticosteroid defined as  10 mg prednisone daily or equivalent. Corticosteroids 
with no or minimal systemic effect (such as topical or inhalation) are permitted. 
Note:  Corticosteroids  10 mg prednisone used for management of contrast 
allergy for study scans is allowed 
Prior/Concurrent Clinical Study Experience 
209 
Currently receiving treatment in another investigational device or drug study, or 
less than 21 days prior to study day 1 since ending treatment on another 
investigational device or drug study(ies).   
Diagnostic Assessments 
210 
Evidence of interstitial lung disease or active, non-infectious pneumonitis. 


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211 
History of any immune-related colitis. Infectious colitis is allowed if evidence of 
adequate treatment and clinical recovery exists and at least 3 months interval 
observed since diagnosis of colitis. 
212 
History of allergic reactions or acute hypersensitivity reaction to antibody 
therapies. 
213 
Positive/Non-negative test for Human Immunodeficiency Virus (HIV). 
214 
Has known active Hepatitis B (eg, hepatitis B antigen [HBsAg] reactive) or 
Hepatitis C (eg, HCV RNA [qualitative] is detected). 
215 
Subject currently has an active infection requiring systemic therapy 
216 
Active or history of any autoimmune disease or immunodeficiencies.  Subjects 
with Type I diabetes, vitiligo, psoriasis, hypo- or hyper-thyroid disease not 
requiring immunosuppressive treatment are permitted.  
217 
Myocardial infarction within 6 months of study day 1, symptomatic congestive 
heart failure (New York Heart Association  class II), unstable angina, or cardiac 
arrhythmia requiring antiarrhythmic medication 
218 
Unresolved toxicities from prior anti-tumor therapy, defined as not having 
resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 grade 1, or are stable and well controlled with minimal, local, or non-invasive 
intervention AND there is agreement to allow by both the investigator and the 
Amgen Medical Monitor.  
Other Exclusions 
219 
Males and females of reproductive potential who are unwilling to practice highly 
effective methods of birth control while on study through 6 months (females) and 
8 months (males) after receiving the last dose of AMG 404, 
 
 
See 
Section 13.6 for additional details regarding contraception requirements).  
220 
Females with a positive pregnancy test. 
221 
Females who are lactating/breast feeding or planning to breastfeed while on 
study through 6 months after receiving the last dose of study drug.  
222 
Females planning to become pregnant while on study through 6 months after 
receiving the last dose of the study drug.  
223 
Males unwilling to abstain from donating sperm during treatment and for an 
additional 8 months after the last dose of AMG 404, 
 
224 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
225 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
226 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 


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investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
227 
Subjects with known sensitivity to any of the products to be administered during 
the study. 


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7.3 
Subject Enrollment 
All screening tests and procedures should be performed within 28 days prior to study 
day 1, unless otherwise indicated.  All blood and urine samples collected for screening 
assessments will be submitted and analyzed by the local laboratory.  Time permitting, 
screening laboratory assessments used to determine subject eligibility may be repeated 
if necessary.  
Subjects who do not meet eligibility criteria within the 28 day screening period will not be 
eligible for enrollment.  Subjects may be re-screened up to 3 additional times at the 
discretion of the investigator.  The subject must be re-consented if a re-screening 
attempt occurs outside of the 28 day screening period.  Subjects who are deemed 
ineligible will be documented as screen failures. 
An Amgen representative will notify the site in writing when a cohort is open to screen 
and enroll subjects.  Subjects may be eligible to enroll once all screening tests and 
procedures are completed and results indicate that all eligibility criteria are met.  A site 
representative will complete and send the enrollment eligibility worksheet to Amgen 
accompanied with medical history, treatment history for the disease being investigated 
and list of current medications.  The eligibility worksheet and accompanying information 
should be completed and emailed to the Amgen representative at least 3 days prior to 
the planned day of first dose.  The Amgen representative will acknowledge receipt of the 
paperwork and send confirmation of the cohort and dose level assignment for the 
subject. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria (date eligibility worksheet been signed by investigator). The 
investigator is to document this decision and date, in the subject’s medical record and 
in/on the enrollment case report form (CRF). 
7.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened.  Refer to Section 10.1.1. 


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8. 
Treatment Procedures 
All investigational and non-investigational products must be prepared and administered 
by a qualified healthcare professional. Subjects should be assessed clinically for 
adverse events/ toxicity prior to each dose using the CTCAE version 5.0. Complete 
blood count with differential and chemistry panels including liver enzyme laboratory tests 
(ALT and AST) and total bilirubin should be obtained according to the Schedule of 
Activities (section 3.2) and the results should be checked within 2 days prior to each 
dose of treatment.  
The treatment cycle interval may be increased due to toxicity. If a subject requires 
corticosteroid dosing of > 10 mg prednisone daily (or equivalent) as supportive care, 
AMG 404 dosing must be held until the corticosteroid dose has decreased to 
< 10 mg prednisone daily (or equivalent).  
 
 
  
8.1 
Investigational and Non-investigational Products 
8.1.1 
Investigational Product:  AMG 404 
AMG 404 will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.  
The investigational product will be dispensed at the research facility by a qualified staff 
member. 
At the beginning of a treatment cycle a physician or nurse trained in emergency medical 
care must be available when the infusion of investigational product is started for 
immediate intervention in case of complications. 
AMG 404 will be delivered using infusion pumps approved for use by the appropriate 
regulatory authority for the country in which the subject is undergoing treatment.  
AMG 404 solution for infusion will be prepared in bags for IV infusion and delivered 
through infusion lines.    
The drug will be administered as an IV infusion at a constant flow rate over 30 minutes. 


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For Cohorts 1-9, each cycle of AMG 404 will be 28 days in length.  Subjects will receive 
240 mg, 480 mg or 1050 mg of AMG 404 depending on the cohort the subject is enrolled 
into.  All subsequent doses will be administered every 28 days (± 3 days).  
 
. 
All safety assessments must be performed within 2 days prior to start of cycle.  
Assessments should be performed as indicated in the Schedule of Activities 
(see section 3.2).  AMG 404 may be withheld or discontinued as necessary for safety 
reasons.  
 


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8.1.2 
Cohorts 1-9 Investigational Product 
 
Table 8-1.  Cohorts 1-9 Investigational Product:  AMG 404 
 
 


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8.1.7 
Medical Devices 
There are no investigational medical devices being used in this study.  
Investigational product must be administered using infusion pumps approved for use by 
the appropriate regulatory authorities for the country in which the subject is undergoing 
treatment in the outpatient setting.  Investigational product solution for infusion will be 
prepared in bags for IV infusion and delivered through infusion lines that are both 
compatible with the investigational product.  Other non-investigational medical devices 
may be used in the conduct of this study as part of standard care.  Non-investigational 
medical devices (eg, syringes, sterile needles), that are commercially available are not 
usually provided or reimbursed by Amgen (except, for example, if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these devices. 
  
 
 


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8.1.9 
Other Treatment Procedures 
There are no other treatment procedures in this study. 
8.1.10 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers, delivery systems, labeling, and inserts. 
This includes any investigational/non-investigational product(s) provisioned and/or 
repackaged/modified by Amgen. AMG 404 
 are the investigational products 
in this study.  


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Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s), supplied by Amgen are to be reported. 
Amgen Rave EDC system is being used to report product complaints. 
Regardless of the reporting method, all product complaints must be reported to Amgen 
within 24 hours of discovery. 
8.1.11 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period 
Any anti-tumor therapy other than the investigational product and protocol-specified 
therapies, including cytotoxic and/or cytostatic drugs, hormonal therapy, systemic 
corticosteroids (except for subjects who were receiving ≤ 10 mg prednisone or 
equivalent at the time of enrollment are permitted to remain on it), immunotherapy or any 
biological response modifiers, any other investigational agent, and other 
immunosuppressive therapies are excluded.  
Primary prophylactic use of hematopoietic growth factors such as granulocyte-colony 
stimulating factor (G-CSF) is not allowed during the DLT-evaluation period.  
Administration of systemic corticosteroids (AMG 404 must be discontinued if ≥ 10 mg 
per day prednisone or equivalent is continued for more than 12 weeks), 
immunomodulators, and hormonal replacement therapy for the management of toxicities 
(eg, immune-related adverse events) is allowed. Corticosteroids with no or minimal 
systemic effect (eg, topical, inhalation) are allowed (
 
 
). 
Any live vaccine therapies for the prevention of infectious disease are excluded.  
Radiotherapy is not permitted except for palliation of symptoms and should be discussed 
with the sponsor’s Medical Monitor first. Investigators should ensure that the need for 
radiation does not indicate progressive disease and that for subjects with measurable 
disease, radiation is not to the sole site of measurable disease. 
The following procedures should also not be undertaken within the timeframes specified 
prior to enrollment and during the study: 
 
Participation in an investigational study (drug or device) within 21 days of study 
day 1 
 
Major surgery within 28 days of study day 1 
 
Enrollment into another investigational drug or device study 


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8.2 
Method of Treatment Assignment 
Subjects who meet the eligibility criteria will be assigned to treatment with AMG 404.  
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment CRF. 
8.3 
Blinding 
This is an open-label study; blinding procedures are not applicable.  
8.4 
Dose Modification 
8.4.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
Planned DLRMs will be held to review data, monitor safety, and recommend dose 
changes or other necessary actions, on a per cohort basis.  Considering each cohort 
independently, a DLRM will occur after the required DLT-evaluable subjects have 
completed the DLT window: 
 
All in Cohorts 1 and 2 
 
The first 6-9 subjects of Cohort 4 
 
 
 
Ad hoc if deemed necessary by the Medical Monitor  
The review team will be composed of the investigators, Amgen Medical Monitor, Amgen 
Global Safety Officer or designated safety scientist, Amgen Early Clinical Development 
Manager, and Biostatistics representative. Additional members may be added as 
needed (eg, Clinical Pharmacologist).  The Medical Monitor must be in attendance and 
cannot be represented by a voting designee or delegate. Voting designees can be 
identified as appropriate by the GSO or site investigators. 
The China/Taiwan/Hong Kong specific DLRT will be composed of the investigators in 
China/Taiwan/Hong Kong or designee, Amgen Medical Monitor, Amgen Global Safety 
Officer or designated safety scientist, Amgen Early Clinical Development Manager, and 
Biostatistics representative. Additional members may be added as needed (eg, Clinical 
Pharmacologist).  
A quorum, defined as the majority (defined as greater than or equal to 50%) of actively 
screening and enrolling investigators or their qualified designee (ie, sub-investigator), 
Amgen Medical Monitor, and the Amgen Global Safety Officer or delegate must be in 
attendance for DLRM to proceed.  The DLRM will be rescheduled if a quorum is not 
reached. 


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Voting members of the DLRM will include the Amgen Medical Monitor, the Amgen 
Global Safety Officer or designated safety scientist, and all actively screening and 
enrolling investigators or their qualified sub-investigator designee.  For cohorts with 
dosing decisions, the team may recommend escalation to the next planned dose, 
escalation to an intermediate dose (a dose lower than the next planned dose), 
continuation or delay in dosing, repetition or expansion of a cohort, de-escalation to a 
lower dose, or termination of the study.  Intra-subject dose escalation is allowed, where 
applicable.  When the subject completes the DLT period the subject may proceed to 480 
mg for the following treatment cycle once Cohort 2 has been deemed safe by the DLRT; 
subjects receiving 480 mg (Cohorts 1-3) who complete the DLT period may proceed to 
the RP2D once determined if a dose higher than 480 mg is selected as the RP2D.  
Subjects enrolled at the safety lead-in dose in Cohort 5 may escalate to the RP2D once 
deemed safe by the China/Taiwan/Hong Kong specific DLRT.  All intra-subject dose 
escalations may occur after consultation with the sponsor as described in Section 6.1.  
The Amgen Medical Monitor and Global Safety Officer or designee and the majority 
(defined as greater than or equal to 50%) of actively screening and enrolling 
investigators participating in the DLRM must cast a positive vote indicating an 
acceptable safety profile was observed for AMG 404 to allow the dose level modification 
and/or cohort continuation/expansion to proceed. All available study data including 
demographics, medical history, concomitant medications, AEs, electrocardiograms 
(ECGs), vital signs, laboratory results, and emerging PK or pharmacodynamics data will 
be reviewed. Data to be reviewed may be unqueried.   
The dosing schedule is described by a schema in the protocol synopsis. 
8.4.2 
DLT Definition 
The DLT window (ie, DLT-evaluable period) will be the first 28 days of AMG 404 
treatment (starting cycle 1, day 1) for Cohorts 1-9.  
 
 
 
  The DLT 
window may also be extended to assess events starting within the window in case the 
DLT definition is time dependent.  
The subject will be DLT evaluable if the subject has completed the DLT window as 
described above, or experienced a DLT any time during the DLT window, or has 
received at least 90% of the planned dose of investigational product(s) and is followed 


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for at least 1 cycle. A subject will not be DLT evaluable if he/she drops out before 
completion of the DLT-evaluable period for reasons other than a DLT. All available 
safety data for subjects who are not DLT-evaluable will still be evaluated and considered 
in DLRT recommendations (see also Section 13.3). 
See Section 6.2.1 for description of replacement of subjects. 
An adverse event will be considered related to study treatment (possibly, probably, or 
definitely related to the study treatment) if there is a suspected “reasonable causal 
relationship” to the study treatment (ICH E2A), and not only a lack of an alternative 
explanation for the toxicity. All toxicities will be graded using the CTCAE version 5.0.  
The occurrence of any of the following toxicities during the DLT evaluation period will be 
considered a DLT, unless the toxicity is clearly and incontrovertibly due to disease 
progression or other extraneous causes:  
 
Any treatment related grade 5 toxicity 
 
Grade 4 neutropenia or thrombocytopenia > 7 days in duration 
 
Febrile neutropenia 
 
Grade 4 anemia 
 
Grade 3 or 4 non-hematologic toxicity, with the following exceptions: 
 
DLT Exemption:  Grade 3 endocrinopathies if manageable with replacement 
therapy 
 
DLT Exemption:  Grade 3 nausea/vomiting or diarrhea < 72 hours in the 
absence of maximal medical therapy 
 
DLT Exemption:  Grade 3 fatigue < 1 week 
 
DLT Exemption:  Asymptomatic ≥ grade 3 electrolyte abnormalities that last 
< 72 hours, is not clinically complicated, and resolved spontaneously or 
responds to conventional medical interventions 
 
DLT Exemption:  ≥ Grade 3 amylase or lipase that is not associated with 
symptoms or clinical manifestations of pancreatitis 
 
DLT Exemption:  Other select lab abnormalities that do not appear to be 
clinically relevant or harmful to the patient and/or can be corrected with 
replacement or modifications (eg, grade 3 lymphopenia, grade 3 
hypoalbuminemia) 
 
Recurrent grade 2 pneumonitis 
 
Delay in cycle 2 treatment for > 14 days due to an adverse event in the dose 
escalation portion of the study due to study drug-related toxicity  
 
Any other toxicity requiring permanent discontinuation of AMG 404 or
per Table 13-2 and section 8.4.3.2 


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Cumulative adverse events profile will be taken into consideration when making 
decisions on dose escalation or de-escalation. 
Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver injury) 
will be considered a DLT.  A Hy’s Law case is defined as:  AST or ALT values of ≥ 3 x 
ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without signs of cholestasis 
and with no other clear alternative reason to explain the observed liver-related laboratory 
abnormalities (see Table 13-2 on hepatotoxicity management and Section 13.8 for 
further explanation of Hy’s law case and Management of Hepatic Function). 
If a subject experiences a DLT during the DLT evaluation period, study treatment should 
be discontinued for that subject.  Additionally, any treatment related toxicity meeting the 
DLT definition after day 28 should result in discontinuation of therapy, unless Table 13-2 
recommends otherwise.  In subjects with PR, CR or evidence of clinical benefit (as 
determined by the investigator), an option to continue at the same or at a reduced dose 
level can be considered once the toxicity returns to the subject’s baseline value or 
CTCAE grade ≤ 1 if deemed appropriate by the investigator and sponsor. 
8.4.3 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation 
The causality of each adverse event will be assessed individually for each 
protocol-mandated therapy.
 
 
 
 
 
8.4.3.1 
Amgen Investigational Product:  AMG 404 
Each subject will stay on the dose level assigned unless treatment needs to be stopped. 
The reason for dose withholds and dose delays is to be recorded on each subject’s 
CRF.  AMG 404 may be temporarily withheld or discontinued as necessary, but a partial 
dose reduction is not permitted. 


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8.4.3.4 
Immune-related Adverse Reactions 
Adverse events following the administration of AMG 404 may represent an immunologic 
etiology. Based on clinical experience with other anti-PD-L1 therapies, these 
immune-related toxicities may occur shortly after the first dose to several months after 
the last dose of treatment and may affect more than one body system simultaneously.  
Early recognition and management are critical to reduce complications.  
Most immune-related adverse events require adequate evaluation to confirm etiology or 
exclude other causes.  Additional procedures or tests, such as bronchoscopy, 
endoscopy, or skin biopsy, may be included as part of the evaluation.  
Based on the type and severity of the immune-related adverse event, withholding or 
permanent discontinuation of AMG 404,
may be required, in addition to 
treatment with corticosteroids and/or other therapies.  Dose modification and toxicity 
management guidelines for immune-related adverse reactions are provided in 
Table 13-2.  
8.4.3.5 
Infusion-related Reactions 
Infusion-related reactions may occur with the administration of AMG 404.  Monitor 
patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, 
rigors, flushing, urticaria, hypotension, dyspnea, wheezing, headache, back pain, and 
abdominal pain.  If an infusion-related reaction is suspected, perform a physical 
examination, monitor vital signs, monitor pulse oximetry, and perform and ECG if the 
patient is experiencing chest pain or sustained tachycardia.  
For mild or moderate infusion-related reactions, interrupt or slow the rate of infusion.  For 
severe or life-threatening infusion-related reactions, permanently discontinue AMG 404, 
  Treatment guidelines for infusion reactions associated with the 
administration of AMG 404 are provided in Table 13-4.  
 
8.4.3.6 
Embryo-fetal Toxicity 
Based on its mechanism of action, AMG 404 may cause fetal harm if administered 
during pregnancy. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 


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pathway can lead to increased risk of immune-mediated rejection of the developing fetus 
resulting in fetal death. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant or father a 
child during treatment and for 6 months (female subjects) or 8 months (male subjects) 
after the last dose of AMG 404.  Refer to Section 13.6 for contraceptive requirements 
during the study. 
Pregnancy testing will be conducted prior to administration of each dose of AMG 404, 
for female subjects of childbearing potential (see section 3.2). 
8.4.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 13.8 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
8.4.5 
Dose Modification Guidelines for SARS-COV2 Infection 
Guidance for dose modifications due to subjects with confirmed SARS-COV2 infection is 
provided below in Table 8-8.  


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Table 8-8. Dose Modification Guidelines for SARS-COV2 Infection 
 
Symptom 
Severity 
Protocol Therapy 
Modification 
Treatment 
Discontinuation 
SARS-COV2 
Infection 
Asymptomatic 
Withhold treatment 
for at least 10 days 
from positive 
RT-PCR test 
Treatment 
per local 
standard of 
care 
For treatment 
delay longer than 
6 weeks, discuss 
with medical 
monitor 
Mild/Moderate 
Withhold treatment 
until resolution of 
clinically relevant 
symptoms and a 
minimum of 10 days 
after symptom onset 
Severe 
Withhold treatment 
until resolution of 
clinically relevant 
symptoms and a 
minimum of 20 days 
after symptom onset 
RT-PCR = reverse transcription polymerase chain reaction; SARS COV2 = severe acute respiratory 
syndrome coronavirus 2 
8.4.6 
Dose Modification Due to Surgery During Study Treatment 
Should significant surgery occur during study treatment, in general it is anticipated that 
study treatment should not be resumed before a 28 day post-operative period.  
Exceptions to the minimum 28 day post-operative period should be approved by the 
medical monitor. 
8.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the 
Investigational Product Instruction Manual. 
8.6 
Treatment Compliance 
Compliance to treatment and the corresponding assessments should be followed 
according to the Schedule of Activities (Section 3.2) and the Treatment Procedures 
(Section 8). 
8.7 
Treatment of Overdose 
AMG 404 Overdose 


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There is no treatment for overdose of this product.  In the event of an overdose, the 
investigator should contact the Amgen Medical Monitor immediately. 
8.8 
Prior and Concomitant Treatment 
8.8.1 
Prior Treatment 
Prior therapies that were being taken for the disease under study will be collected from 
time of initial diagnosis to time of consent. 
8.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 8.1.11.  
Concomitant therapies are to be collected from informed consent through safety follow 
up.  Concomitant therapies collected from safety follow up through end of study are to be 
collected if administered to treat a reportable AE or SAE.  
Collected therapy name, indication, dose, unit, frequency, route, start date, and stop 
date to be recorded in the eCRF. 
8.8.2.1 
SARS-COV2-Vaccination 
Every effort should be made to fully vaccinate subjects prior to 14 days from first dose of 
investigational product.  The use of vaccines except live and live attenuated vaccines will 
be allowed during therapy per regional and institutional standard of care. However, 
SARS-COV2 vaccinations should be avoided during screening (within a minimum of 
14 days from first dose of IP) and should be also avoided in the first treatment cycle for 
better assessment of safety parameters.  Throughout the trial, SARS-COV2 vaccination 


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should be avoided within 3 days after the administration of IP.  Record SARS-COV2 
vaccination as a concomitant medication and collect therapy name, indication, dose, 
unit, frequency, route, and date of administration. 
9. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician at the 
institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 9.1,  and 9.2.2. 
9.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (Section 3.2) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 


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 
Protocol deviation 
 
Non-compliance  
 
Adverse event 
 
Subject request 
 
Disease progression  
 
Pregnancy 
9.2 
Discontinuation From the Study 
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, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 13.7 for further details).  Refer to the Schedule of Activities (Section 3.2) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
9.2.1 
Reasons for Removal From Washout, Run-in or Invasive 
Procedures 
This section is not applicable.  
9.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
9.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 


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 
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
is able to continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly 
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. 
10. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 3.2).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
10.1 
General Study Periods 
10.1.1 
Screening, Enrollment and/or Randomization 
A signed and dated IRB/IEC-approved informed consent must be obtained before any 
study-specific procedures are performed.  Procedures that are part of routine care are 
not considered study-specific procedures and may be used at screening to determine 
eligibility.  All subjects will be screened for eligibility before enrollment.  Only eligible 
subjects will be enrolled into the study.  The screening window is up to 28 days prior to 
day 1. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening up to 3 additional times.  


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10.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Section 3.2).  The date of the first dose of 
study drug administration is defined as day 1.  All subsequent doses and study visits will 
be scheduled based on the day 1 date.   
10.1.3 
Extended Treatment Period 
Visits will occur per the Schedule of Activities (Section 3.2).  Subjects with 
complete response, partial response, stable disease or continued clinical benefit 
at 24 months of treatment, may continue treatment for up to an additional 
24 months (up to 48 months of treatment in total) after discussion with the 
medical monitor.  A separate informed consent for extended treatment must be 
signed. 
10.1.4 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, two safety 
follow-up visits are required.  A safety follow-up visit will be performed approximately 30 
(+ 3) days after the last administration of study drug, and also 140 days (±7 days) after 
the last administration of AMG 404.  Adverse events should continue to be reported 
through 140 days (± 7 days) after the last administration of AMG 404. 
10.1.5 
Long-term Follow-up 
Subjects will be contacted 6 months (± 1 week) after the last dose of study drug.  The 
purpose of the calls is to collect information on survival, start of new therapies and 
disease status.  
10.1.6 
End of Study for a Particular Study Subject 
The end of study for a particular study subject will be the day of the last scheduled long 
term follow up call. 
10.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 


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10.2.1 
General Assessments  
10.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
10.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data may be used to study the impact of the protocol-required 
therapy on 
 PK. 
10.2.1.3 
Medical History 
The Investigator or designee will collect a complete medical and surgical history that 
started prior to screening and through screening until start of treatment.  Medical history 
will include information on the subject's concurrent medical conditions.  Record all 
findings on the medical history CRF.  In addition to the medical history above, the 
condition under study history must date back to the original diagnosis.  The current 
toxicity grade will be collected for each condition that has not resolved. 
10.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care by the investigator or 
designee at screening and at the time points specified in the Schedule of Activities 
(Section 3.2).  The physical examination will include general appearance, including 
examination of the skin, spleen, respiratory, cardiovascular, musculoskeletal, and 
neurological systems.  
The individual performing the physical examination will characterize their findings as 
either normal or abnormal. Abnormal physical examination findings found during 
screening should be reported on the Medical History eCRF.  Abnormal physical 
examination findings found after the subject has received investigational product will be 
reported on the Event eCRF.  
10.2.1.5 
Physical Measurements 
Height should be measured without shoes at screening only.  Weight should be 
measured without shoes at the time points specified in the Schedule of Activities  
(Section 3.2). 


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10.2.1.6 
Performance Status  
Subjects will be graded according to the Eastern Cooperative Oncology Group (ECOG) 
Performance Status.  The ECOG criteria for this protocol are further defined in  
Appendix 8. 
10.2.2 
Efficacy Assessments 
Tumor evaluations (by CT or MRI as appropriate) and tumor markers, if applicable, are 
to be collected at time points specified in the Schedule of Activities (Section 3.2). 
Imaging may also be performed more frequently if clinically necessitated at the 
discretion of the managing physician.  Radiographic response (Complete Response, 
Partial Response) requires confirmation by a repeat, consecutive scan at least 4 weeks 
after the first documentation of response and may be delayed until the next scheduled 
scan to avoid unnecessary procedures.  Radiographic progression (Progressive 
Disease) requires confirmation by a repeat, consecutive assessment 4-6 weeks after the 
first detection of radiological progression.  Upon discussion with the Sponsor, in the 
absence of clinical deterioration and with the subject’s consent (subject must sign 
addendum consent), subjects may continue to receive AMG 404 treatment after 
confirmation of radiographic progressive disease as long as they continue to derive 
clinical benefit, until clinical disease progression, or intolerance of study treatment, or 
clinically significant deterioration of health status requiring discontinuation, or the subject 
withdrawal of consent, whichever occurs first 
 
 
).  In some circumstances it may be difficult to distinguish residual disease from 
scar or normal tissue.  When the evaluation of CR depends on this determination, the 
residual lesion may be further investigated by additional scans to be discussed with 
Sponsor, or possibly fine needle aspirate/biopsy, to confirm the CR status.  Subjects 
who continue on AMG 404 treatment, and/or other cancer therapies following 
confirmation of radiographic progressive disease will have radiological imaging 
assessment every 8 (± 1) weeks thereafter following the confirmation of radiological 
progression for Cohorts 1-9, 
 
 
.  
If a subject discontinues treatment for reasons other than progression, tumor evaluations 
should continue according to the Schedule of Activities (Section 3.2) until progression or 
start of a new treatment regimen. 


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10.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(see Section 3.2). 
10.2.3.1 
Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of adverse events, 
and serious adverse events, and the procedures for completing and transmitting 
serious adverse event reports are provided in Section 13.5. 
10.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
10.2.3.1.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 and is described in 
Section 13.5 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of investigational 
product through the end of the safety follow-up period of 140 days [± 7 days] after last 
dose of IP are reported using the Event CRF.  
10.2.3.1.1.2 
Serious Adverse Events 
For Cohorts 1-
 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 the end of the safety follow-up period of 140 days 
( 7 days) after last dose of IP are reported using the Event CRF.  
 
. 


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All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness of the event, as indicated in 
Section 13.5.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
Since the criteria the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 CTCAE toxicity 
grading scale criteria (eg, laboratory abnormality reported as grade 4 without 
manifestation of life threatening status), it will be left to the investigator’s judgment to 
also report these abnormalities as serious adverse events.  For any adverse event 
that applies to this situation, comprehensive documentation of the event severity 
must be recorded in the subject medical records. 
10.2.3.1.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events suspected to be 
related to investigational products after the protocol-required reporting period (as 
defined in Section 10.2.3.1.1.2) is complete, then these serious adverse events will 
be reported to Amgen within 24 hours following the investigator’s awareness of 
the event on the Events CRF. 
After End of Study, there is no requirement to actively monitor study subjects 
after the study has ended with regards to study subjects treated by the 
investigator.  However, if the investigator becomes aware of serious adverse events 
suspected to be related to investigational product, then these serious adverse 


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events will be reported to Amgen within 24 hours following the investigator’s awareness 
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 and handled accordingly based 
on relationship to investigational product. 
If further safety related data is needed to fulfill any regulatory reporting requirements for 
a reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study. 
10.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
10.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 9.3).  
Further information on follow-up procedures is given in Section 13.5. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
10.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 


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investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
10.2.3.1.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Amgen’s safety surveillance 
and signal management processes. 
10.2.3.1.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male study subjects will be collected after the start of study treatment, and until 6 months 
for female study subjects and 8 months for female partners of male study subjects after 
the last dose of AMG 404.   
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 13.6.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 13.6. 


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10.2.3.2 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure (BP), 
respiratory rate, heart rate and temperature.  Subject must be in rested and calm state 
for at least 5 minutes before BP assessments are conducted.  The position selected for 
a subject should be the same that is used throughout the study and documented on the 
vital sign eCRF. 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/temperature eCRF.  Vital signs 
will be recorded by the investigator or designee at screening and time points specified in 
the Schedule of Activities (see Section 3.2). 
Abnormal measurements may be repeated at the discretion of the investigator and must 
be reported on the corresponding eCRF page.  When vital signs and blood sample 
collection occur at the same time, vital signs should be performed before blood samples 
are drawn. 
10.2.3.3 
Electrocardiograms (ECGs) 
Subject must be in a supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted. If the subject is unable to be in the supine 
position, the subject should be in the most recumbent position as possible. 
ECGs should be performed in accordance with the Schedule of Activities (see  
Section 3.2), in triplicate, in a standardized method, prior to blood draws or other 
invasive procedures. Each ECG must include the following measurements:  QRS, QT, 
QTc, RR, and PR intervals. 
All ECGs will be triplicates with each tracing approximately 30 seconds apart and run 
consecutively. 
For subjects enrolled to Cohorts 1, 2 and 4, triplicate ECGs must be performed at   
 
Screening  
 
Cycle 1:  day 1 predose, end of infusion, and 4 hours postdose 
 
Cycle 2:  day 1 end of infusion 
 
Cycle 3:  day 1 end of infusion 
 
Cycle 4:  day 1 end of infusion 
 
Cycle 5:  day 1 end of infusion 
 
Beginning with Cycle 6, ECGs will be done if clinically indicated 


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For subjects enrolled to Cohort 3, and Cohorts 6-9 triplicate ECGs must be performed at 
screening and then as clinically indicated.  
The PI or designated sub-investigator will review all ECGs. ECGs will be transferred 
electronically to a central Amgen vendor. Once reviewed and signed by PI or 
sub-investigator, 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 will be provided by Amgen for all 
study-related ECG requirements. 
10.2.4 
Clinical Laboratory Assessments 
Refer to Section 13.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 3.2) for the timing and frequency. All tests (except for PK 
) are to be performed at a local laboratory and test results are to be 
recorded in the eCRF. Additional safety laboratory assessments may be performed if 
clinically indicated at the discretion of the investigator.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine 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. 
All protocol-required laboratory assessments, as defined in Section 13.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Section 3.2).  
10.2.4.1 
Pregnancy Testing 
A serum pregnancy test must be performed at screening and within 48 hours of cycle 1 
dose of AMG 404; beginning with cycle 2, a urine or serum pregnancy test must be 


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performed within 48 hours prior to the AMG 404 dose for females of childbearing 
potential (see Schedule of Activities Section 3.2). 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations.    
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 13-3).  Refer to Section 13.6 for contraceptive requirements.  
10.2.5 
Pharmacokinetic Assessments 
All subjects enrolled will have pharmacokinetic samples assessed. 
Blood samples will be collected for measurement of serum concentrations of AMG 404 
as specified in the Schedule of Activities (Section 3.2), 
 
  Instructions for the 
collection and handling of biological samples will be provided by the sponsor.  The actual 
date and time (24-hour clock time) of each sample will be recorded. 


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10.2.7 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Section 3.2) for the measurement of anti-AMG 
404 antibodies.
Samples testing positive for binding antibodies to AMG 404
 may be further 
characterized.  Additional blood samples may be obtained to rule out anti-AMG 404 
 
antibodies during the study. 
Subjects who test positive for anti-AMG 404 
antibodies at the final 
scheduled antibody time point and have clinical sequelae that are considered potentially 
related to an anti-AMG 404 
antibody response will be asked to return for 
additional follow-up testing. Sample collection and testing will occur approximately every 
3 months from the safety follow up visit until:  (1) anti-AMG 404 
antibodies are no longer detectable; or (2) the subject has been followed for a period of 
at least 1 year (± 4 weeks) post administration of AMG 404 
 All follow-up 
results, both positive and negative, will be communicated to the sites.  More frequent 
testing (eg, every month) or testing for a longer period of time may be requested in the 
event of safety-related concerns.  Refer to the Schedule of Activities (Section 3.2), as 
applicable, for specific time points, and the laboratory manual for detailed collection and 
handling instructions. 


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Product:  AMG 404  
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11. 
Statistical Considerations 
11.1 
Sample Size Determination 
Up to 275 evaluable subjects will be enrolled in this study.  Approximately, 2 to 4 
DLT-evaluable subjects will be enrolled in Cohort 1.  Approximately, 6 to 9 
DLT-evaluable subjects will be enrolled each in Cohort 2.  Approximately, 20 subjects 
will be enrolled each in Cohorts 3, 4, and 6 all outside of China.  Approximately, 
12 subjects will be enrolled to Cohort 5 in China/Taiwan/Hong Kong.  Approximately, 
40 subjects, respectively, will be enrolled to Cohort 7, Cohort 8, and Cohort 9.  
 
  
. 
With 2 subjects in Cohort 1, there is a 36 – 55% probability of observing at least 1 DLT. 
With 4 subjects in Cohort 1, there is a 59 - 80% probability of observing at least 1 DLT if 
the true DLT rate is 20 – 33%. 
Similarly, with 6 subjects per cohort, there is a 74 - 91% probability of observing at least 
1 DLT.  With 9 subjects per cohort, there is an 87 - 97% probability of observing at least 
1 DLT if the true DLT rate is 20-33%.  
In Cohorts 3, 4, 6, 
 a subject number of 20 will provide an 88% probability of 
observing at least one adverse event with 10% incident rate. An exact 80% binomial 
confidence interval (CI) will be provided for overall response rate. With the 20 subjects 
and 25% overall response rate, the expected 80% CI would be 13% to 42%.  
In Cohort 5, a subject number of 12 will provide a 72% probability of observing at least 
one adverse event with 10% incident rate.  An exact 80% binomial confidence interval 
(CI) will be provided for overall response rate.  With the 12 subjects and 25% overall 
response rate, the expected 80% CI would be 10% to 48%. 


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In Cohort 7, Cohort 8, and Cohort 9, the sample size is N~40 subjects.  A subject 
number of N~40 subjects will provide an 87% probability of observing at least one 
adverse event with 5% incident rate.  An exact 80% binomial confidence interval (CI) will 
be provided for overall response rate.  With the 40 subjects and 25% overall response 
rate, the expected 80% CI would be 16% to 36%. 
11.2 
Analysis Sets, 
 and Covariates 
11.2.1 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least one dose of 
AMG 404. 
The PK Analysis Set will contain all subjects who have received at least 1 dose of 
AMG 404 and have at least 1 PK sample collected.  These subjects may be evaluated 
for PK analysis unless the number of data points required for analysis is not enough, or 
significant protocol deviations have affected the data, or if key dosing or sampling 
information is missing.   
11.2.2 
Covariates 
The relationship of covariates to efficacy endpoints may be explored if appropriate. 


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11.3 
Adaptive Design 
Dose level decisions are based on a modified toxicity probability interval design (mTPI). 
The mTPI was developed by Ji et al. (2010).  The mTPI models the probability of toxicity 
for each dose level using a Bayesian model where each dose level has the same prior 
on the probability of toxicity, a Beta (1,1).  When subjects are treated at the current dose 
level, the posterior probability of toxicity is updated using the observed data from this 
level.  Dose level recommendation are made based on this posterior probability of 
toxicity, using three toxicity probability intervals (TPI). 
 
Under-dosing TPI:  DLT rate from 0 to < 20%  
 
Target TPI:  DLT rate from 20% to 33%    
 
Over-dosing:  DLT rate > 33% 
For the current dose level and after adjusting for the width of the under-dosing TPI, if the 
DLT rate is most likely in the under-dosing TPI then the recommendation is to dose 
escalate.  If the DLT rate is most likely in the target TPI then the recommendation is to 
stay at the current level.  If the DLT rate is most likely in the over-dosing TPI then the 
recommendation is to stop the enrollment.  If DLTs are observed, the maximum tolerated 
dose (MTD) is the dose level with a DLT toxicity rate closest to 26.7% (Ji et al. 2010). 
During enrollment and treatment at the RP2D using data from cohorts 3 and 6 and 
additionally using data from cohorts 7-9, objective response rate will be monitored with 
futility stopping rules described in Section 11.4.1.1. These futility stopping rules are 
selected using practical considerations. 
During enrollment and treatment at the RP2D using data from cohorts 3 and 6 and 
cohorts 7-9, subject incidence of grade 4 treatment related adverse events will be 
monitored with safety stopping rules described in Section 11.4.1.1.  The safety stopping 
rules use a Bayesian approach proposed by Thall, Simon, and Estey (1995) to terminate 
a cohort if the posterior probability that the subject incidence of grade 4 or higher 
treatment-related adverse events is greater than 20% is > 80%.  The stopping 
boundaries assume a prior distribution of Beta (0.40, 1.60). 
11.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 


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preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 6.3.1. 
11.4.1 
Planned Analyses 
11.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  In the dose level review meetings, 
Amgen, in consultation with the site investigators, will review all available cumulative 
data by cohort prior to making dose determination decisions.  Adverse events and DLTs 
observed in all subjects will be evaluated continually and fully integrated into all dose 
level review meetings and considered in all enrollment and dosing decisions.  
Additional details regarding the dose review meeting are providing in 
Sections 8.4.1 and 13.3. 
There is a planned treatment of N~40 subjects at the RP2D with enrollment to cohorts 3 
and 6. Additionally, there is a planned treatment of N~40 subjects at the RP2D with 
enrollment to Cohort 7, N~40 subjects enrolled to Cohort 8 and N~40 subjects enrolled 
to Cohort 9. For each of these cohorts (Cohort 3/6, Cohort 7, Cohort 8, Cohort 9), futility 
will be assessed after treating 15 and 25 subjects for at least 3 months.  If the observed 
rate of responses is consistent with a lower than 15% response rate, enrollment and 
treatment at the RP2D may be terminated due to futility.  For purposes of assessing 
futility, a response is defined as an objective response per RECIST 1.1. The guidelines 
for early termination due to futility are as follows: 
Number of Treated Subjects 
Futility Termination Guideline 
15 
1 or fewer responders 
25 
4 or fewer responders 
40 
Enrollment to dose expansion cohort complete 
If the true response rate is 15% then these termination guidelines result in a 69.4% 
probability of terminating dose expansion early with an expected sample size of 26.4 
subjects. If the true response rate is 30% then there is a 90% probability of continuing 
enrollment to N~40 total subjects. 
During this enrollment and treatment at the RP2D combining data from cohorts 3, 6, 7, 8 
and 9 (up to 160 total subjects enrolled) 
 
, Amgen will conduct evaluations of the ongoing subject incidence grade 4 
or higher treatment-related adverse event rate to assess if the threshold for possible 
early termination of a cohort has been reached.  If the threshold is met in the combined 


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monotherapy data of expansion cohorts 3, 6, 7, 8, and 9 enrollment to all ongoing 
cohorts in the study, 
, will be halted pending review of safety data 
by the DLRT.  If the threshold is met in a specific cohort, then enrollment to the specific 
cohort will be halted pending review of safety data by the DLRT.  After receiving the 
DLRT recommendation, Amgen will choose to take one of the following actions. 
When overall safety threshold exceeded in combined monotherapy data of expansion 
cohorts 3, 6, 7, 8, and 9: 
1) Terminate the trial  
2) Amend the protocol to potentially improve the benefit/risk for subjects (eg, increase 
safety monitoring, modify dose/schedule, mandate premedication) 
3) Continue monotherapy dose expansion cohorts and other cohorts, as appropriate, 
without any changes 
When cohort-specific safety threshold exceeded:  
1) Terminate enrollment to the cohort  
2) Amend the protocol to potentially improve the benefit/risk for subjects in the cohort of 
concern (eg, increase safety monitoring, modify dose/schedule, mandate 
premedication) 
3) Continue enrollment to the specific cohort (as appropriate) without any changes 
The methods for deriving the stopping boundaries overall for the combined monotherapy 
data of expansion cohorts 3, 6, 7, 8 and 9, or for within a cohort are described in 
Section 11.3 with the stopping boundaries overall for the combined monotherapy data of 
expansion cohorts 3, 6, 7, 8 and 9 presented in Table 11-1 and stopping boundaries for 
within a cohort presented in Table 11-2.  Operating characteristics with pre-specified 
batch size of 10 new subjects per batch are presented in Table 11-3. 
 


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(Overall the combined monotherapy data of expansion cohorts 3, 6, 7, 8 and 9) and in 
Table 11-4 (cohort with planned sample size of 40 subjects).  The operating 
characteristics in Table 11-3 and Table 11-4 provide the probability of stopping the trial 
early for given hypothetical true rate of grade 4 or higher treatment-related adverse 
events, whereas the stopping criteria in Table 11-1 and Table 11-2 are based on 
situations where the empirical evidence would result in a posterior probability of ≥ 80% 
that the true grade 4 or higher treatment-related adverse event rate is ≥ 20%. 
Table 11-1.  Stopping Boundary Overall for Combined Monotherapy Data of 
Cohorts 3, 6, 7, 8, and 9 with Posterior Probability of 80% and Grade 4 or Higher 
Treatment-Related Adverse Event Limit of 20% 
Number of subjects 
Stop study if observing this many subjects with grade 4 or higher 
treatment-related adverse events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
≥ 11 
50 
≥ 13 
60 
≥ 15 
70 
≥ 18 
80 
≥ 20 
90 
≥ 22 
100 
≥ 24 
110 
≥ 26 
120 
≥ 28 
130 
≥ 31 
140 
≥ 33 
150 
≥ 35 
160 
Combined Monotherapy Data for Cohorts 3, 6, 7, 8 and 9 
Complete 


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Table 11-2.  Stopping Boundary for Enrollment within Cohorts 3, 6-
 Individually 
with Posterior Probability of 80% and Subject Incidence of Grade 4 or Higher 
Treatment-Related Adverse Event Limit of 20% 
Number of subjects 
treated 
Stop cohort enrollment if observing this many subjects with grade 
4 or higher treatment-related adverse events 
5 
≥ 3 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Cohort Enrollment Complete* 
* Enrollment for cohorts 7, 8, and 9 completes after n = 40 subjects enrolled.  Enrollment for cohorts 3, 6, 
 
completes after n = 20 subjects enrolled.  
.  Early stopping 
rules (eg, at 5 or 10 treated subjects) are the same regardless of planned maximum sample size in a cohort. 
Table 11-3.  Operating Characteristics with Batch Size of 10 Subjects (Combining 
All Monotherapy Data of Expansion Cohorts 3, 6, 7, 8 and 9) 
True grade 4 or higher 
treatment-related adverse 
event rate 
Probability of early stopping of 
dose expansion 
Average sample size of 
overall combined 
monotherapy data 
0.10 
2.1 % 
156.9 
0.15 
12.7 % 
143.1 
0.20 
46.4 % 
105.8 
0.25 
86.4 % 
58.7 
0.30 
98.9 % 
31.5 
Table 11-4.  Operating Characteristics With Batch Size of 10 Subjects (Cohort-
Specific Enrollment with Maximum Cohort Sample Size of n=40 Subjects) 
True grade 4 or higher 
treatment-related adverse 
event rate 
Probability of early stopping of 
cohort enrollment 
Average cohort sample 
size 
0.10 
2.0 % 
39.5 
0.15 
9.7 % 
37.6 
0.20 
25.8 % 
33.9 
0.25 
47.8 % 
28.8 
0.30 
69.2 % 
23.4 
 
 


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11.4.1.2 
Primary Analysis 
The primary analysis will occur when target enrollment is complete, and each subject 
had the opportunity to complete 6 months on study or withdraws from study.  
11.4.1.3 
Final Analysis 
A final analysis is planned after all cohorts and dose-expansion subjects have ended the 
study.  Primary and final analysis may be combined in case all subjects have ended 
study close to the time point of the primary analysis.  
11.4.2 
Methods of Analyses 
11.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamics 
 by cohort, or time as appropriate.  Descriptive 
statistics on continuous data will include means, medians, standard deviations and 
ranges, while categorical data will be summarized using frequency counts and 
percentages.  Graphical summaries of the data may also be presented.  All descriptive 
statistics and graphical summaries may be presented separately for Cohort 5, 
 
 versus all the other cohorts.  Similarly, all the 
efficacy analyses in Section 11.4.2.2 and all the safety analyses in Section 11.4.2.3 may 
be conducted separately for Cohort 5, 
 
versus all the other cohorts.  
 
. 
Efficacy endpoints will be summarized separately for Cohort 7, Cohort 8, Cohort 9, 
.  
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Person (Clopper & Pearson, 1934). Kaplan-Meier methods will be 
used to estimate the median and percentiles for time to event endpoints with CI 
calculated using the Brookmeyer and Crowley method (Brookmeyer & Crowley, 1982). 
Kaplan-Meier methods will be used to estimate landmarks for time to event endpoints 
(eg, 1-year OS) with the Greenwood formula (Kalbfleisch & Prentice, 1980) used to 
estimate the standard error used in CI calculation.  
11.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
For all subjects treated at the RP2D and separately by cohort, the following 
analyses will be done. The proportion of subjects with an objective tumor 


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response (partial and complete response) and disease control rate (DCR) 
(partial or complete control) with corresponding exact 80 CI will be 
calculated and tabulated. Similarly, the proportion of subjects and 80 CI will 
be tabulated for 1-year duration of overall response, 1-year PFS, 1-year 
duration of stable disease and 1-year OS. Kaplan-Meier curve will be 
presented for duration of overall response, PFS, OS and duration of stable 
disease with estimates for rate and 80 CI at selected weeks if data allows. 
Exploratory 
Not applicable 
 
11.4.2.3 
Safety Analyses 
11.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Unless otherwise specified, statistical analyses on safety endpoints will be 
done using subjects from the safety analysis set, which includes subjects that 
are enrolled and received AMG 404. The statistical analysis methods are 
described in sections 11.4.2.3.2 through 11.4.2.3.6. 
11.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product, and other significant 
treatment emergent adverse events will also be provided.  Subject incidence of 
device-related events, if applicable, will be tabulated by system organ class and 
preferred term. 
11.4.2.3.3 
Laboratory Test Results 
Clinical chemistry, hematology, and urinalysis data will be summarized.  Depending on 
the size and scope of changes in laboratory data, summaries of laboratory data over 
time and/or changes from baseline over time may be provided.  Tables of maximum 
shifts from baseline for selected laboratory values may also be provided. 
11.4.2.3.4 
Vital Signs 
Depending on the size and scope of changes, summaries of vital signs data over time 
and/or changes from baseline over time may be provided. 
11.4.2.3.5 
Physical Measurements 
The analyses of physical measurements may include summary statistics over time by 
treatment cohort.  
11.4.2.3.6 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. Subjects' maximum change from baseline in (QTcF, QTcB) will be 


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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. 
11.4.2.3.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 404 antibodies, 
 
, will be tabulated overall, and 
by cohort.  
11.4.2.3.8 
Exposure to Investigational Product 
Details of AMG 404 administration will be summarized.  
11.4.2.3.9 
Exposure to Other Protocol-required Therapy 
Not applicable. 
11.4.2.3.10 
Exposure to Concomitant Medication 
All medication will be coded using the WHO drug dictionary.  All concomitant 
medications will be summarized.  
11.4.2.4 
Other Analyses 
The PK parameters of AMG 404 including, but not limited to, Cmax, tmax, and AUC for 
serum AMG 404 will be estimated using non-compartmental methods for subjects where 
intense PK sampling was collected (ie, subjects in Cohorts 1-6 
, at least 
10 subjects in Cohorts 7-9). 
.  The 
parameter estimates will be summarized by dose level using means, geometric means, 
standard deviations, coefficients of variation, medians, minimums, and maximums.  
Individual concentration-time profiles will be summarized by dose level.  Serum 
concentrations for AMG 404
at each time point along with PK parameter 
values may be listed for each subject.  Summary statistics will be computed for each 
sampling time and parameter as appropriate.  The relationship between AMG 404 
exposure and efficacy/safety may be conducted.  
 


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Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-
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78-85. 
 


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13. 
Appendices 


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13.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-dependent cellular cytotoxicity 
AML 
Acute Myeloid Leukemia 
AUC 
area under the serum concentration-time curve 
CFR 
U.S. Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
maximum observed serum concentration 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DES 
Amgen data element standard 
DILI 
drug induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
Dose Limiting Toxicity 
ECG 
electrocardiogram 
ECL 
Electrochemiluminiscent 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
Enrollment 
Date of enrollment confirmation letter from Amgen 
EOT 
End of Treatment 
Exposure-Response  
Analysis 
mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic (PK) exposure 
(eg, population pharmacokinetic modeling) and response, which 
may include 
 pharmacodynamic (PD) effects, 
efficacy and safety endpoints. 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 


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Abbreviation or Term 
Definition/Explanation 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early  
End of Study (end of trial) 
defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
FIH 
First in Human 
FSH 
follicle stimulating hormone 
FFPE 
Formalin fixed paraffin embedded 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormone replacement therapy 
HUVEC 
Human Endothelial Cells 
IBG 
Independent Biostatistics Group 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IPRO 
Immunophenotyping receptor occupancy 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IV 
Intravenous 
LLOQ 
Lower limit of quantification 
(m)TPI 
(modified) Toxicity Probability Interval 
ORR 
Overall Response Rate 
PBL 
Peripheral blood leukocytes 
PFS 
Progression free survival 
PPP 
Platelet poor plasma 
SAT 
safety assessment team 


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Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product administered to the subject 
TBL 
total bilirubin 
tmax 
time to achieve Cmax 
SUSAR 
suspected unexpected serious adverse reaction 
TMF 
trial master file 
ULN 
upper limit of normal 
 


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13.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 13-1 will be performed by the local laboratory (unless 
specified otherwise).  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 7.1 and 7.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 13-1.  Analyte Listing 
Local Laboratory: 
Chemistry 
Local 
Laboratory: 
Coagulation 
Local 
Laboratory: 
Urinalysis 
Local  
Laboratory: 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate or 
CO2 
Total protein 
Albumin 
Calcium 
Calcium 
Corrected 
Glucose 
BUN or 
Urea/Total Urea 
Creatinine 
Estimated CrCl 
GFR, MDRD 
calculation 
Total bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
TSH 
Free T4 
 
APTT 
PT/INR 
 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Hemoglobin 
Hematocrit 
MCV  
Platelets 
WBC 
Differential 
• Total Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
 
 
Central 
Laboratory: 
Antibodies 
PK sampling 
Whole blood for 
cytometry 
Serum2 
PD-L1 
dMMR 
MSI  
 
 
Local Laboratory: 
Serum or Urine 
Pregnancy 
Hep B surface 
antigen 
Hep B core 
antibody 
Hep C antibody 
HIV 
ACTH 
ANA 
ANCA 
(cytoplasmic and 
perinuclear) 
PD-L1 
dMMR 
MSI  
 
2 Not applicable to China 
ACTH = Adrenocorticotropic hormone; ANA = Antinuclear Antibodies; ANCA = Antineutrophil cytoplasmic 
antibodies; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; dMMR = Mismatch Repair Deficiency; 
 
 HDL = high density lipoprotein; Hep = hepatitis; HIV = human immunodeficiency virus;  
INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; MSI = Microsatellite Instability;  
PD-L1 = Programmed Death Ligand 1; PK = pharmacokinetics; PT = prothrombin time; APTT = partial 
thromboplastin time;  RBC = red blood cell count; RDW = Red cell distribution width; SGOT = serum 
glutamic-oxaloacetic transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC = white blood cell 
count 


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13.3 
Appendix 3.  Study Governance Considerations 
Committee(s) 
Dose Level Review Team 
Dose level review team (DLRT) meetings will be held to review data, monitor safety, and 
make recommendations on dose determination.  See Section 8.4.1 for detailed 
information on the DLRM and DLRT.   
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  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. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval 
must be sent to Amgen 


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 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations 
from the protocol or other adverse event reports received from Amgen, in 
accordance with local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 
of the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and 
all other applicable local regulations 
Recruitment Procedures 
Site staff may identify potential subjects from their existing patient population and/or may 
seek referral patients through existing professional networks or other community 
sources. All patient-facing materials must be reviewed/approved by the sponsor  
(Amgen Inc.) and the local IRB/IEC prior to use.  
Informed Consent Process 
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 sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative (defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study) will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 


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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 unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject [or a legally acceptable representative] and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 9. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study, if applicable.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 28 days from the previous informed consent form signature 
date. 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 


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signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
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 age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 


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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
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 Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to 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; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
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 must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
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 


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Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
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. 
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. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit 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. 
Retention of study documents will be governed by the Clinical Trial Agreement. 


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Case report forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
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 provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
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.  Source documents may also include data captured in the CRF 
entries if the CRF is the site of the original recording (ie, there is no other written or 
electronic record of data, such as paper questionnaires for a clinical outcome 
assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 


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Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the 
[IRB/IEC] and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, 
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) or combination 
product(s) documentation, as applicable] 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
 


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13.4 
Appendix 4.  Toxicity Management Guidelines 
Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Pneumonitis 
Grade 2 (symptomatic, involves 
more than one lobe of the lung of 
25-50 of lung parenchyma, 
medical intervention indicated, 
limiting instrumental ADL) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Consider additional 
immunosuppressive agent (eg, 
infliximab, mycophenolate, 
cyclophosphamide) if refractory to 
corticosteroids. 
Monitor subjects for signs and 
symptoms of pneumonitis.  
Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging. Add prophylactic 
antibiotics for opportunistic 
infections. 
Grade 3 (severe symptoms, 
hospitalization required, involves 
all lung lobes or  50 of lung 
parenchyma, limiting self-care 
ADL, oxygen indicated) 
Permanently 
discontinue 
Grade 4 (life-threatening 
respiratory compromise, urgent 
intervention indicated [intubation]) 
Page 1 of 8 
Footnotes defined on last page of this table 


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Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Colitis/Diarrhea 
Grade 2 (increase of 4-6 stools 
per day over baseline; moderate 
increase in ostomy output 
compared with baseline) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Consider infliximab if 
symptoms refractory to 
corticosteroids within 2-3 days. 
Monitor subjects for signs and 
symptoms of enterocolitis (eg, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(eg, peritoneal signs and ileus). 
For subjects with grade  2 
diarrhea suspecting colitis, 
consider GI consultation and 
endoscopy to rule out colitis. 
Grade 3 (increase of 7 or more 
stools per day over baseline, 
incontinence; hospitalization 
indicated, severe increase in 
ostomy output compared with 
baseline, limiting self-care ADL) 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
Permanently 
discontinue 
Page 2 of 8 
Footnotes defined on last page of this table 


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Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Hepatitis**1 
Grade 1 (AST or ALT 3 x ULN) 
without elevated total bilirubin 
Continue 
Consider holding for concerning lab 
value trend. 
Monitor with liver function 
tests more frequently until 
returned to baseline or 
stable. Additional 
management per institutional 
and professional society 
guidelines. 
Grade 2 (AST or ALT 3-5 x ULN) 
without elevated total bilirubin  
Withhold 
Consider corticosteroids at an initial 
dose of 0.5 to 1 mg/kg/d prednisone 
(or equivalent) followed by taper. 
Grade 3 (AST or ALT 5-20 x ULN) 
without elevated total bilirubin 
[Without a clear alternative etiology. 
If a clear alternative etiology, then 
withhold, do not discontinue 
AMG 404.]  
Permanently 
discontinue 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Consider mycophenolate 
mofetil if refractory to corticosteroids 
or no improvement after 3 days. 
Grade 4 (AST or ALT  20 x ULN) 
without elevated total bilirubin 
[Without a clear alternative etiology. 
If a clear alternative etiology, then 
withhold, do not discontinue 
AMG 404.]  
Administer corticosteroids at an 
initial dose of 2 mg/kg/d prednisone 
(or equivalent) followed by taper. 
Consider mycophenolate mofetil if 
refractory to corticosteroids or no 
improvement after 3 days. 
Grade  1 (AST or ALT  3 x ULN)  
with total bilirubin  1.5 x ULN 
[Without a clear alternative etiology. 
If a clear alternative etiology, then 
withhold, do not discontinue 
Consider holding for concerning lab 
value trend.  AMG 404.] 
Administer corticosteroids at an 
initial dose of 2 mg/kg/d prednisone 
(or equivalent) followed by taper. 
Consider mycophenolate mofetil if 
refractory to corticosteroids or no 
improvement after 3 days. 
Page 3 of 8 
Footnotes defined on last page of this table 


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Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Hypophysitis 
Grade 3 or 4 (severe symptoms, 
medically significant or  
life-threatening consequences, 
unable to perform ADL) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 mg/kg/d prednisone 
(or equivalent) followed by taper. In 
addition, initiate hormonal 
replacement therapy as clinically 
indicated. 
Monitor for signs and symptoms 
of hypophysitis. Consider 
endocrine consultation. 
Adrenal 
Insufficiency 
Grade 3 or 4 (severe symptoms, 
medically significant or  
life-threatening consequences, 
unable to perform ADL) 
Withhold 
Initiate IV stress-dose 
corticosteroids on presentation 
(hydrocortisone 100 mg or 
dexamethasone 4 mg [if the 
diagnosis is not clear and ACTH 
stimulation testing will be needed]). 
Taper stress-dose corticosteroids 
down to maintenance doses 
(prednisone 5 to 10 mg daily) over 
1-2 weeks after discharge.  
Monitor for signs and symptoms 
of adrenal insufficiency.  
Consider endocrine consultation. 
Hypothyroidism  
Grade 3 or 4 (severe symptoms, 
medically significant or  
life-threatening consequences, 
unable to perform ADL) 
Withhold 
Initiate thyroid hormone 
supplementation. 
Monitor subjects for signs and 
symptoms of hypothyroidism. 
Consider endocrine consultation. 
Hyperthyroidism 
Grade 3 or 4 (severe symptoms, 
medically significant or  
life-threatening consequences, 
unable to perform ADL)  
Withhold 
Initiate -Blocker (eg, atenolol, 
propranolol) for symptomatic relief. 
For severe symptoms or concern for 
thyroid storm, initiate prednisone  
1-2 mg/kg/d (or equivalent) tapered 
over 1-2 weeks. Consider use of 
SSKI or thionamide (methimazole or 
PTU). 
Monitor subjects for signs and 
symptoms of hyperthyroidism. 
Consider endocrine consultation. 
Page 4 of 8 
Footnotes defined on last page of this table 


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Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Diabetes Mellitus 
Grade 3 hyperglycemia ( 250 to 
500 mg/dL [ 13.9 to 
27.8 mmol/L]) 
Withhold 
Initiate insulin therapy. 
Monitor subjects for 
hyperglycemia or other signs and 
symptoms of diabetes. Consider 
endocrine consultation. 
Grade 4 hyperglycemia  
( 500 mg/dL [ 27.8 mmol/L]) 
Nephritis and 
Renal 
Dysfunction 
Grade 2 (serum creatinine 1.5 - 
3.0 x baseline; 1.5 - 3.0 x ULN) 
Withhold 
Administer corticosteroids at an 
initial dose of 0.5 to 1 mg/kg/d 
prednisone (or equivalent) followed 
by taper. If worsening or no 
improvement occurs, increase dose 
of corticosteroids to 1 to 2 mg/kg/d 
prednisone (or equivalent). 
Monitor changes in renal 
function. Evaluate for other 
causes of renal dysfunction (eg, 
recent IV contrast, medications, 
fluid status, etc) 
Grade 3 (serum creatinine 3.0 x 
baseline; 3.0 - 6.0 x ULN) 
Permanently 
discontinue 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. 
Grade 4 (serum creatinine  6 x 
ULN; dialysis indicated) 
Page 5 of 8 
Footnotes defined on last page of this table 


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Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Skin 
Grade 3 rash or suspected 
Stevens-Johnson syndrome 
(SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Treat with topical 
emollients, oral antihistamines, and 
high-potency topical corticosteroids 
as indicated. 
Monitor subjects for suspected 
severe skin reactions and 
exclude other causes (eg, 
infection, an effect of another 
drug, a skin condition linked to 
another systemic disease, etc). 
For signs or symptoms of SJS or 
TEN, withhold study drug and 
refer the patient for specialized 
care for assessment and 
treatment. 
Grade 4 rash or confirmed SJS 
or TEN 
Permanently 
discontinue 
Encephalitis 
Grade 2 (moderate symptoms, 
some interference with ADL) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. Consider empirical antiviral 
(IV acyclovir) and antibacterial 
therapy until CSF results obtained 
and negative for aseptic meningitis. 
Monitor subjects for neurologic 
symptoms and exclude other 
etiologies (eg, infectious). 
Evaluation of patients with 
neurologic symptoms may 
include, but not be limited to, 
consultation with a neurologist, 
brain MRI, and lumbar puncture. 
Grade 3 or 4 (severe symptoms, 
limiting self-care and aids 
warranted) 
Permanently 
discontinue 
Page 6 of 8 
Footnotes defined on last page of this table 


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Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Myocarditis 
Grade 1 (abnormal cardiac 
 testing, including 
abnormal ECG)  
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. 
Monitor patients with 
cardiovascular symptoms. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Grade 2 (abnormal screening 
tests with mild symptoms) 
Grade 3 (moderately abnormal 
testing or symptoms with mild 
activity) 
Permanently 
discontinue 
Grade 4 (moderate to severe 
decompensation, IV medication 
or intervention required, 
life-threatening conditions) 
All Other 
Immune-Related 
Adverse 
Reactions 
Grade 3 adverse reaction 
involving a major organ 
Withhold 
Based on type and severity of 
adverse reaction, administer 
corticosteroids. Refer to ASCO 
Clinical Practice Guidelines for 
additional recommendations. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Life-threatening or Grade 4 
adverse reaction involving a 
major organ 
Permanently 
discontinue 
Page 7 of 8 
Footnotes defined on last page of this table 


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Table 13-2.  Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Reactions Associated With 
AMG 404* 
Immune-Related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Recurrent or 
Persistent 
Immune-Related 
Adverse 
Reactions 
Recurrence of same Grade 3 or 
Grade 4 adverse reaction 
Permanently 
discontinue 
Based on type and severity of 
adverse reaction, administer 
corticosteroids. Additional 
immunosuppressive treatment may 
be required. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Requirement for  10 mg/day 
prednisone (or equivalent) for 
more than 12 weeks 
Persistent grade 2 or 3 adverse 
reactions lasting 12 weeks or 
longer after last dose (ie, does 
not resolve to grade 0 or 1 within 
12 weeks) 
General considerations:  
 Corticosteroid taper should be initiated upon improvement of signs/symptoms and/or laboratory values to Grade 1 or less. Continue 
corticosteroid taper over the course of at least 4 to 6 weeks.  
 If AMG 404 has been withheld, treatment with AMG 404 may be resumed after adverse event (or associated signs/symptoms/laboratory 
parameters) has been reduced to Grade 1 or less and corticosteroid has been tapered to prednisone  10 mg (or equivalent).  
 For severe and life-threatening immune-related adverse reactions, IV corticosteroids should be initiated first followed by oral corticosteroids. 
Other immunosuppressive treatment should be initiated if the event cannot be controlled by corticosteroids.  
Page 8 of 8 
* Recommendations adapted from the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines for the Management of Immune-Related Adverse 
Events in Patients Treated with Immune Checkpoint Inhibitor Therapy (JCO 2018) 
**Immune mediated hepatitis guidance adapted from the National Comprehensive Cancer Network (NCCN) Version 1.2020, Management of Immune Checkpoint 
Inhibitor-Related Toxicities 
1 In addition to Table 13-2, which includes guidance on mitigation/management of suspected immune-mediated hepatitis, the protocol contains Table 12-4 in 
Appendix 8, which offers general mitigation guidance for potential Drug-Induced Liver Injury (DILI). When applicable, first refer to Table 13-2 for managing AST and/or 
ALT and/or total bilirubin elevations, when other liver parameters remain within normal limits (ie INR, ALP). Table 13-2, withholding and discontinuation guidance is 
more conservative than Table 12-4 guidance. 
 


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Table 13-5.  Management of Infusion-Related Reactions With AMG 404 
Severity (CTCAE 
Grade Version 5.0) 
AMG 404 Dose 
Modification 
Management 
Premedication at 
Subsequent 
Dosing 
Grade 1 (mild transient 
reaction; infusion 
interruption not 
indicated; intervention 
not indicated) 
Interrupt or 
slow the rate of 
the infusion to 
50  or less of 
the standard 
rate. 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 If the infusion is 
interrupted, then after 
all symptoms have 
resolved, consider 
rechallenge with a 
reduced infusion rate 
(50  or less of 
standard rate) and 
additional 
premedication (such as 
corticosteroids and 
antihistamines). 
 Treat per institutional 
guidelines. 
None 
Grade 2 (therapy or 
infusion interruption 
indicated but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDS,  
narcotics, IV fluids); 
prophylactic medications 
indicated for  24 hours) 
Interrupt or 
slow the rate of 
the infusion to 
50  or less of 
the standard 
rate.  
For subjects 
who develop 
grade 2 
infusion-related 
reaction despite 
adequate 
premedication, 
permanently 
discontinue 
AMG 404. 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 If the infusion is 
interrupted, then after 
all symptoms have 
resolved, consider 
rechallenge with a 
reduced infusion rate 
(50  or less of 
standard rate) and 
additional 
premedication (such as 
corticosteroids and 
antihistamines). 
 Treat per institutional 
guidelines. Additional 
appropriate medical 
therapy may include but 
is not limited to IV 
fluids, antihistamines, 
NSAIDs, 
acetaminophen, and 
narcotics. 
Subject may be 
premedicated 
1.5 hours  
( 30 minutes) prior 
to infusion of  
AMG 404 with:  
 Diphenhydramine 
50 mg orally (or 
equivalent dose of 
antihistamine). 
 Acetaminophen 
500-1000 mg 
orally (or 
equivalent dose of 
antipyretic). 


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Grade 3 (prolonged [eg, 
not rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion]; recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae) 
 
OR 
 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
Permanently 
discontinue 
study drug. 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 Hospitalization may be 
indicated. 
 Treat per institutional 
guidelines. Additional 
appropriate medical 
therapy may include but 
is not limited to IV 
fluids, antihistamines, 
NSAIDs, 
acetaminophen, 
narcotics, oxygen, 
vasopressors, 
corticosteroids, and 
epinephrine. In cases of 
anaphylaxis, 
epinephrine should be 
used immediately. 
No subsequent 
dosing 


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13.5 
Appendix 5.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device or procedure. 
 
Note:  Treatment emergent adverse event will be defined in the SAP. 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiological scans, vital signs measurements), 
including those that worsen from baseline, that are considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported regardless of 
sequelae. 
 
For situations when an adverse event or serious adverse event is due to the underlying 
disease under study (ie, advanced solid tumor) report all known signs and symptoms.  
Death due to disease progression in the absence of signs and symptoms should be 
reported as the primary tumor type (eg, non-small cell lung cancer, malignant melanoma, 
etc).  Note:  The term “disease progression” should not be used to describe the adverse 
event. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an adverse event or serious adverse event.  Such instances will be captured in the 
efficacy assessments.  However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as adverse event or serious adverse event if they fulfill 
the definition of an adverse event or serious adverse event. 
 
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to 
the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 


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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, meets 
at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are an adverse event.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious.  Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition.  These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
 


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Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory, and 
diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (CRF). 
 
The investigator must assign the following adverse event attributes: 
o 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o 
Dates of onset and resolution (if resolved); 
o 
Did the event start prior to first dose of investigational product, other protocol-required 
therapies; 
o 
Assessment of seriousness; 
o 
Severity (or toxicity defined below); 
o 
Assessment of relatedness to investigational product(s), non-investigational product(s), 
other protocol-required therapies, and/or study-mandated activity and/or procedures;  
o 
Action taken; and 
o 
Outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of resolution, 
record a single event for each level of severity on the Event CRF  
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to sponsor in lieu of completion of the Event CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse 
event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and serious 
adverse event reported during the study.  The assessment of severity will be based on:  
The Common Terminology Criteria for Adverse Events, version 5.0 which is available at the 
following location:  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


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Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational product 
non-investigational product(s), other protocol-required therapies, and/or study-
mandated activity and/or procedure and each occurrence of each adverse event/serious 
adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and has 
provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Amgen to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully 
as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up period as 
defined in Section 10.2.3.1.1, the investigator will provide Amgen with a copy of any 
post-mortem findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen within 
24 hours of receipt of the information. 


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Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic data 
capture (EDC) system.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report the 
information to Amgen using paper-based Serious Adverse Event Contingency Report Form 
(also referred to as the electronic Serious Adverse Event (eSAE) Contingency Report 
Form) (see Figure 13-1) within 24 hours of the investigator’s knowledge of the event. 
 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to prevent 
the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been taken 
off-line, then the site can report this information on a paper-based Serious Adverse Event 
Contingency Report Form. 
 
Once the study has ended, serious adverse event(s) should be reported to Amgen 
(regardless of causality) if the investigator becomes aware of a serious adverse event.  The 
investigator should use the paper-based Serious Adverse Event Contingency Report Form 
to report the event. 


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Figure 13-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
(Paper-Based Form) 
 
 


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13.6 
Appendix 6.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for male and female of childbearing potential 
are outlined in Section 7.2. 
Male and female study subjects of childbearing potential must receive pregnancy 
prevention counseling and be advised of the risk to the fetus if they become pregnant or 
father a child during treatment and for 6 months (female study subjects) and 8 months 
(male study subjects) after the last dose of AMG 404. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  1) 
review of subject’s medical records; 2) subject’s medical examination; or 3) 
subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause.  A high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be 
required to use 1 of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment 


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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of <1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject) 
Contraception Methods for Male Subjects  
 
Sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk associated with protocol-required therapies; the reliability 
of sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject)  
 
Use a condom during treatment and for an additional 8 months after the last dose 
of protocol-required therapies 
The female partner should consider using an acceptable method of effective 
contraception such as:  hormonal, IUD, IUS, female barrier method (diaphragm, cap, 
sponge [a female condom is not an option because there is a risk of tearing when both 
partners use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 


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 
Spermicides only 
 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who 
becomes pregnant while taking protocol-required therapies through 6 months 
after last dose of AMG 404,
 
Information will be recorded on the Pregnancy Notification Form (see 
Figure 13-3).  The form must be submitted to Amgen Global Patient Safety within 
24 hours of learning of a subject’s pregnancy.  (Note:  Sites are not required to 
provide any information on the Pregnancy Notification Form that violates the 
country or regions local privacy laws). 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female 
subject who becomes pregnant while taking protocol-required therapies through 
6 months after last dose of AMG 404,
  
This information will be forwarded to Amgen Global Patient Safety.  Generally, 
infant follow-up will be conducted up to 12 months after the birth of the child (if 
applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious 
adverse event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate 
will be reported as an adverse event or serious adverse event.  Note that an 
elective termination with no information on a fetal congenital malformation or 
maternal complication is generally not considered an adverse event, but still must 
be reported to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as 
a serious adverse event (eg, female subject experiences a spontaneous 
abortion, stillbirth, or neonatal death or there is a fetal or neonatal congenital 
anomaly) the investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which 
is considered reasonably related to the study treatment by the investigator, will 
be reported to Amgen Global Patient Safety as described in Section 13.5.  While 
the investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
 
Any female subject who becomes pregnant while participating will discontinue 
study treatment (see Section 9.1 for details).  


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Male Subjects With Partners Who Become Pregnant  
 
In the event a male subject fathers a child during treatment, 
 
 and/or 
8 months after last dose of AMG 404 the information will be recorded on the 
Pregnancy Notification Form.  The form (see Figure 13-3) must be submitted to 
Amgen Global Patient Safety within 24 hours of the site’s awareness of the 
pregnancy.  (Note:  Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy 
laws). 
 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner 
to obtain additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who 
breastfeeds while taking protocol-required therapies through 6 months after the 
last dose of AMG 404,
 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the 
study as described in exclusion criterion 221. 
 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health 
information and complete the lactation questionnaire on any female subject who 
breastfeeds while taking protocol-required therapies through 6 months after 
discontinuing protocol-required therapies. 
 


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Figure 13-3.  Pregnancy and Lactation Notification Forms 
 


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13.7 
Appendix 7.  Sample Storage and Destruction 
Any blood, 
, PK, and 
  sample collected according to the Schedule of 
Activities (Section 3.2) can be analyzed for any of the tests outlined in the protocol and 
for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
advanced solid tumors,  the dose response and/or prediction of response to AMG 404,  
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 or to alter the 
treatment course, the results of 
 
 are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood, serum 
 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 


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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 13.3 for subject confidentiality. 


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13.8 
Appendix 8.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolosis, hemolysis) 
 
If investigational product(s) is/are withheld, the subject is to be followed for possible 
drug-induced liver injury (DILI) according to recommendations in the last section of 
this appendix.  


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Rechallenge may be considered if an alternative cause for impaired liver tests ALT, AST, 
ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve to 
normal or baseline (see next section in this appendix).  
Table 13-6.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
 3x ULN  
at any time 
 2x ULN 
 
 
OR 
INR 
-- 
 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
 8x ULN at any time 
 5x ULN but  8x ULN for  1 week 
 5x ULN but  8x ULN and unable to 
adhere to enhanced monitoring schedule 
 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 3x ULN (when baseline was  ULN) 
 
OR 
 
ALP 
 8x ULN at any time 
-- 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase;  
INR  international normalized ratio; TBL  total bilirubin; ULN  upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product is to be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Table 13-6) are never to be rechallenged. 


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Drug-induced Liver Injury Reporting and 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 the above, 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 Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to 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 13.5. 
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  
Table 13-6 or who experience AST or ALT elevations  3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
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 (BIL) (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.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


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 
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 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  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 the corresponding CRFs.  


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13.9 
Appendix 9.  ECOG Performance Status and NYHA Classification 
 
Eastern Cooperative Oncology Group Performance Scale  
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
Source:  Oken et al, 1982 
New York Heart Association Functional Classification 
Class I  
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea. 
Class II 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea. 
Class III 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation or dyspnea. 
Class IV 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency may be present even at rest. If any physical activity 
is undertaken, discomfort is increased.  


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13.10 
Appendix 10.  Modified Response Evaluation Criteria in Solid 
Tumors Version 1.1 (Modified RECIST 1.1) 
This study utilizes modified RECIST 1.1 criteria, which includes required confirmation of 
disease progression, and the following modification to RECIST 1.1: 
 
Up to 5 target lesions per organ and 10 total are allowed (compared to 2 per 
organ and 5 total for standard RECIST 1.1) to increase lesion sampling and 
reduce assessment error. 
Definitions 
 
Measurable lesions: 
o Measurable Tumor Lesions – Non-nodal lesions with clear borders that 
can be accurately measured in at least 1 dimension with longest 
diameter  10 mm in CT/MRI scan with slice thickness no greater than 
5 mm.  When slice thickness is greater than 5 mm, the minimum size of 
measurable lesion should be twice the slice thickness. 
o Nodal Lesions - Lymph nodes are to be considered pathologically 
enlarged and measurable, a lymph node must be  15 mm in short axis 
when assessed by CT/MRI (scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Nodal size is normally reported as two dimensions in 
the axial plane.  The smaller of these measures is 
the short axis (perpendicular to the longest axis). 
o Irradiated Lesions - Tumor lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy, are not 
measurable unless there has been demonstrated progression in the 
lesion prior to enrollment. 
 
Non-measurable Lesions 
o 
All other lesions, including small lesions (longest diameter  10 mm or 
pathological lymph nodes with  10 mm but to  15 mm short axis with 
CT scan slice thickness no greater than 5 mm) are considered 
non-measurable and characterized as non-target lesions. 
o 
Other examples of non-measurable lesions include: 
▪ 
Lesions with prior local treatment:  tumor lesions situated in a 
previously irradiated area, or an area subject to other 
loco-regional therapy, should not be considered measurable 
unless there has been demonstrated progression in the lesion. 
▪ 
Biopsied lesions 
▪ 
Categorically, clusters of small lesions, bone lesions, 
inflammatory breast disease, and leptomeningeal disease are 
non-measurable. 


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Methods of Measurement 
 
Measurement of Lesions - The longest diameter of selected lesions should 
be measured in the plane in which the images were acquired (axial plane).  
All measurements should be taken and recorded in metric notation.  All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and not more than 4 weeks before study Day 1. 
 
Methods of Assessment - The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion 
throughout the trial. 
 
CT/ MRI – Contrast-enhanced CT or MRI should be used to assess all 
lesions.  Optimal visualization and measurement of metastasis in solid 
tumors requires consistent administration (dose and rate) of IV contrast as 
well as timing of scanning.  CT and MRI should be performed with  5 mm 
thick contiguous slices. 
Baseline documentation of “Target” and “Non-target” lesions 
 
Target Lesions - All measurable lesions up to a maximum of five (5) lesions 
per organ and ten (10) lesions in total, representative of all involved organs 
should be identified as target lesions and recorded and measured at 
baseline. 
o Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and suitability for accurate repeated 
measurements. 
o Pathologic lymph nodes (with short axis  15 mm) may be identified as 
target lesions.  All other pathological nodes (those with short axis 
 10 mm but  15 mm) should be considered non-target lesions. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum of diameters. The baseline sum of diameters will be used 
as reference by which to characterize objective tumor response. 
 
Non-Target Lesions - All other lesions (or sites of disease) including 
pathological lymph nodes should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions 
are not required, and these lesions should be followed as “present”, 
“absent”, or “unequivocal progression” throughout the study.  In 
addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case report form (eg, “multiple 
enlarged pelvic lymph nodes” or “multiple liver metastases”).  


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Response Criteria 
Evaluation of Target Lesions 
* Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to  10 mm. 
* Partial Response (PR): 
At least a 30 decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum of 
diameters. 
* Progressive Disease (PD): 
At least a relative 20 increase and an absolute increase 
of 5 mm in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study, or the 
appearance of one or more new lesions. 
* Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum of diameters since the treatment started. 
Evaluation of Non-target Lesions 
 
1 To achieve “unequivocal progression” on the basis of the non-target disease, there must be an overall level 
of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest “increase” 
in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. 
Evaluation of Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment or disease progression/recurrence (taking as 
reference for PD the smallest measurements recorded since the treatment started).   
In general, the subject's best response assignment will depend on the findings of both 
target and non-target disease and will also take into consideration the appearance of 
new lesions. 


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Time Point response:  Subjects with Target (/- Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
NE  Not evaluable 
Time Point Response:  Subjects with Non-Target Disease Only 
 


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Overall Response:  Confirmation of Complete Response (CR) and Partial 
Response (PR) required 
 
Special Notes on Response Assessment 
 
Nodal lesions – Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded, even if the nodes regress to below 
10 mm on study.  In order to qualify for CR, each node must achieve a short axis 
 10 mm, NOT total disappearance.  Nodal target lesion short axis measurements 
are added together with target lesion’ longest diameter measurements to create 
the sum of target lesion diameters for a particular assessment (time point). 
 
Target lesions that become “too small to measure” – While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their measurements 
recorded at each subsequent evaluation.  If a lesion becomes less than 5 mm, the 
accuracy of the measurement becomes reduced.  Therefore, lesions less than 
5 mm are considered as being “too small to measure”, and are not measured.  With 
this designation, they are assigned a default measurement of 5 mm.  No lesion 
measurement less than 5 mm should be recorded, unless a lesion totally 
disappears and “0” can be recorded for the measurement. 


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 
New lesions – The term “new lesion” always refers to the presence of a new 
finding that is definitely tumor.  New findings that only may be tumor, but may be 
benign (infection, inflammation, etc.) are not selected as new lesions, until that 
time when the review is certain they represent tumor.   
 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease.  
If repeat scans confirm there is definitely a new lesion, then progression 
should be declared using the date of the initial scan. 
 
A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression, regardless of any response that may be seen in target or 
non-target lesions present from baseline. 
 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.”  Every effort should be made to 
document the objective progression with an additional imaging assessment even 
after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from 
scar or normal tissue.  When the evaluation of complete response (CR) depends 
on this determination, it is recommended that the residual lesion be further 
investigated by fluorodeoxyglucose-positron emission tomography (FDG-PET) or 
PET/computed tomography (PET/CT), or possibly fine needle aspirate/biopsy, to 
confirm the CR status. 
Confirmation Measurement / Duration of Response 
 
Response Confirmation - In non-randomized trials where response is the 
primary endpoint, confirmation of PR and CR is required to ensure 
responses identified are not the result of measurement error. 
 
Duration of overall response – The duration of overall response is 
measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date the recurrent or progressive 
disease is objectively documented. 
 
Duration of Stable Disease - SD is measured from the start of the 
treatment until the criteria for disease progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 
 


Product:  AMG 404 
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Page 1 of 54 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 6 
Protocol Title:  A Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, 
 
 in Patients With Advanced Solid Tumors 
 
Amgen Protocol Number AMG 404 20180143 
EudraCT Number:  2018-004268-80 
NCT Number:  NCT3853109 
 
Amendment Date: 
20 May 2022 
 
Rationale: 
The protocol, dated May 20th, 2022, was amended to discontinue clinical trial activities for 
study 20180143, to allow for extended treatment for an additional 24 months for subjects who 
continue to receive clinical benefit from treatment with AMG 404, to update safety language, 
and to clarify/correct other items in the protocol.  Please note, the study is not being stopped for 
safety reasons or lack of efficacy. 
Changes include: 
 
Updated Section 3.2 Schedule of Activities to include extended treatment for Cohorts 
1-9. 
 
Updated Section 2 Protocol Synopsis and Section 3.1 Study Schema to clarify that 
Cohort 5 was a China/Taiwan/Hong Kong-specific expansion cohort  
 
Updated Section 4.5.3 Risks with current safety information.  
 
Deleted Section 7.2 Exclusion Criteria, exclusion criterion #242 to remove a duplicated 
criterion. 


Product:  AMG 404 
Protocol Number:  20180143 
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Page 2 of 54 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Added Section 10.1.3 Extended Treatment Period for subjects who continue to receive 
clinical benefit from treatment with AMG 404 beyond 24 months of treatment. 
 
Updated Section 10.2.2 Efficacy Assessments to incorporate extended treatment and 
cohort closures. 
 
Updated Section 10.2.3.1.1.3 Serious Adverse Events After the Protocol-required 
Reporting Period to clarify SAE collection post study. 
 
Updated safety template language. 
 
Administration, typographical, and formatting changes were made throughout the 
protocol. 
 


Product:  AMG 404  
Protocol Number:  20180143  
Date:  16 July 2021 
Page 1 of 97 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 5 
Protocol Titile:  A Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 404, a Programmed Death-1 
(PD-1) Antibody, 
 in 
Patients With Advanced Solid Tumors 
Amgen Protocol Number (AMG 404) 20180143 
EudraCT Number:  2018-004268-80 
 
Amendment Date: 
16 July 2021 
 
Rationale: 
The following changes were made to the protocol, dated July 16th, 2021, 
 
 
 
 to expand cohort 5 to include additional NMPA certified sites for 
expanded access to subjects, to provide SARS-COV2 guidance to investigators and site 
staff, to update the AMG 404 stopping rules, and to clarify/correct other items in the 
protocol.  


Product:  AMG 404  
Protocol Number:  20180143  
Date:  16 July 2021 
Page 2 of 97 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 


Product:  AMG 404  
Protocol Number:  20180143  
Date:  16 July 2021 
Page 3 of 97 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 


Product:  AMG 404  
Protocol Number:  20180143  
Date:  16 July 2021 
Page 4 of 97 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 


Product:  AMG 404  
Protocol Number:  20180143  
Date:  16 July 2021 
Page 5 of 97 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Cohort 5 changes include: 
 
Updated overall design (section 6.1) to include NMPA certified sites. 
 
Updated inclusion criterion #111 (section 7.1) to include NMPA certified sites. 
SARS-COV2 changes include: 
 
Added dose modification guidelines (section 8.4.5) for SARS-COV2 infection. 
 
Added SARS-COV2 Vaccination guidance (section 8.8.2.1) for all Cohorts. 
Other changes include: 
 
Updated and added stopping rules for AMG 404 monotherapy (section 11.4.1).  
 
Updated references (section 12). 
 
Updated template safety language. 
 
Administration, typographical and formatting changes were made throughout the 
protocol. 
Description of changes: 
Section:  Global 
Change: The Amgen global version date was changed from 24 November 2020 to 
16 July 2021. 
Section:  Global 
Replace: 
A Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 404,a Programmed Death-1 (PD-1) Antibody, in Patients 
With Advanced Solid Tumors 
With: 
A Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, 
 
 in Patients With Advanced Solid 
Tumors 
Section:  Global 
Replace: Table 2-1 
With: Section 3.2 
Section:  Title Page, Key Sponsor Contact 
Replace: 
Name: 
, MD 
, DSc, MSc 


Product: AMG 404 
Protocol Number: 20180143   
 
Page 1 of 30 
Amgen Proprietary - Confidential 
Amendment 4 
Protocol Title:  A Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, in 
Patients with Advanced Solid Tumors 
 
Amgen Protocol Number (AMG 404) 20180143 
 
Amendment Date: 
24 November 2020 
 
Rationale: 
The following changes were made to the protocol, dated November 24th, 2020, to 
integrate revised contraceptive and safety follow-up requirements based on current 
half-life data, and to clarify/correct other items in the protocol.  
Revised requirements based on current half-life data included:  
 
Updated exclusion criterion #221, 222, and 223 to clarify the time period for 
female and male restrictions regarding pregnancy and contraception. 
 
Updated section 7.4.3.4, section 9.2.3.1.6, and appendix 6 to clarify the time 
period for female and male restrictions regarding pregnancy and contraception. 
Other changes include: 
 
Updated overall design to clarify subjects with complete response treatment 
duration beyond 12 months. 
 
Updated subject eligibility criteria to clarify prior systemic treatments excluded.  
 
Updated study schema formatting. 
 
Updated schedule of activities to reflect protocol updates. 
 
Updated risks in section 3.3.3 to include hypothyroidism.  
 
Updated exclusion criterion #201 to clarify benign asymptomatic tumor exception. 
 
Updated exclusion criterion #202 to clarify the exception of other malignancies 
which do not require systemic therapy. 


Product: AMG 404 
Protocol Number: 20180143   
 
Page 2 of 30 
Amgen Proprietary - Confidential 
 
Updated exclusion criterion #208 to clarify corticosteroid exception.  
 
Updated exclusion criterion #217 to clarify anti arrhythmia medication. 
 
Updated language for AMG 404 interruptions or discontinuations due to safety 
reasons. 
 
Added dose modification due to surgery during study treatment clarification in 
section 7.4.5. 
 
Updated section 9.1.3, section 9.2.3.1.1.1, and section 9.2.3.1.1.2 to align with 
current safety language and requirements. 
 
Updated section 9.1.5 end of study to clarify end of study for a particular study 
subject. 
 
Updated section 9.2.2 efficacy assessments to clarify complete response 
evaluations.   
 
Updated Table 12-3 to clarify instructions for AMG 404 dose modification and 
management of toxicities. 
 
Updated section 9.2.8.5, section 9.2.8.5.1, section 10.4.2.4 to clarify 
pharmacokinetic 
 collections. 
 
Administration, typographical and formatting changes were made throughout the 
protocol 
 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  31 January 2020 
Page 1 of 37 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, in 
Patients With Advanced Solid Tumors 
 
Amgen Protocol Number 20180143 
IND Number 140964 
EudraCT number 2018-004268-80 
 
Amendment Date: 
31 January 2020 
Rationale: 
The purpose of this amendment includes: 
 
To add Cohorts 7-9 to evaluate efficacy of AMG 404;  
 
To add additional subjects are being added to Cohort 4 to gain additional safety 
information at the higher dose; 
 
To revise the purpose, eligibility, statistics and tumor evaluation sections to align 
with the additional cohorts; 
 
To add information on the Recommended Phase 2 Dose selection;  
 
To incorporate China Country Specific Supplement version 1 information; and  
 
To revise the hepatitis toxicity management (Appendix 4) to align with the 
hepatotoxicity stopping rules (Appendix 8). 
In addition, grammatical and typographical errors were corrected throughout the protocol 
document. 
The consent and addendum consent forms were revised to reflect protocol updates.  
The version number and date on all documents was updated  


Product:  AMG 404 
Protocol Number:  20180143 
Date:  15 July 2019 
Page 1 of 25 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, in 
Patients with Advanced Solid Tumors 
 
Amgen Protocol Number 20180143 
IND Number 140964 
EudraCT number 2018-004268-80 
 
Amendment Date: 
15 July 2019 
Rationale: 
This purpose of this amendment is to: 
 
Add Cohort 5, a China specific cohort at the RP2D and added Inclusion Criteria 
111 to define subject population for Cohort 5 
 
Add Cohort 6, additional subjects at the RP2D 
 
Revised Inclusion Criteria 109, decreasing eGFR for subjects enrolled to Cohorts 
3 and 6 based on initial FDA feedback 
 
Dose-limiting toxicity (DLT) section updated based on Japanese Health Authority 
feedback 
 
Removal of Disease Related Events (DRE) to align with Amgen’s internal 
guidelines 
 
Minor revisions/clarifications throughout 
The consent and addendum consent forms were revised to reflect protocol updates.  
The version number and date on all documents was updated  


Product:  AMG 404 
Protocol Number:  20180143 
Date:  02 JAN 2019                                                                                             Page 1 of 9 
Confidential 
 
Amendment 1 
Protocol Title:  Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, in 
Patients with Advanced Solid Tumors 
 
Amgen Protocol Number 20180143 
IND Number 140964 
EudraCT number 2018-004268-80 
 
Amendment Date: 
02 JAN 2019 
 
Rationale: 
This amendment reflects revisions in response to FDA feedback. The consent form was 
revised to reflect protocol updates and an addendum consent was added in response to 
FDA feedback. 
 
The version date on all documents was updated and minor typos were corrected. 
 
Protocol Revisions: 
 
Section: Global 
Replace: 
The version is updated to Amendment 1 and the date is updated to 02 JAN 2019. 
 
Section: 1.0 Protocol Synopsis and Section 4.1 
Replace: Delete strikethrough text, add bolded text 
 
Overall Design 
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study to 
evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of 
AMG 404 in subjects with advanced solid tumors.  The study may be conducted in 
Australia, United States, France, Poland, United Kingdom, Belgium, South Korea, 
Taiwan, Japan, and Canada. Other countries or regions may participate.  The study will 
comprise of 3 4 cohorts to evaluate the safety, tolerability, PK and PD of AMG 404 with 
the following doses: Cohort 1 – 240 mg Cohort 2-  480 mg, Cohort 23 – Expansion at 
the dose of 480 mg, and Cohort 34 – Exploratory Dose of 1050 mg. AMG 404 will be 
administered intravenously (IV) over approximately 30 minutes, every 4 weeks in 
subjects with advanced solid tumors.  Cohorts 23 and 34 can be opened once Cohort 12 
has been completed and determined to be tolerable. The DLT evaluation period will be 
28 days.  The Dose Level Review Meeting (DLRM) may recommend escalation to the 
next planned dose, escalation to an intermediate dose (a dose lower than the next 
planned dose), continuation or delay in dosing, repetition or expansion of a cohort, de-
escalation to a lower dose, or termination of the study.  Administration of AMG 404 (in all 
cohorts) may continue until evidence of disease progression, intolerance to study 
medication, withdrawal of consent, or in the absence of the above up to 12 months if 
subject achieves a complete response, and up to 24 months if partial response or stable 

SAP_001.pdf: 
Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
Page 1 of 44 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of  
AMG 404, a Programmed Death-1 (PD-1) Antibody, 
 
 in Patients With Advanced Solid Tumors 
Short Protocol Title: 
AMG 404 in Patients with Advanced Solid Tumors 
Protocol Number: 
20180143 
Authors: 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
USA 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
Amendment 1 (v2.0)   
Amendment 2 (v3.0) 
25 April 2019 
25 July 2022 
19 August 2022 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
25APR2019 
NA 
Amendment 1 (v2.0)   
25JUL2022 
Aligned with changes made in protocol 
amendment 6 dated 20 May 2022. 
Amendment 2 (v3.0)   
19AUG2022 
Updated BOR, DOR, DoSD, PFS 
definition 
Updated Appendix C 
NCT Number: NCT03853109
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
Page 2 of 44 
CONFIDENTIAL 
Table of Contents 
Table of Contents ............................................................................................................ 2
1.
Introduction ............................................................................................................. 7
2.
Objectives, Endpoints and Hypotheses ................................................................... 7
2.1
Objectives and Endpoints ............................................................................ 7
2.2
Hypotheses and/or Estimations ................................................................... 8
3.
Study Overview ...................................................................................................... 8
3.1
Study Design ............................................................................................... 8
3.2
Sample Size .............................................................................................. 14
3.3
Adaptive Design ........................................................................................ 15
4.
Covariates 
 ................................................................................... 16
4.1
Planned Covariates ................................................................................... 16
5.
Definitions ............................................................................................................. 17
6.
Analysis Sets ........................................................................................................ 23
6.1
Safety Analysis Set ................................................................................... 23
6.2
DLT Evaluable Set .................................................................................... 23
6.3
Pharmacokinetic / Pharmacodynamic Analyses Set(s) .............................. 24
7.
Planned Analyses  ................................................................................................ 24
7.1
Interim Analysis and Early Stopping Guidelines ........................................ 24
7.2
Primary Analysis ....................................................................................... 28
7.3
Final Analysis ............................................................................................ 28
8.
Data Screening and Acceptance ........................................................................... 28
8.1
General Principles ..................................................................................... 28
8.4
Detection of Bias ....................................................................................... 29
8.5
Outliers ..................................................................................................... 29
8.6
Distributional Characteristics ..................................................................... 29
8.7
Validation of Statistical Analyses ............................................................... 29
9.
Statistical Methods of Analysis.............................................................................. 29
9.1
General Considerations ............................................................................. 29
9.2
Subject Accountability ............................................................................... 30
9.3
Important Protocol Deviations ................................................................... 30
9.4
Demographic and Baseline Characteristics ............................................... 31
9.5
Efficacy Analyses ...................................................................................... 31
9.5.1
Analyses of Primary Efficacy Endpoint(s) .................................. 31
9.5.2
Analyses of Secondary Efficacy Endpoint(s).............................. 31


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 3 of 44 
CONFIDENTIAL  
 
 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 31 
9.6 
Safety Analyses ........................................................................................ 31 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 31 
9.6.2 
Adverse Events  ........................................................................ 32 
9.6.3 
Laboratory Test Results ............................................................ 32 
9.6.4 
Vital Signs ................................................................................. 33 
9.6.5 
Physical Measurements ............................................................ 33 
9.6.6 
Electrocardiogram ..................................................................... 34 
9.6.7 
Antibody Formation ................................................................... 34 
9.6.8 
Exposure to Investigational Product .......................................... 35 
9.6.9 
Exposure to Other Protocol-specified Treatment ....................... 35 
9.6.10 
Exposure to Concomitant Medication ........................................ 35 
9.7 
Other Analyses ......................................................................................... 35 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 36 
11. 
Literature Citations / References ........................................................................... 38 
12. 
Prioritization of Analyses....................................................................................... 39 
13. 
Data Not Covered by This Plan............................................................................. 39 
14. 
Appendices ........................................................................................................... 40 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 4 of 44 
CONFIDENTIAL  
 
 
List of Tables 
Table 3-1.  Guideline for Dose Level Decisions for Cohort 2 (480 mg) and 
Cohort 4 (1050 mg) ................................................................................ 11 
Table 7-1.  Stopping Boundary Overall for Combined Monotherapy Data of 
Cohorts 3, 6, 7, 8, and 9 With Posterior Probability of 80 and 
Grade 4 or Higher Treatment-Related Adverse Event Limit of 
20 ........................................................................................................ 27 
Table 7-2.  Stopping Boundary for Enrollment within Cohorts 3, 6-
 
Individually With Posterior Probability of 80 and Subject 
Incidence of Grade 4 or Higher Treatment-Related Adverse 
Event Limit of 20 .................................................................................. 27 
Table 7-3  Operating Characteristics With Batch Size of 10 Subjects 
(Combining All Monotherapy Data of Expansion Cohorts 3, 6, 
7, 8 and 9) .............................................................................................. 28 
Table 7-4.  Operating Characteristics with Batch Size of 10 Subjects (Cohort-
Specific Enrollment With Maximum Sample Cohort Size of 
n40 Subjects) ........................................................................................ 28 
Table 14-2.  BOR per RECIST 1.1 ................................................................................. 43 
List of Appendices 
Appendix B.  Code Fragments ....................................................................................... 42 
Appendix C.  BOR per RECIST (v1.1) Criteria ............................................................... 43 
 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 5 of 44 
CONFIDENTIAL  
 
 
List of Abbreviations and Definition of Terms  
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
AUC 
Area under the serum concentration-time curve 
BOR 
Best overall response 
CI 
Confidence Interval 
Cmax 
Maximum observed serum concentration 
CPMS 
Clinical Pharmacology Modeling and Simulation 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT/MRI 
Computed tomography/ Magnetic resonance imaging 
DCR 
Disease control rate 
DLRM 
Dose level review meeting 
DLRT 
Dose level review team 
DLT 
Dose Limiting Toxicity 
dMMR 
Mismatch repair deficient  
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DoSD 
Duration of stable disease 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
Electronic Source Data 
(eSource)  
Source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
Enrollment 
Date of enrollment confirmation letter from Amgen 
FIH 
First in Human 
ICH 
International Conference on Harmonisation 
IP 
Investigational product 
IPD 
Important protocol deviation 
IV 
Intravenous 
LTFU 
Long term follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MSI-H 
Microsatellite instability-high 
MTD 
Maximum tolerated dose 
(m)TPI 
(modified) Toxicity Probability Interval 
NCI 
National Cancer Institute 
NE 
Not evaluable 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 6 of 44 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
NMPA 
National Medical Products Administration 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
PD 
Progression of disease 
PD 
Pharmacodynamics 
PD-1/PD-L1 
Programmed death-1 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
QTc 
QT interval corrected for heart rate using accepted methodology 
QTcB 
Bazett-corrected QT Interval 
QTcF 
Fridericia-corrected QT Interval 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
TPS 
Tumor Proportion Score 
tmax 
Time to achieve Cmax 
WBC 
White blood cells 
WHO 
World health organization 
 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 7 of 44 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 6 for study 20180143, 
AMG 404 dated 20 May 2022. The scope of this plan includes the primary analyses and 
the final analyses that are planned and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability 
and determine the recommended 
phase 2 dose (RP2D) of AMG 404 in 
patients with advanced solid tumors  
 
Dose limiting toxicities (DLTs), 
treatment-emergent adverse events, 
treatment-related adverse events, 
and changes in vital signs, and 
clinical laboratory tests 
Secondary 
 
To evaluate the pharmacokinetics 
(PK) of AMG 404, as a monotherapy 
 
 
 
PK parameters of AMG 404 
including, but not limited to, 
maximum observed serum 
concentration (Cmax), time to achieve 
Cmax (tmax), and area under the serum 
concentration-time curve (AUC) 
 
To assess the immunogenicity of  
AMG 404, as a monotherapy
 
 
 
Subject incidence of anti-AMG 404 
antibodies 
 
To evaluate the preliminary antitumor 
activity of AMG 404, as a 
monotherapy 
 
 
 
Objective tumor response, duration 
of overall response, progression-free 
survival, disease control rate (DCR), 
and duration of stable disease 
measured by CT/MRI and assessed 
per modified RECIST 1.1 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 8 of 44 
CONFIDENTIAL  
 
 
Exploratory 
2.2 
Hypotheses and/or Estimations 
AMG 404 as a monotherapy 
 is safe and 
well tolerated in patients with advanced solid tumors.  
3. 
Study Overview 
3.1 
Study Design 
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study to 
evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of AMG 404 
as a monotherapy 
, in subjects with 
advanced solid tumors.  The study may be conducted in Australia, United States, 
France, Poland, Spain, Turkey, United Kingdom, Belgium, South Korea, Taiwan, Japan, 
China, Singapore, Canada, Brazil, and Mexico. Other countries or regions may 
participate.  The study will consist of up to 13 cohorts.  Cohorts 1-9 will evaluate the 
safety, tolerability, PK and pharmacodynamics of AMG 404 administered every  
4 weeks (Q4W) with the following doses: Cohort 1 – 240 mg, Cohort 2 – 480 mg,  
Cohort 3 – Expansion at the dose of 480 mg (subjects enrolled outside of China), 
Cohort 4 – Exploratory Dose of 1050 mg, Cohort 5 – China and National Medical 
Products Administration (NMPA) certified sites in Taiwan and/or Hong Kong Specific 
Expansion at the recommended phase 2 dose (RP2D) with a safety lead-in, Cohort 6 – 
Expansion at the RP2D , Cohort 7 – Expansion at the RP2D in specific indications as 
specified in Section 3.1 of protocol , Cohort 8 – Expansion at the RP2D in subjects with 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 9 of 44 
CONFIDENTIAL  
 
 
tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR), and Cohort 9 – Expansion at the RP2D in subjects with non-small cell lung 
cancer (NSCLC) that is PD-L1 positive, Tumor Proportion Score (TPS) ≥ 50% 
(Cohorts 6-9 will enroll subjects outside of China). 
In Cohorts 1-9, AMG 404 will be administered intravenously (IV) over approximately  
30 minutes, every 4 weeks in subjects with advanced solid tumors.  Cohorts 3 and 4 can 
be opened once Cohort 2 has been completed and determined to be tolerable.  
Cohorts 5-9 can be opened once the first 6-9 subjects in Cohort 4 have completed the 
DLT evaluation period and data have been reviewed to determine the RP2D. The DLT 
evaluation period will be 28 days.  The Dose Level Review Meeting (DLRM) may 
recommend escalation to the next planned dose, escalation to an intermediate dose (a 
dose lower than the next planned dose), continuation or delay in dosing, repetition or 
expansion of a cohort, de-escalation to a lower dose, or termination of the study. 
Administration of AMG 404 (in all cohorts) may continue until evidence of disease 
progression, intolerance to study medication, withdrawal of consent, or in the absence of 
the above up to 12 months if subject achieves a complete response, and up to  


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 10 of 44 
CONFIDENTIAL  
 
 
24 months if partial response or stable disease.  Subjects with complete response may 
continue treatment beyond 12 months, up to a maximum of 24 months of total therapy, 
with permission from the medical monitor.  If a subject completes or discontinues 
treatment for reasons other than progression, tumor evaluations should continue 
according to the Schedule of Activities (for Cohorts 1-9, refer to Table 2-1, 
 
 
 from the protocol) until progression or start of a new 
treatment regimen. 
Cohorts 1, 2 and Cohort 4 
The doses of 240 mg, 480 mg and 1050 mg will be examined for safety, tolerability, PK, 
and pharmacodynamics of AMG 404 in subjects with advanced solid tumors. Rules for 
dose determination, and dose expansion are derived using a modified Toxicity 
Probability Interval (mTPI) model (Ji et al. 2010) with a target toxicity probability interval 
(TPI) of 0.20 to 0.33 with a TPI > 0.33 defined as excessive toxicity.   
 
Subjects will not be dosed at a level above the dose level indicated by the mTPI 
model. In particular, subjects will not be dosed at the current dose level or higher 
when the mTPI model indicates stopping enrollment at the current dose level and 
patients will not be dosed at an escalated dose level when the mTPI indicates 
staying at the current dose level. 
 
After reviewing a broad range of safety information including vital signs, 
laboratory values and detailed adverse events profiles, the team may choose to 
dose subjects below the dose level indicated by the mTPI model. For example, 
the team may choose to stop enrollment at the current dose level even if the 
mTPI model indicates staying at the current dose level.  
The Dose Level Review Team (DLRT) will review data, monitor safety, and make 
recommendations on dose modifications based on all subjects that have been enrolled. 
A Dose Level Review Meeting will be conducted after Cohorts 1, 2 and 4 and may 
convene ad hoc to review safety data if deemed necessary.  
Three dose levels are planned to be tested: 
 
Cohort 1: 240 mg every 4 weeks (N = 2-4) 
 
Cohorts 2 and 3: 480 mg every 4 weeks (Cohort 2: N = 6-9; Cohort 3: N = 20) 
 
Cohort 4: 1050 mg every 4 weeks (N = 20) 
Dose escalation will begin with a run-in dose level of 240 mg (Cohort 1). If no DLTs are 
observed in Cohort 1, dose escalation will continue to the next planned dose level in 
Cohort 2. If DLTs are observed in Cohort 1, subsequent dosing will be determined by 


Product:  AMG 404 
Protocol Number:  20180143 
Date:  19 August 2022 
 
 
 
 
 
 
Page 11 of 44 
CONFIDENTIAL  
 
 
Amgen after consulting with the Dose Level Review Team (DLRT) and constrained by 
the mTPI model.  
The table below shows rules for dose determination and dose expansion per the mTPI 
model.  
Table 3-1.  Guideline for Dose Level Decisions for Cohort 2 (480 mg) and Cohort 4 
(1050 mg) 
No. of Subjects 
Number of DLT observed at current dose 
ESCALATEa 
STAY AT CURRENT 
DOSE 
STOP ENROLLMENT 
AT CURRENT DOSE 
3 
N/A 
≤ 1 
≥ 2 
4 
N/A 
≤ 1 
≥ 2 
5 
N/A 
≤ 2 
≥ 3 
6 
0 
1 – 2 
≥ 3 
7 
≤ 1 
2 – 3 
≥ 4 
8 
≤ 1 
2 – 3 
≥ 4 
9 
≤ 1 
Maximum sample size 
reached 
Maximum sample size 
reached  
a For Cohort 4 (1050 mg), if the rules for dose escalation are met, enrollment may be stopped as there is 
sufficient evidence that 1050 mg dose is safe and tolerable; and this is the highest planned dose level 
being investigated on study. 
Cohort 3 
Upon completion of Cohort 2 of the study and depending on data obtained, dose 
expansion may proceed with the planned dose of 480 mg in Cohort 3 (N = 20) outside of 
China.  
Cohorts 5-9  
Upon completion of the first 6-9 subjects in Cohort 4 of the study and depending on data 
obtained, dose expansion may proceed with the RP2D in Cohort 5 with a safety lead-in 
(from China or NMPA certified sites in Taiwan and/or Hong Kong only) and Cohorts 6-9 
(from all countries participating on the study, excluding China).  The RP2D will be 
determined following review of available data obtained in Cohorts 1 through 4 including 
safety, tolerability, PK and pharmacodynamics data. 
Cohort 5 is a China/Taiwan/Hong Kong-specific expansion cohort with a safety lead-in at 
one dose below the RP2D followed by evaluation at RP2D, as appropriate. Up to 12 
subjects will be enrolled in China, and/or in Taiwan, and/or Hong Kong (If Taiwan or 
Hong Kong, only NMPA certified sites will participate). 
 


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Intra-subject dose escalation for Cohorts 1-9 
Intra-Subject dose escalations are allowed on this study for subjects enrolled, where 
applicable. Subjects enrolled to Cohort 1 who complete the DLT period may proceed to 
480 mg once Cohort 2 has been deemed safe by the DLRT; subjects receiving 480 mg 
(in Cohorts 1-3) who complete the DLT period may proceed to the RP2D once 
determined if a dose higher than 480 mg is selected as the RP2D. Subjects enrolled to 
the safety lead-in dose in Cohort 5, may escalate to the RP2D dose level once the RP2D 
is determined safe following the China/Taiwan/Hong Kong specific DLRT 
recommendation.  
All intra-subject dose escalations may occur after consultation with the sponsor if:  
 
No DLT has been reported for this subject during or after completion of the 
DLT period 
Subjects who do not proceed to the higher dose may receive additional cycles at the 
original dose. 


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3.2 
Sample Size 
Up to 275 evaluable subjects will be enrolled in this study. Approximately 2 to 4 DLT-
evaluable subjects will be enrolled in Cohort 1. Approximately 6 to 9 DLT-evaluable 
subjects will be enrolled in Cohort 2, Approximately 20 subjects will be enrolled each in 
Cohorts 3, 4 and 6, all outside of China. Approximately 12 subjects will be enrolled to 
Cohort 5 in China/Taiwan/Hong Kong.  Approximately 40 subjects, respectively, will be 
enrolled to Cohort 7, Cohort 8 and Cohort 9. 
 
 
. 
With 2 subjects in Cohort 1, there is a 36 – 55% probability of observing at least 1 DLT. 
With 4 subjects in Cohort 1, there is a 59 - 80% probability of observing at least 1 DLT if 
the true DLT rate is 20 – 33%. 
Similarly, with 6 subjects per cohort, there is a 74 - 91% probability of observing at least 1 
DLT. With 9 subjects per cohort, there is an 87 - 97% probability of observing at least 1 
DLT if the true DLT rate is 20-33%.  
In Cohorts 3, 4, 6, 
, a subject number of 20 will provide an 88% probability of 
observing at least one adverse event with 10% incident rate. An exact 80% binomial 


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confidence interval (CI) will be provided for overall response rate. With the 20 subjects 
and 25% overall response rate, the expected 80% CI would be 13% to 42%.  
In Cohort 5, a subject number of 12 will provide a 72% probability of observing at least 
one adverse event with 10% incident rate. An exact 80% binomial confidence interval (CI) 
will be provided for overall response rate. With the 12 subjects and 25% overall response 
rate, the expected 80% CI would be 10% to 48%. 
In Cohort 7, Cohort 8, and Cohort 9, the sample size is N~40 subjects. A subject number 
of N~40 subjects will provide an 87% probability of observing at least one adverse event 
with 5% incident rate. An exact 80% binomial confidence interval (CI) will be provided for 
overall response rate. With the 40 subjects and 25% overall response rate, the expected 
80% CI would be 16% to 36%. 
3.3 
Adaptive Design 
Dose level decisions are based on a modified toxicity probability interval design (mTPI). 
The mTPI was developed by Ji et al. (2010). The mTPI models the probability of toxicity 
for each dose level using a Bayesian model where each dose level has the same prior on 
the probability of toxicity, a Beta (1,1). When subjects are treated at the current dose level, 
the posterior probability of toxicity is updated using the observed data from this level. Dose 
level recommendation are made based on this posterior probability of toxicity, using three 
toxicity probability intervals (TPI). 
 
Under-dosing TPI: DLT rate from 0 to < 20%  
 
Target TPI: DLT rate from 20% to 33%    
 
Over-dosing: DLT rate > 33% 


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For the current dose level and after adjusting for the width of the under-dosing TPI, if the 
DLT rate is most likely in the under-dosing TPI then the recommendation is to dose 
escalate.  If the DLT rate is most likely in the target TPI then the recommendation is to 
stay at the current level.  If the DLT rate is most likely in the over-dosing TPI then the 
recommendation is to stop the enrollment. If DLTs are observed, the maximum tolerated 
dose (MTD) is the dose level with a DLT toxicity rate closest to 26.7% (Ji et al. 2010). 
During enrollment and treatment at the RP2D using data from cohorts 3 and 6 and 
additionally using data from cohorts 7-9, objective response rate will be monitored with 
futility stopping rules described in Section 7.1. These futility stopping rules are selected 
using practical considerations. 
During enrollment and treatment at the RP2D using data from cohorts 3 and 6 and cohorts 
7-9, subject incidence of grade 4 treatment related adverse events will be monitored with 
safety stopping rules described in Section 7.1. The safety stopping rules use a Bayesian 
approach proposed by Thall, Simon, and Estey (1995) to terminate a cohort if the posterior 
probability that the subject incidence of grade 4 or higher treatment-related adverse events 
is greater than 20% is > 80%. The stopping boundaries assume a prior distribution of Beta 
(0.40, 1.60). 
4. 
Covariates 
 
4.1 
Planned Covariates 
The relationship of covariates to efficacy endpoints may be explored if appropriate. 


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5. 
Definitions 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
a treatment, combination product, medical device or procedure. 
Age at enrollment 
Subject age at enrollment will be determined using the age in years reported in the 
clinical database. 
AUC 
Area under the concentration-time curve reflects the actual body exposure to drug after 
administration of a dose of the drug (M. Hidalgo et al). 
Baseline  
For any variable, unless otherwise specified the baseline is the last non-missing 
assessment taken prior to the first administration of AMG 404. Where baseline 
measurements are taken on the same day as the study specified treatment and no times 
are present, it will be assumed that these measurements are taken prior to the study 
specified treatment being administered.  
For parameters/assessments not scheduled to be performed (or scheduled but not 
performed) on the same day as the first administration of AMG 404, the baseline value is 
the value from the screening period measured closest to the day of first administration of 
AMG 404. 
Baseline ECG Values in Triplicate 
The baseline ECG is defined as the mean of the sets of triplicate screening ECGs and  
1 set of triplicate ECGs obtained pre-dose on day 1; the mean of values in a triplicate 
should be calculated before taking the mean of the triplicate averages. When an ECG is 
missing within a triplicate, all available data will be averaged.   
Bazett-corrected QT Interval (QTcB) 
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows: QTcB=QT/(RR/1000)1/2. 


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Best Overall Response (BOR) 
In general, the subject's best response assignment will depend on the findings of both 
target and non-target lesions and will also take into consideration the appearance of new 
lesions and confirmation of response. 
Best overall response (BOR) will be based on all post-baseline disease assessments that 
occur prior to the initiation of subsequent anticancer treatment. 
BOR for a subject is the best observed disease response per RECIST 1.1 in the following 
order: CR, PR, SD, PD, or NE. A best overall response of CR and PR require confirmation 
by a repeat, consecutive scan at least 4 weeks after the first documentation of response 
or progression.  
A best overall response of SD requires an on-study imaging of SD or better no earlier than 
7 weeks (49 days) after cycle 1 day 1.  
Please refer Appendix C for deriving BOR algorithm as per RECIST 1.1. 
Change from Baseline  
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline value.  
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value) 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline 
Value] x 100 
Cmax  
The maximum concentration of drug obtained in the serum. 
Disease control rate  
DCR is defined as the proportion of subjects in whom objective response (CR or PR) or 
stable disease (SD) is determined as per RECIST v1.1.  
Dose Limiting Toxicity (DLT) 
Defined as the severe toxicities during the first cycle of cancer therapy. A Dose Limiting 
Toxicity (DLT) is defined as any AE (meeting the criteria listed in section 8.4.2 of protocol) 
occurring during the first treatment cycle of AMG 404 (day 1 through day 28) where 
relationship to AMG 404 cannot be ruled out. 


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The DLT window (ie, DLT-evaluable period) will be the first 28 days of AMG 404 
treatment (starting cycle 1, day 1).  
Duration of Overall Response (DOR) 
Duration of overall response is defined as the time from the first documentation of objective 
response, until the first documentation of disease progression, or death due to any cause, 
whichever occurs first. Only subjects who have achieved objective response will be 
evaluated for DOR. Duration of response will be censored as per PFS censoring rule. 
Duration of Stable Disease (DoSD) 
Duration of stable disease will be measured from the start of treatment until the first 
documentation of disease progression or death due to any cause. DoSD will be calculated 
only in subjects with best overall response SD. 
Duration of stable disease will be censored as per PFS censoring rule. 
End of treatment 
Defined as the last assessment for the protocol specified treatment phase of the study 
for an individual subject. 
End of Study 
The end of study date is defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (ie, last subject last visit), 
following any additional parts in the study (eg, long-term follow-up), as applicable. 
End of Study for a particular subject 
The end of study for a particular study subject will be the day of the last scheduled long 
term follow up (LTFU) call. 
Enrollment  
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria (date eligibility worksheet been signed by investigator). 


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Fridericia-corrected QT Interval (QTcF)  
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  
QTcF=QT/(RR/1000)0.33. 
Investigational Product 
The term investigational product is used in reference to AMG 404. 
Last IP Dose Date  
The last IP dose date for each subject is defined as the latest date IP is administered. 


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Long term follow-up visit 
Long-term follow-up visit will be conducted 6 months (± 1 week) after the last dose of 
AMG 404.  
Measurable baseline disease  
Measurable baseline disease is defined as “Lesions must be accurately measured in at 
least one dimension (longest diameter in the plane of measurement is to be recorded) 
with a minimum size of 10 mm by CT scan or MRI. To be measurable a lymph node 
must be   15mm in short axis when assessed by CT scan or MRI. All tumor 
measurements must be recorded in millimeters. Note: Previously irradiated lesions are 
non-measurable except in cases of documented progression of the lesion since the 
completion of radiation therapy.” 


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Objective Tumor Response  
Objective response is defined as a tumor response assessment of either complete 
response (CR) or partial response (PR) measured by PET/CT, CT or MRI and assessed 
per RECIST v1.1. Subjects who do not experience PR/CR or do not have any follow-up 
tumor assessments will be regarded as non-responders. This endpoint will be 
determined only for subjects with measurable disease at baseline. 
Overall Survival  
Overall survival is defined as the time from the first dose of IP until death due to any cause. 
OS is censored at the last date known to be alive. 
Primary Completion  
The primary completion date is defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the primary endpoint(s), for the 
purposes of conducting the primary analysis, whether the study concluded as planned in 
the protocol or was terminated early. 
Progression Free Survival (PFS) 
Progression-free survival is defined as the time from the first dose of IP until first 
documentation of radiological disease progression or death due to any cause, whichever 
occurs first. PFS will be censored at the last evaluable post-baseline tumor assessment 
date; otherwise, at first dose of IP. Progression will be based on RECIST v1.1. 
Safety Follow-up visit 
Upon permanent discontinuation from the study treatment for any reason, two safety 
follow-up visits are required. A safety follow-up visit will be performed approximately 30 
(+3) days after the last administration of study drug, and also 140 days (±7 days) after the 
last administration of AMG 404. 
Serious Adverse Event 
A serious adverse event (SAE) is defined as an adverse event that 
 
is fatal 
 
is 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 
 
is a congenital anomaly/birth defect 


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 
other medically important serious event 
Study Day  
Post study day: study day= (date - date of Study Day 1) + 1 
Pre-study day: study day= (date – date of Study Day 1) 
Study Day 1  
It is defined as the first day that investigational product is administered to the subject. 
The day before Day 1 is referenced as Day -1. 
tmax 
The time takes to reach a maximum serum concentration of administered drug. 
Treatment emergent AE 
A treatment-emergent adverse event is any adverse event starting on or after the first 
administration of investigational product, as determined by the flag indicating if the AE 
started prior to first dose on the event eCRF and up to and including 140 days after the 
last IP dose date or end of the study, whichever occurs earlier. 
Treatment related AE 
A treatment-related adverse event is any treatment-emergent adverse event that per 
investigator review has a reasonable possibility of being caused by the investigational 
product. In the unlikely event that the relationship is missing, the treatment-emergent 
event will be considered treatment-related and documented in a footnote of the 
treatment-related summary. 
6. 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set. 
6.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects who received at least one dose of  
AMG 404. 
6.2 
DLT Evaluable Set 
The Dose Limiting Toxicity Analysis Set will contain DLT-evaluable subjects. The DLT 
window (ie, DLT-evaluable period) will be the first 28 days of AMG 404 treatment 
(starting cycle 1, day 1) for Cohorts 1-9. 
 
 


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 The subject will be DLT 
evaluable if the subject has completed the DLT window as described above or 
experienced a DLT any time during the DLT window or has received at least 90% of the 
planned dose of investigational product(s) and is followed for at least 1 cycle. A subject 
will not be DLT evaluable if he/she drops out before completion of the DLT-evaluable 
period for reasons other than a DLT. 
The primary assessment of DLT will include DLT-evaluable subjects from dose 
exploration cohorts. If data is available, assessment of DLT including DLT-evaluable 
subjects from dose expansion cohort may be considered.  
6.3 
Pharmacokinetic / Pharmacodynamic Analyses Set(s) 
Pharmacokinetic Analyses Set 
The PK Analysis Set will contain all subjects who have received at least 1 dose of  
AMG 404 and have at least 1 PK sample collected. These subjects will be evaluated for 
PK analysis unless the number of data points required for analysis is not enough, or 
significant protocol deviations have affected the data, or if key dosing or sampling 
information is missing. 
7. 
Planned Analyses  
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  In the dose level review meetings, 
Amgen, in consultation with the site investigators, will review all available cumulative 
data by cohort prior to making dose determination decisions.  Adverse events and DLTs 
observed in all subjects will be evaluated continually and fully integrated into all dose 
level review meetings and considered in all enrollment and dosing decisions.  
Additional details regarding the dose review meeting are provided in sections 8.4.1 and 
13.3 of the protocol. 
There is a planned treatment of N~40 subjects at the RP2D with enrollment to cohorts 3 
and 6. Additionally, there is a planned treatment of N~40 subjects at the RP2D with 
enrollment to Cohort 7, N~40 subjects enrolled to Cohort 8 and N~40 subjects enrolled 
to Cohort 9. For each of these cohorts (Cohort 3/6, Cohort 7, Cohort 8, Cohort 9), futility 
will be assessed after treating 15 and 25 subjects for at least 3 months.  If the observed 
rate of responses is consistent with a lower than 15% response rate, enrollment and 
treatment at the RP2D may be terminated due to futility.  For purposes of assessing 


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futility, a response is defined as an objective response per RECIST 1.1. The guidelines 
for early termination due to futility are as follows: 
Number of Treated Subjects 
Futility Termination Guideline 
15 
1 or fewer responders 
25 
4 or fewer responders 
40 
Enrollment to dose expansion cohort complete 
If the true response rate is 15% then these termination guidelines result in a 69.4% 
probability of terminating dose expansion early with an expected sample size of 26.4 
subjects. If the true response rate is 30% then there is a 90% probability of continuing 
enrollment to N~40 total subjects. 
During this enrollment and treatment at the RP2D combining data from cohorts 3, 6, 7, 8 
and 9 (up to 160 total subjects enrolled) and separately for each cohort including 
cohorts 10-13, Amgen will conduct evaluations of the ongoing subject incidence grade 4 
or higher treatment-related adverse event rate to assess if the threshold for possible 
early termination of a cohort has been reached. If the threshold is met in the combined 
monotherapy data of expansion cohorts 3, 6, 7, 8, and 9 enrollment to all ongoing 
cohorts in the study, 
 will be halted pending review of safety data 
by the DLRT.  If the threshold is met in a specific cohort, then enrollment to the specific 
cohort will be halted pending review of safety data by the DLRT.  After receiving the 
DLRT recommendation, Amgen will choose to take one of the following actions. 
When overall safety threshold exceeded in combined monotherapy data of expansion 
cohorts 3, 6, 7, 8, and 9: 
1) Terminate the trial  
2) Amend the protocol to potentially improve the benefit/risk for subjects (eg, increase 
safety monitoring, modify dose/schedule, mandate premedication) 
3) Continue monotherapy dose expansion cohorts and other cohorts, as appropriate, 
without any changes 


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When cohort-specific safety threshold exceeded:  
1) Terminate enrollment to the cohort  
2) Amend the protocol to potentially improve the benefit/risk for subjects in the cohort of 
concern (eg, increase safety monitoring, modify dose/schedule, mandate 
premedication) 
3) Continue enrollment to the specific cohort  (as appropriate) without any changes 
The methods for deriving the stopping boundaries overall for the combined monotherapy 
data of expansion cohorts 3, 6, 7, 8 and 9, or for within a cohort are described in Section 
11.3 of the protocol with the stopping boundaries overall for the combined monotherapy 
data of expansion cohorts 3, 6, 7, 8 and 9 presented in Table 7-1 and stopping 
boundaries for within a cohort presented in Table 7-2.  Operating characteristics with 
pre-specified batch size of 10 new subjects per batch are presented in Table 7-3 (overall 
the combined monotherapy data of expansion cohorts 3, 6, 7, 8 and 9) and in Table 7-4 
(cohort with planned sample size of 40 subjects).  The operating characteristics in Table 
7-2 and Table 7-4 provide the probability of stopping the trial early for given hypothetical 
true rate of grade 4 or higher treatment-related adverse events, whereas the stopping 
criteria in Table 7-1 and Table 7-2 are based on situations where the empirical evidence 
would result in a posterior probability of ≥ 80% that the true grade 4 or higher treatment-
related adverse event rate is ≥ 20%. 


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Table 7-1.  Stopping Boundary Overall for Combined Monotherapy Data of 
Cohorts 3, 6, 7, 8, and 9 With Posterior Probability of 80% and Grade 4 or Higher 
Treatment-Related Adverse Event Limit of 20% 
Number of subjects 
Stop study if observing this many subjects with grade 4 or 
higher treatment-related adverse events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
≥ 11 
50 
≥ 13 
60 
≥ 15 
70 
≥ 18 
80 
≥ 20 
90 
≥ 22 
100 
≥ 24 
110 
≥ 26 
120 
≥ 28 
130 
≥ 31 
140 
≥ 33 
150 
≥ 35 
160 
Combined Monotherapy Data for Cohorts 3, 6, 7, 8 and 9 
Complete 
Table 7-2.  Stopping Boundary for Enrollment within Cohorts 3, 6-
 Individually 
With Posterior Probability of 80% and Subject Incidence of Grade 4 or Higher 
Treatment-Related Adverse Event Limit of 20%   
Number of subjects 
treated 
Stop cohort enrollment if observing this many subjects with 
grade 4 or higher treatment-related adverse events 
5 
≥ 3 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Cohort Enrollment Complete* 
* Enrollment for cohorts 7, 8, and 9 completes after n=40 subjects enrolled. Enrollment for cohorts 3, 6, 
 
completes after n=20 subjects enrolled.
 
  Early stopping rules (eg, at 5 or 10 treated subjects) are the same regardless of planned 
maximum sample size in a cohort. 


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Table 7-3  Operating Characteristics With Batch Size of 10 Subjects (Combining 
All Monotherapy Data of Expansion Cohorts 3, 6, 7, 8 and 9) 
True grade 4 or higher 
treatment-related adverse 
event rate 
Probability of early stopping of 
dose expansion 
Average sample size of 
overall combined 
monotherapy data 
0.10 
2.1 % 
156.9 
0.15 
12.7  % 
143.1 
0.20 
46.4  % 
105.8 
0.25 
86.4  % 
58.7 
0.30 
98.9  % 
31.5 
Table 7-4.  Operating Characteristics with Batch Size of 10 Subjects (Cohort-
Specific Enrollment With Maximum Sample Cohort Size of n=40 Subjects) 
True grade 4 or higher 
treatment-related adverse 
event rate 
Probability of early stopping of 
cohort enrollment 
Average cohort sample 
size 
0.10 
2.0% 
39.5 
0.15 
9.7% 
37.6 
0.20 
25.8% 
33.9 
0.25 
47.8% 
28.8 
0.30 
69.2% 
23.4 
 
7.2 
Primary Analysis 
The primary analysis will be conducted when target enrollment is complete, and each 
subject had the opportunity to complete 6 months on study or withdraws from study. 
7.3 
Final Analysis 
The final analysis will be conducted after all cohorts and dose-expansion subjects have 
ended the study. Primary and final analysis may be combined in case all subjects have 
ended study close to the time point of the primary analysis.  
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 


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8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort. 
The clinical study team will identify and document the criteria for important protocol 
deviations. 
8.5 
Outliers 
Outliers will not be excluded unless scientifically justified. Pharmacokinetic (PK) serum 
concentration data will be evaluated for outliers by visual inspection, and decisions to  
re-assay individual samples will be made in accordance with standard PK evaluation 
practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures. Tables, figures, and listings will be 
produced with validated standard macro programs where standard macros can produce 
the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamics 
 data by dose cohort or time as appropriate. Unless 
otherwise stated, the data analysis will be conducted using subjects in the Safety 
analysis set. Subjects in the dose escalation part of the analysis will be summarized by 
each AMG 404 dose level. 


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Descriptive statistics on continuous data will include means, medians, standard 
deviations and ranges, while categorical data will be summarized using frequency 
counts and percentages. Graphical summaries of the data may also be presented. When 
data are summarized by time, the values recorded against the scheduled time points 
listed in the protocol will be used. When assessing minimum/maximum increases or 
decreases over the study, all assessments, including unscheduled assessments will be 
used. Data listings will include all available data from all enrolled subjects unless 
specified otherwise. 
All descriptive statistics and graphical summaries may be presented separately for 
Cohort 5, 
 versus all the other cohorts. 
Similarly, all the efficacy and the safety analyses may be conducted separately for 
Cohort 5, 
 versus all the other cohorts.  
Efficacy endpoints will be summarized separately for Cohort 7, Cohort 8, Cohort 9, 
.  
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Person (Clopper & Pearson, 1934). Kaplan-Meier methods will be 
used to estimate the median and percentiles for time to event endpoints with CI calculated 
using the Brookmeyer and Crowley method (Brookmeyer & Crowley, 1982). Kaplan-Meier 
methods will be used to estimate landmarks for time to event endpoints (eg, 1-year OS) 
with the Greenwood formula (Kalbfleisch & Prentice, 1980) used to estimate the standard 
error used in CI calculation.  
9.2 
Subject Accountability 
A summary of subject disposition and investigational product disposition will be provided 
for all subjects enrolled in the study ie, the number and percent of subjects who were 
enrolled, received investigational product, discontinued from investigational product 
(including reasons for discontinuing), completed study, discontinued the study (including 
reasons for discontinuing) will be summarized by cohort. 
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 


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descriptions will be used during the course of the study. The final IPD list is used to 
produce the Summary of IPDs table and the List of Subjects with IPDs. In addition, a 
separate listing of all inclusion and exclusion deviations will be provided. 
A protocol deviation of listing of subjects impacted due to COVID-19 will also be 
provided. 
9.4 
Demographic and Baseline Characteristics 
Demographic characteristics including age, age groups (18 to 65, 66 and above), sex, 
race, ethnicity and baseline characteristics, which may include height, weight, Eastern 
Cooperative Oncology Group (ECOG) performance status, baseline disease stage, 
number of prior anti-cancer therapies, cancer-related surgery and primary tumor type will 
be summarized using descriptive statistics.  
If multiple races have been reported for a subject, the subject will be categorized as 
multiple.  
9.5 
Efficacy Analyses 
In general, the analysis of efficacy endpoints will be based on the Safety Analysis Set 
unless otherwise specified. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
No efficacy parameter is considered in primary endpoints. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
For all subjects treated at the RP2D and separately by cohort, the following analyses will 
be done. The proportion of subjects with confirmed objective tumor response (partial and 
complete response) and disease control rate (DCR) (partial or complete control) with 
corresponding exact 80% CI will be calculated and tabulated. Similarly, the proportion of 
subjects and 80% CI will be tabulated for 1-year duration of overall response, 1-year 
PFS, 1-year duration of stable disease and 1-year OS.  Kaplan-Meier curve will be 
presented for duration of overall response, PFS, OS and duration of stable disease with 
estimates for rate and 80% CI at selected weeks based on the Brookmeyer and Crowley 
method (Brookmeyer & Crowley, 1982) if data allows. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
No efficacy parameter is considered in exploratory endpoints.  
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
 


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Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the safety analysis set, which includes subjects that are enrolled and 
received at least 1 dose of AMG 404.  
The analysis of the subject incidence of dose limiting toxicities (DLT) will be based on 
the DLT evaluable set defined in Section 6.2. A summary of the subject incidence of 
dose limiting toxicities (DLT) with corresponding 95% CI will be provided. 
9.6.2 
Adverse Events  
The most current version of the Medical Dictionary for Regulatory Activities (MedDRA) 
will be used to code all adverse events to a system organ class and a preferred term. 
The identification of adverse events of special interest is a continuous process. Events 
may be identified and documented as the safety profile of the drug is characterized. The 
severity of each adverse event will be graded using CTCAE version 5.0. 
Tables will be provided for Subject incidence of all treatment-emergent, serious, 
treatment-related, those leading to withdrawal of investigational product, events of 
special interests and fatal adverse events by system organ class and preferred term in 
descending order of frequency. Where appropriate the tables will also be presented by 
worst grade.  
Details of each treatment-emergent adverse event will be listed. Listings and/or 
narratives of any on-study deaths, serious treatment-emergent adverse, and grade 3 or 
higher treatment-related adverse, including adverse events leading to discontinuation of 
AMG 404, also will be provided should they occur. 
9.6.3 
Laboratory Test Results 
Laboratory data will be summarized using standard descriptive statistics at each 
scheduled time point in the study. For continuous parameters, a summary of the 
changes from baseline to each post dose laboratory assessment will also be produced. 
Shifts in selected laboratory parameters between baseline and the worst on-study value 
will be summarized according to the NCI CTCAE toxicity grades. Safety Laboratory 
collection includes chemistry, hematology, pregnancy test (for women of childbearing 
potential) either urine or serum. The parameters described in Table 13-1 of the protocol 
will be collected, converted to Amgen standard units. 
Selected individual analytes will be summarized by cohort using standard descriptive 
statistics at each of the scheduled time points through the study up to the safety follow-
up visit. For continuous parameters, a summary of the changes from baseline to each 


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post dose laboratory assessment will be produced for each cohort. Tables of shifts from 
baseline to the worst-case on-study increased and decreased values (graded according 
to the NCI Common Toxicity Grading Criteria) will be provided for selected laboratory 
parameters with available NCI-CTCAE grades. Unscheduled assessments will be 
included in the shift tables.  
Subject incidence of suspected Hy’s law cases (Hy’s law predicts potential for drug-related 
hepatotoxicity) will be summarized by cohort. A listing of alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, and total bilirubin values at each time 
point may be produced for the subjects suspected of Hy’s law case. 
Boxplots may be plotted by time point and cohort for selected analytes. 
Urine analysis 
Blood, protein and glucose will be graded in the following manner: 0=’0 or Trace’, 1=’1+’, 
2=’2+’, 3=’3+’, 4=’4+’. Microscopic parameters (WBC, RBC, epithelial cells, bacteria, 
casts, crystals) will be graded in the following manner: 0=’0-4 none, rare, occasional’, 
1=’5-50 moderate, few’, 2=’>50 many, heavy, too numerous to count’. Data recorded as 
“Present” will not be included in the summary. 
The number and percent of subjects with a worst post-dose presence of blood in the 
urine of ‘0 or Trace’, ‘1+’,’2+’, ’3+’, or ‘4+’ will be presented (also for protein and glucose 
in the urine). 
Depending on the size and scope of changes in urinalysis data, summaries over time 
and/or changes from baseline over time may also be provided. Unscheduled assessments 
will be included in the analysis. 
9.6.4 
Vital Signs 
Depending on the size and scope of changes, summaries of vital signs data (blood 
pressure (BP), respiratory rate, heart rate and temperature) over time and/or changes 
from baseline overtime may be provided. Shifts in vital sign values from baseline over 
time may also be tabulated if required. 
9.6.5 
Physical Measurements 
The analysis of body weight may include summary statistics at selected time points for 
each treatment cohort. 


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9.6.6 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. Subjects' maximum change from baseline in (QTcF, QTcB) will be 
categorized and the number and percentage of subjects in each cohort 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. 
Subjects will be categorized into the following groups per their maximum change from 
baseline in QTcF and QTcB. Unscheduled assessments will be included in the 
determination of the maximum change. 
 
<=30 msec  
 
>30 – 60 msec  
 
>60 msec  
The number and percentage of subjects in each group will be summarized.  
Subjects will also be categorized into the following groups per their maximum post 
baseline QTcF. Unscheduled assessments will be included in the determination of the 
maximum post baseline value.  
 
<=450 msec  
 
>450 – 480 msec  
 
>480 – 500 msec  
 
>500 msec  
The number of subjects in each group will be summarized for each cohort. 
9.6.7 
Antibody Formation 
A listing of subjects who develop anti-AMG 404 antibodies (binding) may be provided. 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities for the measurement of anti-AMG 404 antibodies. 
Samples testing positive for binding antibodies may be further characterized. Additional 
blood samples may be obtained to rule out anti-AMG 404 antibodies during the study. 
Subjects who test positive for anti-AMG 404 antibodies at the final scheduled antibody 
timepoint and have clinical sequelae that are considered potentially related to the 
anti-AMG 404 antibody response will be asked to return for additional follow-up testing. 
Sample collection and testing will occur approximately every 3 months from the safety 
follow up visit until: (1) anti-AMG 404 antibodies are no longer detectable; or (2) the 
subject has been followed for a period of at least 1-year (± 4 weeks) post administration 


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of AMG 404. All follow-up results, both positive and negative, will be communicated to 
the sites. More frequent testing (eg, every month) or testing for a longer period of time 
may be requested in the event of safety-related concerns. 
The incidence and percentage of subjects who develop anti-AMG 404 antibodies, will be 
tabulated overall, and by cohort.  
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment dose. Number of cycles started, Number of doses of investigational product, 
the cumulative dose by unit and average dose delivered per day and duration of exposure 
will be summarized. 
Summaries of the number and percentage of subjects with dose change/withheld and 
reason for change/withheld will be provided. Details for each AMG 404 administration 
will be listed for every subject. In addition, a listing of the unique manufacturing lot 
numbers, and a listing of the subjects administered each manufacturing lot number will 
be provided. 
9.6.9 
Exposure to Other Protocol-specified Treatment 
Not applicable. 
9.6.10 
Exposure to Concomitant Medication 
All medication will be coded using the WHO drug dictionary.  
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term or category. 
9.7 
Other Analyses 


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9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
The PK parameters of AMG 404 including, but not limited to, Cmax, tmax, and AUC for 
serum AMG 404 will be estimated using non-compartmental methods for subjects where 
intense PK sampling was collected (ie, subjects in Cohorts 1-6 
, at least 
10 subjects in Cohorts 7-9).
 The parameter estimates will be summarized by dose level using means, geometric 
means, standard deviations, coefficients of variation, medians, minimums, and 
maximums. Individual concentration-time profiles will be summarized by dose level. 
. Summary statistics will be computed 
for each sampling time and parameter as appropriate. The relationship between AMG 
404 exposure and efficacy/safety may be conducted.  
Nominal sampling times will be used for individual concentration-time plots and tables. 
Actual dose administered and actual sampling times will be used for the calculation of 
PK parameters for each subject. The reasons for excluding any sample from the 
analyses will be provided. Above analyses will be conducted by Amgen Clinical 
Pharmacology Modeling and Simulation (CPMS). 
The relationship between AMG 404 exposure and QT/QTc interval changes may be 
inspected graphically and model-based PK/pharmacodynamic analyses may be 
conducted to examine the relationship further. 


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11. 
Literature Citations / References 
AMG 404 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Brookmeyer, R. and Crowley, J. (1982) A Confidence Interval for the Median Survival 
Time, Biometrics, 38, 29 - 41. 
Clopper CJ, Person ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934; 26:404-413. 
Ji Y, Liu P, Li Yisheng, Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clinical Trials 2010; 7:653-663. 
Kalbfleisch, J.D. and Prentice, R.L. (1980) The statistical analysis of failure time data. 
John Wiley and Sons, New York. 
M. Hidalgo et al. (eds.), Principles of Anticancer Drug Development, Cancer Drug 
Discovery and Development, DOI 10.1007/978-1-4419-7358-0_2. 
Thall, PF, Simon, RM, and Estey, RM. Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Statistics in Medicine. 1995; 14(4):357-
79.   


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12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
Not applicable. 


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14. 
Appendices 


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Appendix B.  Code Fragments 
Example: 
95% Confidence Interval by Clopper Pearson Method:  
proc freq data=<data> ;  
tables <variable>*<variable> / binomial(exact) ;  
run; 
 
Code fragment for K-M method: 
proc lifetest data=data1 method=km conftype=loflog alphaqt=0.05 
by cohortn; 
   time avail*cnsr (1); 
run;  


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Appendix C.  BOR per RECIST (v1.1) Criteria 
The protocol requires that a PD must be confirmed.  The analysis of modified 
RECIST 1.1 BOR endpoints will follow standard RECIST 1.1 convention which 
does not require confirmation of PD. 
Best Overall Response (BOR) determination per RECIST 1.1 is given in below in Table 
14-2, the BOR considered is a Confirmed BOR. 
Table 14-2.  BOR per RECIST 1.1 
Criterion 
Time point 
T1 
Response 
T1 ≥ 49 
days after 
C1D1? 
Time point 
T2 Response 
T2 ≥ 49 days 
after C1D1? 
T2 ≥ 28 days 
after T1? 
BOR 
C1 
CR 
Yes 
CR 
- 
Yes 
CR 
C2 
 
CR 
- 
No 
SD 
C3 
PR, SD 
- 
- 
Query data* 
C4 
PD 
- 
- 
SD 
C5 
NE, No further evaluations 
SD 
C6 
No 
 
CR 
- 
Yes 
CR 
C7 
CR 
Yes 
No 
SD 
C8 
PR, SD 
- 
- 
Query data* 
C9 
PD 
- 
- 
PD 
C10 
NE, No further evaluations 
NE 
C11 
PR 
 
Yes 
CR, PR 
- 
Yes 
PR 
C12 
CR, PR 
- 
No 
SD 
C13 
SD 
- 
- 
SD 
C14 
PD 
- 
- 
SD 
C15 
NE, No further evaluations 
SD 
C16 
No 
CR, PR 
- 
Yes 
PR 
C17 
CR, PR 
Yes 
No 
SD 
C18 
SD 
Yes 
- 
SD 
C19 
PD 
- 
- 
PD 
C20 
NE, No further evaluations 
NE 
C21 
SD 
Yes 
CR, PR, SD, PD, NE, no more evaluation 
SD 
C22 
No 
 
CR, PR, SD 
Yes 
- 
SD 
C23 
CR, PR, SD 
No 
- 
NE 
C24 
PD 
- 
- 
PD 
C25 
NE, No further Evaluations 
NE 
C26 
PD 
- 
-                                            -                         - 
PD 
C27 
NE 
- 
NE, No further evaluations 
NE 
C28 
 
- 
CR, PR, SD 
Yes 
- 
SD 
C29 
 
- 
CR, PR, SD 
No 
- 
NE 
C30 
 
- 
PD 
- 
- 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and  
NE = not evaluable. 


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*If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
A CR must be confirmed by CR, a PR can be confirmed by a PR or CR. 
An unlimited number of intermittent assessments of NE can occur between the initial response and the 
confirmation. For example, BL, CR, NE, NE, NE, CR – the CR at post baseline 1 is confirmed at post 
baseline 5.