Conditions: Non-small Cell Lung Cancer NSCLC
Keywords: AMG 160 Phase 1b
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 3
Healthy volunteers: no

Brief summary:
This study aims to evaluate the safety and tolerability of AMG 160 and to evaluate the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D).

Detailed description:

Arms:
arm 1: The dose exploration part of the study will estimate the MTD and/or the RP2D. arm 2: Participants with non-squamous non-small cell lung cancer (NSCLC) will be administered the RP2D identified from the dose exploration part of the study. arm 3: Participants with squamous NSCLC will be administered the RP2D identified from the dose exploration part of the study.

Interventions: intervention 1: AMG 160
Intervention descriptions: intervention 1: AMG 160 administered as an intravenous (IV) infusion

Protocol document:
Prot_000.pdf: 
Product:  AMG 160 
Protocol Number:  20180273  
Date:  25 March 2022 
Page 1 of 166 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of 
AMG 160 in Subjects with Non-Small Cell Lung 
Cancer 
Short Protocol Title: 
A Phase 1b Study of AMG 160 in Subjects with 
Non-Small Cell Lung Cancer 
Protocol Number: 
20180273 
Investigational Product: 
AMG 160 
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 
Protocol 
Approver 
Name: 
 MD, PhD 
Function: 
VP of Early Development 
 
Key 
Sponsor 
Contact 
Name: 
 MD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
Email Address: 
 
EudraCT Number: 
To be determined 
NCT Number: 
NCT04822298 
Protocol Version Date: 
Document Version 
Date 
Original 
15 July 2020 
Amendment 1.0 
20 October 2020 
Superseded 
Amendment 1.0 
25 January 2021 
Amendment 2.0 
29 July 2021 
Amendment 3.0 
Amendment 4.0 
19 October 2021 
25 March 2022 
Data Elements Standards 
Version: 
7.0 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 


Product:  AMG 160 
Protocol Number:  20180273  
Date:  25 March 2022 
Page 2 of 166 
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; Amgen’s general number in the US, 1-805-447-1000. 


Product:  AMG 160 
Protocol Number:  20180273  
Date:  25 March 2022 
Page 3 of 166 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of AMG 160 in Subjects with Non-Small Cell 
Lung Cancer, dated 25 March 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 or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners 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) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 


Product:  AMG 160 
Protocol Number:  20180273  
Date:  25 March 2022 
Page 4 of 166 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 10 
1.1 
Synopsis ................................................................................................... 10 
1.2 
Study Schema ........................................................................................... 17 
1.3 
Schedule of Activities (SoA) ...................................................................... 18 
2. 
Introduction ........................................................................................................... 34 
2.1 
Study Rationale ......................................................................................... 34 
2.2 
Background ............................................................................................... 35 
2.2.1 
Disease ..................................................................................... 35 
2.2.2 
Amgen Investigational Product Background:  
AMG 160 ................................................................................... 36 
2.2.2.1 
Nonclinical Pharmacology ....................................... 37 
2.2.2.2 
Nonclinical Toxicology ............................................. 37 
2.2.2.3 
Clinical Experience .................................................. 39 
2.3 
Benefit/Risk Assessment ........................................................................... 42 
2.3.1 
Therapeutic Context .................................................................. 43 
2.3.2 
Key Risks .................................................................................. 44 
3. 
Objectives and Endpoints ..................................................................................... 46 
4. 
Study Design ........................................................................................................ 47 
4.1 
Overall Design .......................................................................................... 47 
4.2 
Number of Subjects ................................................................................... 48 
4.2.1 
Replacement of Subjects ........................................................... 48 
4.2.2 
Number of Sites ......................................................................... 49 
4.3 
Justification for Investigational Product Dose ............................................ 49 
4.3.1 
Justification for Non-investigational Product Dose ..................... 50 
4.4 
End of Study ............................................................................................. 50 
4.4.1 
End of Study Definition .............................................................. 50 
4.4.2 
Study Duration for Subjects ....................................................... 50 
4.5 
Patient Input on Study Design ................................................................... 50 
5. 
Study Population .................................................................................................. 51 
5.1 
Inclusion Criteria ....................................................................................... 51 
5.2 
Exclusion Criteria ...................................................................................... 52 
5.3 
Subject Enrollment .................................................................................... 55 
5.4 
Screen Failures ......................................................................................... 56 
6. 
Treatments ........................................................................................................... 56 
6.1 
Treatment(s) Administered ........................................................................ 57 
6.1.1 
Investigational Products ............................................................ 57 
6.1.1.1 
Non-Amgen Investigational Imaging 
Products .................................................................. 60 


Product:  AMG 160 
Protocol Number:  20180273  
Date:  25 March 2022 
Page 5 of 166 
CONFIDENTIAL  
 
 
6.1.2 
Non-investigational Products ..................................................... 60 
6.1.3 
Medical Devices ........................................................................ 60 
6.1.4 
Other Protocol-required Therapies ............................................ 60 
6.1.5 
Other Treatment Procedures ..................................................... 61 
6.1.6 
Product Complaints ................................................................... 61 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 61 
6.2 
Dose Modification ...................................................................................... 62 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 62 
6.2.1.1 
Dose-exploration ..................................................... 62 
6.2.1.2 
Dose Expansion ...................................................... 63 
6.2.1.3 
Dose-limiting Toxicity .............................................. 63 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 65 
6.2.2.1 
Amgen Investigational Product:  AMG 160 .............. 65 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 84 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 84 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 84 
6.4.1 
Method of Treatment Assignment .............................................. 84 
6.4.2 
Blinding ..................................................................................... 84 
6.5 
Treatment Compliance .............................................................................. 84 
6.6 
Treatment of Overdose ............................................................................. 84 
6.7 
Prior and Concomitant Treatment ............................................................. 85 
6.7.1 
Prior Treatment ......................................................................... 85 
6.7.2 
Concomitant Treatment ............................................................. 85 
6.7.2.1 
Supportive Care ...................................................... 86 
6.7.2.2 
Bone Disease Therapy ............................................ 86 
6.7.2.3 
Growth Factors ........................................................ 86 
6.7.2.4 
Tumor Lysis Syndrome ........................................... 86 
6.7.2.5 
Nausea, Vomiting, and Diarrhea.............................. 87 
6.7.2.6 
Vaccines ................................................................. 87 
7. 
Discontinuation Criteria ......................................................................................... 88 
7.1 
Discontinuation of Study Treatment........................................................... 88 
7.2 
Discontinuation From the Study ................................................................ 89 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 89 
7.2.2 
Reasons for Removal From Study ............................................. 89 
7.3 
Lost to Follow-up ....................................................................................... 90 
8. 
Study Assessments and Procedures .................................................................... 90 
8.1 
General Study Periods .............................................................................. 90 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 90 


Product:  AMG 160 
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CONFIDENTIAL  
 
 
8.1.2 
Treatment Period ....................................................................... 91 
8.1.3 
End of Treatment ....................................................................... 92 
8.1.4 
Safety Follow-up ........................................................................ 92 
8.1.5 
Long-term Follow-up .................................................................. 92 
8.1.6 
End of Study Visit ...................................................................... 92 
8.2 
Description of General Study Assessments and Procedures ..................... 92 
8.2.1 
General Assessments ............................................................... 92 
8.2.1.1 
Informed Consent .................................................... 92 
8.2.1.2 
Demographics ......................................................... 92 
8.2.1.3 
Medical History ........................................................ 92 
8.2.1.4 
Physical Examination .............................................. 93 
8.2.1.5 
Neurological Examination ........................................ 93 
8.2.1.6 
Physical Measurements .......................................... 93 
8.2.1.7 
Substance Abuse History ........................................ 93 
8.2.1.8 
Performance Status................................................. 93 
8.2.2 
Efficacy Assessments ................................................................ 94 
8.2.3 
Safety Assessments .................................................................. 94 
8.2.3.1 
Vital Signs ............................................................... 94 
8.2.3.2 
Pulse Oximetry ........................................................ 95 
8.2.3.3 
Electrocardiograms (ECGs) ..................................... 95 
8.2.3.4 
Vital Status .............................................................. 96 
8.2.4 
Adverse Events and Serious Adverse Events ............................ 96 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 97 
8.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 98 
8.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 98 
8.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 98 
8.2.4.5 
Safety Monitoring Plan ............................................ 99 
8.2.4.6 
Pregnancy and Lactation ......................................... 99 
8.2.5 
Clinical Laboratory Assessments ............................................. 100 
8.2.6 
Pharmacokinetic Assessments ................................................ 100 
9. 
Statistical Considerations .................................................................................... 103 
9.1 
Statistical Hypotheses ............................................................................. 103 
9.2 
Sample Size Determination ..................................................................... 103 
9.3 
Analysis Sets, Subgroups, and Covariates .............................................. 104 


Product:  AMG 160 
Protocol Number:  20180273  
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CONFIDENTIAL  
 
 
9.3.1 
Analysis Sets ........................................................................... 104 
9.3.2 
Covariates ............................................................................... 105 
9.3.4 
Handling of Missing and Incomplete Data ................................ 105 
9.4 
Statistical Analyses ................................................................................. 105 
9.4.1 
Planned Analyses .................................................................... 105 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................. 105 
9.4.1.2 
Primary Analysis ................................................... 109 
9.4.1.3 
Final Analysis ........................................................ 109 
9.4.2 
Methods of Analyses ............................................................... 109 
9.4.2.1 
General Considerations ......................................... 109 
9.4.2.2 
Efficacy Analyses .................................................. 110 
9.4.2.3 
Safety Analyses .................................................... 111 
9.4.2.4 
Other Analyses ...................................................... 112 
10. 
References ......................................................................................................... 113 
11. 
Appendices ......................................................................................................... 116 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 116 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 120 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 122 
Dose Level Review Team ....................................................................... 122 
Regulatory and Ethical Considerations .................................................... 123 
Informed Consent Process ...................................................................... 124 
Data Protection/Subject Confidentiality ................................................... 126 
Publication Policy .................................................................................... 126 
Data Quality Assurance ........................................................................... 128 
Source Documents .................................................................................. 129 
Study and Site Closure............................................................................ 130 
Compensation ......................................................................................... 130 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 131 
Definition of Adverse Event ..................................................................... 131 
Definition of Serious Adverse Event ........................................................ 132 
Recording Adverse Events and Serious Adverse Events ........................ 133 
Evaluating Adverse Events and Serious Adverse Events ........................ 134 
Reporting of Serious Adverse Event ........................................................ 135 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 140 
Definition of Females of Childbearing Potential ....................................... 140 
Collection of Lactation Information .......................................................... 143 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 146 


Product:  AMG 160 
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CONFIDENTIAL  
 
 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 148 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity.......................................................................... 148 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 149 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 150 
11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse 
Events ..................................................................................................... 152 
11.9 
Appendix 9.  Modified Toxicity Probability Interval Design (mTPI) ........... 153 
11.10 Appendix 10.  Specific Guidance for Cytokine Release 
Syndrome, Tumor Lysis Syndrome, and Immune-effector 
Cell-associated Neurologic Syndrome ..................................................... 155 
11.10.1 
Specific Guidance for Cytokine Release Syndrome ................. 155 
11.10.2 
Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading ............................................................. 156 
11.10.3 
Specific Guidance for Immune-effector Cell-
associated Neurologic Syndrome ............................................ 158 
11.11 Appendix 11.  Performance Status According to Eastern 
Cooperative Oncology Group (ECOG) .................................................... 161 
11.12 Appendix 12.  Response Evaluation Criteria in Solid Tumors 
Version 1.1 (modified RECIST 1.1) ......................................................... 162 
11.13 Appendix 13.  COVID-19 Guidance ......................................................... 166 
 
 
List of Tables 
Table 1-1.  Schedule of Activities if 
 is 
Initiated (Cycle 1 Only) ........................................................................... 19 
Table 1-2.  Schedule of Activities if 
 is Initiated (Cycle 1 
Only) ....................................................................................................... 23 
Table 1-3.  Schedule of Activities if 
 is Initiated (Cycle 1 
Only) ....................................................................................................... 26 
Table 1-4.  Schedule of Activities (Cycle 2 and Beyond) ................................................ 29 
Table 1-5.  Schedule of Pharmacokinetic Samples (All time points relative to 
AMG 160 dosing) .................................................................................... 32 
Table 1-6.  Schedule of Imaging Assessments (Cycle Independent) ............................. 33 
Table 2-1.  Key Safety Risks for AMG 160 .................................................................... 45 
Table 6-1.  Study Treatments ........................................................................................ 58 
Table 6-2.  Study 20180101 Planned Doses per Dose Cohort Level ............................. 62 


Product:  AMG 160 
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CONFIDENTIAL  
 
 
Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent 
Discontinuation and Management of Adverse Events Including 
Dose Reductions .................................................................................... 69 
Table 8-1.  Vital Sign Time Points .................................................................................. 95 
Table 9-1.  Stopping Boundary for Dose Expansion With Posterior Probability 
of 80% and Grade 4 or Higher Treatment-related Adverse 
Event Limit of 20% ................................................................................ 106 
Table 9-2.  Operating Characteristics With Batch Size of 10 Subjects ......................... 106 
Table 9-3.  Objective Response Rate Stopping Boundary ........................................... 107 
Table 11-1.  Laboratory Analyte Listing ....................................................................... 120 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 149 
Table 11-3.  mTPI Trial Monitoring Table ..................................................................... 154 
Table 11-4.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome ................. 156 
Table 11-5.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 157 
Table 11-6.  ASBMT Immune Effector Cell-associated Neurotoxicity 
Syndrome (ICANS) Consensus Grading for Adults ............................... 159 
Table 11-7.  Assessment and Supportive Care Recommendations ............................. 160 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 17 
Figure 9-1.  The Probability of Stopping The Trial Early ............................................... 108 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form ................ 137 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 144 


Product:  AMG 160 
Protocol Number:  20180273  
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Page 10 of 166 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
and Efficacy of AMG 160 in Subjects with Non-Small Cell Lung Cancer 
Short Protocol Title:  A Phase 1b Study of AMG 160 in Subjects with Non-Small Cell 
Lung Cancer 
Study Phase:  Phase 1b 
Indication:  Non-Small Cell Lung Cancer (NSCLC) 
Rationale 
AMG 160 (acapatamab) is a novel half-life extended (HLE) bispecific T-cell engager 
(BiTE®) molecule designed to redirect T effector cells to lyse prostate-specific membrane 
antigen (PSMA)-expressing cells, with a single chain fragment crystallizable (scFc) 
moiety for half-life extension.  Immunohistochemistry (IHC) studies demonstrate that 
PSMA is expressed on the surface of endothelial cells within the tumor vasculature of 
many tumor types, including non-small cell lung cancer (NSCLC), and is not expressed 
on normal vasculature (Schmidt et al, 2017; Wang et al, 2015; Chang, et. al 1999).  
PSMA-targeted radioligands have also shown the potential to identify PSMA-positive 
lung cancer (Shetty et al, 2016; Milowsky et al, 2007).  Previous studies have shown that 
angiogenesis inhibitors can inhibit tumor growth by blocking new blood vessel formation 
and depriving the tumor of critical nutrients.  More recent studies suggest 
anti-angiogenesis treatments may enhance immune responses by altering the tumor 
microenvironment (Fukumura et al, 2018).  Given the selective expression of PSMA on 
the neovasculature in lung tumors, AMG 160 may lead to anti-tumor activity by 
disrupting the tumor neovasculature and by facilitating immune cell infiltration.  This is a 
phase 1b study to assess safety, tolerability, pharmacokinetics (PK), and anti-tumor 
activity of AMG 160 in adult subjects with NSCLC. 


Product:  AMG 160 
Protocol Number:  20180273  
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CONFIDENTIAL  
 
 
Objective(s)/Endpoint(s) 
 
 
Overall Design 
This is an open label phase 1b study evaluating the safety, tolerability, PK, and efficacy 
of AMG 160 monotherapy in subjects with relapsed, refractory non small cell lung cancer 
(NSCLC).  
AMG 160 monotherapy will be administered as a short-term IV infusion every 2 weeks 
after the target dose is reached in a 28-day cycle in subjects with relapsed, refractory 
NSCLC.  
 
.  The starting dose of AMG 160 will be 1 dose 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of AMG 160 
 
To evaluate the maximum 
tolerated dose (MTD) or the 
recommended phase 2 dose 
(RP2D) 
 
Dose-limiting toxicities (DLT) 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs and clinical 
laboratory tests 
Secondary 
 
To characterize the 
pharmacokinetics (PK) of 
AMG 160 
 
PK parameters for AMG 160 
following intravenous (IV) 
administration including but not 
limited to, maximum serum 
concentration (Cmax), minimum 
serum concentration (Cmin), area 
under the concentration-time 
curve (AUC) over the dosing 
interval, accumulation, and 
half-life (t1/2) 
 
To evaluate the preliminary 
anti-tumor activity of AMG 160 
 
Objective response (OR) per 
modified Response Evaluation 
Criteria in Solid Tumors 
(RECIST) 1.1  
 
Overall Survival 
 
Progression-free survival 
(radiographic [rPFS], clinical)  
 
Time to response 
 
Time to progression (radiographic, 
clinical) 
 
Duration of response  
 
Time to subsequent therapy 


Product:  AMG 160 
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CONFIDENTIAL  
 
 
level below the recommended phase 2 dose (RP2D) as determined in the ongoing first 
in human (FIH) study of AMG 160 in subjects with metastatic castration-resistant 
prostate cancer (mCRPC; 20180101).  A safety cohort of 2 to 4 subjects will initially be 
enrolled to assess the tolerability of AMG 160.  If the dose is tolerated (based on target 
dose-limiting toxicity [DLT] rate  30%), the dose level will be increased to the RP2D (or 
RP2D1) identified in Study 20180101.  Alternative dosing schedules, including further 
dose escalation may be explored based on emerging safety and PK data.  Additional 
subjects (up to 20) may be enrolled at 1 or more monotherapy dose levels that have 
been shown to be safe and tolerable (defined as backfill enrollment).  This backfill 
enrollment may be done to better estimate the RP2D and better characterize the safety, 
efficacy, PK, and 
 of AMG 160 monotherapy and may be concurrent 
with dose escalation to identify the MTD. 
Number of Subjects 
Approximately 10 subjects will initially be enrolled in Part 1 (dose exploration) of the 
study.  Additional subjects (up to 20) may be enrolled in 1 or more monotherapy dose 
levels that have been shown to be safe and tolerable (defined as backfill enrollment).  
This backfill enrollment may be done to better estimate the RP2D and better 
characterize the safety, efficacy, PK, and 
 of AMG 160 monotherapy 
and may be concurrent with dose escalation to identify the MTD.  If 1 or more objective 
responses (OR) are observed (per modified Response Evaluation Criteria in Solid 
Tumors [RECIST] 1.1 criteria) in Part 1, additional subjects (up to 40) will be enrolled in 
Part 2 (dose expansion) of the study.   
Summary of Subject Eligibility Criteria 
Adult subjects ( 18 years of age) with relapsed/refractory (RR) NSCLC with a 
histological or cytological diagnosis of non-squamous NSCLC (stage 4 or recurrent) are 
eligible to participate in Part 1.  In Part 2, adult subjects with RR NSCLC with a 
histological or cytological diagnosis of NSCLC (stage 4 or recurrent) are eligible to 
participate.  Subjects without a driver mutation are required to have had disease 
progression following at least 1 line of prior chemotherapy and anti-programmed cell 
death protein 1 (PD1)/programmed death-ligand 1 (PDL1) therapy to be eligible.  
Subjects with a driver mutation (epidermal growth factor receptor [EGFR] mutation 
[exon 19 deletion, L858R point mutation or T790M], BRAF V600E mutation, RET gene 
fusion, anaplastic lymphoma kinase [ALK] gene rearrangement, MET exon 14 skipping 
mutation or neurotrophic tropomyosin-related kinase [NTRK] gene fusion) must 
experience disease progression on at least 1 targeted therapeutic agent to be eligible.  


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CONFIDENTIAL  
 
 
Subjects are required to have disease with detectable PSMA assessed by 68Gallium 
(68Ga)-PSMA-11 positron emission tomography (PET)/computed tomography (CT) 
imaging 
 
 to be eligible (see inclusion criteria for full details).  Eligible subjects must have 
measurable disease per modified RECIST 1.1 criteria, Eastern Cooperative Oncology 
Group (ECOG) performance status (PS) of 0-2, and adequate organ function (see 
inclusion criterion 112). 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
Investigational product (AMG 160) will be administered as a short-term IV infusion 
(approximately 60 minutes) every 2 weeks after the target dose is reached.  The starting 
dose and dosing schedule of AMG 160 
 will be 
1 dose level below the RP2D from the ongoing FIH monotherapy study (20180101) in 
subjects with mCRPC.  
 
 
 
 
  
Sites are required to have tocilizumab or siltuximab (if tocilizumab not available) on site 
for potential treatment of CRS.  
In addition to the approaches listed above, per DLRT recommendations additional 
prophylaxis may be implemented, 
 
 
 
 
 


Product:  AMG 160 
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CONFIDENTIAL  
 
 
To reduce the potential of CRS, the cycle 1 dosing schedule will be initiated with one or 
more of the following measures as the study continues, as per the emerging cumulative 
data from the ongoing FIH monotherapy study (20180101) in subjects with mCRPC.  


Product:  AMG 160 
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CONFIDENTIAL  
 
 
To further assess the safety of the subjects, the subject must return for safety follow-up 
visit approximately 30 (3) days after the last dose of AMG 160 or prior to initiation of 
other therapy, whichever occurs first.  Long-term follow-up will be conducted every 
6 months up to 3 years from the first dose of AMG 160 for all subjects who have not 
withdrawn consent by clinic visit, telephone or chart review to assess for survival and/or 
the commencement of subsequent cancer therapy. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Section 1.3. 
Statistical Considerations 
All subjects who are enrolled and receive at least 1 dose of AMG 160 will be included in 
the analysis, unless otherwise specified.  A formal interim analysis of available safety 
and efficacy data will occur when the first 10 evaluable subjects enrolled have had the 
opportunity to complete 4 months on study.  This interim analysis will estimate maximum 
tolerated dose (MTD), support the determination of RP2D, conduct futility analysis of 
ORR, and support the evaluation of benefit/risk profile of AMG 160 as a monotherapy.  
A futility analysis of ORR will be performed using Bayesian predictive probability 
(Lee and Liu, 2008) when the first 10 evaluable subjects reach month 4.  If the predictive 
probability of observing objective response rate (ORR) response > 15 at the end of the 
study with 50 evaluable subjects is less than 30, the study may stop early (pT  0.25).  
Equivalently, if we observe 1 objective responder in the first 10 subjects, additional 
subjects (up to 40) will be enrolled into the expansion cohort.  The predictive probability 
is calculated with a noninformative, Jeffreys prior, Beta (0.5, 0.5).  
The primary analysis for the dose exploration phase will occur when target enrollment is 
complete and each subject either completes 6 months on the study or withdraws from 
the study.  
The primary analysis for the study will occur when target enrollment is complete for the 
dose expansion phase and each subject either completes 1 year on study or withdraws 
from the study.  The final analysis will occur when target enrollment is complete for both 
phases and all subjects have ended the study.  
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
AMG 160 will be safe and tolerated at a dose level with evidence of anti-tumor activity in 
subjects with NSCLC.  No formal statistical hypotheses will be tested in this phase 1b 
study. 


Product:  AMG 160 
Protocol Number:  20180273  
Date:  25 March 2022 
Page 16 of 166 
CONFIDENTIAL  
 
 
Sponsor Name:  Amgen Inc. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 17 of 166 
CONFIDENTIAL  
 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
Safety Follow-up
Long-term Follow-up
Phase 1b Study
Screening (up to 28 days)
Enrollmentb
End of Treatment
If ≥ 1 OR
Part 1a: Dose Exploration 
(n = 10)
AMG 160 
(1 dose level below
starting dose)c
AMG 160 c
(1 dose level below FIH 20180101 
MTD/RP2D)c
Part 2: Dose Expansion 
(n = 40)
Screening (up to 28 days)
Enrollmentb
Cohort 1 
AMG 160d (n = 30) 
(non-squamous NSCLC)
End of Treatment
Safety Follow-up
Long-term Follow-up
AMG 160 
(1 dose level above
starting dose)c
Cohort 2 
AMG 160d (n = 10)
(squamous NSCLC)  
 
CT  computed tomography; FIH  first in human; 68Ga  68Gallium; IV = intravenous; MTD  maximum tolerated dose; NSCLC  non-small cell lung cancer; 
OR  objective response; PET  positron emission tomography; PSMA  prostate-specific membrane antigen; RP2D  recommended phase 2 dose. 
a Subjects with nonsquamous NSCLC.  Up 20 additional subjects may be enrolled in 1 or more monotherapy dose levels that have been shown to be safe and tolerable 
(defined as backfill enrollment) to better estimate the RP2D and better characterize the safety, efficacy, PK, and 
 of AMG 160 monotherapy and 
may be concurrent with dose escalation to identify the MTD.   
b Subjects are required to have detectable PSMA expression by 68Ga-PSMA-11 PET/CT imaging 
 to enroll (see Section 5.1). 
c MTD/RP2D for Part 1 will be determined by the first in human AMG 160 study (Study 20180101). 
d Part 2 will be determined by dose recommended in Part 1 of this study. 
 
Study Periods: 
 Screening:  up to 28 days before enrollment 
 Treatment:  AMG 160 administered IV every 2 weeks 
 treatment continues until confirmed 
progression  
 End of treatment:  should occur as soon as possible (within 14 days) after the last dose of AMG 160 
 Safety follow-up:  approximately 30 (3) days after the last dose of AMG 160 or prior to initiation of other therapy, whichever occurs first 
 Long-term follow-up:  every 6 months up to 3 years from the first dose of AMG 160 for all subjects who have not withdrawn consent 
 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 18 of 166 
CONFIDENTIAL  
 
 
1.3 
Schedule of Activities (SoA) 
 
Quick link to SoA 
Table Title 
Table 1-1 
Schedule of Activities if 
 
Table 1-2 
Schedule of Activities if 
 
Table 1-3 
Schedule of Activities if 
 
Table 1-4 
Schedule of Activities (Cycle 2 and Beyond) 
Table 1-5 
Schedule of Pharmacokinetic Samples 
Table 1-6 
Schedule of Imaging Assessments (Cycle Independent) 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 19 of 166 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities if 
 is Initiated (Cycle 1 Only) 
Study Period/Treatment Cycle SCRa 
Cycle 1b 
Infusion-
free 
interval 
Notes 
Weekc  
1 
2 
3 
4 
5 
Dayc 
1 2 3 4 5 
6 
8 9 10 15 17 22 23 24 
29 
GENERAL/SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation 
(X) 
X X X X 
X X X X X X X X 
X 
Includes physical exam, ECOG, and weight (neurological 
examination, if clinically indicated) (see Section 8.2.1).   
(X):  Additionally at screening:  demographics, medical history, 
and height. 
 
Vital signs, pulse ox 
X 
X 
X X 
X 
X X X 
(X) 
X 
X 
(X):  Refer to Section 8.2.3.1 for detailed vital sign collection time 
points. 
 
12-lead ECG 
X 
(single 
read) 
[X]  
(X)  
 
 
 (X)  
 
 
[X]:  Collected pre-dose at baseline prior to start of infusion. 
Triplicate ECGs will only be collected if the dose being evaluated 
is higher than the MTD established in the monotherapy study in 
subjects with mCRPC.  If the dose being evaluated is less than or 
equal to the MTD in subjects with mCRPC, single read ECGs are 
to be collected at the defined time points. 
 
 
(X):  Collected pre- and post-dose on days 8 and 22 
ECHO or MUGA scan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Review 
 
Continually through SFU 
 
SAE Review 
Continually throughout study 
 
Prior/concomitant medication 
Continually through SFU 
 
Page 1 of 3 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 20 of 166 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities if 
 is Initiated (Cycle 1 Only) 
Study Period/Treatment 
Cycle SCRa 
Cycle 1b 
Infusion-free 
interval 
Notes 
Weekc  
1 
2 
3 
4 
5 
Dayc 
1 
2 3 4 
5 
6 
8 
9 10 15 17 22 23 24 
29 
LOCAL LABORATORY TESTSd 
CBC with differential 
X 
X X X X 
 
X X X X X X X X 
X 
Laboratory assessments that were done within 24 hours prior to 
infusion do not need to be repeated.  Blood samples must not be 
collected until at least 24 hours after PSMA PET/CT. 
 
Coagulation 
X 
X X 
 
X 
 
X X 
 
X X X X 
 
 
Chemistry panel 
X 
X X X X 
 
X X X X X X X X 
X 
Pregnancy test (serum) 
X 
(X)  
 
 
 
 
 
 
 
 
 
 
 
 
(X):  Collected pre-infusion of AMG 160. 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY TESTS 
PK sample collection 
 
 
(X) 
(X):  See Table 1-5 for detailed AMG 160 PK collection schedule 
during treatment period. 
Page 2 of 3 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 21 of 166 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities if 
 is Initiated (Cycle 1 Only) 
Study Period/Treatment 
Cycle SCRa 
Cycle 1b 
Infusion-free 
interval 
Notes 
Weekc  
1 
2 
3 
4 
5 
Dayc 
1 
2 3 4 
5 
6 
8 
9 10 15 17 22 23 24 
29 
STUDY TREATMENT AND OTHER ASSESSMENTS/PROCEDURES 
Imaging 
(X) 
(X):  See Table 1-6 – assessments are cycle independent 
Page 3 of 3 
NOTE:  This schedule of activities only applies to cycle 1.  After cycle 1 day 28, there is a 1-week infusion-free interval.  Then resume Table 1-4 Schedule of Activities 
beginning in cycle 2. 
AE  adverse event; C1D1  cycle 1 day 1; CBC  complete blood count; CT  computed tomography;
 ECG  electrocardiogram; 
ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; 
 EOI  end of infusion; IPIM  Investigational Product 
Instruction Manual; IV  intravenous; mCRPC  metastatic castration-resistant prostate cancer; MTD = maximum tolerated dose; MUGA scan  multigated 
acquisition scan;
 PET  positron emission tomography; PK  pharmacokinetic; PSMA  prostate-specific membrane 
antigen; SAE  serious adverse event; SCR  screening; SFU  safety follow-up 
a All screening procedures should be performed within 28 days prior to cycle 1 day 1 dosing.  Exception:  serum pregnancy testing at screening is to be 
performed within 7 days of initiation of investigational product for females of childbearing potential. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 22 of 166 
CONFIDENTIAL  
 
 
b All assessments on AMG 160 dosing days are performed pre-infusion.  Assessments should not be performed from the infusion line.  End of infusion (EOI) 
assessments or procedures are to be completed after the AMG 160 post-infusion flush as defined by the IPIM. 
c Each visit week and day is relative to day 1 of each cycle.  Cycle 1 visits have a  1-day window from designated time point unless otherwise specified. 
d Any blood samples collected during the screening window must be collected within 28 days of cycle 1 day 1. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 23 of 166 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities if 
 is Initiated (Cycle 1 Only) 
Study Period/ 
Treatment Cycle SCRa 
Cycle 1b 
Notes 
Weekc  
1 
2 
3 
4 
Dayc 
1 
2 3 
8 
9 10 15 16 17 22 26 
GENERAL/SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
  
Clinical evaluation 
(X) 
X 
X X 
X 
X X 
X 
X X X X 
Includes physical exam, ECOG, and weight (neurological examination, if clinically 
indicated) (see Section 8.2.1).   
(X):  Additionally at screening:  demographics, medical history, and height. 
Vital signs, pulse ox 
X 
X 
X 
X 
X 
X 
X X X (X):  Refer to Section 8.2.3.1 for detailed vital sign collection time points. 
12-lead ECG 
X 
(single 
read) 
(X) 
 
 
(X) 
 
 
(X) 
 
 
 
 
(X):  Collected pre- and post-infusion of AMG 160. 
Triplicate ECGs will only be collected if the dose being evaluated is higher than the 
MTD established in the monotherapy study in subjects with mCRPC.  If the dose being 
evaluated is less than or equal to the MTD in subjects with mCRPC, single read ECGs 
are to be collected at the defined time points. 
ECHO or MUGA scan 
X 
 
 
 
 
 
 
 
 
 
 
  
AE Review 
 
Continually through SFU 
 
SAE Review 
Continually throughout study 
 
Prior/concomitant medication 
Continually through SFU 
 
LOCAL LABORATORY TESTINGd 
CBC with differential 
X 
X 
X X 
X 
X X 
X 
X X X X Laboratory assessments that were done within 24 hours prior to infusion do not need 
to be repeated.  Blood samples must not be collected until at least 24 hours after 
PSMA PET/CT. 
Coagulation 
X 
X 
X X 
X 
X X 
 
X X X X 
Chemistry panel 
X 
X 
X X 
X 
X X 
X 
X X X X 
Pregnancy test (serum) 
X 
(X) 
 
 
 
 
 
 
 
 
 
 (X):  Collected pre-infusion of AMG 160. 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 24 of 166 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities if 
 is Initiated (Cycle 1 Only) 
Study Period/ 
Treatment Cycle SCRa 
Cycle 1b 
Notes 
Weekc  
1 
2 
3 
4 
Dayc 
1 
2 3 
8 
9 10 15 16 17 22 26 
CENTRAL LABORATORY TESTS 
PK sample collection 
 
(X) 
(X):  See Table 1-5 for detailed AMG 160 PK collection schedule during treatment 
period. 
STUDY TREATMENT AND OTHER ASSESSMENTS/PROCEDURES 
Imaging 
(X) 
(X):  See Table 1-6 – assessments are cycle independent 
AMG 160 IV infusion 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Hospitalization/monitoring 
 
X 
 
X 
 
X 
 
 
 See Table 6-1 for additional guidance regarding hospitalization.   
Page 2 of 2 
NOTE:  This schedule of activities only applies to cycle 1.  Then resume Table 1-4 Schedule of Activities beginning in cycle 2. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 25 of 166 
CONFIDENTIAL  
 
 
AE  adverse event; CBC  complete blood count; CT  computed tomography;
 ECG  electrocardiogram; ECHO  echocardiogram; 
ECOG  Eastern Cooperative Oncology Group; EOI  end of infusion; IPIM  Investigational Product Instruction Manual; IV  intravenous; mCRPC  metastatic 
castration-resistant prostate cancer; MTD  maximum tolerated dose; MUGA scan  multigated acquisition scan; 
 
PET  positron emission tomography; PK  pharmacokinetic; PSMA  prostate-specific membrane antigen; SAE  serious adverse event; 
SCR  screening; SFU  safety follow-up 
a All screening procedures should be performed within 28 days prior to cycle 1 day 1 dosing.  Exception:  serum pregnancy testing at screening is to be 
performed within 7 days of initiation of investigational product for females of childbearing potential. 
b All assessments on AMG 160 dosing days are performed pre-infusion.  Assessments should not be performed from the infusion line.  End of infusion (EOI) 
assessments or procedures are to be completed after the AMG 160 post-infusion flush as defined by the IPIM. 
c Each visit week and day is relative to day 1 of each cycle.  Cycle 1 visits have a  1-day window from designated time point unless otherwise specified (except for PK 
and 
 collections days). 
d Any blood samples collected during the screening window must be collected within 28 days of cycle 1 day 1. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 26 of 166 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities if 
 is Initiated (Cycle 1 Only) 
Study Period/ 
Treatment Cycle SCRa 
Cycle 1b 
Infusion-free 
interval 
Notes 
Weekc 
 
1 
2 
3 
4 
5 
Dayc 
1 
2 3 
8 
9 10 15 16 17 22 23 24 
29 
GENERAL/SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluation 
(X) 
X 
X X 
X 
X X 
X 
X X 
X 
X X 
X 
Includes physical exam, ECOG, and weight (neurological 
examination, if clinically indicated) (see Section 8.2.1).   
(X):  Additionally at screening:  demographics, medical history, and 
height. 
Vital signs, pulse ox 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
 
X 
(X):  Refer to Section 8.2.3.1 for detailed vital sign collection time 
points. 
12-lead ECG 
X 
(single 
read) 
 
 
 
(X) 
 
 
(X) 
 
 
(X) 
 
 
 
(X):  Collected pre- and post-infusion of AMG 160. 
Triplicate ECGs will only be collected if the dose being evaluated is 
higher than the MTD established in the monotherapy study in subjects 
with mCRPC.  If the dose being evaluated is less than or equal to the 
MTD in subjects with mCRPC, single read ECGs are to be collected at 
the defined time points. 
ECHO or MUGA scan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Review 
 
Continually through SFU 
 
 
SAE Review 
Continually throughout study 
 
 
Prior/concomitant 
medication 
Continually through SFU 
 
 
LOCAL LABORATORY TESTINGd 
CBC with differential 
X 
X 
X X 
X 
X X 
X 
X X 
X 
X X 
X 
Laboratory assessments that were done within 24 hours prior to 
infusion do not need to be repeated.  Blood samples must not be 
collected until at least 24 hours after PSMA PET/CT. 
Coagulation 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Chemistry panel 
X 
X 
X X 
X 
X X 
X 
X X 
X 
X X 
 
Pregnancy test (serum) 
X 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
(X):  Collected pre-infusion of AMG 160. 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 27 of 166 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities if 
 is Initiated (Cycle 1 Only) 
Study Period/ 
Treatment Cycle SCRa 
Cycle 1b 
Infusion-free 
interval 
Notes 
Weekc 
 
1 
2 
3 
4 
5 
Dayc 
1 
2 3 
8 
9 10 15 16 17 22 23 24 
29 
CENTRAL LABORATORY TESTS 
PK collection 
 
(X) 
 
(X):  See Table 1-5 for detailed AMG 160 PK collection schedule 
during treatment period. 
STUDY TREATMENT AND OTHER ASSESSMENTS/PROCEDURES 
Imaging 
(X) 
(X):  See Table 1-6 – assessments are cycle independent 
AMG 160 IV infusion 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Hospitalization/monitoring 
 
X 
 
X 
 
X 
 
X 
 
 
See Table 6-1 for additional guidance regarding hospitalization.   
Page 2 of 2 
NOTE:  This schedule of activities only applies to cycle 1.  Then resume Table 1-4 Schedule of Activities beginning in cycle 2. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 28 of 166 
CONFIDENTIAL  
 
 
AE = adverse event; CBC  complete blood count; CT  computed tomography; 
 ECG  electrocardiogram; ECHO  echocardiogram; 
ECOG  Eastern Cooperative Oncology Group; EOI  end of infusion; IPIM  Investigational Product Instruction Manual; IV  intravenous; mCRPC  metastatic 
castration-resistant prostate cancer; MTD  maximum tolerated dose; MUGA scan = multigated acquisition scan;
PET  positron emission tomography; PK  pharmacokinetic; PSMA  prostate-specific membrane antigen; SAE  serious adverse event; SCR  screening; 
SFU  safety follow-up 
a All screening procedures should be performed within 28 days prior to cycle 1 day 1 dosing.  Exception:  serum pregnancy testing at screening is to be performed 
within 7 days of initiation of investigational product for females of childbearing potential. 
b All assessments on AMG 160 dosing days are performed pre-infusion.  Assessments should not be performed from the infusion line.  End of infusion (EOI) 
assessments or procedures are to be completed after the AMG 160 post-infusion flush as defined by the IPIM. 
c Each visit week and day is relative to day 1 of each cycle.  Cycle 1 visits have a ± 1-day window from designated time point unless otherwise specified. 
d Any blood samples collected during the screening window must be collected within 28 days of cycle 1 day 1. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 29 of 166 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities (Cycle 2 and Beyond) 
Study Period/ 
Treatment Cycle 
Cycle 2a 
Cycle 3+ 
EOTb 
SFU c 
LTFUd 
Notes 
Weeke 
1 
2 
3 
4 
1 
3 
 
 
 
Daye 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
 
 
GENERAL/SAFETY ASSESSMENTS 
Clinical evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Includes physical exam, ECOG, and weight (neurological examination, if clinically 
indicated) (see Section 8.2.1).   
Vital signs, pulse ox 
(X) 
X 
(X) 
X 
X 
X 
X 
X 
 
(X):  Refer to Section 8.2.3.1 for detailed vital sign collection time points. 
12-lead ECG  
(X)¥ 
 
 
(X) 
 
 
(X) (X) 
 
 
 
(X):  Collected pre- and post-infusion of AMG 160. 
¥ Triplicate ECG on C2D1 will only be collected if the dose being evaluated is 
higher than the MTD established in the monotherapy study in subjects with 
mCRPC (Study 20180101).  If the dose being evaluated is less than or equal to 
the MTD in Study 20180101, single read ECGs are to be collected at the defined 
time points. 
AE review 
Continually through SFU 
 
 
SAE review 
Continually throughout study 
X  
Prior/concomitant 
medication 
Continually through SFU 
 
 
Survival status and/or 
subsequent cancer therapy 
 
 
 
 
 
 
 
 
 
 
X  
LOCAL LABORATORY TESTS 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples must not be collected until at least 24 hours after PSMA PET/CT 
scans. 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (serum) 
(X) 
 
 
 
 
 
(X) 
 
 
X 
 
(X):  Collected pre-infusion of AMG 160. 
Urinalysis 
X 
 
 
 
 
 
(X) 
 
 
 
 
(X):  Collected D1 of every other cycle (C2, C4, C6, etc.) 
Page 1 of 2 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 30 of 166 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities (Cycle 2 and Beyond) 
Study Period/ 
Treatment Cycle 
Cycle 2a 
Cycle 3+ 
EOTb 
SFU c 
LTFUd 
Notes 
Weeke 
1 
2 
3 
4 
1 
3 
 
 
 
Daye 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
 
CENTRAL LABORATORY TESTS 
STUDY TREATMENT AND OTHER ASSESSMENTS/PROCEDURES 
PK sample collection 
X 
 
 
 
See Table 1-5 for detailed AMG 160 PK collection schedule during treatment 
period. 
Imaging 
(X) 
 
(X):  See Table 1-6 – assessments are cycle independent 
Hospital stay 
X 
 
X 
 
 
X 
X 
 
 
 
See Table 6-1 for additional guidance regarding hospitalization.  In cycles 3 and 
4, subject should be monitored in hospital or outpatient clinic for at least 4 hours 
post-infusion. 
AMG 160 IV infusion 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Page 2 of 2 
AE = adverse event; C  cycle; CBC = complete blood count; CT  computed tomography;
 D  day; ECG  electrocardiogram; 
ECOG  Eastern Cooperative Oncology Group; EOI  end of infusion; EOT  end of treatment; IPIM  Investigational Product Instruction Manual; IV  intravenous; 
LTFU  long-term follow-up; mCRPC  metastatic castration-resistant prostate cancer; MRI = magnetic resonance imaging; MTD = maximum tolerated dose; 
 PET  positron emission tomography; PK  pharmacokinetic; PSMA  prostate-specific membrane antigen; 
SAE  serious adverse event; SFU = safety follow-up 
a Please follow Table 1-1, Table 1-2, and  
Table 1-3 for the procedures/activities for cycle 1 and Table 1-4 for cycle 2 and subsequent cycles.  
  All 
assessments on AMG 160 dosing days are performed pre-infusion.  Assessments should not be performed from the infusion line.  End of infusion assessments or 
procedures are to be completed after the AMG 160 post-infusion flush as defined by the IPIM. 


Product:  AMG 160 
Protocol Number:  20180273 
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Page 31 of 166 
CONFIDENTIAL  
 
 
b For subjects who discontinue investigational product, an end of treatment visit should occur as soon as possible (within 14 days) after the last dose of investigational 
product. 
c Upon permanent discontinuation from the study treatment for any reason, a safety follow-up visit will be performed approximately 30 (+3) days after the end of the last 
dose of investigational product or prior to initiation of other therapy, whichever occurs first. 
d Assessed every 6 months up to 3 years from the first dose of AMG 160 for all subjects who have not withdrawn consent by clinic visit, telephone or chart review to 
assess for survival and/or the commencement of subsequent cancer therapy.  During the long-term follow-up phase, serious adverse events regardless of causality 
(including fatal events) will be reported to Amgen. 
e Each visit week and day is relative to day 1 of each cycle.  Cycle 2 visits have a  1-day window from designated time point unless otherwise specified.  All 
subsequent visits beginning in cycle 3 will have a  3-day window. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 32 of 166 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Pharmacokinetic Samples (All time points relative to AMG 160 dosing)  
 
Preinfusion a 
End of infusion b 
Hours after end of infusion c 
2 
6 
24 
48 
72 
96 
120 
168 
AMG 160 PK Sample Collection 
Cycle 
 only (days 1, 8, 
and 15) 
X 
X 
 
X 
 
X 
 
 
 
 
Cycle 1 
 only (days 1, 8, 
15, and 22) 
X 
X 
 
X 
 
X 
 
 
 
 
Cycle 1 
 (day 1) 
Xe 
 
 
 
Cycle 1 
 (day 1) 
Xf 
 
 
 
 
Cycle 1 
 (day 1) 
Xg 
 
Cycle 1 
 - target dose 
only (days 8 and 22) 
X 
X 
 
X 
 
X 
 
 
 
X 
Cycle 2 (days 1 and 15) 
X 
X 
 
X 
 
X 
 
 
 
X 
Cycle 3 (day 1) 
X 
X 
 
 
 
 
 
 
 
 
Cycle 4 (day 1) 
X 
X 
 
 
 
 
 
 
 
 
Cycle 5 (day 1) 
X 
X 
 
 
 
 
 
 
 
 
Cycle 6 through C12d (day 1) 
X 
 
 
 
 
 
 
 
 
 
eCRF = electronic case report form; IV = intravenous; PK = pharmacokinetic 
a For pre-infusion, PK can be collected up to 30 minutes prior to dosing of AMG 160.  
b For end of infusion, PK samples to be collected within 30 minutes after AMG 160 infusion. 
c The samples for 
 need to be collected as close to the sampling time point for the infusion duration.  For any samples after end of infusion time 
point, PK can be collected ± 30 minutes within the scheduled sample collection time.  Date and time of collection should be recorded in eCRF.  Samples collected 
outside of the collection window will not be considered as a protocol deviation. 
d PK samples to be collected until end of cycle 12 only. 
e For the 
 in cycle 1, PK samples should be collected pre-infusion and 2, 6, 24, 48, and 72 hours after start of infusion.   
f For the 
 in cycle 1, PK samples should be collected pre-infusion and 2, 6, 24, and 48 hours after start of infusion.   
g For the 
 in cycle 1, PK samples should be collected pre-infusion and 2, 6, 24, 48, 72, 96, and 120 hours after start of infusion.   


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 March 2022 
Page 33 of 166 
CONFIDENTIAL  
 
 
Table 1-6.  Schedule of Imaging Assessments (Cycle Independent) 
 
SCR 
Treatment Perioda 
EOT 
SFU 
LTFU 
Notes 
MRI brain 
X 
 
 
 
 
All subjects must have MRI of the brain performed within 
28 days prior to the first dose of AMG 160.  All brain 
scans on protocol are required to be MRI unless MRI is 
contraindicated, then CT with contrast is acceptable.  
Subsequently, MRI brain can be performed at any time if 
clinically indicated per standard of care. 
CT/MRI and tumor burden 
assessment (chest, 
abdomen and pelvis) 
X 
Weeks 1-24 
Every 
8 weeks 
Weeks 25+ 
Every 
8 weeks 
X 
X 
Xb 
Radiologic imaging (CT/MRI) is required at the EOT or 
SFU visit if the subject has not had radiologic imaging 
performed within 6 weeks of the visit.   
68Ga-PSMA-11 PET/CT 
X 
At week 8 and week 16  
X 
 
 
 
 
CT = computed tomography; EOT = end of treatment; 68Ga = 68-Gallium; 
; LTFU = longterm follow-up; MRI = magnetic resonance 
imaging; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RECIST = Response Evaluation Criteria in Solid Tumors; 
SCR = screening; SFU = safety follow-up;  
a Timing is based on first dose of AMG 160 (cycle 1 day 1)  7 days for imaging assessments. 
b For subjects who discontinued treatment for any reason other than confirmed disease progression, every effort should be made to perform radiographic imaging 
(CT/MRI) of the chest, abdomen, pelvis, and all other known sites of disease every 3 months until documentation of confirmed disease progression per modified 
RECIST 1.1, clinical progression, start of new anticancer therapy, or up to 3 years after the first dose of AMG 160, whichever occurs first. 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 34 of 166 
CONFIDENTIAL  
 
 
2. 
Introduction 
2.1 
Study Rationale 
AMG 160 (acapatamab) is a novel half-life extended (HLE) bispecific T-cell engager 
(BiTE®) molecule designed to redirect T effector cells to lyse prostate-specific membrane 
antigen (PSMA)-expressing cells, with a single chain fragment crystallizable (scFc) 
moiety for half-life extension.  AMG 160 induces potent T cell redirected lysis of prostate 
cancer cells, with half-maximal effective concentrations of 6-55 pM against prostate 
cancer cell lines in vitro that express as low as 6881 PSMA copies per cell (Bailis et al, 
2019).  The BiTE mechanism of action is effective against even very low levels of target 
(< 1000 copies per cell; Owen et al, 2019).  PSMA has been shown to be highly 
expressed in metastatic and castration-resistant prostate cancer (von Eyben et al, 2018).  
Immunohistochemical analysis has shown intense and homogenous expression of 
PSMA on prostate cancer cells within metastatic lesions localized to the bones, lymph 
nodes, soft tissue and the lungs (Chang et al, 2001; Sweat et al, 1998; Murphy et al, 
1996).  Numerous PSMA-targeted therapies in prostate cancer are currently under 
development.  PSMA has also been shown to be expressed on the surface of 
endothelial cells within the tumor vasculature of many tumor types, including non-small 
cell lung cancer (NSCLC), and is not expressed in the vasculature of normal endothelial 
tissues (Chang et al, 1999).  Several recent reports confirm PSMA expression on the 
tumor vasculature of NSCLC, with recent studies showing 49-77% of NSCLC samples 
noting PSMA expression in the tumor vasculature (Schmidt et al, 2017; Wang et al, 
2015).  PSMA-targeted radioligands have also shown the potential to identify 
PSMA-positive lung cancer. (Shetty et al, 2016; Milowsky et al, 2007).  In vitro, PSMA 
expression can be induced on endothelial cells cultured in conditioned media from 
cancer cell lines (Nguyen et al, 2016; Liu et al, 2011).  In vivo, angiogenesis was 
significantly impaired in PSMA-null mice or PSMA wild-type mice treated with a PSMA 
inhibitor, suggesting that PSMA participates in tumor-specific neovasculature growth 
(Nguyen et al, 2016; Conway et al, 2006).  Targeting of PSMA with a radiolabeled 
PSMA-ligand demonstrates selective killing of PSMA-positive neovasculature in 
preclinical models (Morgenroth et al, 2019).  Previous studies have shown that 
angiogenesis inhibitors can inhibit tumor growth by blocking new blood vessel formation 
and depriving the tumor of critical nutrients.  More recent studies suggest 
anti-angiogenesis treatments may enhance immune responses by altering the tumor 
microenvironment (Fukumura et al, 2018).  AMG 160 has the potential both to redirect 
T cells to lyse any PSMA-positive endothelial cells in tumor vasculature, and to promote 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 35 of 166 
CONFIDENTIAL  
 
 
T cell proliferation.  This is a phase 1b study to assess safety, tolerability, 
pharmacokinetics (PK) and anti-tumor activity of AMG 160 in adult subjects with NSCLC. 
2.2 
Background 
2.2.1 
Disease 
Lung cancer is the leading cause of cancer-related mortality world-wide, with NSCLC 
accounting for 85% of lung cancer cases (Brahmer et al, 2018).  In the United States, 
lung cancer-related deaths will account for an estimated 142 670 deaths in 2019.  
NSCLC accounts for approximately 85% of all primary lung cancers, with most patients 
presenting with advanced, unresectable disease at the time of diagnosis 
(Arbour et al, 2019).  Until recently, cytotoxic chemotherapy has been considered the 
mainstay of treatment for advanced NSCLC.  More recently, however, the GHYHORSPHQW
RILPPXQRWKHUDS\WUHDWPHQWVWKDWGLVUXSWWKHSURJUDPPHGFHOOGHDWK3'DQG3'/
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PDL1 immune checkpoint pathway inhibitors have demonstrated an overall survival (OS) 
benefit and have been approved either by the United States Food and Drug 
Administration (FDA) and/or the European Medicines Agency (EMA) for use in patients 
with NSCLC:  QLYROXPDEDQGSHPEUROL]XPDEERWKWDUJHWLQJWKH3'UHFHSWRUDVZHOO
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Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 36 of 166 
CONFIDENTIAL  
 
 
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2.2.2 
Amgen Investigational Product Background:  AMG 160 
BiTE molecules are designed to direct T effector cells to kill target cells.  The BiTE 
molecule WULJJHUV target cell specific cytotoxicity which closely resembles standard 
cytotoxic T lymphocyte activation.  Blinatumomab (BLINCYTO), cluster of differentiation 
(CD)19 BITE molecule, is approved for the treatment of acute lymphoblastic leukemia 
(ALL). 
AMG 160 is DQ HLE BiTE molecule designed to direct T effector cells (via CD3 binding) 
to prostate cancer cells expressing PSMA.  In addition to binding domains specific for 
CD3 and PSMA, AMG 160 contains the N-terminus of an immunoglobulin (Ig)G scFc 
region.  The fusion to the Fc domain is a well-established strategy to prolong the half-life 
of protein therapeutics, such as cytokines, growth factors, and bispecific antibodies, with 
several approved for the treatment of cancer (Kontermann, 2011). 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 37 of 166 
CONFIDENTIAL  
 
 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AMG 160 
is provided in the AMG 160 Investigator’s Brochure. 
2.2.2.1 
Nonclinical Pharmacology 
In vitro experiments demonstrated that AMG 160 activity requires the simultaneous 
binding to PSMA-positive cells and T cells.  The pharmacological effect of AMG 160 is 
mediated by specific redirection of previously primed cytotoxic CD3 positive 
T lymphocytes to kill PSMA expressing cells.  AMG 160 is a potent molecule showing 
mean half maximal lysis of human tumor cell lines by human effector cells in vitro over a 
range of 6 to 55 pM (0.636 to 5.83 ng/mL). 
AMG 160 monotherapy significantly inhibited the growth of established subcutaneous 
(SC) PSMA expressing human prostate cancer cell line (22Rv1) tumors in mouse 
xenograft studies with reconstituted human T cells. 
2.2.2.2 
Nonclinical Toxicology 
The nonclinical safety assessment of AMG 160 was conducted in male cynomolgus 
monkeys by intravenous (IV) administration in a 33-day GLP study.   


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 38 of 166 
CONFIDENTIAL  
 
 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 39 of 166 
CONFIDENTIAL  
 
 
2.2.2.3 
Clinical Experience 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 40 of 166 
CONFIDENTIAL  
 
 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
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CONFIDENTIAL  
 
 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 42 of 166 
CONFIDENTIAL  
 
 
2.3 
Benefit/Risk Assessment 
This is a phase 1b study of AMG 160 monotherapy in adult subjects with NSCLC.  
Based on nonclinical toxicity studies of AMG 160, and clinical experience with AMG 160 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 43 of 166 
CONFIDENTIAL  
 
 
in patients with metastatic castration-resistant prostate cancer (mCRPC), the anticipated 
benefit/risk profile favors clinical development of AMG 160 for subjects with NSCLC.  
The following benefit risk assessment supports the conduct of this clinical trial.  Please 
</0/<>9>2/8@/=>31+>9<N=<9-2?</09<0?<>2/<.+>+98	 
2.3.1 
Therapeutic Context 
PSMA targeted therapies have recently shown promise in mCRPC.  In a phase 2 study 
involving mCRPC patients refractory to standard of care therapies, 177Lu-PSMA-617 
demonstrated evidence of clinical activity as well as improvements in quality of life 
assessments (Hofman et al, 2018).  Key outstanding issues for PSMA 
radiopharmaceuticals involve grade 3 to 4 bone marrow toxicities driven by the 
radioactive moiety as well as primary resistance to therapy and lack of response 
durability.  While PSMA has been established as a therapeutic target for mCRPC, it is 
currently not an established therapeutic target in NSCLC.  Given PSMA expression on 
the tumor vasculature of NSCLC and the limited therapeutic options for patients with 
advanced NSCLC following progression on standard of care treatments, there is a need 
for new PSMA targeted therapies with novel modalities that permit improved safety, 
patient access, and durability of responses.  
The GHYHORSPHQWRIimmunotherapytreatmentsWKDWGLVUXSWWKHSURJUDPPHGFHOOGHDWK
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immune checkpoint pathway inhibitors have demonstrated an overall survival (OS) 
benefit and have been approved either by the United States Food and Drug 
Administration (FDA) and/or the European Medicines Agency (EMA) for use in patients 
with NSCLC.  'HVSLWHWKHVHUHFHQWDGYDQFHVORQJWHUPGXUDEOHUHVSRQVHVUHPDLQ
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,9LQIXVLRQ&OLQLFDOWULDOVLQODWHVWDJHKHPDWRORJLFDOPDOLJQDQFLHVGHPRQVWUDWHGDQ


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 44 of 166 
CONFIDENTIAL  
 
 
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2.3.2 
Key Risks 
Based on biological mechanism, nonclinical toxicity studies of AMG 160, and/or clinical 
experience, CRS 
 
 
 
  
Other potential safety concerns based on preclinical studies and experience with other 
BiTE molecules include gastrointestinal and neurologic toxicities, and tumor lysis 
syndrome (TLS) (see Table 2-1).   


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 45 of 166 
CONFIDENTIAL  
 
 
Table 2-1.  Key Safety Risks for AMG 160 
Safety Risk 
Description 
Identified Risk 
 
Cytokine release 
syndrome (CRS) 
Signs and symptoms may include the following: 
 
constitutional - fever, rigors, fatigue, malaise 
 
neurologic – confusion, headache, mental status changes, 
dysphasia, tremors, dysmetria, gait abnormalities, seizure 
(refer to immune-effector cell associated neurologic 
syndrome [ICANS] guidance in Section 11.10) 
 
respiratory - dyspnea, tachypnea, hypoxemia 
 
cardiovascular - tachycardia, hypotension 
 
gastrointestinal - nausea, vomiting, diarrhea  
 
hepatic - transaminitis, hyperbilirubinemia 
 
hematology - anemia, bleeding, hypofibrinogenemia, 
elevated D-dimer 
 
skin - rash 
Potential Safety Concerns 
Gastrointestinal toxicities  
Signs and symptoms may include nausea, vomiting, diarrhea, 
abdominal pain, and gastrointestinal inflammation and ulceration; 
mostly associated with CRS. 
Neurologic toxicities 
(Section 11.10) 
Signs and symptoms include confusional state, headache, 
dizziness, encephalopathy, tremor, aphasia, syncope; mainly 
observed with CRS. 
Tumor lysis syndrome 
Signs and symptoms may include hyperkalemia, 
hyperphosphatemia, hyperuricemia, hyperuricosuria, and 
hypocalcemia, potentially causing lethal cardiac arrhythmias, 
seizures, and/or renal failure. 
BiTE = bi-specific T-cell engagers; CD = cluster of differentiation 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 46 of 166 
CONFIDENTIAL  
 
 
Clinical signs and symptoms of CRS and 
 
 gastrointestinal and neurologic 
toxicities, TLS, along with other safety labs, will be monitored during the study and at the 
appropriate time points to ensure subjects’ safety.  Refer to Table 6-3, Section 6.1.4, and 
Section 11.10 for specific recommendations regarding the mitigation and management 
of these risks. 
Coronavirus disease 2019 (COVID-19) infection may theoretically increase the signs and 
symptoms of CRS.  Subjects with acute symptoms of COVID-19 disease within 10 days 
prior to first dose of AMG 160 (counted from day of positive test for asymptomatic 
subjects) are excluded from study.  See Section 11.13 for additional guidance related to 
COVID-19. 
Please refer to the AMG 160 Investigator’s Brochure for further description of the key 
safety risks. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of AMG 160 
 
To evaluate the maximum 
tolerated dose (MTD) or the 
recommended phase 2 dose 
(RP2D) 
 
Dose-limiting toxicities (DLT) 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs and clinical 
laboratory tests 
Secondary 
 
To characterize the 
pharmacokinetics (PK) of 
AMG 160 
 
PK parameters for AMG 160 
following intravenous (IV) 
administration including but not 
limited to, maximum serum 
concentration (Cmax), minimum 
serum concentration (Cmin), area 
under the concentration-time 
curve (AUC) over the dosing 
interval, accumulation, and 
half-life (t1/2) 
 
To evaluate the preliminary 
anti-tumor activity of AMG 160 
 
Objective response (OR) per 
modified Response Evaluation 
Criteria in Solid Tumors 
(RECIST) 1.1  
 
Overall Survival 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
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CONFIDENTIAL  
 
 
 
 
 
Exploratory 
4. 
Study Design 
4.1 
Overall Design 
This is an open label phase 1b study evaluating the safety, tolerability, PK, and efficacy 
of AMG 160 monotherapy in subjects with relapsed, refractory non--small cell lung 
cancer (NSCLC).  
AMG 160 will be administered as a short-term IV infusion every 2 weeks after the target 
dose is reached in a 28-day cycle as monotherapy therapy in subjects with relapsed, 
refractory NSCLC.  The starting dose of AMG 160 will be 1 dose level below the 
recommended phase 2 dose (RP2D) as determined in the ongoing first in human (FIH) 
study of AMG 160 in subjects with mCRPC.  To mitigate the risk of CRS 
 
  Based on the 
maximum tolerated dose (MTD) or RP2D and the associated dosing schedule selected 
in Study 20180101, one of the following 
  
 (see Table 6-1 for further details).  A safety cohort of 
2 to 4 subjects will initially be enrolled to assess the tolerability of AMG 160.  If the dose 
 
Progression-free survival 
(radiographic [rPFS], clinical)  
 
Time to response 
 
Time to progression (radiographic, 
clinical) 
 
Duration of response  
 
Time to subsequent therapy 


Product:  AMG 160  
Protocol Number:  20180273  
Date:  25 March 2022 
Page 48 of 166 
CONFIDENTIAL  
 
 
is tolerated (based on target DLT rate > 28%), the dose level will be increased to the 
RP2D (or RP2D+1) identified in Study 20180101.  Alternative dosing schedules, 
including further dose escalation as per the ongoing mCRPC trial (Study 20180101), 
may be explored based on emerging safety and PK data.  Additional subjects (up to 20) 
may be enrolled in 1 or more monotherapy dose levels that have been shown to be safe 
and tolerable (defined as backfill enrollment).  This backfill enrollment may be done to 
better estimate the RP2D and better characterize the safety, efficacy, PK, and 
 of AMG 160 monotherapy and may be concurrent with dose 
escalation to identify the MTD. 
If 1 or more objective responses (OR) are observed (per modified RECIST 1.1 criteria) in 
Part 1, additional subjects (up to 40) will be enrolled in Part 2 (dose expansion) of the 
study at the MTD/RP2D identified in Part 1.  In Part 2, 2 cohorts will be opened:  
Cohort 1 (up to 30 subjects with non-squamous NSCLC) and Cohort 2 (up to 10 subjects 
with squamous NSCLC).  Based on emerging safety and tolerability data in Cohort 2, the 
dose of AMG 160 could be lowered 1 dose level below the starting dose identified in 
Part 1 if necessary. 
Based on emerging safety and efficacy data from Part 1 and/or Part 2, the protocol may 
be amended (and sample size increased) to include a combination of AMG 160 with an 
anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PDL1) agent.  
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.2 
Number of Subjects 
Approximately 10 subjects will initially be enrolled in Part 1 (dose exploration) of the 
study.  If 1 or more objective responses (OR) are observed (per modified RECIST 1.1 
criteria) in Part 1, additional subjects (up to 40) will be enrolled into an expansion cohort 
in Part 2 (dose expansion) of the study.  The protocol may be amended to increase 
enrollment based on emerging clinical data. 
Participants in this clinical investigation shall be referred to as “subjects”.  For the 
sample size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
Subjects who discontinue from the study prior to completing the DLT assessment 
window for reasons other than a DLT will be considered non evaluable for dose 
escalation decisions and MTD determination and may be replaced by an additional 


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subject at that same dose level, as necessary, to ensure that all dose escalation 
decisions are made with sufficient safety data (eg, safety data from at least 2 evaluable 
subjects in a multi subject cohort). 
Subjects who receive supportive care during the DLT assessment window that 
confounds the evaluation of DLTs may be replaced at the discretion of the medical 
monitor or DLRT. 
4.2.2 
Number of Sites 
Approximately 5 investigative sites in the United States, Australia, and/or Europe will be 
included in the study in Part 1.  Approximately 7 additional sites in Europe, United 
States, and Australia will be included in Part 2.  Sites that do not enroll subjects within 
4 months of site initiation may be closed. 
4.3 
Justification for Investigational Product Dose 
AMG 160 dose and dosing schedule (regimen) for this study in males and female 
subjects with NSCLC will be based on the dose levels that have been deemed safe and 
tolerable (with evidence of preliminary efficacy) in the ongoing AMG 160 phase 1 
monotherapy study (20180101) in subjects with mCRPC.  It is anticipated that AMG 160 
at the RP2D regimen in subjects with NSCLC will demonstrate a comparable safety and 
tolerability profile to that determined in subjects in mCRPC.  In addition, this regimen is 
expected to show clinical activity in subjects with NSCLC based on the preliminary 
evidence of efficacy in subjects with mCRPC.  Safety and tolerability data for AMG 160 
thus far is only available in male subjects with mCRPC.  Based on the published 
literature for approved biologics, after adjusting for bodyweight, no clinically meaningful 
differences in exposures have been reported between males and females (Dirks and 
Meibohm, 2010).  Although expression levels of PSMA may differ between subjects with 
mCRPC and NSCLC, the safety and tolerability profile for AMG 160 in female subjects is 
expected to be similar to that of male subjects at the same dose levels.  Therefore the 
starting dose in this study for both males and female subjects with NSCLC will be 1 dose 
level below the RP2D established in male subjects with mCRPC. 
Based on Study 20180101, it is expected that the MTD/RP2D regimen will include 
 
 
 followed by the maintenance dosing every 
2 weeks thereafter.  These dosing approaches have been implemented to mitigate the 
risk of CRS.  The potential doses of AMG 160 to be used for 
 


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 which are under evaluation in Study 20180101. 
4.3.1 
Justification for Non-investigational Product Dose 
68Gallium (68Ga)-PSMA-11 is a non-Amgen investigational product administered as part 
of positron emission tomography/computed tomography (PET/CT) imaging assessments 
in this study and will be used to enroll patients who are PSMA positive defined as at 
least 1 site of disease exceeding blood pool activity by visual assessment 
 
 
. 
4.4 
End of Study 
4.4.1 
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). 
The study-specific primary completion date is the date when data for the primary 
endpoint are last collected. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
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, 
additional antibody testing), as applicable. 
4.4.2 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for up to 3 years.  
This includes a screening period lasting up to 28 days, a treatment period lasting until 
disease progression and a follow-up period lasting up to 3 years from the first dose of 
AMG 160.   
4.5 
Patient Input on Study Design 
There was no patient input on study design. 


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5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included 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 
Subject is ≥ 18 years of age at the time of signing the informed consent. 
103 
Part 1 only:  have a histologically or cytologically confirmed diagnosis of stage 4 
or recurrent non-squamous NSCLC. 
104 
Part 2 only:  have a histologically or cytologically confirmed diagnosis of stage 4 
or recurrent NSCLC (squamous cell histology/cytology allowed in Part 2).   
105 
Subjects without a driver mutation are required to have disease progression 
following at least one line of prior chemotherapy (or are deemed unsuitable to be 
treated with chemotherapy or have actively refused treatment with 
chemotherapy) and at least 1 prior anti-PD1/PDL1 therapy.  This includes 
subjects who have experienced disease progression during or after combination 
treatment with platinum-based chemotherapy plus anti-PD1/PDL1 therapy and 
subjects who have developed recurrent or metastatic disease after definitive 
chemoradiation followed by anti-PD1/PDL1 therapy.  Subjects who have received 
adjuvant or neoadjuvant platinum-based chemotherapy and developed recurrent 
or metastatic disease within 12 months of completing therapy and have received 
prior anti-PD1/PDL1 therapy are eligible.  Subjects who developed recurrent or 
metastatic disease greater than 12 months after completing adjuvant or 
neoadjuvant platinum-based chemotherapy are required to receive at least 1 line 
of additional chemotherapy and at least 1 line of prior anti-PD1/PDL1 therapy to 
be eligible. 
106 
Subjects with a driver mutation (EGFR mutation [exon 19 deletion, L858R point 
mutation or T790M], BRAF V600E mutation, RET gene fusion, ALK gene 
rearrangement, MET exon 14 skipping mutation or NTRK gene fusion, 
KRAS G12C mutation) must experience disease progression on at least 
1 approved targeted therapeutic agent to be eligible.  
107 
Subjects with treated brain metastases are eligible provided they meet the 
following criteria: 


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 
Treatment (surgery or radiation, including stereotactic radiation) was 
completed at least 2 weeks prior to the first dose of AMG 160. 
 
There is no evidence of radiographic central nervous system (CNS) 
progression following treatment and by the time of study screening.  Subjects 
with new brain metastases detected or progression of previously treated 
lesions at the time of screening must receive therapy (surgery or radiation) to 
be eligible.  Following definitive treatment, subjects may then be eligible 
without the need for additional brain imaging. 
 
Any CNS disease is clinically stable for at least 7 days and the subject is off 
high-dose steroids 
 for at least 7 days 
(physiologic doses of steroids are permitted).
109 
Measurable disease by modified RECIST 1.1 criteria.  Target lesions may be 
located in a previously irradiated field if there is documented (radiographic) 
disease progression at that site. 
110 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 
111 
Life expectancy of greater than or equal to 3 months 
112 
Adequate organ function, defined as follows: 
 
absolute neutrophil count  1 x 109/L (without growth factor support within 
7 days from screening assessment) 
 
platelet count  100 x 109/L (without platelet transfusion within 7 days from 
screening assessment) 
 
hemoglobin  9 g/dL (90 g/L) (without blood transfusion within 7 days from 
screening assessment) 
 
estimated glomerular filtration rate based on MDRD (Modification of Diet in 
Renal Disease) calculation ≥ 30 ml/min/1.73 m2 
 
AST and ALT  3 x upper limit of normal (ULN) (or  5 x ULN for subjects 
with liver involvement) 
 
TBL  1.5 x ULN (or  2 x ULN for subjects with liver metastases) 
 
Cardiac function:  
 
left ventricular ejection fraction  50% (2-D transthoracic echocardiogram 
[ECHO] is the preferred method of evaluation; multi-gated acquisition 
scan is acceptable if ECHO is not available) 
 
baseline electrocardiogram (ECG) QTcF ≤ 470 msec 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 


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201 
Radiographic evidence of intratumor cavitation. 
202 
Radiographic evidence of major blood vessel invasion or encasement by cancer. 
203 
Subjects with previous malignancies (except non-melanoma skin cancers, and 
the following in situ cancers:  bladder, gastric, colon, cervical/dysplasia, 
endometrial, melanoma, or breast) are excluded unless a complete remission 
was achieved at least 2 years prior to study entry and no additional therapy is 
required or anticipated to be required during the study period 
Other Medical Conditions 
204 
Unresolved toxicities from prior anti-tumor therapy not having resolved to 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, 
with the exception of alopecia or toxicities that are stable and well-controlled and 
there is agreement to allow by both the investigator and sponsor. 
205 
Untreated (includes new lesions or progression in previously treated lesions) or 
symptomatic brain metastases and leptomeningeal disease. 
206 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures once or more per month.  Indwelling catheters are 
permissible.   
207 
History of hemoptysis (≥ one-half teaspoon of bright red blood per  episode) 
within 3 months prior to first dose. 
208 
History or evidence of gastrointestinal inflammatory bowel disease (ulcerative 
colitis or Crohn disease). 
209 
Myocardial infarction, unstable angina, cardiac arrhythmias requiring medication, 
and/or symptomatic congestive heart failure (New York Heart Association 
> class II) within 12 months prior to start of dosing. 
210 
Vasculitis or grade 3/4 gastrointestinal bleeding within 3 months prior to first 
dose. 
211 
History of significant vascular disease (eg, aortic aneurysm requiring surgical 
repair or recent peripheral arterial thrombosis) within 6 months of first dose. 
212 
Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to start of 
dosing. 
213 
Interstitial lung disease or a history of pneumonitis that required oral or 
intravenous glucocorticoids to assist with treatment. 
214 
Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation). 
215 
Serious, non-healing would, active ulcer, or untreated bone fracture. 
Prior/Concomitant Therapy 
216 
Needing chronic systemic corticosteroid therapy
or any other immunosuppressive therapies (including 
anti-tumor necrosis factor-alpha [TNF-α] therapies) unless stopped 7 days prior 
to first dose. 
217 
Any biological therapy or immunotherapy within 3 weeks of start of first dose.  


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 
Subjects who received conventional chemotherapy or a targeted therapeutic 
agent are eligible if at least 14 days have elapsed and if all treatment-related 
toxicity has been resolved to Grade ≤1. 
218 
Currently receiving treatment in another investigational device or drug study, or 
less than 4 weeks since ending treatment on another investigational device or 
drug study. 
219 
Radiation therapy within 2 weeks of first dose. 
220 
Major surgery within 4 weeks of first dose (thoracentesis, indwelling catheter 
placement or line placement is permissible). 
221 
Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents 
for therapeutic purposes that has not been stable for > 2 weeks prior to first dose. 
 
The use of full-dose oral or parenteral anticoagulants is permitted as long as 
the international normalized ratio (INR) or activated partial thromboplastin 
time (aPTT) is within therapeutic limits (according to the medical standard of 
the enrolling institution) and the subject has been on a stable dose of 
anticoagulants for at least 2 weeks prior to start of dosing. 
 
Prophylactic anticoagulation for the patency of venous access devices is 
allowed, provided the activity of the agent results in an INR prolongation and 
aPTT is within normal limits within 14 days prior to start of dosing 
 
Prophylactic use of low-molecular-weight heparin (ie, enoxaparin 40 mg/day) 
is permitted 
222 
Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials 
for management within 7 days of dosing. 
NOTE:  Simple urinary tract infections and uncomplicated bacterial pharyngitis 
are permitted if responding to active treatment and after consultation with 
sponsor.  Screening for chronic infectious conditions is not required. 
223 
Known human immunodeficiency virus (HIV) infection, hepatitis C infection 
(subjects with hepatitis C that achieve a sustained virologic response following 
antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B 
surface antigen [SAg] or core antibody that achieve sustained virologic response 
with antiviral therapy directed at hepatitis B are allowed).  Screening for these 
conditions is not required. 
224 
Active autoimmune disease or any other diseases requiring immunosuppressive 
therapy (ie, with the use of disease modifying agents, corticosteroids, or 
immunosuppressive drugs).  Replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal insufficiency or 
pituitary insufficiency, etc) is allowed.  
225 
Current or recent (within 10 days of first dose) use of high-dose aspirin 
(≥ 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and 
clostazol. 
Other Exclusions 
226 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 4 months after the last dose of 
AMG 160.   


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227 
Female subjects of childbearing potential unwilling to use 1 acceptable method of 
effective contraception during treatment and for an additional 4 months after the 
last dose of AMG 160.  Refer to Section 11.5 for additional contraceptive 
information. 
228 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at screening by a serum pregnancy test.   
229 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use 
contraception during treatment and for an additional 4 months after the last dose 
of AMG 160.  Refer to Section 11.5 for additional contraceptive information. 
230 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional 4 months after the last dose 
of AMG 160. 
231 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 4 months after the last dose of AMG 160. 
232 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
233 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge. 
234 
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 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
235 
Live vaccination is not allowed for at least 4 weeks prior to the start of AMG 160 
treatment, during treatment, and until end of last study dose. 
236 
History or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infection unless agreed upon with Medical Monitor and meeting the 
following criteria: 
 
Negative test for SARS-CoV-2 RNA by reverse transcriptase-polymerase 
chain reaction (RT-PCR) within 72 hours of first dose of AMG 160  
 
No acute symptoms of SARS-CoV-2 disease within 10 days prior to first dose 
of AMG 160 (counted from day of positive test for asymptomatic subjects) 
5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or their legally authorized representative must personally sign and date the 
IRB/IEC and Amgen approved informed consent before commencement of study-
specific procedures. 


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A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria and has received the enrollment confirmation from sponsor.  The 
investigator, designee, or staff member is to document this decision and date in the 
subject’s medical record and in/on the enrollment case report form (CRF).  Following 
enrollment, study treatment should begin as soon as possible but no later than 7 days 
after enrollment. 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the informed consent) receives a unique subject identification 
number before any study-related activities/procedures are performed.  The subject 
identification number will be assigned via interactive response technology (IRT).  This 
number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
5.4 
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 once.  Refer to Section 8.1.1. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 6-1 below. 


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6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 


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Table 6-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
AMG 160 
Dosage Formulation 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
Part 1 
The starting target dose of AMG 160 will be 1 dose level below the RP2D or otherwise the highest dose level deemed safe and 
tolerable as determined in the phase 1 monotherapy study (20180101).  AMG 160 will be administered every 2 weeks after 
target dose is reached. 
 
 
Part 2 
This is a dose expansion study.  AMG 160 will be administered intravenously every 2 weeks 28-day cycle.  The starting dose of 
AMG 160 will be the dose level that has been recommended as safe and tolerable in Part 1 of this study.  To mitigate CRS, the 
cycle 1 dosing schedule may also be adapted the same way as Part 1 of this study. 
Route of Administration 
Short-term IV infusion (approximately 60 minutes). 


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Study Treatment Name 
Amgen Investigational Product:a 
AMG 160 
Accountability 
The planned dose, dose received, start date/time, stop date/time, and lot number of investigational product are to be recorded 
on each subject’s eCRF(s). 
Dosing Instructions 
AMG 160 will be delivered using infusion pumps approved for use by the appropriate regulatory authority for the country in which 
the subject is undergoing treatment.   
See pharmacy file for more detailed information regarding the storage, preparation, destruction, and administration of AMG 160. 
Hospitalization Guidance 
All subjects will be hospitalized for intensive monitoring for at least 48 hours post AMG 160 infusion during cycle 1
 
.  The subjects may be 
discharged after the 48-hour period if there are no clinically significant symptoms of CRS or other acute toxicities.  Minimum 
hospitalization times for subjects will be as follows: 
 
cycle 1:  48 hours after each infusion 
 
 
 
cycle 2: 
 
24 hours after first infusion (48 hours in case a subject experienced grade  2 CRS or infusion reaction in cycle 1 
(see Section 11.10.1 for grading of CRS) 
 
24 hours after each subsequent infusion 
 
for cycles 1 and 2:  study sites must have immediate access to a medical intensive care unit staffed by critical care 
providers 
 
cycles 3 and 4:  subject should be monitored in hospital or outpatient clinic for at least 4 hours after start of each infusion 
 
cycle 5 and subsequent cycles:  hospitalization not required unless a subject experiences an adverse event requiring 
hospitalization as described in Table 6-3, or if clinically indicated 
 
re-start of treatment after an interruption due to adverse event:  8 hours  
Hospitalization beyond these recommended timelines based on adverse events may be allowed per investigator discretion. 
C1D1  cycle 1 day 1; CRS  cytokine release syndrome; DLRT  Dose Level Review Team; eCRF  electronic case report form; IPIM  Investigational Product 
Instruction Manual; IV  intravenous; IVSS  intravenous solution stabilizer; MTD  maximum tolerated dose; PK  pharmacokinetic(s); RP2D  recommended phase 2 
dose; WFI  water for injection. 
a AMG 160 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures.


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6.1.1.1 
Non-Amgen Investigational Imaging Products 
68Ga-PSMA-11 is a non-Amgen investigational product administered as part of PET/CT 
imaging assessments in this study. 
6.1.2 
Non-investigational Products 
No non-investigational products will be used in this study. 
6.1.3 
Medical Devices 
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.   
6.1.4 
Other Protocol-required Therapies 
All other protocol-required therapies, including glucocorticoids and 
tocilizumab/siltuximab, that are commercially available are not provided or reimbursed 
by Amgen (except if required by local regulation).  The investigator will be responsible 
for obtaining supplies of these protocol-required therapies. 


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For administration of 
 or tocilizumab/siltuximab after occurrence of CRS, 
follow guidance in Table 6-3.  Tocilizumab should be administered according to warning 
and precautions guidelines for tuberculosis provided in the tocilizumab regional 
prescribing information.  
 
 
 
. 
Sites are required to have tocilizumab or siltuximab (if tocilizumab not available) on site 
for potential treatment of CRS.  See Section 9.4.1.1.1 for siltuximab stopping rules.  
6.1.5 
Other Treatment Procedures 
Sites are required to have tocilizumab or siltuximab (if tocilizumab not available) on site 
for potential treatment of CRS. 
6.1.6 
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 and 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 (ie, AMG 160). 
Any product complaint(s) associated with an investigational or non-investigational 
product supplied by Amgen are to be reported according to the instructions provided in 
the IPIM. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period 
The following treatments and/or procedures are excluded during the treatment period of 
the study (unless approved by Amgen medical monitor): 
 
any anticancer therapy other than AMG 160, such as: 
 
cytotoxic and/or cytostatic drugs 
 
radiation therapy (with the exception of radiotherapy for symptom control, 
such as bone or brain metastases after discussion with the medical monitor).  
The radiation therapy should not include the thoracic field and must have 
been completed at least 7 days before the subsequent dose of AMG 160.  


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 
immunotherapy 
 
chronic systemic corticosteroid therapy (
 
) or any other immunosuppressive therapies (except for the 
management of acute, treatment-related toxicities such as transient [ie, for up to 
2 weeks] use of corticosteroids and tocilizumab) 
 
high-dose corticosteroid therapy (
) 
is only allowed for up to 7 days 
 
any other investigational agent with the exception of 68Ga-PSMA-11 
(if applicable) 
 
any major surgery (exceptions can be discussed with the medical monitor and 
may be permissible) 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
6.2.1.1 
Dose-exploration 
The dose-exploration part of the study will estimate the MTD/RP2D of AMG 160 in 
NSCLC.  The starting dose of AMG 160 will be 1 dose level below the RP2D or 
otherwise the highest dose level deemed safe and tolerable as determined in the 
phase 1 monotherapy study (20180101; planned dose levels show in Table 6-2). 
Table 6-2.  Study 20180101 Planned Doses per Dose Cohort Level 
Cohort Number 
Dose (mg) IV Every 2 Weeks 
IV = intravenous 
Dose Level Determination 
Dose exploration will begin with 2 to 4 subjects.  The study DLT window is 28 days (see 
Section 6.2.1.3).  To be DLT evaluable, subjects must receive all planned cycle 1 doses 
of AMG 160.  After a minimum of 2 subjects enrolled at a certain dose level are DLT 


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evaluable, a DLRT meeting will be convened.  Depending on observed safety data, the 
following may occur: 
1. additional enrollment to dose Level 1; or 
2. dose de-escalation to 1 dose below the starting dose; or 
3. alternative dosing schedules, including further dose escalation, as per the 
ongoing mCRPC trial (Study 20180101), may be explored based on emerging 
safety and PK data. 
Rules for dose-escalation/de-escalation are derived using a modified toxicity probability 
interval (mTPI) model with a target toxicity probability of 0.28. 
Dose level decisions are made based on this posterior probability of toxicity, using 
3 toxicity probability intervals (TPI): 
 
under-dosing TPI:  DLT rate from 0 to  23% 
 
target TPI:  DLT rate from 23% to 33%, inclusive 
 
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 or stay at the current level.  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 de-escalate.  If DLTs are observed, the 
MTD is the dose level with a DLT toxicity rate closest to 28%. 
6.2.1.2 
Dose Expansion 
If 1 or more OR are observed in dose exploration, dose expansion will be conducted to 
confirm the safety and tolerability of the selected dose and to further evaluate the 
efficacy of AMG 160.  Dose modification may occur as a result of interim analyses as 
described in Section 9.4.1.1. 
6.2.1.3 
Dose-limiting Toxicity 
Dose-limiting toxicities are defined as any adverse event with an onset within first 
28 days following first dose of AMG 160 with any of the following criteria unless clearly 
attributable to causes other than AMG 160 treatment: 
 
grade 5 toxicity (eg, death not due to disease progression) 
 
grade 3 adverse event lasting more than 3 days (with the exception of fatigue) 
 
grade 4 adverse event regardless of duration 


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 
grade 3 nausea, vomiting, or diarrhea that do not improve to grade  1 within 
72 hours despite maximum supportive care 
 
grade  3 neurologic events that do not improve to grade  1 within 7 days with 
treatment interruption and routine medical management 
 
grade 3 febrile neutropenia that cannot be attributed to CRS 
 
AST or ALT values of > 3 x ULN AND with serum TBL level of > 2 x ULN without 
signs of cholestasis or there is no other clear alternative to explain the observed 
liver-related laboratory abnormalities (ie, criteria for Hy’s Law indicative of severe 
drug-induced liver injury [DILI])  
 
grade 4 neutropenia lasting > 7 days  
 
grade 4 thrombocytopenia lasting > 7 days  
 
grade 3 or higher thrombocytopenia with clinically significant bleeding regardless 
of duration of thrombocytopenia  
 
grade 4 anemia 
 
grade 4 non-hematologic laboratory abnormality of any duration  
The following adverse events will NOT be adjudicated as DLT regardless of the duration: 
 
lymphopenia or lymphocyte count decreased of any grade 
 
grade 3 fever (defined as a temperature ≥ 40°C with a duration of ≤ 24 hours) 
occurring outside the context of CRS 
 
laboratory parameters of grade  3, not considered clinically relevant, and 
improved to grade  2 within 72 hours. 
 
grade ≥ 3 transaminitis associated with CRS that resolves to grade ≤ 1 within 
5 days 
Determination of whether a subject is evaluable for DLT assessment will be made in 
accordance with the following rules: 
 
Subjects who receive study treatment and remain on study through the DLT 
assessment window will be considered DLT-evaluable. 
 
Subjects who do not complete safety assessments during the DLT assessment 
window for reasons other than a DLT will be considered nonevaluable for dose 
escalation decisions and MTD determination and may be replaced by an 
additional subject at that same dose level. 
Subjects who receive supportive care during the DLT assessment window that 
confounds the evaluation of DLTs may be replaced at the discretion of the medical 
monitor or DLRT.  See Section 9.4.1.1.1 for the stopping rules for siltuximab 
intervention. 


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6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  AMG 160 
The reason for dose change of AMG 160 is to be recorded on each subject’s electronic 
case report form (eCRF). 
For treatment interruptions, delays, and discontinuations, refer to AMG 160 guidance in 
Table 6-3 in consultation with the Amgen medical monitor.   
If any of the following events occur, further accrual will be suspended and a safety 
analysis conducted and submitted to FDA for review prior to resuming enrollment. 
 
any 1 treatment-related grade 5 adverse event or  
 
any 2 of the same treatment-related, clinically significant grade 4 adverse events 
at least possibly related to AMG 160  
6.2.2.1.1 
Infusion Interruptions/Delays/Withholding and Re-start in Case of 
Technical/Logistical Issues 
Events leading to infusion interruption or delay for technical/logistical reasons may 
include:  technical problem with the infusion pump or the investigational product is 
incorrectly prepared or administered. 
Infusion Interruptions due to Technical/Logistical Issues 
The administration of AMG 160 should not be interrupted for short-term (approximately 
60 minute) or 
, if possible.  In case of infusion interruption, due to 
any technical or logistic reason, the interruption should be as short as possible and the 
infusion continued at the earliest time possible. 
In case of infusion interruption, immediately consult with Amgen medical monitor to 
determine if: 
 
investigational product stability is sufficient to administer the remaining infusion 
or  
 
a new infusion can be administered or  
 
the dose should be withheld  
For short-term (approximately 60 minute) infusions, if the remaining infusion can be 
administered, no specific precautions have to be taken.  If a new infusion can be 
administered, follow the procedures in the Schedule of Activities (see Section 1.3) or the 
cycle day on which the original (interrupted) infusion was administered.  
 
  If the 


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infusion will need to be withheld, follow the instructions for re-start after interruptions due 
to adverse events described below for the next infusion.  
Any interruption of an infusion should be recorded in the eCRF, providing the start and 
stop date/time of the infusion if the interruption is > 2 hours. 
Infusion Delay due to Technical/Logistical Issues 
If the infusion delay was ≤ 72 hours, the dose can be administered without specific 
precautions.  Procedures performed will follow the schedule of assessments for the 
cycle day on which the infusion was originally planned.  The following infusion should 
then be administered after 14 (± 1) days; eg, if the day 8 infusion needs to be delayed 
for logistical issues, and could only be administered on day 10, the next infusion should 
be administered on day 24 (± 1 day) rather than the regular day 22.  The ± 1-day window 
is allowed until the original dosing schedule is met again. 
If the delay of the next infusion was > 72 hours, the dose will need to be skipped and the 
instructions for re-start after interruptions due to adverse events described below should 
be followed. 
6.2.2.1.2 
Infusion Interruptions/Delays/Withholding and Re-start due to 
Adverse Events 
6.2.2.1.2.1 
General Guidelines 
Subjects should be assessed for toxicity before each infusion of AMG 160.  The severity 
of the toxicity will be graded using the CTCAE version 5.0, with the exception of CRS, 
which must be graded using the criteria referenced in the publication by Lee et al, 2014; 
TLS, which must be graded according to the Cairo Bishop criteria referenced in the 
publication by Coiffier et al, 2008; and immune-effector cell associated neurologic 
syndrome (ICANS) will be using the criteria referenced in the publication by 
Lee et al, 2019.  Infusion modification and dose reduction due to a toxicity will be 
performed according to the instructions described below and outlined in Table 6-3. 


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6.2.2.1.2.2 
Infusion Interruptions due to Adverse Events 
Events occurring during the infusion and requiring treatment interruption will be 
managed by immediate infusion interruption.  The site should record any unscheduled 
interruption of an infusion on the eCRF and provide the start and stop date/time of the 
infusion.  
Events requiring an infusion interruption are listed in Table 6-3. 
6.2.2.1.2.3 
Delay of Subsequent Infusion due to Adverse Events 
Events occurring after the end of the infusion and requiring a delay of treatment will be 
managed by delay of the subsequent infusion.  The site should record any delay of an 
infusion on the eCRF and provide the start and stop date/time of the infusion.  
Events requiring a delay of the subsequent infusion are listed in Table 6-3. 
Infusion interruptions or delays for other reasons need to be discussed with the Amgen 
medical monitor. 
6.2.2.1.2.4 
Re-start of Infusion 
Re-starting treatment after an interruption/delay due to an adverse event or if the 
interruption/ delay was > 72 hours, regardless of the reason, should be performed under 
medical supervision.  
 
.  The 
following assessments should be performed as for days 1, 2, and 3 per the Schedule of 
Activities for cycle 1 (see Section 1.3).  


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 
vital signs, pulse oximetry 
 
physical examination 
 
neurological examination (only in case the treatment interruption was due to a 
neurologic event) 
 
weight 
 
ECOG 
 
safety labs (hematology, chemistry, coagulation, urinalysis) 
The subject should be hospitalized for at least 48 hours after re-start of the infusion. 
6.2.2.1.2.5 
Dose Adjustments and Re-start at a Lower Dose Level 
For adverse events for which restart of treatment is allowed according to the guidelines 
outlined in Table 6-3, treatment may be resumed at the same or lower dose. 
Re-start at a lower dose level: 
In the following cases, the next infusion administered should be at the previous (lower) 
dose level: 
If the event occurred during the infusion and caused an interruption of the infusion for 
more than 72 hours and therefore the affected dose was withheld, or 
If the event started after the end of an infusion and administration of the next infusion 
had to be delayed for more than 72 hours due to the event. 
For specific events as outlined in Table 6-3. 
In either case, re-escalation to the target dose can be considered for the next infusion if 
treatment at the lower dose has been well tolerated with no events requiring dose 
interruption or delay as described in Table 6-3.  After the dose re-escalation, the 
following assessments should be performed as for day 8 through day 11 per the 
Schedule of Activities for cycle 1 (see Section 1.3).  
 
vital signs, pulse oximetry 
 
physical examination 
 
neurological examination (only in case the treatment interruption was due to a 
neurologic event) 
 
safety labs (hematology, chemistry, coagulation, urinalysis) 
The subject should be hospitalized for at least 48 hours after re-escalation. 
In case an additional dose de-escalation is required, permanently discontinue treatment. 


Product:  AMG 160 
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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Description of Severity 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Infusion-related Reaction 
1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
N/A 
Consider medication to 
control infusion reaction 
as deemed appropriate 
by the investigator 
according to local 
standard of care and 
institutional guidelines. 
Increase monitoring of 
vital signs as medically 
indicated until the subject 
is deemed medically 
stable 
N/A 
N/A 
2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for 
 24 hours 
Short-term infusion:  
Immediate 
interruption/delay 
until event has 
improved to 
grade  1 
 
 
Re-start possible, if successfully managed and 
improvement to  grade 1 in  14 days. 
For short-term (approximately 60 minute) infusions, 
in case of infusion interruption, continue treatment 
with next scheduled infusion (do not resume prior 
infusion) 
 
Delay of the next infusion: 
 
< 7 days:  administer the delayed infusion 
(as long as the next scheduled infusion is 
> 6 days from delayed infusion) and follow 
the schedule of assessments for the cycle 
day on which the infusion was originally 
planned.   
 
 7 days:  skip the delayed infusion and 
resume schedule of assessments for the 
next scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same dose or 
reduce to next lower dose, if clinically indicated  
 
Additional measures:  
 and 
additional assessments as indicated in 
Section 6.2.2.1.2.4 
If subject missed 
more than 
2 consecutive 
doses of 
AMG 160 
Page 1 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Description of 
Severity 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent Discontinuation 
Infusion-related Reaction (continued) 
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 
Immediate 
interruption/ delay until 
event has improved to 
grade  1 
Consider supportive 
therapy including 
steroids as clinically 
indicated. 
Increase monitoring of 
vital signs as medically 
indicated until the subject 
is deemed medically 
stable.  
 
As for grade 2 
infusion-related reaction, with 
the exception of mandatory 
dose modification:  reduce to 
next lower dose 
If subject missed more than 
2 consecutive doses of AMG 160 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
N/A 
As for grade 3 
infusion-related reaction 
N/A 
Immediately stop the infusion (if 
applicable) and permanently 
discontinue AMG 160 
Page 2 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Description of 
Severitya 
Interruption/
Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome 
1 
Symptoms are not 
life-threatening and 
require symptomatic 
treatment only, 
eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
Avoid 
treatment 
interruption 
Administer symptomatic treatment 
(eg, paracetamol/ acetaminophen for fever). 
Monitor for CRS symptoms including vital 
signs and pulse oximetry at least Q2 hours for 
12 hours or until resolution, whichever is 
earlier. 
N/A 
N/A 
2 
Symptoms require 
and respond to 
moderate 
intervention 
 Grade 1 CRS 
symptoms, AND 
 Oxygen 
requirement 
 40%, OR  
 Hypotension 
responsive to 
fluids or low dose 
of 1 vasopressorb, 
OR 
 Grade 2 organ 
toxicity or grade 3 
transaminitis per 
CTCAE criteria 
Immediately 
interrupt/ 
delay 
AMG 160 
until event 
improves to 
CRS 
grade  1. 
 
Administer:  
 Symptomatic treatment (eg, paracetamol/ 
acetaminophen for fever) 
 Supplemental oxygen when oxygen 
saturation is  90% on room air 
 Intravenous fluids or low dose vasopressor 
for hypotension when systolic blood pressure 
is  85 mmHg.  Persistent tachycardia (eg, 
 120 bpm) may also indicate the need for 
intervention for hypotension. 
Monitor for CRS symptoms including vital 
signs and pulse oximetry at least Q2 hours for 
12 hours or until resolution to CRS grade  1, 
whichever is earlier. 
For subjects with extensive co-morbidities or 
poor performance status, manage per grade 3 
CRS guidance below. 
Persistent tachycardia with complications 
(eg, atrial fibrillation) should be managed with 
rate control medications (eg, metoprolol) along 
with cardiology consultation. 
 Re-start possible if successfully managed 
and improved to  grade 1 within 7 days. 
 Consult with Amgen medical monitor first. 
 In case of infusion interruption, continue 
treatment with next planned dose (do not 
resume prior infusion). 
 Delay of next infusion: 
 < 7 days:  administer the delayed 
infusion (as long as the next 
scheduled infusion is > 6 days from 
delayed infusion) and follow the 
schedule of assessments for the cycle 
day on which the infusion was 
originally planned.   
  7 days:  skip the infusion and 
resume schedule of assessments for 
the next scheduled infusion  
 Hospitalization:  48 hours 
 Dose modification:  resume at the same 
dose or reduce to next lower dose, if 
clinically indicated  
 Additional measures:  
 and 
additional assessments as indicated in 
Section 6.2.2.1.2.4 
If there is no 
improvement to 
CRS  grade 1 
within 7 days 
OR 
If subject missed 
more than 
2 consecutive 
doses of 
AMG 160 
Page 3 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Description of 
Severitya 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome (continued) 
3  
Symptoms require 
and respond to 
aggressive 
intervention 
 Grade 1 CRS 
symptoms, AND 
 Oxygen 
requirement 
 40%, OR 
 Hypotension 
requiring 
high-doseb or 
multiple 
vasopressors, OR 
 Grade 3 organ 
toxicity or grade 4 
transaminitis per 
CTCAE criteria 
Immediately 
interrupt / delay 
AMG 160 until event 
improves to CRS 
grade  1. 
Admit to intensive care unit for close 
clinical and vital sign monitoring per 
institutional guidelines (unless related to 
asymptomatic elevation of liver 
enzymes). 
Administer 
 (or 
equivalent) IV at a dose maximum of 
3 doses of 8 mg (24 mg/day).  The dose 
should then be reduced step-wise. 
AND/OR 
Investigators should also consider use 
of tocilizumabc,d,eas an additional 
therapy in this setting at a dose of 
4 - 8 mg/kg IV as a single dose. 
Persistent tachycardia with 
complications (eg, atrial fibrillation) 
should be managed with rate control 
medications (eg, metoprolol) along with 
cardiology consultation. 
 Re-start possible if successfully 
managed and improved to  grade 1 
within 7 days. 
 Consult Amgen medical monitor. 
 In case of infusion interruption, continue 
treatment with next planned dose (do 
not resume prior infusion). 
 Delay of next infusion: 
 
< 7 days:  administer the delayed 
infusion (as long as the next 
scheduled infusion is > 6 days from 
delayed infusion) and follow the 
schedule of assessments for the 
cycle day on which the infusion was 
originally planned.   
 
 7 days:  skip the infusion and 
resume schedule of assessments 
for the next scheduled infusion  
 Hospitalization:  48 hours 
 Dose modification:  reduce to next lower 
dose (continuation at same dose with 
 may be 
allowed – consult with medical monitor) 
Additional measures:  
 and 
additional assessments as indicated in 
Section 6.2.2.1.2.4 
If there is no 
improvement to 
CRS  grade 1 
within 7 days. 
OR 
If subject missed 
more than 
2 consecutive 
doses of AMG 160 
 
Decision to 
discontinue should 
be made in 
consultation with 
Amgen medical 
monitor. 
Page 4 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Description of 
Severitya 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome (continued) 
4 
Life-threatening 
symptoms 
 Grade 1 CRS 
symptoms, AND 
 Requirement for 
ventilator support 
OR 
 Grade 4 organ 
toxicity (excluding 
transaminitis) per 
CTCAE criteria 
 
Admit to intensive care unit for close clinical 
and vital sign monitoring per institutional 
guidelines. 
Administer 
 (or equivalent) IV 
at a dose maximum of 3 doses of 8 mg 
(24 mg/day).  Further corticosteroid use 
should be discussed with the Amgen medical 
monitor. 
Additionally, tocilizumabc,d,e should be 
administered if regionally available at a dose 
of 4 - 8 mg/kg as a single dose and may be 
repeated once within 24 to 48 hours based on 
clinical assessment. 
Persistent tachycardia with complications (eg, 
atrial fibrillation) should be managed with rate 
control medications (eg, metoprolol) along 
with cardiology consultation. 
N/A 
Immediately stop the 
infusion (if applicable) and 
permanently discontinue 
AMG 160 
Page 5 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent Discontinuation 
Tumor Lysis Syndrome (TLS) – Grading according to Cairo-Bishop Criteria 
2 (clinical 
TLS) 
Immediate interruption/ delay 
until event has improved to 
grade  1 
TLS should be 
managed according the 
local standard of care 
and institutional 
guidelines. 
 
Re-start possible if successfully managed and 
improvement to  grade 1 in  14 days 
 
Consult Amgen medical monitor. 
 
In case of infusion interruption, continue treatment 
with next schedule infusion (do not resume prior 
infusion). 
 
Delay of next infusion: 
 
< 7 days:  administer the delayed infusion (as 
long as the next scheduled infusion is > 6 days 
from delayed infusion) and follow the schedule 
of assessments for the cycle day on which the 
infusion was originally planned.   
 
 7 days:  skip the infusion and resume 
schedule of assessments for the next 
scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  reduce to next lower dose  
 
Additional measures:  
 and additional 
assessments as indicated in Section 6.2.2.1.2.4 
If subject missed more than 
2 consecutive doses of 
AMG 160 
OR 
In case of repeat grade 2 TLS 
event despite dose reduction. 
 3 (clinical 
TLS) 
N/A 
TLS should be 
managed according to 
the local standard of 
care and institutional 
guidelines 
 
N/A 
Immediately stop the infusion 
(if applicable) and 
permanently discontinue 
AMG 160 
Page 6 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Neurological events related to AMG 160 
 2 
Interruption/ delay until event 
has improved to grade  1 
For CRS-related 
neurological events, use 
ICANS grading and 
management system 
Consider administration 
of corticosteroids (and 
tocilizumabc,d,e if 
associated with CRS). 
Following a seizure:  
administer anti-seizure 
medication according to 
the local standard of 
care and institutional 
guidelines 
For grade 3 events, 
contrast-enhanced 
magnetic resonance 
imaging (MRI) of the 
head should be 
performed.  A neurology 
consult is recommended.  
 
Re-start possible if successfully managed and 
improvement to  grade 1 in  14 days. 
 
In case of infusion interruption, continue treatment with 
next scheduled infusion (do not resume prior infusion). 
 
Delay of next infusion: 
 
< 7 days:  administer the delayed infusion (as long 
as the next scheduled infusion is > 6 days from 
delayed infusion) and follow the schedule of 
assessments for the cycle day on which the 
infusion was originally planned. 
 
 7 days:  skip the infusion and resume schedule of 
assessments for the next scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same dose or reduce 
to next lower dose if clinically indicated 
 
Additional measures:  
 and additional 
assessments as indicated in Section 6.2.2.1.2.4 
If grade 4 event 
OR 
In case of more than 
1 seizure 
OR 
If resolution or 
improvement to  grade 1 
in  14 days 
OR 
In case of repeat 
 grade 2 event despite 
dose reduction 
Page 7 of 14 
Abbreviations and footnotes defined on last page of table. 
 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Gastrointestinal events related to AMG 160 
2 
Interruption/ delay required if 
deemed intolerable by the 
subject or investigator and 
not responding to 
appropriate medical 
management until event has 
improved to grade  1 
GI toxicities should be 
managed according the 
local standard of care 
and institutional 
guidelines 
 
Re-start possible if successfully managed and 
improvement to  grade 1 in  14 days. 
 
In case of infusion interruption, continue treatment with 
next scheduled infusion (do not resume prior infusion). 
 
Delay of next infusion: 
 
< 7 days:  administer the delayed infusion (as long 
as the next scheduled infusion is > 6 days from 
delayed infusion) and follow the schedule of 
assessments for the cycle day on which the 
infusion was originally planned. 
 
 7 days:  skip the infusion and resume schedule of 
assessments for the next scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same dose or reduce 
to next lower dose if clinically indicated 
 
Additional measures:  
 and additional 
assessments as indicated in Section 6.2.2.1.2.4 
If subject missed more 
than 2 consecutive doses 
of AMG 160 
Page 8 of 14 
Abbreviations and footnotes defined on last page of table. 
 
 
 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/Delay 
Specific Management 
Re-start guidance 
Permanent Discontinuation 
Gastrointestinal events related to AMG 160 (continued) 
 3 
Interruption/ delay 
until event has 
improved to grade  1 
GI toxicities should be 
managed according the 
local standard of care 
and institutional 
guidelines  
 
Re-start possible if successfully managed and 
improvement to  grade 1 in  14 days. 
 
In case of infusion interruption, continue treatment with 
next scheduled infusion (do not resume prior infusion). 
 
Delay of next infusion: 
 
< 7 days:  administer the delayed infusion (as long as 
the next scheduled infusion is > 6 days from delayed 
infusion) and follow the schedule of assessments for 
the cycle day on which the infusion was originally 
planned. 
 
 7 days:  skip the infusion and resume schedule of 
assessments for the next scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same dose or reduce to 
next lower dose if clinically indicated 
 
Additional measures:  
 and additional 
assessments as indicated in Section 6.2.2.1.2.4 
If subject missed more than 
2 consecutive doses of 
AMG 160 
OR 
In case of reappearance of 
same event at grade 4 
OR 
In case of repeat grade  3 
event despite dose reduction 
Page 9 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Any other AMG 160-related events not meeting DLT criteria 
 3 
Interruption/ delay required if 
deemed intolerable and/or 
clinically significant by the 
subject or investigator and not 
responding to appropriate 
medical management until 
event has improved to grade  1 
 
 
Re-start possible if successfully managed and improvement to 
 grade 1 in  14 days. 
 
In case of infusion interruption, continue treatment with next 
scheduled infusion (do not resume prior infusion). 
 
Delay of next infusion: 
 
< 7 days:  administer the delayed infusion (as long as the 
next scheduled infusion is > 6 days from delayed infusion) 
and follow the schedule of assessments for the cycle day 
on which the infusion was originally planned.   
 
 7 days:  skip the infusion and resume schedule of 
assessments for the next scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same dose or reduce to next 
lower dose if clinically indicated 
 
Additional measures:  
 and additional 
assessments as indicated in Section 6.2.2.1.2.4 
If subject missed more 
than 2 consecutive doses 
of AMG 160 
OR 
In case of reappearance 
of same event at grade 4 
OR 
In case of repeat 
grade  3 event despite 
dose reduction 
Page 10 of 14 
Abbreviations and footnotes defined on last page of table. 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Any Non-AMG 160-related events 
4 
Interruption/ delay required if 
deemed intolerable by the 
subject or investigator and 
not responding to 
appropriate medical 
management until event has 
improved to grade  1 
 
 
Re-start possible if successfully managed and improvement to  
 grade 1 in  28 days. 
 
In case of infusion interruption, continue treatment with next 
scheduled infusion (do not resume prior infusion). 
 
Delay of next infusion: 
 
< 7 days:  administer the delayed infusion (as long as the next 
scheduled infusion is > 6 days from delayed infusion) and follow 
the schedule of assessments for the cycle day on which the 
infusion was originally planned. 
 
 7 days:  skip the infusion and resume schedule of assessments 
for the next scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same dose or reduce to next lower 
dose if clinically indicated 
 
Additional measures:  
 and additional assessments as 
indicated in Section 6.2.2.1.2.4 
If subject missed more 
than 2 consecutive doses 
of AMG 160 
OR 
In case of reappearance 
of same event at grade 4 
Page 11 of 14 
Abbreviations and footnotes defined on last page of table. 
 
 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Hepatotoxicity 
For Stopping and Rechallenge Rules please refer to Section 11.7. 
Page 12 of 14 
Abbreviations and footnotes defined on last page of table. 
 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
SARS CoV2 infection and COVID19 disease 
asympto
matic 
Interruption required until at 
least 10 days since positive 
SARS-CoV-2 test. 
UNLESS patient previously 
fully vaccinated against 
SARS-CoV-2.  If patient 
previously vaccinated and 
tests positive, then discuss 
with Medical Monitor. 
Follow local 
guidelines 
and standard 
of care for 
COVID-19 
treatment and 
isolation 
Contact 
Amgen 
Medical 
Monitor within 
1 business 
day to ensure 
appropriate 
documentatio
n & 
management 
of study 
activities 
 
Re-start possible upon agreement between Investigator and Amgen 
Medical Monitor provided: 
o 
There are no new findings on physical exam related to 
SARS-CoV-2, AND 
o 
Subject tests negative for SARS-CoV-2 by RT-PCR,  
OR 
o 
If subject continues to test positive for SARS-CoV-2 more 
than 10 days after initial positive test, or If subject initially 
tests positive in the setting of prior COVID vaccination, 
resume IP only after discussion with patient and 
reassessment of individual risk/benefit 
 
Consider chest imaging, ECG, ECHO, and cardiology assessment 
prior to re-start  
 
Consider hospitalization for re-start of IP based on length of treatment 
interruption, risk of CRS at restart, and amount of time since patient 
was last treated 
 
Dose modification:  resume at the same dose or reduce to next lower 
dose if clinically indicated 
 
 and assessments:  follow guidance in Section 1.3 
Immediately stop the 
infusion (if applicable) and 
permanently discontinue 
IP therapy, if: 
Subject required 
treatment interruption 
greater than 28 days and 
upon discussion with 
Amgen Medical Monitor 
the decision is made to 
permanently discontinue 
treatment 
OR 
Initial benefit/risk 
assessment for individual 
patient is not maintained 
any longer 
Page 13 of 14 
Abbreviations and footnotes defined on last page of table. 
 
 
 
 
 
 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of Adverse Events 
Including Dose Reductions 
Grade 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
SARS CoV2 infection and COVID19 disease (continued) 
symptom
atic 
Interruption required until at 
least 10 days since 
complete resolution of acute 
symptoms 
Follow local 
guidelines 
and standard 
of care for 
COVID-19 
treatment and 
isolation 
Contact 
Amgen 
Medical 
Monitor within 
1 business 
day to ensure 
appropriate 
documentatio
n & 
management 
of study 
activities 
 
Re-start possible upon agreement between Investigator and Amgen 
Medical Monitor provided: 
o 
There are no new findings on physical exam and chest 
imaging, related to SARS-CoV-2 
o 
Subject tests negative for SARS-CoV-2 by RT-PCR,  
OR 
o 
If subject continues to test positive for SARS-CoV-2 more 
than 10 days after initial positive test, resume IP only after 
discussion with patient and reassessment of individual 
risk/benefit 
 
Consider chest imaging, ECG, ECHO, and cardiology assessment 
prior to re-start  
 
Consider hospitalization for re-start of IP based on length of treatment 
interruption, risk of CRS at restart, and amount of time since patient 
was last treated  
 
Dose modification:  resume at the same dose or reduce to next lower 
dose if clinically indicated 
 
 and assessments: follow guidance in Section 1.3 
Immediately stop the 
infusion (if applicable) and 
permanently discontinue 
IP therapy if: 
Subject required 
treatment interruption 
greater than 28 days due 
to severe or 
life-threatening COVID-19 
OR 
Initial benefit/risk 
assessment for individual 
patient is not maintained 
any longer 
Page 14 of 14 
CRS = cytokine release syndrome; COVID-19 = coronavirus disease 2019; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; 
ECHO = echocardiogram; GI = gastrointestinal; ICANS = immune-effector cell associated neurologic syndrome; IL-6 = interleukin 6; IP = investigational product; 
IV = intravenous; MRI = magnetic resonance imaging; N/A = not applicable; NSAIDS = non-steroidal anti-inflammatory drugs; PK = pharmacokinetics; Q2 = every 2; 
RT-PCR = real time polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TLS = tumor lysis syndrome; US = United States 
a Revised grading system for CRS (Lee et al, 2014) 
b High dose vasopressors (all doses are required for  3 hours):  Norepinephrine monotherapy  20 g/min; Dopamine monotherapy  10 g/kg/min, Phenylephrine 
monotherapy  200 g/min, Epinephrine monotherapy  10 g/min; If on vasopressin, vasopressin + norepinephrine equivalent of  10 g/min; If on combination 
vasopressors (not vasopressin), norepinephrine equivalent of  20 g/min 


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c All sites will ensure that CRS rescue medications are available on-site, including corticosteroids and (for sites in regions where tocilizumab is approved and available, 
eg, the US and Germany) 2 doses of tocilizumab per study subject  
d If tocilizumab is not available, siltuximab (an anti-IL-6 monoclonal antibody) may be used in the management of cytokine release syndrome, following the criteria 
outlined in the Management of Adverse Events table.  The recommended dose of siltuximab is 11 mg/kg administered over 1 hour as an intravenous infusion, 
consistent with the prescribing information for the treatment of multicentric Castleman’s disease (Sylvant Prescribing Information), and the CARTOX Working Group 
Guidelines for CRS management (Neelapu, 2018).  Siltuximab may be repeated if needed, in the event that CRS recurs after a subsequent infusion of AMG 
160.  Siltuximab may not be repeated in an individual subject that develops anaphylaxis to siltuximab, or gastrointestinal perforation after siltuximab. 
e A subgroup analysis for subjects treated with siltuximab will be evaluated, including CRS outcomes, safety, and PK data. 


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6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding DILI guidelines, as specified in the Guidance 
for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product and other protocol-required therapies during the 
study are provided in the IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be assigned to treatment with AMG 160. 
6.4.2 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
6.5 
Treatment Compliance 
AMG 160 will be administered at the study center by a qualified staff member.  A 
physician must be available at the time of administration of investigational product.  
Information regarding investigational product administration including date, time, dose, 
start and stop time of infusion, and other essential information are to be recorded on the 
individual subject’s Investigational Product Administration eCRF per the eCRF 
completion guidelines.  Please refer to IPIM for more details on treatment compliance. 
6.6 
Treatment of Overdose 
The effects of overdose of this product are not known. 
The administered AMG 160 dose may be up to 10% lower or higher than specified in the 
protocol.  A dose of up to 10% higher than the intended dose may not require specific 
intervention. 
In any case of overdose, consultation with the Amgen medical monitor is required for 
prompt reporting of clinically apparent or laboratory adverse events possibly related to 
overdosage.  Consultation with the Amgen medical monitor is also required even if there 
are no adverse events, in order to discuss further management of the subject.  If the 
overdose results in clinically apparent or symptomatic adverse events, the subject 
should be followed carefully until all signs of toxicity are resolved or returned to baseline 
and the adverse event(s) should be recorded/reported per Section 11.4. 


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A dose of > 10% higher than the intended AMG 160 dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 11.4. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior therapies that were being taken/used from 1 month prior to signing informed 
consent will be collected.  For all prior therapies not taken for NSCLC, collect therapy 
name, indication, dose, unit, frequency, route, start and stop dates.  All prior cancer 
treatment therapies will be collected. 
For all prior therapies taken for NSCLC (eg, chemotherapy, immunotherapy, biological 
therapy or targeted therapy), collect (in the order they were administered): 
 
therapy name 
 
indication 
 
dose and schedule of the agent(s) 
 
unit 
 
frequency 
 
start and stop dates 
 
disease state in which it was administered 
 
reason for discontinuation (disease progression, clinical progression, toxicity, 
subject’s decision, investigator’s decision) 
Additionally, details of the dates, portals, and total administered dose by portal should be 
recorded for all courses of radiation therapy, including those directed at the primary and 
metastatic site(s).  Details of prior radioisotope therapy should also be recorded. 
6.7.2 
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 6.1.7. 
Concomitant therapies are to be collected from informed consent through the end of the 
safety follow-up period. 


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For concomitant therapies being taken for the disease under study (eg, pain medication), 
collect therapy name, indication, dose, unit, frequency, start and stop dates.  For all 
other concomitant therapies (including vaccines), collect therapy name, dose, start and 
stop dates (for SARS-CoV2 vaccines collect indication also). 
6.7.2.1 
Supportive Care 
Subjects can receive supportive care according to local guidelines for blood product 
support, antibiotics, antivirals, analgesics, etc.  Details of supportive care measures 
should be recorded for subjects in dose expansion phase. 
6.7.2.2 
Bone Disease Therapy 
Treatment of lung cancer-related bone disease, hypercalcemia, and bone pain should be 
done according to institutional standards.  This may include concurrent treatment with 
bisphosphonates or denosumab.  Radiotherapy for palliative care such as bone pain is 
permitted after discussion with Amgen medical monitor and details should be recorded 
for subjects in dose expansion phase. 
6.7.2.3 
Growth Factors 
The use of growth factors such as erythropoiesis-stimulating proteins as well as 
granulocyte colony stimulating factor (G-CSF) will be allowed during therapy per regional 
and investigator standard of care.  However, growth factors are not allowed at inclusion 
(within 7 days of applicable screening assessment) and should be avoided, if subject`s 
condition allows, in the first treatment cycle for better assessment of safety parameters. 
6.7.2.4 
Tumor Lysis Syndrome 
TLS is a severe, life-threatening disorder that can occur in highly proliferative 
malignancies or with debulking of extensive tumor burden.  Tumor lysis syndrome is 
characterized by a group of metabolic disorders caused by the massive and abrupt 
release of cellular metabolites into the blood including lactase dehydrogenase, uric acid, 
phosphorus, potassium, and calcium after lysis of the malignant cells (Coiffier et al, 
2008).  The metabolic complications predispose patients with cancer to various clinical 
complications included renal failure, seizures, cardiac arrhythmias, and even sudden 
death.  To allow for early diagnosis, all subjects must be monitored closely for laboratory 
and clinical evidence of a possible TLS as outlined in Section 11.10.2. 
To prevent TLS, ensure all subjects are well hydrated and provided supportive care 
measures before administration of AMG 160.  To prevent TLS, before administration of 
AMG 160 all subjects should receive, at the discretion of the investigator, appropriate 


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hydration and supportive measures according to local standard of care and institutional 
guidelines.  Monitor for evidence of TLS during treatment and manage promptly 
including interruption of AMG 160 infusion as outlined in Table 6-3.  Subjects who 
experience TLS should be managed according to the local standard of care and 
institutional guidelines.   
6.7.2.5 
Nausea, Vomiting, and Diarrhea 
The causes of nausea, vomiting, and diarrhea in subjects with cancer can be 
multifactorial.  Therefore, a careful assessment which includes a detailed history, 
physical examination, and investigations for causes is vital.  Management of nausea, 
vomiting, and diarrhea should be tailored to the individual subject’s clinical situation. 
6.7.2.5.1 
Nausea and Vomiting 
Antiemesis prophylaxis may be given according to local standard of care institutional 
standards if clinically indicated at the investigator's discretion.  Treatment of nausea and 
vomiting with antiemetics such as metoclopramide should be considered according to 
the local standard of care and institutional guidelines.  In cases with nausea and 
vomiting lasting for > 24 hours, additional treatment with corticosteroids (
 
) should be considered depending on tolerability/duration of previous 
 administration. 
6.7.2.5.2 
Diarrhea 
All subjects who experience diarrhea should be advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not feasible, fluid, and electrolytes should be 
substituted via IV infusion.  Consider gastrointestinal consultation and endoscopy to 
confirm or rule out colitis. 
Treatment with loperamide (starting dose of 4 mg, followed by 2 mg every 2 hours) 
should start after occurrence of the first episode of diarrhea.  In cases with diarrhea 
lasting for > 24 hours, additional treatment with corticosteroids (
 
 should be considered depending on tolerability/duration of previous 
 administration.  Additional work-up and/or gastrointestinal (GI) 
consultation may be considered, as needed. 
6.7.2.6 
Vaccines 
Every effort should be made to fully vaccinate subjects prior to 14 days from first dose of 
AMG 160.  The use of vaccines except live and live-attenuated vaccines (live-attenuated 
vaccines for SARS-CoV-2 are allowed per local regulatory and institutional guidelines) 


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will be allowed during therapy per regional and institutional standard of care.  If possible, 
SARS-CoV-2 vaccinations should be avoided during screening (within a minimum of 14 
days from first dose of AMG 160) and should be also avoided in the first treatment cycle 
for better assessment of safety parameters.  Throughout the study, SARS-CoV-2 
vaccination should be avoided within 3 days before and after the administration of AMG 
160 due to the potential of CRS development. In the event where a subject requires 
steroids for CRS prophylaxis or treatment of adverse events, vaccination should be 
avoided while on steroids. 
7. 
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 or 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 7.1, 7.2.1, and 7.2.2. 
7.1 
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 (see 
Section 1.3) 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. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 


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local country’s regulatory mechanism, based on parameters consistent with 
Section 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 
 
Confirmed disease progression as defined by modified RECIST 1.1 criteria or 
disease progression accompanied by worsening of symptoms or deterioration of 
the subject’s general condition 
 
Requirement for alternative therapy 
 
Pregnancy 
7.2 
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 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Not applicable for this study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 


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 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
7.3 
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: 
 
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. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(Section 1.3).  
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. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure 
(standard of care radiographic assessments performed before signing of informed 


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consent may be used for screening purposes if performed within 28 days of subject 
enrollment) or discontinuation of standard therapy for any disallowed therapy.  After the 
subject has signed the informed consent form, the site will register the subject in the IRT 
and screen the subject in order to assess eligibility for participation.  The screening 
window is up to 28 days.  Any blood samples collected during the screening 
window must be collected within 28 days of cycle 1 day 1. 
For a subject to be eligible for study participation, detectable PSMA expression by 
68Ga-PSMA-11 PET/CT imaging 
 
 must be demonstrated during 
screening.  
 
 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
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 1 time. 
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28 day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Section 1.3).  On-study visits may be 
completed within ± 1 day (except for PK collections days) during cycle 1 and cycle 2 and 
within ± 3 days cycle 3 onward.  The date of the first dose of AMG 160 is defined as 
day 1.  All subsequent doses and study visits will be scheduled based on the day 1 date.  
Assessments are done pre-infusion unless otherwise specified in the schedule of 
activities.  


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8.1.3 
End of Treatment 
For subjects who discontinue investigational product, an end of treatment visit should 
occur as soon as possible (within 14 days) after the last dose of investigational product. 
8.1.4 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, a safety 
follow-up visit will be performed approximately 30 (+3) days after the end of the last dose 
of investigational product or prior to initiation of other therapy, whichever occurs first. 
8.1.5 
Long-term Follow-up 
The procedures to be completed during long-term follow-up are indicated in the 
Schedule of Activities (Section 1.3).  Long term follow-up will be conducted every 
6 months up to 3 years from the first dose of AMG 160 for all subjects who have not 
withdrawn consent by clinic visit, telephone or chart review to assess for survival and/or 
the commencement of subsequent cancer therapy. 
8.1.6 
End of Study Visit 
The end of study visit is defined as the date of the final study visit (eg, final long-term 
follow-up visit) when assessments and/or procedures are performed. 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC and Amgen approved informed consent before any study-specific procedures 
are performed. 
8.2.1.2 
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 will be used to study the impact on biomarkers variability 
and PK of AMG 160.  
8.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started prior to enrollment through the time of consent.  Medical history will include 


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information on the subject’s concurrent medical conditions.  Record all findings on the 
medical history eCRF. 
A complete medical history, including antecedent hematologic or oncologic disease, 
other diseases/symptoms such as fatigue, bleeding and infection (resolved and ongoing) 
will be collected.  The current toxicity grade will be collected for each condition that has 
not resolved.  Any unresolved medical history will be graded according to Common 
Toxicology Criteria for Adverse Events (CTCAE) version 5.0 (Section 11.4) unless 
specified otherwise. 
8.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.5 
Neurological Examination 
If clinically indicated, subjects will be specifically queried for neurological symptoms 
observed in the interval since the last extended neurological examination.  Abnormalities 
of the following should be recorded:  level of consciousness, orientation, vision, cranial 
nerves and brain stem functions, pyramidal and extra pyramidal motor system, reflexes, 
muscle tone and trophic findings, coordination, sensory system, neuropsychological 
findings (eg, speech, cognition and emotion). 
The individual performing the neurological examination will characterize the findings as 
either normal or abnormal.  Abnormal findings found pre-dose will be reported on the 
medical history page of the CRF.  Abnormal findings found after the subject is dosed will 
be reported on the Event page of the CRF. 
A more detailed neurological assessment may be performed in subjects at selected 
sites. 
8.2.1.6 
Physical Measurements 
Height (in centimeters) and weight (in kilograms) should be measured without shoes. 
8.2.1.7 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of tobacco. 
8.2.1.8 
Performance Status  
The subject’s PS will be assessed using the ECOG performance scale (see 
Section 11.11). 


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8.2.2 
Efficacy Assessments 
Efficacy will be determined by radiographic assessments.   
Radiographic assessments will be obtained as scheduled in Table 1-6 irrespective of 
cycle duration including dose delays and treatment discontinuation. 
Standard radiological assessments should take place until clinically significant disease 
progression or deterioration, withdrawal of consent, or start of new anticancer therapy.  
Every assessment must include the chest, abdomen, and pelvis, all other known sites of 
disease and magnetic resonance imaging (MRI) of the brain if a subject has signs or 
symptoms suggestive of CNS metastases.  The MRI/CT can be obtained earlier if 
clinical deterioration necessitates an earlier scan at the discretion of the managing 
physician.  The same contrast and modality used at screening should be used for all 
subsequent assessments.  
 
 
 
.   
Tumor burden assessments will be performed based on modified RECIST 1.1 criteria.  
To confirm PD, a second MRI/CT scan must be performed 4 to 6 weeks after the first 
detection of radiographical progression.  Responses (PR and complete response [CR]) 
require confirmation by a repeat consecutive assessment at least 4 weeks after the first 
detection of radiographical response.  Refer to the imaging manual for details on 
imaging assessments. 
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Section 1.3). 
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 


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the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
After each AMG 160 monotherapy infusion for the first 2 cycles (during the 72-,48-, or 
24-hour hospitalization), vital signs should be assessed accordingly during the following 
time points: 
Table 8-1.  Vital Sign Time Points 
For 
 
target doses 
 
Every 60 minutes during infusion and during first 4 hours 
after end of infusion (EOI) 
 
Every 2 hours from 4 to 12 hours EOI 
 
Every 4 hours from 12 to 24 hours EOI 
 
Every 24 hours EOI, vital signs should be assessed per 
institutional standards 
For cycle 1 
 
 dosing 
 
Every 2 hours from 0 to 12 hours after start of infusion 
 
Every 4 hours from 12 to 24 hours after start of infusion 
 
After 24 hours after start of infusion, vital signs should be 
assessed per institutional standards 
8.2.3.2 
Pulse Oximetry 
Oxygen saturation will be measured using a standard pulse oximeter.  The subject must 
be in a rested and calm state for at least 5 minutes before pulse oximetry assessments 
are completed. 
8.2.3.3 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in the most recumbent position as possible.  ECGs 
should be performed in a standardized method, in triplicate (where applicable), and run 
consecutively.  Each triplicate, which consists of three 10-second tracings, should be 
completed within a total of five minutes from the start of the first to the completion of the 
third, prior to blood draws or other invasive procedures.  Each ECG must include the 
following measurements:  QRS, QT, QTc, RR, and PR intervals.  
Triplicate ECGs (to be only performed if the dose being evaluated is higher than the 
MTD established in subjects with mCRPC [Study 20180101]) 
At pre-dose on cycle 1 day 1, baseline ECGs should be collected at 3 time points 
 5 minutes apart, with each baseline ECG performed in triplicate, and with at least 


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5 minutes between the end of each triplicate and the start of the next (total 9 ECGs).  
During cycle 1 and cycle 2 (at the time points per Schedule of Activities), each ECG 
should be performed in triplicate (total 3 ECGs).  See Section 1.3 for ECG collection time 
points. 
Safety ECGs 
As listed in Section 1.3, single ECGs where applicable will be performed and will be 
referred to as safety ECGs. 
The PI or designated site physician will review all ECGs.  ECGs will be transferred 
electronically to an ECG central vendor per Amgen instructions.  Once signed, the 
original ECG tracing will be retained with the subject's source documents.  At the request 
of the sponsor, a copy of the original ECG will be made available to Amgen. 
8.2.3.4 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
8.2.4 
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 11.4. 


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8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Section 11.4.  CRS, which will be graded using the criteria referenced in the 
publication by Lee et al (2014) (see Section 11.10.1) and TLS, which will be graded 
according to the Cairo Bishop criteria referenced in the publication by 
Coiffier et al (2008) (see Section 11.10.2), and ICANS will be using the criteria 
referenced in the publication by Lee et al (2019) (see Section 11.10.3). 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of AMG 160 through the 
safety follow-up visit are reported using the Event CRF. 
8.2.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the safety follow-up visit are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s knowledge of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events. 
8.2.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events (including fatal events) after 
the protocol-required reporting period (as defined in Section 8.2.4.1.2) is complete, these 
serious adverse events will be reported to Amgen (regardless of causality).  The 
investigator will report these serious adverse events 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 investigator.  
However, if the investigator becomes aware of serious adverse events suspected 
to be related to investigational product, then these serious adverse events will be 


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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 if the subject ends the study. 
8.2.4.1.4 
Reporting a Safety Endpoint as a Study Endpoint 
Safety endpoints (any fatal event occurring outside the protocol required reporting 
period) that are study endpoints are reported on the Event CRF.  All endpoints that also 
meet the criteria of serious adverse event must also be transmitted to safety within 
24 hours of the investigator’s knowledge of the event (refer to Section 11.4).  
8.2.4.2 
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. 
8.2.4.3 
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 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional followup 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. 
8.2.4.4 
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. 


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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 holding the relevant Investigational New Drug/Clinical Trial Application for 
either AMG 160 or 68Ga-PSMA-11 has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of AMG 160 or 
68Ga-PSMA-11, respectively, under clinical 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. 
8.2.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.2.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until 
4 months after the last dose of AMG 160. 
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 11.5.  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 11.5. 


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8.2.5 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) for the timing and frequency.  
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 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Section 1.3).  
Pregnancy Testing 
A high sensitive (serum) pregnancy test should be completed at screening and within 
7 days of initiation of investigational product for females of childbearing potential.   
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 11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional pregnancy testing should be performed at monthly intervals during treatment 
with protocol-required therapies and 4 months after the last dose of protocol-required 
therapies.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.2.6 
Pharmacokinetic Assessments 
All subjects enrolled will have PK samples assessed. 
Whole blood samples of approximately 2.5 mL will be collected for measurement of 
serum concentrations of AMG 160 as specified in the Schedule of Activities (Section 1.3) 
Instructions for the collection and handling of biological samples will be provided by the 


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sponsor.  The actual date and time (24-hour clock time) of each sample will be recorded 
in the eCRF. 


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
No formal statistical hypotheses will be tested. 
9.2 
Sample Size Determination 
Up to 50 subjects will be enrolled in the study (approximately 10 subjects in a dose 
exploration phase and up to 40 subjects in a dose expansion phase).  Additional 
subjects (up to 20) may be enrolled in 1 or more monotherapy dose levels that have 


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been shown to be safe and tolerable (defined as backfill enrollment).  This backfill 
enrollment may be done to better estimate the RP2D and better characterize the safety, 
efficacy, PK, 
 of AMG 160 monotherapy and may be concurrent 
with dose escalation to identify the MTD. 
An initial 2 to 4 subjects will be enrolled and treated with Dose Level 1 (1 dose level 
below RP2D of AMG 160 Study 20180101).  Rules for dose-escalation/de-escalation are 
derived using an mTPI model with a target toxicity probability of 0.28 (see 
Section 6.2.1.1).  If the dose is not tolerated (based on target DLT rate > 28%), the dose 
level will be reduced 1 level below the starting dose.  Alternative dosing schedules, 
including further dose escalation as per the ongoing mCRPC trial (Study 20180101), 
may be explored based on emerging safety and PK data.  The sample size in the dose 
exploration phase is based on practical consideration and is consistent with conventional 
oncology studies with the objective to estimate the MTD. 
With 2 subjects in a cohort, there is a 19% to 55% probability of observing at least 1 DLT 
if the true DLT rate is 10% to 33% and with 4 subjects in a cohort, there is a 34% to 80% 
probability.  With 6 subjects in a cohort, there is a 47% to 91% probability of observing at 
least 1 DLT if the true DLT rate is 10% to 33% and with 10 subjects in a cohort, there is 
a 65% to 98% probability. 
In the dose expansion phase, a subject number of 40 will provide a 87% probability of 
observing at least 1 adverse event with 5% incidence rate.  An exact 95% binomial CI 
will be provided for overall response rate.  With the 40 subjects and 20% overall 
response rate, the expected 95% CI would be 9% to 36%. 
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
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 1 dose of 
AMG 160. 
The analysis of DLT will be conducted on the DLT Analysis Set defined as all subjects 
that are enrolled and receive at least 1 dose of AMG 160 with an evaluable DLT 
endpoint.  The DLT endpoint is evaluable if either: 1) the subject experiences a DLT; or 
2) the subject does not experience a DLT after receiving all planned doses within the 
28-day DLT window in cycle 1. 


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9.3.2 
Covariates 
The relationship between covariates and efficacy endpoints may be explored if 
appropriate. 
9.3.4 
Handling of Missing and Incomplete Data 
Descriptive statistics will be used to identify the extent of missing data.  Missing or 
incomplete dates that are critical to efficacy and safety analysis (eg, date of death, 
adverse event start date) will be imputed.  Detailed imputation rules will be documented 
in statistical analysis plan. 
9.4 
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 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis. 
During dose exploration and formally during DLRMs, Amgen, in consultation with the site 
investigators, will review all available cumulative data by cohort prior to making dose 
escalation or dose de-escalation recommendations.  Adverse events and DLTs 
observed in all subjects will be evaluated continually and fully integrated into all DLRMs 
and considered in all enrollment and dosing decisions.  During dose expansion, Amgen 
will conduct evaluations of the ongoing grade 4 or higher treatment-related adverse 
event rate to assess if the threshold for possible early trial termination has been 
reached.  If this threshold is met, enrollment to dose expansion 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. 
1) Terminate the trial 


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2) Amend the protocol to potentially improve the benefit/risk for subjects (eg, 
increase safety monitoring, modify dose/schedule, mandate 
) 
3) Continue dose expansion without any changes 
The stopping rules use a Bayesian approach proposed by Thall et al, 1995 to terminate 
the study if the posterior probability that the grade 4 or higher treatment-related adverse 
event rate is greater than 20% is > 80%.  The stopping boundaries assume a prior 
distribution of Beta (0.40, 1.60) are presented in Table 9-1 and the operating 
characteristics with pre-specified batch size of 10 new subjects per batch are presented 
in Table 9-2.  The operating characteristics in Table 9-2 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 9-2 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 9-1.  Stopping Boundary for Dose Expansion With Posterior Probability 
of 80% and Grade 4 or Higher Treatment-related Adverse Event Limit of 20% 
Number of Subjects 
Stop Study if Observing These Many Grade 4 or Higher 
Treatment-related Adverse Events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Dose Expansion Complete 
Table 9-2.  Operating Characteristics With Batch Size of 10 Subjects 
True Grade 4 or Higher 
Treatment-related Adverse 
Event Rate 
Probability of Early Stopping of 
Dose Expansion 
Average Dose Expansion 
Sample Size 
0.10 
2.0% 
39.5 
0.15 
9.1% 
37.6 
0.20 
23.2% 
33.9 
0.25 
42.2% 
28.8 
0.30 
61.6% 
23.4 
A formal interim analysis of available safety and efficacy data will occur when the first 
10 evaluable subjects enrolled have had the opportunity to complete 4 months on study.  
This interim analysis will estimate MTD, support the determination of RP2D, conduct 
futility analysis of objective response rate (ORR), and support the evaluation of 
benefit/risk profile of AMG 160 as a monotherapy.  


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A futility analysis of ORR will be performed using Bayesian predictive probability 
(Lee and Liu, 2008) when the first 10 evaluable subjects reach month 4.  If the predictive 
probability of observing ORR response > 15% at the end of the study with 50 evaluable 
subjects is less than 30%, the study may stop early (pT = 0.25).  Equivalently, if we 
observe ≥ 1 objective responder in the first 10 subjects, an additional subjects (up to 40) 
will be enrolled into the expansion cohort.  The predictive probability is calculated with a 
noninformative prior, Jeffreys prior, Beta(0.5, 0.5).  
Similarly, futility analyses will also be conducted during the expansion cohort.  The 
stopping boundaries are presented in Table 9-3.  The operating characteristics in 
Figure 9-1 provide the probability of stopping the trial early for given hypothetical true 
rate of ORR. 
Table 9-3.  Objective Response Rate Stopping Boundary 
Number of Evaluable 
Subjects Each Month 4 
Stop Study if Observed Objective Response Rate (ORR) 
Response 
10 
< 1 
20 
< 2 
30 
< 3 
40 
< 4 
50 
Study Complete 


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Figure 9-1.  The Probability of Stopping The Trial Early 
 
9.4.1.1.1 
Stopping Rules for Treatment With Siltuximab 
Amgen will conduct evaluations of the treatment and outcome of the CRS events treated 
with siltuximab on an ongoing basis to assess if the threshold for pausing siltuximab 
treatment has been reached as outlined in the table below.  If these stopping rules are 
met, an ad hoc DLRM will be triggered to review safety data and available PK, 
, and efficacy data.  If recommended by DLRT, the use of siltuximab 
will resume.  The stopping rules to trigger an adhoc DLRM to review siltuximab 
treatment use a Bayesian approach proposed by Thall et al, 1995; an adhoc DLRM will 
be triggered if the posterior probability that the CRS progression to grade 3 rate is 
greater than 30% is > 80% or the posterior probability that the CRS progression to grade 
4 rate is greater than 10% is  80%; or observation of any grade 5 CRS after the event 
has been treated with siltuximab.  The stopping boundaries presented below assume a 
prior distribution of Beta (0.6, 1.4) for progression to grade 3 CRS and a prior distribution 
of Beta (0.2, 1.8) for progression to grade 4 CRS.  The evaluations could occur more 
Probability of Futility (%)
0
10
20
30
40
50
60
70
Number of Evaluable Subjects
10
20
30
40
50
True ORR
0.1
0.15
0.2
0.25
0.3
0.5


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frequently if necessary to address emerging safety concerns.  If the triggered adhoc 
DLRM coincides with the regular DLRM, they may be combined. 
Number of 
subjects treated 
with siltuximab 
Trigger DLRM if severity of any CRS event treated with siltuximab 
progresses to Grade 5   
Or this number of subjects with 
severity of CRS progressed to 
Grade 3 after being treated with 
siltuximab 
Or this number of subjects with 
severity of CRS progressed to 
Grade 4 after being treated with 
siltuximab 
5 
 3 
 2 
10 
 5 
 3 
15 
 7 
 3 
20 
 8 
 4 
25 
 10 
 5 
30 
 12 
 5 
35 
 13 
 6 
40 
 15 
 6 
9.4.1.2 
Primary Analysis 
The primary analysis for the dose exploration phase will occur when target enrollment is 
complete and each subject either completes 6 months on the study or withdraws from 
the study.  
The primary analysis for the study will occur when target enrollment is complete for the 
dose expansion phase and each subject either completes 1 year on study or withdraws 
from the study.  
9.4.1.3 
Final Analysis 
The final analysis will occur when target enrollment is complete for both phases and all 
subjects have ended the study. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, efficacy, 
 by dose, dose schedule, and time as appropriate.  Descriptive 
statistics on continuous data will include means, medians, standard deviations and 
ranges, while categorical data will be summarized using frequency counts and 
percentages.  Graphical summaries of the data may also be presented. 


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Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Pearson (Clopper and 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 (Brookmeyer and Crowley, 1982) method.  
Kaplan-Meier methods will be used to estimate landmarks for time to event endpoints 
(eg, 1-year overall survival [OS]) with the Greenwood formula 
(Kalbfleisch and Prentice, 1980) used to estimate the standard error used in CI 
calculation. 
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable. 
Secondary 
Listings of secondary efficacy endpoints will be produced for all 
subjects. 
The proportion of subjects with an OR (per modified RECIST 1.1) and 
95% CI will be tabulated by planned dose level. 
For all subjects treated at the MTD and/or RP2D, Kaplan-Meier 
methods will be used to estimate the time to event curve, median time 
to event and percentiles with 95% CI for 1) duration of response; 
2) time to progression; 3) progression-free survival; 4) time to 
subsequent therapy; 5) overall survival; 6) time to response.  For all 
subjects treated at the MTD and/or RP2D, Kaplan-Meier methods will 
be used to estimate landmarks for time to event endpoints (eg, 1-year 
PFS) with 95% CI). 
 


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9.4.2.3 
Safety Analyses 
9.4.2.3.1 
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 160.  
The analysis of DLTs will be conducted on the DLT Analysis Set.  
Subject incidence of DLT will be tabulated by planned dose level.  The 
statistical analysis methods for other safety endpoints are in 
Section 9.4.2.3 below. 
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term and grade.  Tables of fatal adverse events, serious 
adverse events, adverse events leading to withdrawal from investigational product or 
other protocol-required therapies, and significant treatment emergent adverse events will 
also be provided.  A subgroup analysis of safety with CRS outcome and PK will be 
performed for subjects who were administered siltuximab. 
9.4.2.3.3 
Laboratory Test Results 
Clinical chemistry, hematology, and urinalysis data will be reviewed for each subject.  
Depending on the size and scope of changes in laboratory data the analyses of safety 
laboratory endpoints will include summary statistics over time and/or changes from 
baseline over time may be provided.  Shifts in grades of safety laboratory values from 
baseline for selected laboratory values may also be provided 
9.4.2.3.4 
Vital Signs 
Vital signs data will be reviewed for each subject.  The analyses of vital signs will include 
summary statistics over time and/or changes from baseline over time may be provided. 
9.4.2.3.5 
Physical Measurements 
Physical measurements will be reviewed for each subject. 
9.4.2.3.6 
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 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 cohort will be summarized.  All on-study ECG data will be 
listed and select parameters of interest plotted. 


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9.4.2.3.8 
Exposure to Investigational Product 
Details of AMG 160 administration will be listed for every subject. 
9.4.2.3.9 
Exposure to Non-investigational Product 
Subject-level data may be provided instead of the summary if the subject incidence is 
low or single dose is given.  The number of days on non-investigational product, the 
daily dose, and the proportion of subjects receiving each dose level will be summarized 
using descriptive statistics. 
Compliance with non-investigational product will summarized for each subject using 
descriptive statistics.  
9.4.2.3.10 
Exposure to Other Protocol-required Therapy 
Descriptive statistics of total dose (mg/kg), total dose (mg), average daily dose, 
cumulative dose and number of cycles will be produced to describe the exposure to 
AMG 160 by planned dose level. 
9.4.2.3.11 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category for each treatment group as coded by the World Health 
Organization Drug dictionary. 
9.4.2.4 
Other Analyses 
Pharmacokinetic parameters will be determined from the time concentration profile using 
standard non-compartmental approaches and considering the profile over the complete 
sampling interval.  
 
 
 
. 


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10. 
References 
American Cancer Society.  Cancer Facts & Figures.  Atlanta, Ga:  American Cancer 
Society; 2020. 
AMG 160 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
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Bailis J, Deegen P, Thomas O, et al.  Preclinical evaluation of AMG 160, a 
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BLINCYTO (blinatumomab) United States Prescribing Information.  Thousand Oaks, 
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Bristol-Myers Squibb Company.  Opdivo (nivolumab):  Highlights of Prescribing 
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Brahmer JR, Govindan R, Anders RA, et al.  The Society for Immunotherapy of Cancer 
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Chang SS, Reuter VE, Heston WD, et al.  Comparison of Anti-Prostate-Specific 
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Chang SS, Reuter VE, Heston WD, et al.  Five Different Anti-Prostate-Specific 
Membrane Antigen (PSMA) Antibodies Confirm PSMA Expression in Tumor-Associated 
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Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
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Coiffier B, Altman A, Pui CH, Younes A, Cairo MS.  Guidelines for the management of 
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Conway RE, Petrovic N, Li Z, et al.  Prostate-specific membrane antigen regulates 
angiogenesis by modulating integrin signal transduction.  Mol Cell Biol.  
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Dirks NL and Meibohm B.  Population Pharmacokinetics of Therapeutic Monoclonal 
Antibodies.  Clin Pharmacokinet.  2010;49:633-659. 
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours:  Revised RECIST guideline (version 1.1).  Eur J Cancer.  2009;45:228-247. 
Eli Lily and Company.  Cyramza (ramucirumab):  Highlights of Prescribing Information.  
2014. 
Folkman J.  Tumor Angiogenesis:  Therapeutic Implications.  NEJM.  
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Fukumura D, Kloepper J, Amoozgar Z, et al.  Enhancing Cancer Immunotherapy Using 
Antiangiogenics:  Opportunities and Challenges.  Nat Rev Clin Oncol.  2018;15:325-340. 


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Genentech Inc.  Tecentriq (atezolizumab):  Highlights of Prescribing Information.  2019. 
Genentech Inc.  Avastin (bevacizumab):  Highlights of Prescribing Information.  2009. 
Hofman MS, Violet J, Hicks RJ. [177Lu]-PSMA-617 radionuclide treatment in patients 
with metastatic castration-resistant prostate cancer (LuPSMA trial):  a single-centre, 
single-arm, phase 2 study.  Lancet Oncol.  2018;19(6):825-833. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Kalbfleisch JD, Prentice RL.  The statistical analysis of failure time data.  John Wiley & 
Sons, New York; 1980. 
Kontermann RE.  Strategies for Extended Serum Half-Life of Protein Therapeutics.  Curr 
Opin Biotechnol.  2011;22:868-876. 
Lee JJ, Liu DD.  A predictive probability design for phase II cancer clinical trials.  Clinical 
Trials. 5(2):93-106. 2008 
Lee DW, Santomasso BD, Locke FL, et al.  ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated With Immune Effector Cells.  Biol 
Blood Marrow Transplant.  2019;25:625-638. 
Lee DW, Gardner R, Porter DL, et al.  Current Concepts in the Diagnosis and 
Management of Cytokine Release Syndrome.  Blood.  2014;124:188-195. 
Levey AS, Bosch JP, Lewis JB, et al.  A More Accurate Method To Estimate Glomerular 
Filtration Rate from Serum Creatinine:  A New Prediction Equation.  Ann Intern Med.  
1999;130:461-470. 
Liu T, Jabbes M, Nedrow-Byers JR, et al.  Detection of Prostate-Specific Membrane 
Antigen on HUVECs in Response to Breast Tumor-Conditioned Medium.  Int J Oncol.  
2011;38:1349-1355. 
Merck Sharp & Dohme Corp.  Keytruda (pembrolizumab):  Highlights of Prescribing 
Information.  2018. 
Milowsky MI, Nanus DM, Kostakoglu L, et al.  Vascular Targeted Therapy With Anti-
Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Advanced Solid 
Tumors.  J Clin Oncol.  2007;25:540-547. 
Morgenroth A, Tinkir E, Vogg ATJ, et al.  Targeting of prostate-specific membrane 
antigen for radio-ligand therapy of triple-negative breast cancer.  Breast Cancer 
Research.  2019;21:116. 
Murphy GP, Barren RJ, Erickson SJ, et al.  Evaluation and comparison of two new 
prostate carcinoma markers.  Free-prostate specific antigen and prostate specific 
membrane antigen.  Cancer.  1996;78:809-818. 
Neelapu SS, Tummala S, Kebriaei P, et al.  Chimeric antigen receptor T-cell therapy — 
assessment and management of toxicities.  Nat Rev Clin Oncol.  2018;15:47-62. 
Nguyen DP, Xiong PL, Liu H, et al.  Induction of PSMA and Internalization of an 
Anti-PSMA mAb in the Vascular Compartment.  Mol Cancer Res.  2016;14:1045-1053. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649–655. 
Owen DH, Giffin MJ, Bailis JM, et al.  DLL3:  An Emerging Target in Small Cell Lung 
Cancer.  J Hematol Oncol.  2019;12:61. 


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Pakkala S and Ramalingam SS.  Personalized Therapy for Lung Cancer:  Striking a 
Moving Target.  JCI Insight.  2018;3:e120858. 
Pennock GK and Chow LQM.  The Evolving Role of Immune Checkpoint Inhibitors in 
Cancer Treatment.  Oncologist.  2015;20:812-822. 
Reck M, Barlesi F, Crino L, et al.  Predicting and Managing the Risk of Pulmonary 
Haemorrhage in Patients With NSCLC Treated With Bevacizumab: A Consensus Report 
From a Panel of Experts.  Ann Oncol.  2012;23:1111-1120. 
Reiss KA, Forde PM, Brahmer JR.  Harnessing the Power of the Immune System via 
Blockade of PD-1 and PD-L1:  A Promising New Anticancer Strategy.  Immunotherapy.  
2014;6:459-475. 
Russo A, Lopes AR, McCusker MG, et al.  New Targets in Lung Cancer (Excluding 
EGFR, ALK, ROS1).  Curr Oncol Rep.  2020;22:48. 
Schmidt LH, Heitkotter B, Schulze AB, et al.  Prostate Specific Membrane Antigen 
(PSMA) Expression in Non-Small Cell Lung Cancer.  PLoS One.  2017;12:e0186280. 
Shetty D, Loh H, Bui C, et al.  Elevated 68Ga Prostate-Specific Membrane Antigen 
Activity in Metastatic Non-Small Cell Lung Cancer.  Clin Nucl Med.  2016;41:414-416. 
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Is Greatest in Prostate Adenocarcinoma and Lymph Node Metastases.  Urology.  
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Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for single-arm 
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Lung Cancer Cells and Tumor Neovasculature Endothelial Cells and Its Clinical 
Significance.  PLoS One.  2015;10:e0125924.


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11. 
Appendices 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADR 
adverse drug reaction 
ALK 
anaplastic lymphoma kinase 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BiTE 
bispecific T-cell engager 
Cmax 
maximum serum concentration 
Cmin 
minimum serum concentration 
CAR-T 
chimeric antigen receptor T cells 
CD 
cluster of differentiation 
CFR 
U.S. Code of Federal Regulations 
CI 
confidence intervals 
COVID-19 
coronavirus disease 2019 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTC0 
circulating tumor cell zero 
DILI 
drug-induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose-limiting toxicities 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 


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Abbreviation or Term 
Definition/Explanation 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Follow-up 
defined as when the last subject completes the last protocol-
specified assessment in the study   
EOI 
end of infusion 
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the 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 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FIH 
first in human 
FSH 
follicle stimulating hormone 
68Ga 
68Gallium 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GSO 
Global Safety Officer 
HIV 
human immunodeficiency virus 
HLE 
half-life extended 
HNSTD 
highest nonseverely toxic dose 
HRT 
hormone replacement therapy 
ICANS 
immune-effector cell associated neurologic syndrome 
ICE 
immune effector cell associated encephalopathy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICP 
intracranial pressure 
IEC 
Independent Ethics Committee 


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Abbreviation or Term 
Definition/Explanation 
Ig 
immunoglobulin 
IL-6 
interleukin-6 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
IUD 
intrauterine device 
IV 
intravenous 
mCRPC 
metastatic castration-resistant prostate cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
MUGA scan 
multigated acquisition scan 
NA 
not available 
NCT 
National Clinical Trials 
ND 
not done 
NTRK 
neurotrophic tropomyosin-related kinase 
NSCLC 
non-small cell lung cancer 
OR 
objective response(s) 
ORR 
objective response rate 
OS 
overall survival 
PCWG3 
Prostate Cancer Working Group 3 
PD 
disease progression 
PD1 
programmed cell death protein 1 
PDL1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response 
PS 
performance status 
PSA 
prostate specific antigen 


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Abbreviation or Term 
Definition/Explanation 
PSMA 
prostate-specific membrane antigen 
rPFS 
progression-free survival (radiographic) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
relapsed/refractory 
RP2D 
recommended phase 2 dose 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
SAg 
surface antigen 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
scFc 
single chain fragment crystallizable 
SC 
subcutaneous 
SD 
stable disease 
SLD 
sum of the longest diameters 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
t1/2 
half-life 
TBL 
total bilirubin 
TLS 
tumor lysis syndrome 
TPI 
toxicity probability intervals 
TPS 
tumor proportion score 
TNF 
anti-tumor necrosis factor 
UE 
unable to evaluate 
ULN 
upper limit of normal 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests will be performed by the local laboratory or by the central laboratory 
(Table 11-1).  Additional analyte test results may be reported by the local or central 
laboratory, in accordance with standard laboratory procedures (eg, components of a 
hematology panel).  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 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 11-1.  Laboratory Analyte Listing 
LOCAL LABORATORY 
Chemistry 
Urinalysis 
Hematology 
Coagulation 
sodium 
potassium 
chloride 
bicarbonate  
total protein 
albumin 
calcium 
adjusted calcium 
magnesium 
phosphorus 
glucose 
BUN or urea 
creatinine 
uric acid 
total bilirubin 
direct bilirubin 
AST (SGOT) 
ALT (SGPT) 
ALP 
LDH 
CRP 
ferritin 
eGFRa 
specific gravity 
pH 
blood 
protein 
glucose 
bilirubin 
WBC 
RBC 
epithelial cells 
bacteria 
casts 
crystals 
RBC 
hemoglobin 
hematocrit 
reticulocytes 
platelets 
WBC differential: 
• neutrophils 
•bands/stabs 
(if available) 
•segmented 
neutrophils (if 
available) 
• eosinophils 
• basophils 
• lymphocytes 
• monocytes 
ANC 
aPTT 
PT/INR 
fibrinogen 
D-dimer 
Other Labs 
Pregnancy test 
CENTRAL LABORATORY 
PK collection 


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ALTalanine aminotransferase; ALP  alkaline phosphatase; ANC  absolute neutrophil count; 
aPTT  activated partial thromboplastin time; AST  aspartate aminotransferase; BUN  blood urea 
nitrogen; Cr  creatinine; CRP  C-reactive protein;
; eGFR  estimated 
glomerular filtration rate; HRR  homologous recombination repair; INR  international normalized ratio; 
LDH  lactate dehydrogenase; MDRD  Modification of Diet in Renal Disease;
 PK  pharmacokinetics; PSMA  prostate-specific membrane antigen; PT  prothrombin 
time; RBC  red blood cell count; SGOT  serum glutamic-oxaloacetic transaminase; SGPT  serum 
glutamic-pyruvic transaminase; WBC  white blood cell 
a eGFR will be based on Modification of Diet in Renal Disease (MDRD) equation (Levey et al, 1999): 
 eGFR = 186 x (Serum Cr-1.154) x (age-0.203) x 1.212 (if subject is black) x 0.742 (if subject is 
female) 
 use serum creatinine (Cr) in mg/dL for this formula 


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11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Team 
Dose Level Review Meetings (DLRM) 
A Dose Level Review Meeting (DLRM) is conducted to review and interpret safety data 
for the purposes of making recommendations about dose-level escalation (either to the 
next planned dose or to an intermediate dose), dose level de-escalation, cohort 
continuation, or cohort expansion; making recommendations about non-dose escalation 
cohorts (eg, expanded, highest dose and/or final cohort); modifying the 
 
 and evaluating safety signals for purposes of applying Dose Cohort Stopping 
Rules.  Per DLRT recommendations additional prophylaxis may be implemented, 
including IV hydration (eg, 1 L normal saline), acetaminophen (eg, 975 mg PO single 
dose), and/or tocilizumab (4-8 mg/kg IV single dose) prior to or immediately after each 
AMG 160 doses in cycle 1.  
 
 
  The 
required Dose Level Review Team (DLRT) members are the medical monitor, Global 
Safety Officer (GSO), and Site Investigators.  The DLRT will include all Site 
Investigators.  The medical monitor, GSO, and Site Investigators are the only voting 
DLRT members.  The following non-voting Amgen representatives may also be part of 
the DLRT:  clinical study manager, biostatistician, or pharmacokinetics (PK) scientist. 
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 Investigator(s).  A Site Investigator may identify a delegate (eg, sub-Investigator) 
who is listed in the Delegation of Authority.  If a Site Investigator does this, the Site 
Investigator must provide written agreement with the designee or delegate’s vote.   
For a DLRM to occur, the medical monitor must attend, and the GSO or delegate must 
attend.  In addition, a quorum of Site Investigators must be present.  A quorum is defined 
as more than 50% of the participating investigators or their qualified designee.  The 
DLRM will be rescheduled if these requirements are not met.  
All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, electrocardiogram (ECG), 
vital signs, and laboratory results will be reviewed.  Data to be reviewed will be 
cleaned/queried. 


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DLRM voting will occur as follows:  there will be a total of 3 votes, 1 for the medical 
monitor, 1 for the GSO or delegate, and 1 for all of the Site Investigators or delegates 
combined.  Regardless of how many Site Investigators there are, all of the Site 
Investigators combined will have a total of 1 vote decided by a majority of the 
investigators (defined as greater than or equal to 50%). 
DLRM recommendations to escalate to the next planned cohort, or to an intermediate 
cohort, must be by unanimous vote.  If the voting members of the DLRT are not able to 
reach a unanimous recommendation on whether to escalate to the next planned cohort 
or to an intermediate cohort, then this should be reflected in the DLRM Memo.  Other 
recommendations, such as expanding a cohort or lowering a dose will be made by a 
majority vote. 
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 Council for 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 that Amgen distributes to the site.  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. 


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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 
 
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 
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 7. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
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 30 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 
interactive response technology (IRT) system (if used, such as subject ID and 
randomization number) and 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. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 


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 
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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11.4 
Appendix 4.  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 events will be defined in the statistical 
analysis plan (SAP). 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], 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 non-small 
cell lung cancer (NSCLC) report all known signs and symptoms.  Death due to 
disease progression in the absence of signs and symptoms should be reported as 
the primary tumor type (eg, metastatic pancreatic cancer).  Note:  The term 
“disease progression” should not be used to describe the 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.  


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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. 
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 


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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. 
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 Assessment of seriousness; 
o Severity (or toxicity defined below); 
o assessment of relatedness to investigational product, other 
protocol-required therapies, and/or study-mandated procedure including 
68Gallium (68Ga)- prostate-specific membrane antigen (PSMA)-11, and 
o Action taken. 
 
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 Amgen 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. 


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 
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. 
Cytokine release syndrome (CRS), which will be graded using the criteria referenced 
in the publication by Lee et al (2014) (see Section 11.10.1) and tumor lysis syndrome 
(TLS), which will be graded according to the Cairo Bishop criteria referenced in the 
publication by Coiffier et al (2008) (see Section 11.10.2), and immune-effector cell 
associated neurologic syndrome (ICANS) will be using the criteria referenced in the 
publication by Lee et al (2019) (see Section 11.10.3). 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies, and/or study-mandated procedure including 
68Ga-PSMA-11 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 and/or Product 
Information, for marketed products, 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 


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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, 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. 
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 via the Safety Report Form.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an electronic Serious Adverse Contingency Report 
Form (see Figure 11-1) 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 
Serious Adverse Event Report Form (see Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related 
to investigational product will be reported to Amgen if the investigator 


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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 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information 
Study-specific contraception requirements for male and female of childbearing potential 
are outlined in Section 5.2. 
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 4 months after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and/or for an increased length of time.  In addition, male 
subjects may also be required to use contraception.  The investigator must discuss 
these contraceptive changes with the subject. 
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: 
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
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 
 
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. 
 
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 
Acceptable Methods of Effective Contraception 
 
Combined (estrogen and progestogen containing) or progestogen-only hormonal 
methods given via oral, intravaginal, transdermal, injectable, or implantable route) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
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) 
 
Male or female condom with or without spermicide 
 
Cap, diaphragm or sponge with spermicide 
 
Double barrier method:  the male uses a condom and the female may choose either 
a cap, diaphragm, or sponge with spermicide (a female condom is not an option due 
to the risk of tearing when both partners use a condom) 
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 4 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 4 months after the last 
dose of AMG 160. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
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 4 months after 
the last dose of the study drug.  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 11.4.  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 7.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
4 months after discontinuing protocol-required therapies, the information will be 


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recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) 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). 
 
Males with pregnant partners or whose partners become pregnant during treatment 
and for an additional 4 months must practice sexual abstinence or use a condom 
through 4 months. 
 
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 4 months after the last dose of 
AMG 160. 
 
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 226. 
 
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 4 months after discontinuing protocol-
required therapies. 


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Figure 11-2.  Pregnancy and Lactation Notification Forms 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood, 
, or pharmacokinetics (PK) samples collected according to 
the Schedule of Activities (Section 1.3) can be analyzed for any of the tests outlined in 
the protocol and for any tests necessary to minimize risks to study subjects.  This 
includes testing to ensure analytical methods produce reliable and valid data throughout 
the course of the study.  This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
lung cancer, the dose response and/or prediction of response to AMG 160, 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 
sample types (eg, blood, 
) samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 


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The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
 


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11.7 
Appendix 7.  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, rhabdomylosis, 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 11-2.  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 
> 3 x ULN  
at any time 
> 2 x ULN 
 
 
OR 
INR 
-- 
> 1.5 x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8 x ULN at any time 
> 5 x ULN but < 8x ULN for 
≥ 2 weeks 
> 5 x ULN but < 8 x ULN and unable 
to adhere to enhanced monitoring 
schedule 
> 3 x 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 
> 3 x ULN (when baseline was < ULN) 
 
OR 
ALP 
> 8 x 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 and 
other protocol-required therapies, as appropriate is to be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Table 11-2) 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 11.4. 
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 11-2 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:  
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic (PK) 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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11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse Events 
Anticipated serious adverse events are events that are anticipated to occur in the study 
population at some frequency independent of investigational product exposure and do 
not need to be reported individually as an FDA IND safety report by the sponsor.  
Identification and reporting of anticipated serious adverse events is the responsibility of 
the sponsor; the investigator is responsible for reporting adverse events and serious 
adverse events as described in Section 11.4. 
Anticipated Serious Adverse Events for Study 20180273 
Preferred Terma 
Brain metastases 
Cancer pain bone pain 
Fatigue 
Hemoptysis 
Hypercalcemia 
Leukopenia 
Pathologic fracture 
Shortness of breath 
Spinal cord compression 
a MedDRA Version 22 
 


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11.9 
Appendix 9.  Modified Toxicity Probability Interval Design (mTPI)  
Trial monitoring rules are based on a modified toxicity probability interval design (mTPI).  
Prespecified monitoring rules are based on mTPI to determine the maximum tolerated 
dose (MTD) with target dose-limiting toxicity (DLT) rate of 28% (Table 11-3).  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).  The safety will 
be assessed based on mTPI Dose Decision Outcomes with a 28% Target DLT Rate.  
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 decisions are made based 
on this posterior probability of toxicity, using three toxicity probability intervals (TPI). 
 
Under-dosing TPI:  DLT rate from 0 to < 23%  
 
Target TPI:  DLT rate from 23% to 33%, inclusive    
 
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 de-escalate.  If DLTs are observed, MTD is the dose level with a 
DLT toxicity rate closest to 28%.  
All subjects who are enrolled and receive at least 1 dose of AMG 160 will be included in 
the analysis, unless otherwise specified.  A formal interim analysis of available safety 
and efficacy data will occur when all remaining dose escalation subjects have had the 
opportunity to complete 28 days on study.  This interim analysis will estimate the MTD1 
and MTD2 associated with the AMG 160 step dose and target doses, support the 
determination of the recommended phase 2 dose (RP2D), and support the evaluation of 
benefit/risk profile of AMG 160.  


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Table 11-3.  mTPI Trial Monitoring Table 
Number of Subjects at current dose 
# of DLTs 2 
3 
4 
5 
6 
7 
8 
9 
10 
0 E 
E 
E 
E 
E 
E 
E 
E 
E 
1 S 
S 
S 
S 
S 
E 
E 
E 
E 
2 DU 
D 
S 
S 
S 
S 
S 
S 
S 
3  
DU 
DU 
D 
D 
S 
S 
S 
S 
4  
DU 
DU 
DU 
DU 
D 
S 
S 
5  
DU 
DU 
DU 
DU 
DU 
D 
6  
DU 
DU 
DU 
DU 
DU 
7  
DU 
DU 
DU 
DU 
8  
DU 
DU 
DU 
9  
DU 
DU 
10  
DU 
 
 E:  Escalate to the next higher dose, if feasible; Otherwise, stay at the same dose; 
S:  Stay at the same dose; D:  De-escalate to the previous lower dose; 
DU:  De-escalate to the previous lower dose and the current dose will never be used 
again in the trial 


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11.10 
Appendix 10.  Specific Guidance for Cytokine Release Syndrome, 
Tumor Lysis Syndrome, and Immune-effector Cell-associated 
Neurologic Syndrome 
11.10.1 
Specific Guidance for Cytokine Release Syndrome 
Cytokine release syndrome (CRS) is clinically defined and may have various 
manifestations.  There are no established diagnostic criteria.  Signs and symptoms of 
CRS may include: 
 
constitutional:  fever, rigors, fatigue, malaise 
 
neurologic:  headache, mental status changes, dysphasia, tremors, dysmetria, gait 
abnormalities, seizure 
 
respiratory:  dyspnea, tachypnea, hypoxemia 
 
cardiovascular:  tachycardia, hypotension 
 
gastrointestinal (GI):  nausea, vomiting, transaminitis, hyperbilirubinemia 
 
hematology:  bleeding, hypofibrinogenemia, elevated D-dimer 
 
skin:  rash 
Subjects may be at an increased risk for CRS during the first few days following 
administration of protocol-required therapies.  CRS may be life threatening or fatal.  
Infusion reactions may be clinically indistinguishable from manifestations of CRS.  
Throughout the treatment with protocol-required therapies, monitor subjects for clinical 
signs (eg, fever, tachycardia, dyspnea, tremors) and laboratory changes 
(eg, transaminase increase) which may be related to CRS. 
Refer to the main protocol body for the more information on the following: 
 
grading and management of CRS (based on the adopted grading system referenced 
in Lee et al, 2014) should be performed according to the guidelines provided 
 
general guidance for re-start of infusion after interruptions/delay/withholding and 
dose modifications. 
 
dose-limiting toxicity (DLT) considerations for grade 3 and 4 CRS 
Fever reported outside the context of CRS will be graded per Common Toxicology 
Criteria for Adverse Events (CTCAE) version 5.0. 


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11.10.2 
Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 classifies tumor 
lysis syndrome (TLS) in grade 3 (present), grade 4 (life threatening consequences; 
urgent intervention indicated) and grade 5 (death).  Presence of TLS is not clearly 
defined by CTCAE version 5.0.  Cairo and Bishop developed a system for defining and 
grading TLS based on Hande-Garrow classification of laboratory or clinical TLS 
(Coiffier et al, 2008).  For this trial, the Cairo-Bishop classification will be used to define 
presence of TLS, ie, presence of laboratory TLS (see Table 11-4) and clinical TLS 
(see Table 11-5) including grading. 
Based on the Cairo and Bishop system, laboratory TLS is defined as any 2 or more 
abnormal serum values present within 3 days before or 7 days after initiation of 
treatment in the setting of adequate hydration (with or without alkalinization) and use of a 
hypouricemic agent (Table 11-4). 
Table 11-4.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
Element 
Value 
Change from Baseline 
Uric acid 
 476 mol/L or 8 mg/dL 
25% increase 
Potassium 
 6.0 mmol/L or 6 mg/L 
25% increase 
Phosphorus 
 2.1 mmol/L for children or 
 1.45 mol/L for adults 
25% increase 
Calcium 
 1.75 mmol/L 
25% decrease 
Note:  Two or more laboratory changes within 3 days before or 7 days after cytotoxic therapy will constitute 
laboratory tumor lysis syndrome. 
Clinical TLS requires the presence of laboratory TLS in addition to 1 or more of the 
following significant complications:  renal insufficiency, cardiac arrhythmias/sudden 
death, and seizures (Table 11-5).  The grade of clinical TLS is defined by the maximal 
grade of the clinical manifestations as detailed in Table 11-5. 


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Table 11-5.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
Grade 
Creatininea,b 
Cardiac Arrhythmiaa 
Seizurea 
0 
 1.5 x ULN 
None 
None 
1 
1.5 x ULN 
Intervention not 
indicated 
-- 
2 
 1.5 – 3.0 x ULN 
Non-urgent medical 
intervention indicated 
One brief, generalized seizure; 
seizure(s) well controlled by 
anticonvulsants or infrequent focal 
motor seizures not interfering with 
ADL 
3 
 3.0 – 6.0 x ULN 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (eg, 
defibrillator)  
Seizure in which consciousness is 
altered; poorly controlled seizure 
disorder; with breakthrough 
generalized seizures despite 
medical intervention 
4 
 6.0 x ULN 
Life-threatening (eg, 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Seizure of any kind which are 
prolonged, repetitive or difficult to 
control (eg, status epilepticus, 
intractable epilepsy) 
5 
Death 
Death 
Death 
Note.  Laboratory TLS and at least 1 clinical complication will constitute clinical TLS. 
ADL = activities of daily living; CHF = congestive heart failure; TLS = tumor lysis syndrome; ULN = upper 
limit of normal 
a Not directly or probably attributable to therapeutic agent. 
b If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:   1 to  12 years of 
age, both male and female, 61.6 mol/L;  12 to  16 years, both male and female, 88 mol/L;  16 years, 
female 105.6 mol/L, male 114.4 mol/L. 


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11.10.3 
Specific Guidance for Immune-effector Cell-associated Neurologic 
Syndrome 
For this trial, immune-effector cell associated neurologic syndrome (ICANS) will be using 
the criteria referenced in the publication by Lee et al (2019).  While the grading system 
has been developed in large part from chimeric antigen receptor T cells (CAR-T) 
therapies, symptoms of ICANS may be shared among immune effector-cell associated 
therapies such as bispecific T-cell engager (BiTE) molecules.  Although there may be a 
wide range of symptoms associated with ICANS, subjects may have a stereotypic 
course of a specific set of symptoms.  The earliest manifestations of ICANS are tremor, 
dysgraphia, mild difficulty with expressive speech (especially in naming objects), 
impaired attention, apraxia, and mild lethargy. 
ICANS grade is determined by the most severe event (eg, depressed level of 
consciousness, seizure, motor findings, raised intracranial pressure [ICP]/cerebral 
edema) not attributable to any other cause.  Refer to the immune effector cellassociated 
encephalopathy (ICE) score below for grading of ICANS. 
Immune Effector Cell-associated Encephalopathy (ICE) Assessment Tool 
 
Orientation:  Orientation to year, month, city, hospital:  4 points  
 
Naming:  ability to name 3 objects (eg, point to clock, pen, button):  3 points 
 
Following commands:  ability to follow simple commands (eg, “Show me two fingers” 
or “Close your eyes and stick out your tongue”):  1 point 
 
Writing:  ability to write a standard sentence (eg, “Our national bird is the bald 
eagle”):  1 point 
 
Attention:  ability to count backwards from 100 by 10:  1 point 
ICE scoring 
 
7-9, grade 1 
 
3-6, grade 2 
 
0-2, grade 3 
 
0 due to subject unarousable and unable to perform ICE 
 
Assessment, grade 4 


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Table 11-6.  ASBMT Immune Effector Cell-associated Neurotoxicity Syndrome 
(ICANS) Consensus Grading for Adults 
Neurotoxicity 
Domaina 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scoreb 
7-9 
3-6 
0-2 
0 (subject is 
unarousable and unable 
and unable to perform 
ICE) 
Depression level 
of consiousnessc 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to 
tactile stimulus 
Subject is unarousable 
or requires vigorous or 
repetitive tactile stimuli 
to arouse. 
Stupor or coma  
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly 
or nonconvulsive 
seizures on EEG that 
resolve with 
intervention 
Life-threatening 
prolonged seizure 
(> 5 min); or repetitive 
clinical or electrical 
seizures without return 
to baseline in between 
Motor findings 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimagingd 
Diffuse cerebral edema 
on neuroimaging; 
Decerebrate or 
decorticate posturing; or 
Cranial nerve VI palsy; 
or Papilledema; or 
Cushing’s triad 
ASBMT = American Society for Blood and Marrow Transplantation; CTCAE = Common Terminology Criteria 
for Adverse Events; EEG = electroencephalogram; ICANS = immune-effector cell associated neurologic 
syndrome; ICE = immune effector cell-associated encephalopathy; ICP = intracranial pressure; N/A = not 
applicable. 
a Other signs and symptoms such as headache, tremor, myoclonus, asterixis, and hallucinations may occur 
and could be attributable to immune effector-cell engaging therapies.  Although they are not included in 
this grading scale, careful attention and directed therapy may be warranted.  
b A subject with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a 
subject with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
c Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication).  
d Intracranial haemorrhage with or without associated edema is not considered a neurotoxicity feature and is 
excluded from ICANS grading It may be graded according to CTCAE v5.0. 
Source:  Lee et al, 2019 
Assessment and Supportive Care Recommendations (all grades) 
 
Neurologic assessment and grading at least twice a day to include cognitive 
assessment and motor weakness 
 
MRI of the brain with and without contrast (or brain computed tomography (CT) if 
MRI is not feasible) for ≥ grade 2 neurotoxicity 
 
Neurology consultation at first sign of neurotoxicity 


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 
Conduct electroencephalogram (EEG) for seizure activity for ≥ grade 2 neurotoxicity 
 
Aspiration precautions; IV hydration 
 
Use caution when prescribing medications that can cause central nervous system 
(CNS) depression (aside from those needed for seizure prophylaxis/treatment) 
Table 11-7.  Assessment and Supportive Care Recommendations 
Treatment 
by Grade 
No Concurrent CRS 
Additional Therapy if 
Concurrent CRS 
Grade 1 
 
Supportive care 
In the setting of grade ≥ 3 CRS 
with hypotension, tocilizumabe,f 
8 mg/kg IV over 1 h (not to exceed 
800 mg/dose) d 
Grade 2c 
 
Supportive care 
 
Dexamethasone 10 mg IV x 1.  Can repeat 
every 6 hours or methylprednisolone 1 mg/kg IV 
every 12 h if symptoms worsen. 
Anti-IL-6 therapy as per grade 1d 
Consider transferring subject to 
ICU if neurotoxicity associated 
with grade ≥2 CRS 
Grade 3c 
 
 Supportive care 
 
Dexamethasone 10 mg IV every 6 h or 
methylprednisolone, 1 mg/kg IV every 12 ha 
 
Consider repeat neuroimaging (CT or MRI) 
every 2-3 days if subject had persistent 
grade ≥ 3 neurotoxicity. 
Anti-IL-6 therapy as per grade 1d 
Grade 4c 
 
ICU care, consider mechanical ventilation for 
airway protection. 
 
High-dose corticosteroids a,b 
 
Consider repeat neuroimaging (CT or MRI) 
every 2-3 days if subject has persistent 
grade ≥ 3 neurotoxicity. 
 
Treat convulsive status epilepticus per 
institutional guidelines. 
Anti-IL-6 therapy as per grade 1d 
CRS = cytokine release syndrome; CT = computed tomography; ICU = intensive care unit; 
IL-6 = interleukin-6; IV = intravenous; MRI = magnetic resonance imaging; PK = pharmacokinetics. 
a Antifungal prophylaxis should be strongly considered in subjects receiving steroids for the treatment of 
CRS and/or neurotoxicity. 
b For example, methylprednisolone IV 1000 mg/day for 3 days, followed by rapid taper at 250 mg every 
12 hours for 2 days, and 60 mg every 12 hours for 2 days. 
c Diagnostic lumbar puncture for grade 3-4 neurotoxicity; consider for grade 2. 
d Repeat tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing supplemental 
oxygen.  Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. 
e If tocilizumab is not available, siltuximab (an anti-IL-6 monoclonal antibody) may be used in the 
management of cytokine release syndrome, following the criteria outlined in the Management of Adverse 
Events table.  The recommended dose of siltuximab is 11 mg/kg administered over 1 hour as an 
intravenous infusion, consistent with the prescribing information for the treatment of multicentric 
Castleman’s disease (Sylvant Prescribing Information), and the CARTOX Working Group Guidelines for 
CRS management (Neelapu, 2018).  Siltuximab may be repeated if needed, in the event that CRS recurs 
after a subsequent infusion of AMG 160.  Siltuximab may not be repeated in an individual subject that 
develops anaphylaxis to siltuximab, or gastrointestinal perforation after siltuximab. 
f A subgroup analysis for subjects treated with siltuximab will be evaluated, including CRS outcomes, safety, 
and PK data. 
.


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11.11 
Appendix 11.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) 
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 house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group. 
Source:  Oken et al, 1982


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11.12 
Appendix 12.  Response Evaluation Criteria in Solid Tumors 
Version 1.1 (modified RECIST 1.1) 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) are guidelines 
for assessing tumor burden changes in response to treatment (Eisenhauer et al, 2009).  
Additional patterns of response have been observed with immune-enhancing therapies, 
including delayed clinical response, leading to criteria modifications to capture treatment 
responses more accurately (Wolchok JD et al, 2009; Nishino M et al, 2013).  This study 
utilizes modified RECIST 1.1 criteria which applies aspects of the immune-related 
response criteria (including requiring confirmation of disease progression) to RECIST 1.1 
as outlined below. 
Modified RECIST 1.1 tumor response assessment 
 
All measurable and non-measurable lesions should be assessed at screening, all 
defined tumor assessment time points (Schedule of Assessment), and any 
unscheduled imaging visits. 
Measurable lesions: 
 
Non-nodal lesions with clear borders that can be measured accurately and 
serially in one dimension in the axial plane (longest diameter ≥ 10 mm measured 
by MRI/CT with scan slice thickness ≤ 5 mm). 
 
Nodal lesions with the longest diameter perpendicular to the long axis (short axis) 
≥ 15 mm on MRI/CT.  
 
Must exclude simple cysts, pleural/pericardial effusions and ascites. 
Non-measurable lesions: 
 
All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 mm but < 15 mm short axis) are considered 
non-measurable and characterized as non-target lesions.   
 
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.  See Imaging 
Procedural Manual provided by the central imaging core laboratory for 
additional guidance. 


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Target lesions and measurable tumor burden: 
 
Target lesions: 
 
Measurable lesions (≤ 5 lesions per organ, ≤ 10 total) selected at baseline 
on the basis of  
▪ 
Size and suitability for accurate repeated measurements by 
imaging.   
▪ 
Representative of the subject’s tumor burden, all organs involved 
and overall disease status  
Non-target lesions: 
 
All measurable lesions not selected as target lesions and non-measurable 
lesions   
 
Non target lesions will be qualitatively evaluated  
 
Values: ‘Present’, ‘absent’ or ‘unequivocal progression’.   
 
Other definitions 
 
Unable to evaluate (UE):  Any lesion present at baseline which was not 
assessed or was unable to be evaluated leading to an inability to 
determine the status of that particular tumor for that time point 
 
Not Available (NA):  Scan not available 
 
Not Done (ND):  Radiologic imaging was not performed at this time point 
to evaluate the target lesions 
Target lesion response: 
 
At baseline and all subsequent tumor assessments, measurable tumor burden is 
the sum of the longest diameters (SLD) of all target lesions 
 
Complete Response (CR) – disappearance of all measurable lesions 
 
Pathologic lymph nodes must have reduction in short axis to < 10 mm  
 
Partial Response (PR) – decrease of 30% or greater in tumor burden compared 
with baseline 
 
Stable Disease (SD) - not meeting the criteria for CR, PR, or progressive disease 
 
Progressive Disease – increase of 20% or greater in tumor burden compared 
with nadir, or the appearance of one or more new lesions 
Non-target lesion response: 
 
CR – disappearance of all non-target lesions 
 
Pathologic lymph nodes must have reduction in short axis to < 10 mm 
 
SD – persistence of one or more non-target lesions, not meeting the criteria for 
CR or progressive disease   
 
Progressive disease – unequivocal progression of existing non-target lesions, or 
the appearance of one or more new lesions    


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Overall response: 
 
CR 
o Complete disappearance of all lesions 
▪ 
Pathologic lymph nodes must have reduction in short axis to 
< 10 mm 
o Confirmation scan required - repeat, consecutive assessment no less 
than 4 weeks from the date of the first documented response 
o CR is dated at time of confirmation scan 
 
PR 
o Decrease in tumor burden ≥ 30% relative to baseline, or 
o Complete disappearance of all target lesions with presence of non-target 
lesions 
o Confirmation scan required - repeat, consecutive assessment no less 
than 4 weeks from the date of the first documented response 
o PR is dated at time of confirmation scan 
 
SD 
o Target lesions not meeting criteria for CR, PR or progressive disease, or  
o In subjects with only non-target disease, persistence of one or more 
non-target lesions 
 
Progressive Disease 
o Radiologic detection of ≥ 20% increase in tumor burden relative to nadir 
and at least 5 mm absolute increase, or  
o Unequivocal progression of non-target lesions, or 
o The presence of new lesions  
 
Confirmation scan required - repeat, consecutive assessment 4-6 weeks 
from the date of the first documented response 
▪ 
Radiographic progressive disease is confirmed at repeat 
imaging (progressive disease on two consecutive scans 
4-6 weeks apart) if: 
 
Tumor burden remains increased by ≥ 20% and at least 
5 mm absolute increase relative to nadir, or  
 
Unequivocal progression of non-target lesions is 
observed, or 
 
New lesions are present  
▪ 
Subjects with a global deterioration of health status requiring 
discontinuation of treatment prior to radiologic confirmation of 
disease progression should have the reason for treatment 
discontinuation classified as ‘clinical disease progression’ not 
‘radiographic progressive disease’.  Every effort should be made 
to radiologically confirm progression even after discontinuation of 
treatment. 


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Summary of Measurement and Tumor Response Assessment Based on Modified 
RECIST 1.1 
Measurable lesions 
 
Non-nodal lesions: ≥ 10 mm (unidimensional 
measurement)  
 
Pathologic lymph nodes:  longest diameter short axis 
≥ 15 mm 
Measurement of each lesion 
 
Non-nodal lesions:  The longest diameter (mm) in the 
axial plane 
 
Pathologic lymph nodes:  short axis (mm)  
Tumor burden 
 
Sum of the longest diameters (SLD) of all target lesions 
 
Up to 5 lesions per organ, up to 10 total 
Response assessment:  target 
lesions 
(calculated from % change in 
tumor burden) 
 
CR:  Disappearance of all lesions  
 Pathologic lymph nodes short axis < 10 mm 
 
PR: ≥ 30% decrease from baseline  
 
SD:  Does not meet criteria for CR, PR or progressive 
disease. 
 
Progressive disease: ≥ 20% increase (and ≥ 5 mm 
absolute increase) from nadir  
Response assessment:  
non-target lesions 
 
CR:  Disappearance of all lesions  
 Pathologic lymph nodes short axis < 10 mm 
 
SD:  Persistence of one or more non-target lesion(s) 
 
Progressive disease:  Unequivocal progression of 
existing non-target lesions 
New Lesions 
The presence of new lesion(s) defines progression  
Confirmation 
Confirmation by subsequent assessment after ≥4 weeks 
required for CR, PR and progressive disease. 
 
Summary of modified RECIST 1.1 Overall Response Assessment 
Target lesions (tumor 
burden)a, % 
Non-target lesions 
New lesions 
Overall Response using 
modified RECIST 1.1 
↓ 100% 
Absent 
Absent 
CRb 
Noned 
Absent 
Absent 
CRb 
↓ 100% 
Present  
Absent 
PRb 
↓ >30% 
Absent/Present 
Absent 
PRb 
↓ <30% to ↑ <20% 
Absent/Present 
Absent 
SD 
Noned 
Present 
Absent 
SD 
↑ >20% 
Any 
Any 
Progressive diseasec 
Any 
Unequivocal progression 
Any 
Progressive diseasec 
Any 
Any 
Present 
Progressive diseasec 
NA/ND/UE 
Absent/Present 
Absent 
UE 
Noned 
NA/ND/UE 
Absent 
UE 
CR = complete response; NA = not available; ND = not done; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease; UE = unable to evaluate 
a Decrease assessed relative to baseline.  Increase assessed relative to nadir. 
b Response:  CR and PR require a confirmation assessment after ≥4 weeks, may also wait until the next 
scheduled imaging 
c Progression:  Progressive disease requires a confirmation assessment 4-6 weeks after initial radiographic 
progressive disease is observed 
d Subjects with non-target lesions only 


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11.13 
Appendix 13.  COVID-19 Guidance 
 
Subjects who test positive for coronavirus disease 2019 (COVID-19) using a test 
consistent with the institutional standard of care or who are exhibiting symptoms 
consistent with COVID-19 should not be enrolled in the study until complete 
resolution of symptoms. 
 
If an enrolled subject is exhibiting symptoms consistent with COVID-19, contact the 
Amgen Medical Monitor within 1 business day to ensure appropriate documentation 
and management of study activities. 
 
If a subject is unable to travel to the site for protocol-specified study visits and 
procedures, he/she can remain in the trial, provided that safety monitoring can occur.  
Alternatives, such as telemedicine to conduct visits, should be considered. 
 
On-site monitoring visits may be replaced by remote monitoring visits during 
COVID-19.  Additionally, remote source document verification may be utilized for 
critical data points.  
 
Additional COVID-19 guidance from Food and Drug Administration (FDA) and 
European Medicines Agency (EMA) should be followed in consultation with Amgen 
medical monitor. 
 


Product:  AMG 160 
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Date:  25 March 2022 
Page 1 of 12 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
and Efficacy of AMG 160 in Subjects with Non-Small Cell Lung Cancer 
 
Amgen Protocol Number (AMG 160) 20180273 
NCT Number:  NCT04822298 
 
Amendment Date: 
25 March 2022 
 
Rationale: 
This protocol is being amended due to a change in the key safety risks for AMG 160.  
 
 
 
 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  19 October 2021 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
and Efficacy of AMG 160 in Subjects with Non-Small Cell Lung Cancer 
 
Amgen Protocol Number AMG 160 20180273 
EudraCT number:  to be determined 
NCT Number:  NCT04822298 
 
Amendment Date: 
19 October 2021 
 
Rationale: 
This protocol is being amended to address site shortages of tocilizumab.  Applicable sections of 
the protocol are being modified to clarify the use of siltuximab in place of tocilizumab for the 
treatment of potential cytokine release syndrome (CRS) during a treatment-related adverse 
event.  
 
.  Additional language was 
included to update/clarify other items in the protocol.  The following changes were incorporated 
into the study: 
 
Electrocardiograms (ECGs) were removed from the primary endpoints. 
 
 
 
  
 
Added language to Overall Design in Sections 1.1 and 4.1 to allow additional subjects to 
be enrolled at 1 or more monotherapy dose levels that have been shown to be safe and 
tolerable. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  19 October 2021 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Subject Enrollment in Section 5.3 was modified to incorporate designee or staff 
members as additional personnel responsible for the documentation of subject 
enrollment to study.   
 
Added language to Subject Enrollment in Section 5.3 to clarify that: 
o subject enrollment in study will need additional confirmation from sponsor 
o study treatment should begin following study enrollment but no later than 7 days 
after enrollment 
 
Treatment/Other Protocol-Required Therapies Section 6.1.5 was added to clarify that 
sites are required to have tocilizumab or siltuximab for potential treatment of CRS.  
 
Criteria for use of siltuximab in place of tocilizumab, justification for the proposed dose 
and schedule, and safety stopping rules were included as Section 6.2.1.4. 
 
Added language to Concomitant Treatments Section 6.7.2 to clarify site availability of 
tocilizumab or siltuximab for CRS treatment.  
 
Added language to Section 8.1.1 to clarify that the use of standard of care radiographic 
assessments can be used for the screening process prior to signing of informed consent. 
 
Vital Sign Time Points Table 8-1 was updated to incorporate vital sign measurements for 
short term infusions. 
 
Added footnotes to Tables 6-3 and 11-7 to clarify the alternative use of siltuximab when 
tocilizumab is unavailable, and to incorporate a subgroup analysis that evaluates CRS 
outcomes, safety, and pharmacokinetic (PK) data of siltuximab-treated subjects.  
 
Administrative, typographical, and formatting changes throughout the protocol. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  29 July 2021 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 160 in Subjects with Non-Small Cell Lung 
Cancer 
Amgen Protocol Number AMG 160 (acapatamab) 20180273 
 
Amendment Date: 
29 July 2021 
Rationale: 
The rationale for this protocol amendment is to include the following updates: 
 
Updated to include guidance relating to coronavirus disease 2019 (COVID-19): 
 
Eligibility criteria was updated to exclude subjects that have severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
 
Guidance for COVID-19 vaccinations was added (Sections 6.7.2 and 6.7.2.6) 
 
Table 6-3 was updated to include management for subjects with asympotomatic 
and symptomatic SARS-COV-2 infection and COVID-19 disease 
 
Update to include minor clarifications regarding Statistical Considerations such as 
the modified toxicity probability interval (mTPI) (Section 9.2 and Table 11-3) and the 
futility analysis (Section 9.4.1.1) 
 
Several sections of the protocol have been updated to include required alignments 
with current Amgen protocol template (Sections 8.2.4, 8.2.4.1.3, 11.2, 11.3, 11.13). 
 
Administrative and editorial changes (including grammatical, typographical, and 
formatting) have been made throughout the protocol. 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 January 2021 
Page 1 of 52 
Amgen Proprietary - Confidential 
Superseded Amendment 1 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 160 in Subjects with Non-Small Cell Lung 
Cancer 
Amgen Protocol Number AMG 160 20180273 
 
Amendment Date: 
Superseded Amendment 
Date: 
20 October 2020 
25 January 2021 
 
Rationale: 
- 
Potential differences in prostate specific membrane antigen (PSMA) expression 
between castrate-resistant prostate cancer (CRPC) and non-small cell lung 
cancer (NSCLC) may lead to disease-related safety profile differences. Given the 
potential for a different safety profile in NSCLC, the starting dose has been 
adjusted to begin at 1 dose level below the RP2D identified in Study 20180101 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  25 January 2021 
Page 2 of 52 
Amgen Proprietary - Confidential 
- 
The dose limiting toxicity (DLT) definition has been modified to include additional 
life-threatening events, including Grade 4 anemia, Grade 4 non-hematologic 
laboratory abnormality of any duration and Grade 3 or higher thrombocytopenia 
with clinically significant bleeding regardless of duration of thrombocytopenia. 
Additionally, the DLT definition has been updated to include Grade 4 neutropenia 
lasting > 7 days, Grade 4 thrombocytopenia lasting > 7 days and Grade 3 
transaminitis associated with CRS that resolves to grade 1 within 5 days. DLT 
criteria has also been updated to include AST/ALT/bilirubin elevations meeting 
Hy’s law criteria as a DLT 
- 
Updated inclusion criteria # 105 regarding prior adjuvant or neoadjuvant 
chemotherapy to specify platinum-based adjuvant or neoadjuvant chemotherapy 
and to adjusted inclusion criteria # 105 to allow subjects who progress on at least 
1 prior anti-PD1/PDL1 therapy and deemed unsuitable for treatment with 
chemotherapy or actively refused treatment with chemotherapy to be eligible 
On 25 January 2021, the protocol was superseded to correct minor typographical errors 
in the approved amendment. 
 
 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  20 October 2020 
Page 1 of 50 
Amgen Proprietary - Confidential 
Amendment 1 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 160 in Subjects with Non-Small Cell Lung 
Cancer 
Amgen Protocol Number AMG 160 20180273 
 
Amendment Date: 
20 October 2020 
 
Rationale: 
- 
Potential differences in prostate specific membrane antigen (PSMA) expression 
between castrate-resistant prostate cancer (CRPC) and non-small cell lung 
cancer (NSCLC) may lead to disease-related safety profile differences. Given the 
potential for a different safety profile in NSCLC, the starting dose has been 
adjusted to begin at 1 dose level below the RP2D identified in Study 20180101 
- 
The dose limiting toxicity (DLT) definition has been modified to include additional 
life-threatening events, including Grade 4 anemia, Grade 4 non-hematologic 


Product:  AMG 160 
Protocol Number:  20180273 
Date:  20 October 2020 
Page 2 of 50 
Amgen Proprietary - Confidential 
laboratory abnormality of any duration and Grade 3 or higher thrombocytopenia 
with clinically significant bleeding regardless of duration of thrombocytopenia. 
Additionally, the DLT definition has been updated to include Grade 4 neutropenia 
lasting > 7 days, Grade 4 thrombocytopenia lasting > 7 days and Grade 3 
transaminitis associated with CRS that resolves to grade 1 within 5 days. DLT 
criteria has also been updated to include AST/ALT/bilirubin elevations meeting 
Hy’s law criteria as a DLT 
- 
Updated inclusion criteria # 105 regarding prior adjuvant or neoadjuvant 
chemotherapy to specify platinum-based adjuvant or neoadjuvant chemotherapy 
and to adjusted inclusion criteria # 105 to allow subjects who progress on at least 
1 prior anti-PD1/PDL1 therapy and deemed unsuitable for treatment with 
chemotherapy or actively refused treatment with chemotherapy to be eligible 
 

SAP_001.pdf: 
Product:  AMG 160  
Protocol Number:  20180273 
Date:  11 October 2022 
Page 1 of 50 
CONFIDENTIAL  
 
 
Confidential General and Administrative 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of AMG 
160 in Subjects with Non-Small Cell Lung Cancer 
Short Protocol Title: 
A Phase 1b Study of AMG 160 in Subjects with Non-
Small Cell Lung Cancer 
Protocol Number: 
20180273 
NCT Number: 
NCT04822298 
Authors: 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
SAP Date: 
Document Version 
Original (v1.0) 
Date 
21 September 2021 
Amendment (v2.0) 
11 October 2022 


Product:  AMG 160  
Protocol Number:  20180273 
Date:  11 October 2022 
Page 2 of 50 
CONFIDENTIAL  
 
 
Confidential General and Administrative 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
21SEP2021 
Original SAP 
Amendment (v2.0) 
11OCT2022 
Changes related to protocol 
amendment 3 dated 19 October 2021 
and protocol amendment 4 dated 25 
March 2022. 
Updated the Definitions for TEAE, 
TRAE, Clinical progression, time to 
radiographic progression, subsequent 
therapy, Baseline triplicate, . 
Added Recist 1.1 evaluable analysis 
set. 
Updated Appendix C, added BOR 
derivation, added interim analysis 
response definitions. 
Updated Appendix B and Appendix D 
Added Appendix E. 
 


Product:  AMG 160  
Protocol Number:  20180273 
Date:  11 October 2022 
Page 3 of 50 
CONFIDENTIAL  
 
 
Confidential General and Administrative 
Table of Contents 
1. 
Introduction ............................................................................................................. 8 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 8 
2.1 
Objectives and Endpoints/Estimands .......................................................... 8 
2.2 
Hypotheses and/or Estimations ................................................................... 9 
3. 
Study Overview ...................................................................................................... 9 
3.1 
Study Design ............................................................................................... 9 
3.2 
Sample Size .............................................................................................. 11 
4. 
Covariates and Subgroups ................................................................................... 12 
4.1 
Planned Covariates ................................................................................... 12 
5. 
Definitions ............................................................................................................. 13 
5.1 
Study Endpoints ........................................................................................ 13 
5.1.1 
Primary Endpoints Definitions .................................................... 13 
5.1.2 Secondary Endpoints Definitions ...................................................... 13 
5.2 
Study Time Points ..................................................................................... 16 
5.3 
Demographics and Baseline Related Definitions ....................................... 17 
6. 
Analysis Sets ........................................................................................................ 18 
6.1 
Safety Analysis Set ................................................................................... 18 
6.2 
RECIST 1.1 Evaluable Analysis Set .......................................................... 18 
6.3       DLT Analysis Set ...................................................................................... 18 
7. 
Planned Analyses ................................................................................................. 18 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 18 
7.1.1 
Stopping Rules for Treatment With Siltuximab ........................... 21 
7.2 
Primary Analysis ....................................................................................... 23 
7.3 
Final Analysis ............................................................................................ 23 
8. 
Data Screening and Acceptance ........................................................................... 23 
8.1 
General Principles ..................................................................................... 23 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 23 
8.3 
Handling of Missing and Incomplete Data ................................................. 23 
8.4 
Detection of Bias ....................................................................................... 24 
8.5 
Outliers ..................................................................................................... 24 
8.6 
Distributional Characteristics ..................................................................... 24 
8.7 
Validation of Statistical Analyses ............................................................... 24 
9. 
Statistical Methods of Analysis.............................................................................. 24 
9.1 
General Considerations ............................................................................. 24 
9.2 
Subject Accountability ............................................................................... 25 
9.3 
Important Protocol Deviations ................................................................... 25 


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Protocol Number:  20180273 
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CONFIDENTIAL  
 
 
Confidential General and Administrative 
9.4 
Demographic and Baseline Characteristics ............................................... 26 
9.5 
Efficacy Analyses ...................................................................................... 26 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 26 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 26 
9.6 
Safety Analyses ........................................................................................ 28 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 28 
9.6.2 
Adverse Events ......................................................................... 29 
9.6.3 
Laboratory Test Results ............................................................ 29 
9.6.4 
Vital Signs and ECOG ............................................................... 30 
9.6.5 
Physical Measurements ............................................................ 30 
9.6.6 
Electrocardiogram ..................................................................... 30 
9.6.8 
Exposure to Investigational Product .......................................... 30 
9.6.9 
Exposure to Non Investigational Product ................................... 30 
9.6.10 
Exposure to Other Protocol-required Therapy ........................... 31 
9.6.11 
Exposure to Concomitant Medication ........................................ 31 
9.7 
Other Analyses ......................................................................................... 31 
9.7.1 
Analyses of Pharmacokinetic or Pharmacogenetic 
Endpoints .................................................................................. 31 
10. 
Changes From Protocol-specified Analyses.......................................................... 31 
11. 
Literature Citations / References ........................................................................... 32 
12. 
Prioritization of Analyses....................................................................................... 32 
13. 
Data Not Covered by This Plan............................................................................. 32 
14. 
Appendices ........................................................................................................... 33 
Appendix B.  Code Fragments ....................................................................................... 37 
Appendix C.  RECIST (v1.1) Criteria ............................................................................. 38 
Appendix D.  Additional Definition ................................................................................. 45 
Appendix E.  Censoring Rules ....................................................................................... 47 
 
 
List of Table 
Table 7-1.  Stopping Boundary for Dose Expansion With Posterior Probability 
of 80% and Grade 4 or Higher Treatment-related Adverse 
Event Limit of 20% .................................................................................. 20 
Table 7-2.  Operating Characteristics With Batch Size of 10 Subjects ........................... 20 


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Table 7-3.  Objective Response Rate Stopping Boundary ............................................. 21 
Table 9-1.  Secondary Efficacy Endpoint Summary Table ............................................. 27 
Table 9-2.  Exploratory Efficacy Endpoint Summary Table ............................................ 29 
Table 9-3.  Primary Safety Endpoint Summary Table .................................................... 29 
List of Figures 
Figure 7-1   The Probability of Stopping The Trial Early  ................................................ 21 
List of Appendices 
Appendix B.  Code Fragments ....................................................................................... 37 
Appendix C.  RECIST (v1.1) Criteria ............................................................................. 38 
Appendix D.  Additional Definition ................................................................................. 45 
Appendix E.  Censoring Rules ....................................................................................... 47 
 


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List of Abbreviations 
 
Abbreviation or Term 
Definition/Explanation 
AUC 
area under the concentration-time curve 
Cmax 
maximum serum concentration 
Cmin 
minimum serum concentration 
CI 
confidence intervals 
CR 
complete response 
CRS 
cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT 
computed tomography 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose-limiting toxicities 
ECG 
electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOI 
end of investigational product 
FIH 
first in human 
68Ga 
68Gallium 
ICANS 
immune-effector cell associated neurologic syndrome 
IV 
Intravenous 
mCRPC 
metastatic castration-resistant prostate cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
disease progression 
PD1 
programmed cell death protein 1 
PDL1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
 
 


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Abbreviation or Term 
Definition/Explanation 
PSMA 
prostate-specific membrane antigen 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase 2 dose 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
stable disease 
t1/2 
half-life 
TPI 
toxicity probability intervals 
 


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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 4 for study  20180273, 
AMG 160 dated 25 March 2022.  The scope of this plan includes the interim analysis, 
the primary analysis and the final analysis 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/Estimands 
 
 
Objectives 
 
Endpoints 
 
Primary 
 
To evaluate the safety and 
tolerability of AMG 160 
 
To evaluate the maximum 
tolerated dose (MTD) or the 
recommended phase 2 dose 
(RP2D) 
 
Dose-limiting toxicities (DLT) 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs, 
electrocardiograms (ECGs), and 
clinical laboratory tests 
 
Secondary 
 
To characterize the 
pharmacokinetics (PK) of 
AMG 160 
 
PK parameters for AMG 160 
following intravenous (IV) 
administration including but not 
limited to, maximum serum 
concentration (Cmax), minimum 
serum concentration (Cmin), area 
under the concentration-time 
curve (AUC) over the dosing 
interval, accumulation, and 
half-life (t1/2) 
 
To evaluate the preliminary 
anti-tumor activity of AMG 160 
 
Objective response (OR) per 
modified Response Evaluation 
Criteria in Solid Tumors 
(RECIST) 1.1  
 
Overall Survival 
 
Progression-free survival 
(radiographic, clinical)  
 
Time to response 
 
Time to progression (radiographic, 
clinical) 
 
Duration of response  
 
Time to subsequent therapy 


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Exploratory 
 
2.2 
Hypotheses and/or Estimations 
No formal statistical hypotheses will be tested. 
3. 
Study Overview 
3.1 
Study Design 
This is an open label phase 1b study evaluating the safety, tolerability, pharmacokinetics 
(PK), and efficacy of AMG 160 monotherapy in subjects with relapsed, refractory non-
small cell lung cancer (NSCLC). There are 2 parts in the study, 
 
Dose-exploration 
 
Dose-expansion 
Dose-exploration 
The dose-exploration part of the study will estimate the MTD/RP2D of AMG 160 in 
NSCLC where the AMG 160 monotherapy will be administered as a short-term IV 
infusion every 2 weeks after target dose is reached in a 28-day cycle as monotherapy 
therapy.  The starting dose of AMG 160 will be 1 dose level below the RP2D or 
otherwise the highest dose level deemed safe and tolerable as determined in the 
ongoing first in human (FIH) study of AMG 160 (Study 20180101) in subjects with 
mCRPC. 
To mitigate the risk of CRS 
 
  Based on the MTD or RP2D and the associated dosing schedule 


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selected in Study 20180101, one of the following 
 schedules will be 
implemented:  
 infusion (see Table 6-1 in protocol for 
further details). 
Dose Level Determination 
Dose exploration will begin with 2 to 4 subjects.  The study DLT window is 28 days. To 
be DLT evaluable, subjects must receive all planned cycle 1 doses of AMG 160.  After a 
minimum of 2 subjects enrolled at a certain dose level are DLT evaluable, a DLRT 
meeting will be convened.  Depending on observed safety data, the following may occur: 
1. additional enrollment to dose Level 1; or 
2. dose de-escalation to 1 dose below the starting dose; or 
3. alternative dosing schedules, including further dose escalation, as per the ongoing 
mCRPC trial (Study 20180101), may be explored based on emerging safety and PK 
data. 
Rules for dose-escalation/de-escalation are derived using a modified toxicity probability 
interval (mTPI) model with a target toxicity probability of 0.28. 
Dose level decisions are made based on this posterior probability of toxicity, using 
3 toxicity probability intervals (TPI): 
 
under-dosing TPI:  DLT rate from 0 to  23% 
 
target TPI:  DLT rate from 23% to 33%, inclusive 
 
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 or stay at the current level.  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 de-escalate.  If DLTs are observed, the 
MTD is the dose level with a DLT toxicity rate closest to 28%. The mTPI Trial monitoring 
table is described in Table 3.1


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Table 3.1 .  mTPI Trial Monitoring Table 
Number of Subjects at current dose 
# of DLTs 2 
3 
4 
5 
6 
7 
8 
9 
10 
0 E 
E 
E 
E 
E 
E 
E 
E 
E 
1 S 
S 
S 
S 
S 
E 
E 
E 
E 
2 DU 
D 
S 
S 
S 
S 
S 
S 
S 
3  
DU 
DU 
D 
D 
S 
S 
S 
S 
4  
DU 
DU 
DU 
DU 
D 
S 
S 
5  
DU 
DU 
DU 
DU 
DU 
D 
6  
DU 
DU 
DU 
DU 
DU 
7  
DU 
DU 
DU 
DU 
8  
DU 
DU 
DU 
9  
DU 
DU 
10  
DU 
E:  Escalate to the next higher dose, if feasible; Otherwise, stay at the same dose; 
S:  Stay at the same dose; D:  De-escalate to the previous lower dose; DU:  De-escalate 
to the previous lower dose and the current dose will never be used again in the trial 
Dose Expansion 
If 1 or more objective responses (OR) are observed (per modified RECIST 1.1 criteria) in 
dose exploration, additional subjects (up to 40) will be enrolled in dose expansion of the 
study at the MTD/RP2D identified in dose exploration.  In dose expansion, 2 cohorts will 
be opened: 
 
Cohort 1 (up to 30 subjects with non-squamous NSCLC) and 
 
Cohort 2 (up to 10 subjects with squamous NSCLC). 
Based on emerging safety and tolerability data in Cohort 2, the dose of AMG 160 could 
be lowered 1 dose level below the starting dose identified in dose exploration if 
necessary. Dose modification may occur as a result of interim analysis as described in 
Section 7.1. 
3.2 
Sample Size 
Up to 50 subjects will be enrolled in the study (approximately 10 subjects in a dose 
exploration phase and up to 40 subjects in a dose expansion phase). Additional 
subjects (up to 20) may be enrolled in 1 or more monotherapy dose levels that 


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have been shown to be safe and tolerable (defined as backfill enrollment). This 
backfill enrollment may be done to better estimate the RP2D and better 
characterize the safety, efficacy, PK, and 
 of AMG 160 
monotherapy and may be concurrent with dose escalation to identify the MTD. 
An initial 2 to 4 subjects will be enrolled and treated with Dose Level 1 (1 dose level 
below RP2D of AMG 160 Study 20180101). Rules for dose-escalation/de-escalation are 
derived using an mTPI model with a target toxicity probability of 0.28. If the dose is not 
tolerated (based on target DLT rate > 28%), the dose level will be reduced 1 level below 
the starting dose.  Alternative dosing schedules, including further dose escalation as per 
the ongoing mCRPC trial (Study 20180101), may be explored based on emerging safety 
and PK data.  The sample size in the dose exploration phase is based on practical 
consideration and is consistent with conventional oncology studies with the objective to 
estimate the MTD. 
With 2 subjects in a cohort, there is a 19% to 55% probability of observing at least 1 DLT 
if the true DLT rate is 10% to 33% and with 4 subjects in a cohort, there is a 34% to 80% 
probability.  With 6 subjects in a cohort, there is a 47% to 91% probability of observing at 
least 1 DLT if the true DLT rate is 10% to 33% and with 10 subjects in a cohort, there is 
a 65% to 98% probability. 
In the dose expansion phase, a subject number of 40 will provide a 87% probability of 
observing at least 1 adverse event with 5% incidence rate.  An exact 95% binomial CI 
will be provided for overall response rate.  With the 40 subjects and 20% overall 
response rate, the expected 95% CI would be 9% to 36%. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The relationship between covariates and efficacy endpoints may be explored if 
appropriate and will be finalized in the Statistical Analysis plan before the database 
lock. 


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5. 
Definitions 
5.1 
Study Endpoints  
5.1.1 
Primary Endpoints Definitions 
Dose-limiting Toxicities (DLTs): 
Investigators determine whether a TEAE qualifies as a DLT per the definition described 
in protocol section 6.2.1.3. For an adverse event to qualify as DLT, the start date must 
be within 28 days from the date of first dose of AMG 160. 
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) 
Treatment-Emergent Adverse Event (TEAE): 
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product (AMG 160) as determined by the flag indicating if the AE 
started prior to the first dose on the Events eCRF and including 30 days after the 
last dose of investigational product (AMG 160) or End of Study date or start of 
new anti-cancer therapy, whichever is earlier.  
Treatment-Related Adverse Event (TRAE): 
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 (AMG 160) determined by the flag indicating an event may 
have been caused by the investigational product (AMG 160) on the events eCRF. 
In the unlikely event that the flag is missing, the TEAE will be considered 
treatment-related. 
5.1.2 Secondary Endpoints Definitions  
Objective Response (OR) per RECIST 1.1: 
Objective Response is defined as a best overall response (Appendix C) of either 
Complete Response (CR) or Partial Response (PR) per RECIST 1.1. Radiographic 
response (Complete Response, Partial Response) requires confirmation by a repeat, 
evaluable scan at least 28 days after the first documentation of response. 
Subjects who do not experience a PR/CR or do not have any follow-up tumor 
assessments will be regarded as non-responders. 


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Overall Survival (OS): 
Overall survival is defined as the time from the date of Study Day 1 until death due to 
any cause: 
OS time (Days) = date of death - Study Day 1 + 1. 
Any subject not known to have died at the time of analysis will be censored based on the 
last recorded date on which the subject was alive. 
Duration of Response (DOR): 
The duration of response is defined as time from first evidence of CR or PR to disease 
progression or death due to any cause, whichever occurs first. DOR will be calculated 
only for subjects who achieve a best overall response of PR or CR. 
DOR (months) = (PD / death date - response start date + 1) ×12 / 365.25 
 
The time of the initial response will be defined as the earliest of the dates contributing 
towards the first visit response of PR or CR. 
o For confirmed responders whose PR or CR are confirmed in two 
evaluable assessments, the first PR/CR assessment among the two 
evaluable assessments will be used to calculate DOR. 
o For unconfirmed responders awaiting follow-up confirmation scans, the 
PR or CR assessment that is awaiting confirmation scan will be used to 
calculate DOR. 
Censoring rules for Duration of Response (DOR): 
 
Data for responders who are alive and without disease progression or new anti-
cancer therapy are censored at the time of last evaluable tumor assessment 
by CT/MRI scan. 
 
Data for responders who are alive and without disease progression but who 
start new anti-cancer therapy are censored at the time of last evaluable tumor 
assessment by CT/MRI scan before the start of new anti-cancer therapy. 
 
Data for responders who die or have disease progression after two or more 
missed evaluable tumor assessments are censored at the time of last evaluable 
tumor assessments by CT/MRI scan before the two or more missed evaluable 
tumor assessments. 
Details about the censoring rules are included in Appendix E. 


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Radiographic Progression: 
Disease progression per RECIST 1.1.occurs.  
Radiographic Progression-free Survival (radiographic PFS): 
Radiographic PFS is defined as the interval from Study Day 1 to the earlier of a 
radiographic progression or death from any cause; otherwise PFS is censored based 
on criteria in Appendix E. 
Clinical Progression: 
Clinical disease progression is based on clinical symptoms and are not 
associated with radiologic progression. 
This is recorded by the field ‘disease progression is equal to clinical progression’ 
on the EOIP eCRF page. 
Details about the censoring rules are included in Appendix E. 
Clinical Progression-free Survival (clinical PFS): 
Clinical PFS is the time from Study Day 1 to clinical disease progression or death from 
any cause. 
Details about the censoring rules are included in Appendix E. 
Time to Response (TTR): 
TTR is defined as the time from the date of Study Day 1 to the date of the first 
documented CR or PR that is subsequently confirmed per RECIST1.1. For a subject 
who did not respond, time to response will be censored at the latest evaluable 
radiological assessment date. If a subject has no tumor evaluation in the study, time to 
response will be censored at the date of Study Day 1. 
The time of the initial response will be defined as the earliest of the dates contributing 
towards the first visit response of PR or CR. 
o For confirmed responders whose PR or CR are confirmed in two 
evaluable assessments, the first PR/CR assessment among the two 
evaluable assessments will be used to calculate TTR.  
o For unconfirmed responders awaiting follow-up confirmation scans, the 
PR or CR assessment that is awaiting confirmation scan will be used to 
calculate TTR. 


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Time to Radiographic Progression:  
Time to radiographic progression is defined as the interval from Study Day 1 to 
radiographic progression; otherwise, time to radiographic progression is 
censored based on the criteria in Appendix E.  
Time to Clinical Progression: 
Time to clinical progression is defined as the interval from Study Day 1 to clinical 
progression; otherwise, time to clinical progression is based on the criteriain Appendix 
E. 
Subsequent Therapy: 
Subsequent therapy is defined as subjects receiving anti-cancer therapies 
intended to treat NSCLC or any other anti-cancer therapies prior to end of study. 
Time to Subsequent Therapy: 
The time from Study Day 1 to the time a patient starts/receives the subsequent cancer 
therapy/subsequent therapy; otherwise time to subsequent therapy is censored  at the 
last known date of any of the study assessment prior to initiating the subsequent cancer 
therapy/subsequent therapy. 
5.2 
Study Time Points  
Enrollment Date: 
A subject is considered as enrolled when the investigator decides that the subject has 
met all eligibility criteria. The investigator should document this decision and date in the 
subject’s medical record and in the enrollment case report form. 
Study Day 1: 
Study Day 1 is defined as the date of the first dose of the AMG 160 administered to the 
subject. 
End of Study for Individual Subject: 
End of study for individual subject is defined as the date of the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study eCRF page. 
End of Treatment: 
End of treatment is defined as the date the decision was made to end investigational 
product (AMG 160) as recorded on the End of Investigational Page eCRF page. 


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Safety follow-up Visit: 
Safety follow-up visit is defined as upon permanent discontinuation from the study 
treatment for any reason, a safety follow-up visit will be performed approximately  
30 (+3) days after the end of the last dose of AMG 160, or prior to initiation of other 
therapy, whichever occurs first. 
Long-term follow-up Visit: 
Long-term follow-up visit will be conducted every 6 months up to 3 years from the first 
dose of AMG 160 for all subjects who have not withdrawn consent by clinic visit, 
telephone or chart review to assess for survival and/or the commencement of 
subsequent cancer therapy. 
5.3 
Demographics and Baseline Related Definitions  
Age at enrollment: 
Subject age at enrollment will be collected in years reported in the clinical database. 
Baseline: 
The baseline is defined as the last non-missing value on or prior to the pre-dose 
assessments of AMG 160 on cycle 1 day 1. 
Baseline for Triplicate ECG: 
Baseline for ECG is defined as mean of the 3 triplicate ECG results. If fewer than 3 
triplicate ECG results are available, the mean of available triplicate should be 
calculated. For all post-baseline ECG, the mean of one triplicate ECG results at the 
same assessment will be calculated and used in the analysis.  
When an ECG is missing within a triplicate, all available data will be averaged for 
that timepoint. 
Triplicate ECGs (to be only performed if the dose being evaluated is higher than 
the MTD established in subjects with mCRPC [Study 20180101])". 
Change from Baseline:  
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline. 
Change from Baseline = (Post-baseline Value – Baseline Value). 
Investigational Product: 
The term investigational product is used in reference of AMG 160 (acapatamab). 


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Percent Change from Baseline: 
Percent change from baseline is the arithmetic difference between post-baseline and 
baseline divided by baseline values times 100.  
Change (Percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline 
Value] x 100. 
6. 
Analysis Sets 
The following sub-sections describe the analysis sets to be used. 
6.1 
Safety Analysis Set 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 160. 
6.2 
RECIST 1.1 Evaluable Analysis Set 
RECIST 1.1 Evaluable Analysis Set is defined as all subjects that are enrolled, 
receive at least 1 dose of investigational product (AMG 160) and have measurable 
baseline disease per RECIST 1.1 per protocol and have the opportunity to be 
followed for at least 9 weeks starting from Study Day 1. Subjects who stopped 
disease assessment prior to 9 weeks will be included in this analysis set if the 
data cutoff is at least 9 weeks after their Study Day 1. 
6.3 DLT Analysis Set 
The analysis of DLT will be conducted on the DLT Analysis Set defined as all subjects 
that are enrolled and receive at least 1 dose of AMG 160 with an evaluable DLT 
endpoint. 
The DLT endpoint is evaluable if either: 
 1) the subject experiences a DLT; or  
 2) the subject does not experience a DLT after receiving all planned doses within the 
28-day DLT window in cycle 1. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis. 
During dose exploration and formally during dose level review meetings (DLRMs), 
Amgen, in consultation with the site investigators, will review all available cumulative 
data by cohort prior to making dose escalation or dose de-escalation recommendations.  


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Adverse events and DLTs observed in all subjects will be evaluated continually and fully 
integrated into all DLRMs and considered in all enrollment and dosing decisions.  During 
dose expansion, Amgen will conduct evaluations of the ongoing grade 4 or higher 
treatment-related adverse event rate to assess if the threshold for possible early trial 
termination has been reached.  If this threshold is met, enrollment to dose expansion 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. 
1) Terminate the trial 
2) Amend the protocol to potentially improve the benefit/risk for subjects (eg, 
increase safety monitoring, modify dose/schedule, mandate 
) 
3) Continue dose expansion without any changes 
The stopping rules use a Bayesian approach proposed by Thall et al, 1995 to terminate 
the study if the posterior probability that the grade 4 or higher treatment-related adverse 
event rate is greater than 20% is > 80%.  The stopping boundaries assume a prior 
distribution of Beta (0.40, 1.60) are presented in Table 7-1 and the operating 
characteristics with pre-specified batch size of 10 new subjects per batch are presented 
in Table 7-2. The operating characteristics in Table 7-2 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 7-2 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 7-1.  Stopping Boundary for Dose Expansion With Posterior Probability of 
80% and Grade 4 or Higher Treatment-related Adverse Event Limit of 20% 
Number of Subjects 
Stop Study if Observing These Many Grade 4 or Higher 
Treatment-related Adverse Events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Dose Expansion Complete 
Table 7-2.  Operating Characteristics With Batch Size of 10 Subjects 
True Grade 4 or Higher 
Treatment-related Adverse 
Event Rate 
Probability of Early Stopping of 
Dose Expansion 
Average Dose Expansion 
Sample Size 
0.10 
2.0% 
39.5 
0.15 
9.1% 
37.6 


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0.20 
23.2% 
33.9 
0.25 
42.2% 
28.8 
0.30 
61.6% 
23.4 
A formal interim analysis of available safety and efficacy data will occur when the first 
10 evaluable subjects enrolled have had the opportunity to complete 4 months on study.  
This interim analysis will estimate MTD, support the determination of RP2D, conduct 
futility analysis of objective response rate (ORR), and support the evaluation of 
benefit/risk profile of AMG 160 as a monotherapy. 
When deemed necessary, the scope of this interim analysis may include other endpoints 
mentioned in Section 2.1 if applicable. However, analysis of DOR and time-to-event 
endpoints will not be conducted unless there are more than 10 events. 
A futility analysis of ORR will be performed using Bayesian predictive probability 
(Lee and Liu, 2008) when the first 10 evaluable subjects reach month 4.  If the predictive 
probability of observing ORR response > 15% at the end of the study with 50 evaluable 
subjects is less than 30%, the study may stop early (pT = 0.25). Equivalently, if we 
observe ≥ 1 objective responder in the first 10 subjects, an additional subjects (up to 40) 
will be enrolled into the expansion cohort.  The predictive probability is calculated with a 
noninformative prior, Jeffreys prior, Beta(0.5, 0.5). 
Similarly, futility analysis will also be conducted during the expansion cohort.  The 
stopping boundaries are presented in Table 7-3. The operating characteristics in Figure 
7-1 provide the probability of stopping the trial early for given hypothetical true rate of 
ORR. 
Table 7-3.  Objective Response Rate Stopping Boundary 
Number of Evaluable 
Subjects Each Month 4 
Stop Study if Observed Objective Response Rate (ORR) 
Response 
10 
< 1 
20 
< 2 
30 
< 3 
40 
< 4 
50 
Study Complete 


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Figure 7-1.  The Probability of Stopping The Trial Early 
 
Data will be subject to ongoing checks for integrity, completeness and accuracy in 
accordance with the Data Management Plan, however there is no requirement to resolve 
outstanding data issues ahead of the snapshot. The data will be taken “as-is” on the day 
of snapshot for futility analysis.  No locking is performed and the “as-is” snapshot of the 
database will be used in the futility analysis. Data will be subject to ongoing checks for 
integrity, completeness and accuracy in accordance with the Data Management Plan 
with the expectation that all outstanding data issues are resolved ahead of the snapshot 
for the formal interim analysis. The data will be locked to prevent further changes, and a 
snapshot of the locked database will be used in the formal interim analysis. 
7.1.1 
Stopping Rules for Treatment With Siltuximab 
Amgen will conduct evaluations of the treatment and outcome of the CRS events 
treated with siltuximab on an ongoing basis to assess if the threshold for pausing 
siltuximab treatment has been reached as outlined in the table below. If these 
stopping rules are met, an ad hoc DLRM will be triggered to review safety data and 
available PK, 
, and efficacy data. If recommended by DLRT, the 
use of siltuximab will resume. The stopping rules to trigger an adhoc DLRM to 
Probability of Futility (%)
0
10
20
30
40
50
60
70
Number of Evaluable Subjects
10
20
30
40
50
True ORR
0.1
0.15
0.2
0.25
0.3
0.5


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review siltuximab treatment use a Bayesian approach proposed by Thall et al, 
1995; an adhoc DLRM will be triggered if the posterior probability that the CRS 
progression to grade 3 rate is greater than 30% is > 80% or the posterior 
probability that the CRS progression to grade 4 rate is greater than 10% is  80%; 
or observation of any grade 5 CRS after the event has been treated with 
siltuximab. The stopping boundaries presented below assume a prior distribution 
of Beta (0.6, 1.4) for progression to grade 3 CRS and a prior distribution frequently 
if necessary to address emerging safety concerns. If the triggered adhoc DLRM 
coincides with the regular DLRM, they may be combined. 
Number of 
subjects treated 
with siltuximab 
Trigger DLRM if severity of any CRS event treated with 
siltuximab progresses to Grade 5 
Or this number of 
subjects with 
severity of CRS 
progressed to 
Grade 3 after 
being treated with 
siltuximab 
Or this number of subjects with 
severity of CRS progressed to Grade 4 
after being treated with siltuximab 
5 
 3 
 2 
10 
 5 
 3 
15 
 7 
 3 
20 
 8 
 4 
25 
 10 
 5 
30 
 12 
 5 
35 
 13 
 6 
40 
 15 
 6 
 


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7.2 
Primary Analysis 
The primary analysis for the dose-exploration phase will occur when target enrollment is 
complete and each subject either completes 6 months on the study or withdraws from 
the study. 
The primary analysis for time to event endpoints (eg, duration of response, PFS, and 
1-year overall survival [OS]) will occur when target enrollment is complete for the dose 
expansion phase and each subject either completes 1 year on study or withdraws from 
the study. 
Data will be subject to ongoing checks for integrity, completeness and accuracy in 
accordance with the Data Management Plan with the expectation that all outstanding 
data issues are resolved ahead of the snapshot. The data will be locked to prevent 
further changes, and a snapshot of the locked database will be used in the analysis. 
7.3 
Final Analysis 
The final analysis will occur when target enrollment is complete for both phases and all 
subjects have ended the study. 
Data will be subject to ongoing checks for integrity, completeness and accuracy in 
accordance with the Data Management Plan with the expectation that all outstanding 
data issues are resolved ahead of the snapshot. The data will be locked to prevent 
further changes, and a snapshot of the locked database will be used in the  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. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
Subjects may miss specific data points for a variety of causes. In general, data could be 
missing due to a subject’s early withdrawal from the study, a missed visit, or inability to 
evaluate an endpoint at a particular point in time. 
In general, the safety analysis set will be used without any imputation for missing data 
for the primary and secondary endpoints. 
 


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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. The clinical study 
team will identify and document the criteria for important protocol deviations. 
8.5 
Outliers 
Pharmacokinetics (PK) concentration data will be evaluated for outliers by visual 
inspection, and decision to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
Descriptive statistics will be used to identify potential outliers in key variables. Suspected 
outliers will be included in the analyses unless there is sufficient scientific justification to 
exclude them. 
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, 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, efficacy, 
 by dose, dose schedule, and time as appropriate.  Descriptive 


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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. 
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Pearson (Clopper and 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 (Brookmeyer and Crowley, 1982) method.  
Kaplan-Meier methods will be used to estimate landmarks for time to event endpoints 
(eg, 1-year overall survival [OS]) with the Greenwood formula 
(Kalbfleisch and Prentice, 1980) used to estimate the standard error used in CI 
calculation. 
Greenwood formula will be used for landmark analysis, and for other time-to event 
analysis the Brookmeyer and Crowley formula will be used. We will be only doing the  
landmark analysis for OS. 
9.2 
Subject Accountability 
The number and percent of subjects who were enrolled and received the investigational 
product, discontinued from AMG 160 (including reasons for discontinuing), completed 
study, discontinued the study (including reasons for discontinuing) will be summarized. 
Key study dates for the first subject enrolled, the last subject enrolled, and last subject’s 
end of study will be presented. 
A subject listing and summary noting inclusion in each analysis subset will be provided 
for all subjects enrolled. A subject listing noting AMG 160 administration start and end 
time, reason for discontinuation of treatment, and reason for discontinuing the study will 
be provided. A list of subjects screened but not enrolled (screen failures) may be 
provided. 
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 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. 
The final IPD list is used to produce the summary of IPDs table and list the subjects with 
IPDs. In addition, a separate listing of all inclusion and exclusion deviations will be 


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provided. Important protocol deviations thought to potentially impact the safety of 
subjects or the interpretation of the analyses will be listed and tabulated using incidence 
and percentages by deviation type. 
The number of subjects reporting Protocol Deviation due to COVID-19 will be 
summarized in a table. A Protocol Deviation listing of subjects impacted due to 
COVID-19 will also be provided. 
9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of demographics and baseline characteristics will 
be summarized. 
Demographics: 
 
Age (years) at enrollment (continuous summary statistics) 
 
Age categories (number and percent of subjects 18-64, 65-74, 75-84, >=85 
years) 
 
Sex (number and percentages of males and females) 
 
Race (number and percentages of subjects in each category or combinations) 
 
Ethnicity (number and percentages of subjects in each category) 
Baseline Characteristics: 
 
Height and Weight (continuous summary statistics) 
 
ECOG performance status (frequency and percentages) 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
Not applicable to this study. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
For the secondary efficacy endpoints mentioned below, we will consider the endpoints to 
be derived and presented separately for the Central review and the Investigator’s review 
except for the overall survival, clinical progression-free survival, time to clinical 
progression and time to subsequent therapy. 
Table 9-1.  Secondary Efficacy Endpoint Summary Table 
Endpoint 
Statistical Analysis 
Analysis Set  
Objective response per 
modified Response 
Evaluation Criteria in 
The proportion of subjects 
with an objective response 
per modified RECIST 1.1 
along with the corresponding 
RECIST 1.1 Evaluable 
Analysis Set 
 
 


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Endpoint 
Statistical Analysis 
Analysis Set  
Solid Tumors (RECIST) 
1.1 
 
exact 95% CI will be 
calculated using the Clopper-
Pearson method (Clopper 
and Pearson, 1934) 
 
Waterfall plots for the 
maximum percent decrease 
from baseline in sums of 
longest diameters will also be 
provided. 
 
 
 
 
 
 
Applicable for all subjects 
with measurable baseline 
disease and at least one 
post-baseline evaluable 
tumor response 
assessment 
Overall Survival (OS) 
OS will be estimated and the 
median and other percentiles, 
as appropriate, will be 
presented using the Kaplan-
Meier curve and 95% CI 
using Greenwood’s formula to 
estimate the standard error of 
the landmark estimates, see 
(Kalbfleisch and Prentice, 
1980).   
Safety Analysis Set 
Radiographic 
Progression Free 
Survival (PFS)  
Clinical Progression 
Free Survival (clinical 
PFS) 
The median and other 
percentiles as appropriate, 
will be presented using the 
Kaplan-Meier curve and 95% 
CI using the Brookmeyer and 
Crowley (Brookmeyer and 
Crowley, 1982) method. 
Safety Analysis Set 
Time to Response 
(TTR) 
The median and other 
percentiles as appropriate, 
will be presented using the 
Kaplan-Meier curve and 95% 
CI using the Brookmeyer and 
Crowley (Brookmeyer and 
Crowley, 1982) method. 
RECIST 1.1 Evaluable 
Analysis Set 
 
Time to Progression 
(TTP) Radiographic 
 
Time to Progression 
(TTP) Clinical 
The median and other 
percentiles as appropriate, 
will be presented using the 
Kaplan-Meier curve and 95% 
CI using the Brookmeyer and 
Crowley (Brookmeyer and 
Crowley, 1982) method. 
Safety Analysis Set 
Duration of Response 
(DOR) 
The median and other 
percentiles as appropriate, 
will be presented using the 
Kaplan-Meier curve and 95% 
CI using the Brookmeyer and 
RECIST 1.1 Evaluable 
Analysis Set 
 


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Endpoint 
Statistical Analysis 
Analysis Set  
Crowley (Brookmeyer and 
Crowley, 1982) method. 
Time to subsequent 
therapy 
The median and other 
percentiles as appropriate, 
will be presented using the 
Kaplan-Meier curve and 95% 
CI using the Brookmeyer and 
Crowley (Brookmeyer and 
Crowley, 1982) method. 
Safety Analysis Set 
 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Table 9-3.  Primary Safety Endpoint Summary Table 
Endpoint 
Statistical Analysis  
Analysis Set 
Dose Limiting 
Toxicities 
(DLTs) 
Subject incidence of DLT will be 
tabulated by planned dose level. A 
table of DLT will be provided. The 
probability of subject having a DLT by 
DLT Analysis Set 


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dose level will be estimated using a 
modified Toxicity Probability Interval 
(mTPI) model.  
 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term and grade. The severity of each adverse event will be graded using 
CTCAE version 5.0 with the exception of CRS, TLS, and ICANS. 
CRS must be graded using the criteria referenced by Lee et al, 2014, TLS must be 
graded using the criteria referenced by Coiffier et al, 2008, and ICANS must be graded 
using the criteria referenced by Lee et al, 2019. 
The subject incidence of all treatment-emergent adverse events, treatment-related 
adverse events, serious adverse events, adverse events leading or discontinuation of 
investigational product or other protocol required therapies, and fatal adverse events will 
be summarized and tabulated by system organ class and preferred term in alphabetical 
order. 
Subject incidence of all CRS, TLS, and ICANS events will be summarized. 
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
Medical Queries) will also be summarized according to their categories, preferred term, 
and worst severity grade. 
Treatment emergent adverse events occurring on or after the COVID-19 infection will be 
summarized. 
A subgroup analysis of safety with CRS outcome and PK will be performed for 
subjects who were administered siltuximab. 
9.6.3 
Laboratory Test Results 
Clinical chemistry, hematology, and urinalysis data will be reviewed for each subject.  
Depending on the size and scope of changes in laboratory data the analyses of safety 
laboratory endpoints will include summary statistics over time and/or changes from 
baseline over time may be provided. 
Shifts in grades of safety laboratory values from baseline for selected laboratory values 
may also be provided. 


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9.6.4 
Vital Signs and ECOG 
Vital signs data will be reviewed for each subject.  The analyses of vital signs will include 
summary statistics over time and/or changes from baseline over time may be provided. 
Shifts in scores for ECOG performance status scores between the baseline and each 
assessed time point will be tabulated and ECOG performance status scores will be 
summarized at each assessed time points. 
9.6.5 
Physical Measurements 
Physical measurements will be reviewed and listed for each subject. 
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 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 cohort will be summarized.  All on-study ECG data will be 
listed and select parameters of interest plotted. 
9.6.8 
Exposure to Investigational Product 
Details of AMG 160 administration will be listed for every subject. A listing of unique 
manufacturing lot numbers and a listing of the subjects administered each manufacturing 
lot number will be provided. 
Descriptive statistics of the total dose (mg), duration of usage, number of cycles, 
cumulative dose, number and percentage of subjects with dose modifications, reasons 
for modifications will be produced to describe the exposure to investigational product by 
treatment group. 
9.6.9 
Exposure to Non Investigational Product  
Subject-level data may be provided instead of the summary if the subject incidence is 
low or single dose is given.  The number of days on non-investigational product, the 
daily dose, and the proportion of subjects receiving each dose level will be summarized 
using descriptive statistics. 
Compliance with non-investigational product will summarized for each subject using 
descriptive statistics. 


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9.6.10 
Exposure to Other Protocol-required Therapy 
Descriptive statistics of total dose (mg/kg), total dose (mg), average daily dose, 
cumulative dose, and number of cycles will be produced to describe the exposure to 
each of the other protocol-required therapy. 
9.6.11 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category for each treatment group as coded by the World Health 
Organization Drug dictionary. 
9.7 
Other Analyses 
The other analyses included in the study are described as below. These exploratory 
analyses may not be part of the clinical study report. 
9.7.1 
Analyses of Pharmacokinetic or Pharmacogenetic Endpoints 
Serum concentrations of AMG 160 will be determined using a validated assay. PK 
parameters will include but are not limited to maximum observed concentration (Cmax), 
minimum observed concentration (Cmin) and area under the concentration-time curve 
over the dosing interval [AUC] and if feasible half-life (t1/2). Pharmacokinetic parameters 
will be estimated using standard non-compartmental approaches based on the PK 
analysis set and summarized by dose level using descriptive statistics but not limited to 
means, standard deviations, medians, minimums, and maximums. 
Above analysis will be conducted by Amgen Clinical Pharmacology Modeling and 
Simulation (CPMS). 
10. 
Changes From Protocol-specified Analyses 
RECIST 1.1 Evaluable Analysis Set is added for secondary efficacy endpoint 
evaluation. 
Nomenclature referring to rPFS has been removed as rPFS is a specific endpoint 
for prostate cancer. For this study, the terminology radiographic PFS will be used 
to assess the RECIST 1.1 endpoints referring to radiographic progression and 
radiographic progression-free survival. 


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11. 
Literature Citations / References 
Bailis J, Deegen P, Thomas O, et al.  Preclinical evaluation of AMG 160, a 
next-generation bispecific T cell engager (BiTE) targeting the prostate-specific 
membrane antibody PSMA for metastatic castration-resistant prostate cancer (mCRPC).  
J Clin Oncol.  2019;37:(suppl 7S; abstr 301).  
Brahmer JR, Govindan R, Anders RA, et al.  The Society for Immunotherapy of Cancer 
Consensus Statement on Immunotherapy for the Treatment of Non-Small Cell Lung 
Cancer (NSCLC).  J Immunother Cancer.  2018;6:75. 
Brookmeyer R, Crowley J.  A Confidence Interval for the Median Survival Time.  
Biometrics.  1982;38(1):29-41. 
Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
the binomial.  Biometricka.  1934;26:404-413. 
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS.  Guidelines for the management of 
pediatric and adult tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26:2767-2778. 
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours:  Revised RECIST guideline (version 1.1).  Eur J Cancer.  2009;45:228-247. 
Kalbfleisch JD, Prentice RL.  The statistical analysis of failure time data.  John Wiley & 
Sons, New York; 1980. 
Lee DW, Gardner R, Porter DL, et al.  Current concepts in the diagnosis and 
management of cytokine release syndrome.  Blood.  2014;124:188-195. 
Lee DW, Santomasso BD, Locke FL, et al.  ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells.  Biol 
Blood Marrow Transplant.  2019;25(4):625-638. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649–655. 
Shetty D, Loh H, Bui C, et al.  Elevated 68Ga Prostate-Specific Membrane Antigen 
Activity in Metastatic Non-Small Cell Lung Cancer.  Clin Nucl Med.  2016;41:414-416. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-
arm clinical trials with multiple outcomes. Statistics in Medicine. 1995;14:357-379. 
12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
Exploratory data include in this plan may be analyzed later or may be analyzed by a 
different Amgen department. 


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14. 
Appendices 


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Appendix B.  Code Fragments 
95% Confidence Interval by Clopper Pearson Method: 
proc freq data=<data> ; 
tables <variable>*<variable> / binomial (exact); 
run;  
Kaplan Meier Method and 95% Confidence Interval by Brookmeyer and Crowley 
Method: 
proc lifetest data=<data> method = km conftype = linear alpha = 0.05; 
time T * status (0) ; 
run ; 
Where T is time to event, status is censoring variable and 0 is flagged for censored 
observation.  
 


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Appendix C.  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. 
 
Objective response (OR) per Response Evaluation Criteria in Solid Tumors  
(RECIST) 1.1 
 
Timepoint Response by Investigator: 
Timepoint response by Investigator is the overall tumor response collected on the 
Overall Response modified RECIST 1.1 CRF at each tumor assessment. 
 
Confirmed BOR by Investigator: 
Best Overall Response (BOR) by Investigator is derived from the timepoint response by 
investigator using RECIST 1.1 criteria.  At each time point, BOR will be derived based 
upon the evaluated time points up to and including the current assessment. The 
following rules will apply to BOR: 
 
CR is better than PR; PR is better than SD; SD is better than PD; PD is better 
than NE. 
 
For a BOR of SD, a duration of SD ≥ 49 days since study day 1 is required. 
 
For a BOR of CR and PR, confirmation is required by a repeat assessment 
at least ≥ 28 days after the initially observed assessment of CR or PR   
o A CR must be confirmed by CR, a PR can be confirmed by a PR or 
CR. 
o For confirmation of 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 1st assessment is confirmed at post-baseline 5th 
assessment. 
o For confirmation of PR, an unlimited number of intermittent 
assessments of SD can occur between the initial PR and the 
confirmation. It is reasonable to consider a patient with time 
point response of PR-SD-SD-PR as a confirmed response i.e., 
confirmed PR. 
Table 14.1 provides the BOR determination per RECIST 1.1 for trials where confirmation 
of response is required. A BOR determined by Table 14.1 is considered as confirmed 


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BOR. Table 14.2 outlines the steps to derive Confirmed_BOR (step 1) given 
investigator’s timepoint assessments. 
 
Interim BOR by Investigator: 
At interim futility analysis, due to lack of sufficient follow-up time for confirmation scan, 
study team may choose to report both confirmed responders and unconfirmed 
responders (subjects had an initial PR or CR and still has potential for future 
confirmative scans). Interim BOR is defined to include unconfirmed responders in 
addition to those who achieve confirmed BOR. 
 
Timepoint Response by Central Review: 
Timepoint response by Central Review is the Overall response at each tumor 
assessment as assessed by Central radiographic reader(s). This data is usually non-
CTDB dataset transferred from Central Review vendor. 
Confirmed BOR by Central Review: 
Confirmed BOR by Central Review will be derived from the Timepoint Response by 
Central Review in the same way as Confirmed BOR by Investigator. 
Interim BOR by Central Review: 
Interim BOR by Central Review will be derived from Timepoint response by Central 
Review in the same way as Interim BOR by Investigator. 
Best Overall Response (BOR): 
The best overall response is the best observed disease response recorded from the start 
of the study treatment until disease progression/recurrence, the start of new anticancer 
therapy or the end of study.  Confirmed BOR by Investigator, Interim BOR by 
Investigator, Confirmed BOR by Central Review, Interim BOR by Central Review have 
been separately defined above. 


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The followings steps would be followed to derive ORR as per RECIST 1.1. 
 
 
Table 14.1. BOR per RECIST 1.1 where confirmation of CR/PR is required 
 
Criterion Time 
point T1 
Response 
T1 ≥ 49 
days after 
Baseline? 
Time point 
T2 
Response 
T2 ≥ 49 
days after 
Baseline? 
T2 ≥ 28 
days after 
T1? 
Confirmation 
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. 
*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 


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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. 
Note: The UE response collected on eCRF will be mapped to NE for all the derivations 
and analysis. 


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Deriving Objective Response Rate (ORR) per RECIST 1.1 
ORR is defined as the proportion of subjects with Objective Response while on study as 
defined by RECIST 1.1. All subjects that do not meet the criteria for objective response 
by the analysis cut-off date will be considered as non-responders. 
ORR = (Number of Subjects with Objective Response) / Total number of subjects in the 
analysis set. 
Note: Study allows NE between CR and its confirmation scan (CR-NE-CR), and 
NE/SD between PR and its confirmation scan (PR-SD-PR or PR-NE-PR).  
 
Note: We will be deriving two sets of ORR and presenting, namely Objective Response 
Rate by Central Review and Objective Response Rate by Investigator Review. 
Unconfirmed Responses for Interim Analysis 
For a study where CR/PR confirmation is required, due to lack of sufficient follow-
up time at interim analysis, both confirmed responders and unconfirmed 
responders will be reported. Subjects with any objective response (i.e., CR or PR) 
that is not confirmed as defined in Section 5.1.2 will be summarized based on 
below definitions.  
Interim response of unconfirmed CR awaiting confirmatory scan: 
A subject will have an interim response of unconfirmed CR awaiting confirmatory 
scan if and only if each of the following requirements is met: 1) the confirmed best 
overall response is not a confirmed CR and 2) the last evaluable tumor 
assessment prior to data cutoff (DCO) is a CR and 3) none of the following events 
are recorded (end of study date, death date, new anti-cancer therapy, end of 
radiographic follow up date, progression date). 
Interim response of unconfirmed PR awaiting confirmatory scan:  
A subject will have an interim response of unconfirmed PR awaiting confirmatory 
scan if and only if each of the following requirements is met: 1) the confirmed best 
overall response is not a confirmed CR and not a confirmed PR and 2) the last 
evaluable non-SD tumor assessment prior to data cutoff (DCO) is a PR and 3) 
none of the following events are recorded (end of study date, death date, new anti-
cancer therapy, end of radiographic follow up date, progression date). 
 
Interim response of unconfirmed response awaiting confirmatory scan: 


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A subject will have an interim unconfirmed response awaiting confirmatory scan if 
the subject has either an unconfirmed PR or an unconfirmed CR, awaiting a 
confirmatory scan. 
Interim response of unconfirmed CR and not confirmed at next evaluable scan:  
A subject will have an interim response of unconfirmed CR and not confirmed at 
next evaluable scan if and only if each of the following requirements is met: 1) the 
confirmed best overall response is not a confirmed CR and 2) any evaluable tumor 
assessment prior to data cutoff (DCO) is a CR and 3) either of the following 
occurs:  
 
A CR is recorded at the last evaluable tumor assessment and any of the 
following events are recorded (end of study date, death date, new anti-cancer 
therapy, end of radiographic follow up date, progression date) or 
 
For any CR recorded prior to the last evaluable tumor assessment, the 
subsequent evaluable tumor assessment is never a CR. 
Interim response of unconfirmed PR and not confirmed at next evaluable scan:  
A subject will have an interim response of unconfirmed PR and not confirmed at 
next evaluable scan if and only if each of the following requirements is met: 1) the 
confirmed best overall response is not a confirmed CR and not a confirmed PR 
and 2) the subject does not have an interim response of unconfirmed CR and 3) 
any evaluable tumor assessment prior to data cutoff (DCO) is a PR and 4) either of 
the following occurs:  
 
A PR is recorded at the last evaluable non-SD tumor assessment and any of 
the following events are recorded (end of study date, death date, new anti-
cancer therapy, end of radiographic follow up date, progression date) or 
 
For any PR recorded prior to the last evaluable non-SD tumor assessment, the 
subsequent evaluable tumor assessment is never a PR or CR. 
 
Interim response of unconfirmed response and not confirmed at next scan: 


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A subject will have an interim unconfirmed response and not confirmed at next 
scan if the subject is classified as either unconfirmed PR or an unconfirmed CR, 
not confirmed at next scan. 
 


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Appendix D.  Additional Definition   
 
Information described below will be reported from eCRF 
 
Partial Response (PR): 
Partial response (PR) is defined as at least a 30% decrease in the sum of longest 
diameters of target lesions, taking as reference the baseline sum diameters. There can 
be no appearance of new lesions. 
Complete disappearance of all index lesions with presence of non-index lesions. 
Confirmation scan required by a repeat assessment no less than 4 weeks from the date 
of the first documented response. 
Complete Response (CR): 
The disappearance of all target lesions, non-target lesions, and normalization of tumor 
markers. Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. There can be no appearance of new lesions. 
Confirmation scan required by a repeat assessment no less than 4 weeks from the date 
of the first documented response. 
Progressive Disease (PD): 
Progressive disease (PD) is defined as radiologic detection of ≥ 20% increase in tumor 
burden relative to nadir and at least 5 mm absolute increase or unequivocal progression 
of non-index lesions and confirmation of new lesions. 
Stable Disease (SD): 
Stable disease (SD) is defined as neither sufficient shrinkage of CR to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum of diameters 
since the treatment started. 
Unable to evaluate (UE): 
Any lesion present at baseline which was not assessed or was unable to be evaluated 
leading to an inability to determine the status of that particular tumor for that time point. 
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 just 


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be >=15mm in short axis when assessed by CT scan or MRI. All tumor measurements 
must be recorded in millimeters.  
Evaluable tumor assessment: 
Either of the following assessment must be performed for an evaluable tumor 
assessment (on or before subsequent anti-cancer therapy): 
 
CT/MRI scan to assess tumor response per RECIST 1.1 
The results must be adequate to define a visit response, i.e., a visit overall 
response other than not evaluable (NE) for RECIST 1.1. 
 


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Appendix E.  Censoring Rules 
Censoring rules for PFS or TTP (radiographic): 
Situation up to DCO/EOS 
Date of Event or 
Censoring 
Outcome 
No evaluable post-
baseline or on-study 
disease assessment;    
On study without PD or 
death 
Date of the first dose of 
investigational product 
(AMG 160) 
Censored 
PD prior to new anti-
cancer therapy 
Date of PD 
Event 
No PD, but death 
recorded without new 
anti-cancer therapy 
PFS: Date of death; 
TTP: Date of last 
evaluable radiographic 
tumor assessment 
PFS: Event; 
TTP: Censored 
Start of new anti-cancer 
therapy prior to PD or 
death, or prior to any 
other disease 
assessment if there is no 
PD or death recorded 
Date of last evaluable 
radiographic tumor 
assessment prior to the 
start of new anti-cancer 
therapy 
Censored 
No PD or death, no new 
anti-cancer therapy 
Date of last evaluable 
radiographic tumor 
assessment 
Censored 
Death or PD immediately 
after more than one 
consecutively missed 
tumor assessment** 
Date of last evaluable 
radiographic tumor 
assessment prior to the 
missing assessments* 
Censored 
DCO: data cutoff; EOS: end of study; PD: progressive disease 
* This supersedes the previous rules that result in Event at date of PD or death 
**Implementation details: censoring with death or PD immediately after more than 
one consecutively missed tumor assessment 


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Scenarios of PD or Death 
Censoring Rule 
X Days in 
Censoring Rule 
While on treatment 
If PD or death is X days after 
the last scan, censor at the 
last scan 
119 
 
Censoring rules for Duration Of Response (CT/MRI assessment): 
Situation up to DCO/EOS 
Date of Event or 
Censoring 
Outcome 
PD prior to new anti-
cancer therapy 
Date of PD 
Event 
No PD, but death 
recorded without new 
anti-cancer therapy 
Date of death 
Event 
Start of new anti-cancer 
therapy prior to PD or 
death, or prior to any 
other disease 
assessment if there is no 
PD or death recorded 
Date of last evaluable 
tumor assessment by 
CT/MRI prior to the start 
of new anti-cancer 
therapy 
Censored 
No PD or death, no new 
anti-cancer therapy 
Date of last evaluable 
tumor assessment by 
CT/MRI 
Censored 
Death or PD immediately 
after more than one 
consecutively missed 
tumor assessment** 
Date of last evaluable 
tumor assessment by 
CT/MRI prior to the 
missing assessments* 
Censored 
DCO: data cutoff; EOS: end of study; PD: progressive disease  
* This supersedes the previous rules that result in Event at date of PD or death 
**Implementation details: censoring with death or PD immediately after more than 
one consecutively missed tumor assessment 


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Scenarios of PD or Death 
Censoring Rule 
X Days in 
Censoring Rule 
While on treatment 
If PD or death is X days after 
the last scan, censor at the 
last scan 
119 
 
 
Censoring rules for Clinical Progression-free Survival: 
Situation up to DCO/EOS 
Date of Event or 
Censoring 
Outcome 
No evaluable baseline or  
on-study disease 
assessment; on study 
withoutdisease 
progression or death 
recorded. 
Date of the first dose of 
investigational product 
(AMG 160) 
Censored 
Clinical progression 
Date of clinical 
progression 
Event 
Death 
Date of death 
Event 
All other scenarios 
Date of last assessment  
Censored 
DCO: data cutoff; EOS: end of study; 
Censoring rules for Time to Clinical Progression: 
Situation up to DCO/EOS 
Date of Event or 
Censoring 
Outcome 
No evaluable baseline or 
on-study disease 
assessment; on study 
without disease 
progression or death 
recorded. 
Date of the first dose of 
investigational product 
(AMG 160) 
Censored 


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Clinical progression 
Date of clinical 
progression 
 Event; 
All other scenarios 
Date of last assessment  
Censored 
DCO: data cutoff; EOS: end of study;