Conditions: Gastric and Gastroesophageal Junction Adenocarcinoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 15
Healthy volunteers: no

Brief summary:
To evaluate the safety and tolerability of AMG 910 in adult subjects, and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D)

Detailed description:

Arms:
arm 1: For Cycles 1 and 2, participants received AMG 910 as a short-term intravenous (IV) infusion (approximately 60 minutes) at a dose of 6.5 μg twice a week on Days 1 and 3 of each week in a 28-day cycle. For Cycles 3 to 6, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 6.5 μg weekly, ie, Days 1, 8, 15 and 22 in a 28-day cycle. arm 2: For Cycle 1 Week 1, participants received AMG 910 as an extended IV (eIV) infusion (approximately 96 hours) at a dose of 6.5 μg. For the remainder of Cycles 1 and 2, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 6.5 μg twice a week on Days 1 and 3 of each week in a 28-day cycle. For Cycles 3 to 6, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 6.5 μg weekly, ie, Days 1, 8, 15 and 22 in a 28-day cycle. arm 3: For Cycle 1 Week 1, participants received AMG 910 as an eIV infusion (approximately 96 hours) at a dose of 15 μg. For the remainder of Cycles 1 and 2, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 15 μg twice a week on Days 1 and 3 of each week in a 28-day cycle. For Cycles 3 to 6, participants received AMG 910 as a short-term IV infusion (approximately 60 minutes) at a dose of 15 μg weekly, ie, Days 1, 8, 15 and 22 in a 28-day cycle.

Interventions: intervention 1: AMG 910
Intervention descriptions: intervention 1: IV Infusion

Protocol document:
Prot_000.pdf: 
Product:  AMG 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 1 of 175 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Global Phase 1 Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of 
the Half-life Extended Bispecific T-cell Engager 
AMG 910 in Subjects With Claudin 18.2-Positive 
Gastric and Gastroesophageal Junction 
Adenocarcinoma 
Short Protocol Title: 
A Phase 1 Study of AMG 910 in Subjects with 
CLDN18.2-Positive Gastric and 
Gastroesophageal Junction Adenocarcinoma 
Protocol Number: 
20180292 
Investigational Product: 
AMG 910 
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
+1 (805) 447-1000 
 
Key 
Sponsor 
Contact 
Name: 
, PhD, MSc 
Title: 
Medical Director, Early Development 
Telephone Number: 
Email Address: 
 
Name: 
 
Title: 
Global Early Clinical Development Manager 
Telephone Number: 
Email Address: 
 
 
EudraCT Number: 
Not available 
NCT Number: 
NCT04260191 
Protocol Version Date: 
Document Version 
Date 
Original 
21 November 2019 
Amendment 1 
17 January 2020 
Amendment 2 
14 October 2020 
Amendment 3 
02 March 2021 
Data Elements Standards 
Version: 
6.1 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures. 


Product:  AMG 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 2 of 175 
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 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 3 of 175 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Global Phase 1 Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of the Half-life Extended Bispecific T-cell 
Engager AMG 910 in Subjects With Claudin 18.2-Positive Gastric and 
Gastroesophageal Junction Adenocarcinoma, dated 02 March 2021, 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) 
 


Product:  AMG 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 4 of 175 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Protocol Summary ................................................................................................ 10 
1.1 
Synopsis ................................................................................................... 10 
1.2 
Study Schema ........................................................................................... 15 
1.3 
Schedule of Activities (SoA) ...................................................................... 17 
2. 
Introduction ........................................................................................................... 24 
2.1 
Study Rationale ......................................................................................... 24 
2.2 
Background ............................................................................................... 24 
2.2.1 
Disease ..................................................................................... 24 
2.2.2 
Amgen Investigational Product Background:  
AMG 910 ................................................................................... 25 
2.2.2.1 
Nonclinical Pharmacology ....................................... 26 
2.2.2.2 
Nonclinical Pharmacokinetics .................................. 26 
2.2.2.3 
Toxicology ............................................................... 27 
2.3 
Benefit/Risk Assessment ........................................................................... 28 
2.3.1 
Therapeutic Context .................................................................. 30 
2.3.2 
Key Benefits .............................................................................. 31 
2.3.3 
Key Risks .................................................................................. 31 
3. 
Objectives and Endpoints ..................................................................................... 33 
4. 
Study Design ........................................................................................................ 34 
4.1 
Overall Design .......................................................................................... 34 
4.2 
Number of Subjects ................................................................................... 35 
4.2.1 
Replacement of Subjects ........................................................... 36 
4.2.2 
Number of Sites ......................................................................... 36 
4.3 
Justification for Investigational Product Dose ............................................ 36 
4.4 
End of Study ............................................................................................. 39 
4.5 
Patient Input on Study Design ................................................................... 39 
5. 
Study Population .................................................................................................. 39 
5.1 
Inclusion Criteria ....................................................................................... 39 
5.2 
Exclusion Criteria ...................................................................................... 41 
5.3 
Subject Enrollment .................................................................................... 44 
5.4 
Screen Failures ......................................................................................... 45 
6. 
Treatments ........................................................................................................... 45 
6.1 
Treatment(s) Administered ........................................................................ 45 
6.1.1 
Investigational Products ............................................................ 45 
6.1.2 
Non-investigational Products ..................................................... 47 
6.1.3 
Medical Devices ........................................................................ 48 
6.1.4 
Other Protocol-required Therapies ............................................ 48 


Product:  AMG 910 
Protocol Number:  20180292  
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CONFIDENTIAL  
 
 
6.1.5 
Other Treatment Procedures ..................................................... 49 
6.1.6 
Product Complaints ................................................................... 49 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 49 
6.2 
Dose Modification ...................................................................................... 50 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 50 
6.2.1.1 
Dose-exploration Phase .......................................... 50 
6.2.1.2 
Dose-expansion Phase ........................................... 54 
6.2.1.3 
Dose-limiting Toxicity .............................................. 54 
6.2.1.4 
Extension of Treatment Duration ............................. 55 
6.2.1.5 
Retreatment Group ................................................. 56 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 56 
6.2.2.1 
Amgen Investigational Product:  AMG 910 .............. 56 
6.2.2.2 
Infusion Interruptions/Delays/Withholding 
and Re-start in Case of 
Technical/Logistical Issues ...................................... 56 
6.2.2.3 
Infusion Interruptions/Delays/Withholding 
and Re-start due to Adverse Events ........................ 58 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 83 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 83 
6.4 
Treatment Compliance .............................................................................. 83 
6.5 
Treatment of Overdose ............................................................................. 83 
6.6 
Prior and Concomitant Treatment ............................................................. 84 
6.6.1 
Prior Treatment ......................................................................... 84 
6.6.2 
Concomitant Treatment ............................................................. 84 
6.6.2.1 
Supportive Care ...................................................... 85 
6.6.2.2 
Growth Factors ........................................................ 85 
6.6.2.3 
Tumor Lysis Syndrome ........................................... 85 
6.6.2.4 
Nausea, Vomiting, and Diarrhea.............................. 85 
7. 
Discontinuation Criteria ......................................................................................... 86 
7.1 
Discontinuation of Study Treatment........................................................... 87 
7.2 
Discontinuation From the Study ................................................................ 88 
7.2.1 
Reasons for Removal From Study ............................................. 88 
7.3 
Lost to Follow-up ....................................................................................... 88 
8. 
Study Assessments and Procedures .................................................................... 89 
8.1 
General Study Periods .............................................................................. 89 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 89 
8.1.2 
Treatment Period ....................................................................... 90 
8.1.3 
Safety Follow-up ........................................................................ 90 
8.1.4 
Long-term Follow-up .................................................................. 90 
8.1.5 
End of Study .............................................................................. 91 


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CONFIDENTIAL  
 
 
8.2 
Description of General Study Assessments and Procedures ..................... 91 
8.2.1 
General Assessments ............................................................... 91 
8.2.1.1 
Informed Consent .................................................... 91 
8.2.1.2 
Demographics ......................................................... 91 
8.2.1.3 
Medical History ........................................................ 91 
8.2.1.4 
Physical Examination .............................................. 91 
8.2.1.5 
Neurological Examination ........................................ 92 
8.2.1.6 
Gastroscopy ............................................................ 92 
8.2.1.7 
Physical Measurements .......................................... 92 
8.2.1.8 
Performance Status................................................. 92 
8.2.2 
Efficacy Assessments ................................................................ 92 
8.2.3 
Safety Assessments .................................................................. 93 
8.2.3.1 
Vital Signs ............................................................... 93 
8.2.3.2 
Pulse Oximetry ........................................................ 94 
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 .................. 96 
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 ............................................... 99 
8.2.5.1 
Pregnancy Testing .................................................. 99 
8.2.6 
Pharmacokinetic Assessments ................................................ 100 
8.2.7 
Pharmacodynamic Assessments ............................................. 100 
8.2.8 
Pharmacogenetic Assessments............................................... 100 
.................................. 101 
8.2.10 
Biomarkers .............................................................................. 101 
8.2.10.1 
Biomarker Assessment to Determine 
Eligibility ................................................................ 101 
8.2.10.2 
Optional Tumor Biopsies ....................................... 102 
.......... 103 
9. 
Statistical Considerations .................................................................................... 104 
9.1 
Statistical Hypotheses ............................................................................. 104 
9.2 
Sample Size Determination ..................................................................... 104 
9.3 
Analysis Sets, Subgroups, and Covariates .............................................. 105 
9.3.1 
Analysis Sets ........................................................................... 105 


Product:  AMG 910 
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CONFIDENTIAL  
 
 
9.3.2 
Covariates ............................................................................... 105 
9.3.3 
Subgroups ............................................................................... 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 ................................................... 107 
9.4.1.3 
Final Analysis ........................................................ 108 
9.4.2 
Methods of Analyses ............................................................... 108 
9.4.2.1 
General Considerations ......................................... 108 
9.4.2.2 
Efficacy Analyses .................................................. 108 
9.4.2.3 
Safety Analyses .................................................... 109 
9.4.2.4 
Other Analyses ...................................................... 110 
10. 
References ......................................................................................................... 111 
11. 
Appendices ......................................................................................................... 113 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 114 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 119 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 121 
Dose Level Review Team ....................................................................... 121 
Regulatory and Ethical Considerations .................................................... 122 
Informed Consent Process ...................................................................... 123 
Data Protection/Subject Confidentiality ................................................... 124 
Publication Policy .................................................................................... 125 
Investigator Signatory Obligations ........................................................... 126 
Data Quality Assurance ........................................................................... 126 
Source Documents .................................................................................. 127 
Study and Site Closure............................................................................ 128 
Compensation ......................................................................................... 128 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .................................... 129 
Definition of Adverse Event ..................................................................... 129 
Definition of Serious Adverse Event ........................................................ 130 
Recording Adverse Events and Serious Adverse Events ........................ 131 
Evaluating Adverse Events and Serious Adverse Events ........................ 132 
Reporting of Serious Adverse Event ........................................................ 133 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 138 
Definition of Females of Childbearing Potential ....................................... 138 
Collection of Pregnancy Information ........................................................ 140 
Collection of Lactation Information .......................................................... 141 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 144 


Product:  AMG 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 8 of 175 
CONFIDENTIAL  
 
 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 146 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity.......................................................................... 146 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 147 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 148 
11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse 
Events ..................................................................................................... 150 
11.9 
Appendix 9.  Operating Characteristic for 2-parameter BLRM 
Design ..................................................................................................... 151 
11.10 Appendix 10.  Performance Status According to Eastern 
Cooperative Oncology Group (ECOG) Scale  ......................................... 156 
11.11 Appendix 11.  Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1.............................................................................. 157 
11.12 Appendix 12.  Immune Response Evaluation Criteria in Solid 
Tumors (iRECIST) ................................................................................... 159 
11.13 Appendix 13.  Specific Guidance for Cytokine Release 
Syndrome................................................................................................ 165 
11.14 Appendix 14.  Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading............................................................................. 166 
11.15 Appendix 15.  Protocol Amendment 2 Schedule of Activities 
(SoA) for Cohort 1 ................................................................................... 168 
 
List of Tables 
Table 1-1.  Schedule of Activities ................................................................................... 17 
Table 1-2.  Schedule of Pharmacokinetic Samplesa ...................................................... 22 
Table 1-3.  Schedule of Imaging Assessments (Cycle Independent) ............................. 23 
Table 2-1.  Key Risks for AMG 910 ............................................................................... 32 
Table 6-1.  Study Treatments ........................................................................................ 46 
Table 6-2.  Planned AMG 910 Target Doses per Dose Cohort Level ............................. 50 
Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent 
Discontinuation* and Management of Adverse Events 
Including Dose Reductions for Short-term Intravenous 
Infusions ................................................................................................. 61 
Table 6-4.  Infusion Interruptions/Delays/Withholding/Permanent 
Discontinuation* and Management of Infusion-related 
Reactions Including Dose Reductions During Extended 
Intravenous (eIV) Infusions ..................................................................... 78 


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CONFIDENTIAL  
 
 
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 ................................................................................ 107 
Table 9-2.  Operating Characteristics With Batch Size of 10 Subjects ......................... 107 
Table 11-1.  Local Laboratory Analyte Listing .............................................................. 119 
Table 11-2.  Central Laboratory Analyte Listing ........................................................... 120 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 147 
Table 11-4.  True Probability of DLT by Scenario ........................................................ 153 
Table 11-5.  True Probability of DLT or Grade 2 Related Adverse Event by 
Scenario ............................................................................................... 153 
Table 11-6.  Probability by Planned Dose Level for Initiating Multiple Subject 
Cohorts by Scenario ............................................................................. 154 
Table 11-7.  Operating Characteristics by Scenario ..................................................... 154 
Table 11-8.  The Rate of MTD Selected and the Number of Subjects 
Assigned at Each Dose Level by Scenario ........................................... 155 
Table 11-9.  iRECIST Target Lesion Assessments ...................................................... 161 
Table 11-10.  iRECIST Non-target Assessments ......................................................... 162 
Table 11-11.  iRECIST Overall Response ................................................................... 163 
Table 11-12.  iCPD Requirements Summary ............................................................... 164 
Table 11-13.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome ............... 166 
Table 11-14.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 167 
List of Figures 
Figure 1.  Study Schema ............................................................................................... 15 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ..................................................................................................... 135 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 142 


Product:  AMG 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 10 of 175 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Global Phase 1 Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of the Half-life Extended Bispecific T-cell Engager 
AMG 910 in Subjects With Claudin 18.2-Positive Gastric and Gastroesophageal Junction 
Adenocarcinoma 
Short Protocol Title:  A Phase 1 Study of AMG 910 in Subjects with CLDN18.2-Positive 
Gastric and Gastroesophageal Junction Adenocarcinoma 
Study Phase:  1 
Indication:  Gastric and Gastroesophageal Junction Adenocarcinoma 
Rationale 
Combining a highly selective therapeutic target with a T cell-mediated killing mechanism 
has been shown to constitute an effective anticancer treatment.  AMG 910 is a novel 
half-life extended (HLE) bispecific T cell engager (BiTE®) molecule designed to direct 
T cells towards Claudin-18 isoform 2 (CLDN18.2)-expressing cells.  The 
pharmacological effect of AMG 910 is mediated by redirection of cytotoxic CD8+ or 
CD4+ T lymphocytes to kill CLDN18.2-expressing cells and the cytotoxic potency was 
demonstrated in in vitro and in vivo experiments.  Based on its mechanism of action, 
nonclinical data, and clinical experience, both with CLDN18.2-targeting drugs and with 
an approved BiTE therapy, AMG 910 may address an unmet need for patients with 
gastric and gastroesophageal junction (GEJ) cancer.   
This is a first-in-human study in adult subjects with CLDN18.2-positive gastric or GEJ 
adenocarcinoma, collectively referred to as “gastric cancer” in this clinical investigation 
to assess the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of 
AMG 910, with additional exploratory objectives to 
 
 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of AMG 910 in adult 
subjects 
 
To determine the maximum 
tolerated dose (MTD) and/or 
recommended phase 2 dose 
(RP2D) 
 
Dose-limiting toxicities (DLT) 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs, 
electrocardiogram (ECG), and 
clinical laboratory tests 
 
Objectives 
Endpoints 
Secondary 
 
To characterize the PK of 
AMG 910 
 
PK parameters for AMG 910 
following short-term intravenous 
(IV) and extended IV (eIV) 
administration including but not 
limited to maximum serum 
concentration (Cmax), minimum 
serum concentration (Cmin), area 


Product:  AMG 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 11 of 175 
CONFIDENTIAL  
 
 
under the concentration-time 
curve (AUC) over the dosing 
interval, accumulation following 
multiple dosing, and, if feasible, 
half-life (t1/2) 
 
To evaluate preliminary anti-tumor 
activity of AMG 910 
 
Objective response (OR) per 
Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 and 
iRECIST 
 
Duration of response (DOR) 
 
Time to progression 
 
Progression-free survival (PFS), 
6-month and 1-year PFS 
 
Overall survival (OS), 1 and 
2-year OS 
 
 
Overall Design 
This is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 910 in 
subjects with CLDN18.2-positive gastric and GEJ adenocarcinoma.  The study will 
consist of: 
 
Dose-exploration phase 
 
Dose-expansion phase 
The dose-exploration phase of the study will estimate the MTD of AMG 910 using a 
Bayesian logistic regression model (BLRM).  A RP2D may be identified based on 
emerging safety, efficacy, and pharmacodynamic data prior to reaching an MTD.  
Following the dose-exploration phase, a dose-expansion phase will be conducted to 
confirm safety, PK, and pharmacodynamics at the MTD or RP2D and to obtain further 
safety and efficacy data and enable correlative biomarker analysis. 
Because of the observation of cytokine release syndrome (CRS) events in 
cohort 1, the dosing of AMG 910 and the dose escalation schedule will be adapted 
and AMG 910 will be administered in cycle 1 week 1 as an extended intravenous 
(IV) infusion (eIV) for 96 hours starting on day 1 followed by weekly short-term IV 
infusions (approximately 60 minutes) for all cycles of subjects enrolled in next 
cohorts (cohorts 1b and beyond). 
Number of Subjects 
Approximately 70 subjects will be enrolled in this study. 
Summary of Subject Eligibility Criteria 
Key Inclusion Criteria: 
 
Subjects with histologically or cytologically confirmed metastatic or locally 
advanced unresectable gastric or GEJ adenocarcinoma positive for CLDN18.2 
as defined by the test described herein (Section 8.2.10.1).  Prior treatment with 
any CLDN18.2-targeting product requires testing of a tissue sample obtained 
after the treatment with the CLDN18.2-targeting product (not applicable for 
re-treatment with AMG 910). 


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CONFIDENTIAL  
 
 
 
Subjects should not be eligible for curative surgery and should have been 
refractory to or have relapsed after 2 or more prior lines of standard systemic 
therapy that included a platinum, a fluoropyrimidine, either a taxane or irinotecan, 
and an approved vascular endothelial growth factor receptor (VEGFR) 
antibody/tyrosine kinase inhibitor (TKI) and depending on country-specific 
standards and approvals. 
 
For subjects eligible for human epidermal growth factor receptor 2 (HER2) 
directed therapy, prior systemic therapy should have included a HER2 targeting 
antibody approved for treatment of gastric cancer. 
 
Subjects may also be included if the aforementioned therapeutic options were 
medically not appropriate for them.  In these cases, the reason(s) why required 
prior therapies for gastric cancer were medically not appropriate should be 
documented in the subject’s electronic case report form (eCRF). 
 
For dose-expansion only:  Subjects with at least 1 measurable lesion ≥ 10mm 
which has not undergone biopsy within 3 months of screening scan.  This lesion 
cannot be biopsied at any time during the study. 
Key Exclusion Criteria: 
 
Any anticancer therapy or immunotherapy within 4 weeks of start of first dose 
(14 days for palliative radiation). 
 
Untreated or symptomatic central nervous system (CNS) metastases, 
leptomeningeal disease, or spinal cord compression. 
 
Autoimmune disorders requiring chronic systemic steroid therapy or any other 
form of immunosuppressive therapy while on study, eg, ulcerative colitis, Crohn’s 
disease, or any other gastrointestinal autoimmune disorder causing chronic 
nausea, vomiting, or diarrhea.  Recent or current use of inhaled steroids or 
physiological substitution in case of adrenal insufficiency is not exclusionary.   
 
Evidence or history within last 3 months of gastrointestinal inflammatory 
conditions not associated with the underlying cancer disease including 
gastrinomas, duodenitis, proven gastric ulcer, duodenal ulcer, pancreatitis, or 
subjects with recent gastric bleeding.  Subjects may be included if the 
symptomatic/immunosuppressive treatment is discontinued more than 4 weeks 
prior to the first dose of AMG 910, symptoms have resolved, and gastroscopy 
does not indicate signs of active disease.   
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
Investigational product (AMG 910) will be administered as a short-term IV infusion 
(approximately 60 minutes) or as extended IV (eIV) infusion over 96 hours (in 
cycle 1 week 1) over six 28-day cycles following the doses and dosing schedule 
outlined in Table 6-2 and Section 6.1.  There will be treatment-free intervals of 
2 weeks after cycles 2 and 4.  There will be no further scheduled treatment interruptions 
between any other cycles. 
The following premedication may be used: 
Dexamethasone and a proton pump inhibitor may be used as prophylactic measures 
before each infusion as defined in Section 6.1.4. 


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Page 13 of 175 
CONFIDENTIAL  
 
 
Procedures 
After written informed consent has been obtained, all screening tests and procedures will 
be performed within 21 days prior to cycle 1 day 1 dosing, unless otherwise noted.  
Serial clinical safety and study evaluations as per the Schedule of Activities (SoA) will be 
performed including physical examination, vital signs, clinical laboratory tests, 
radiological assessment, PK, anti-drug antibody and biomarker sample collections.  All 
subjects will receive baseline assessment by contrast-enhanced computed tomography 
(CT) scan before dosing.  Endoscopic evaluation of the upper digestive system including 
esophagus, stomach and first part of the small intestine according to local standards will 
be done as scheduled in Table 1-1 and after occurrence of toxicity observations as 
detailed in Table 6-3 (eg, pain in the upper abdomen, vomiting, bleeding). 
All subjects will be hospitalized for intensive monitoring for 4 days of eIV infusion 
in days 1 to 5 of cycle 1 week 1 and for 48 hours after dosing on day 8, and for 
24 hours after weekly short-term IV dosing on days 15 and 22 (days 10, 15, 17, 22, 
and 24 in a twice-weekly short-term IV dosing schedule) during the first cycle and 
day 1 during the third cycle.  Subjects may be discharged after this period if there are 
no grade ≥ 2 adverse events at least possibly related to AMG 910.  Minimum 
hospitalization times for subjects are described in detail in Table 6-1.  For all dosing 
visits that do not require hospitalization, subjects will be intensely monitored for an 
observation period of at least 4 hours after end of each AMG 910 infusion in cycles 2 
through 6 and for 8 hours after end of infusion (EOI) on cycle 3 day 8. 
Routine radiological imaging (contrast-enhanced CT scans) and tumor burden 
assessments will be performed as outlined in the Schedule of Activities.  Assessment of 
disease response will be determined based on RECIST 1.1 and iRECIST guidelines. 
To further assess the risk of delayed adverse events, the subject must return for a safety 
follow-up visit at least 30 (+3) days after the last dose of AMG 910.  Long-term follow-up 
will be conducted every 6 months up to 2 years from the first dose of AMG 910 by clinic 
visit, telephone, chart review or by access of public databases to assess for survival, 
serious adverse events, and/or the commencement of subsequent cancer therapy for all 
subjects who have not withdrawn consent.  Subjects who remain on the treatment for 
more than 2 years do not need to have additional long-term follow-up.  They will 
complete the study 30 (+3) days following discontinuing treatment. 
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 Table 1-1. 
Statistical Considerations 
All subjects who are enrolled and receive at least 1 dose of AMG 910 will be included in 
the analysis, unless otherwise specified.  A formal interim analysis of available safety 
and efficacy data will occur when all dose-escalation subjects have had the opportunity 
to complete 28 days on study.  This interim analysis will estimate the MTD, support the 
determination of the RP2D, and support the evaluation of the benefit/risk profile of 
AMG 910. 
The primary analysis for the safety endpoints, PK endpoints, and objective 
response endpoints will occur when enrollment is complete, and each subject has 
had the opportunity to receive at least 6 cycles of treatment.  The primary analysis 
for time to event endpoints will occur when enrollment is complete, and each 
subject has had the opportunity to be on the study for at least 2 years.  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. 


Product:  AMG 910 
Protocol Number:  20180292  
Date:  02 March 2021 
Page 14 of 175 
CONFIDENTIAL  
 
 
Statistical Hypotheses 
AMG 910 will demonstrate acceptable safety and tolerability in subjects with gastric or 
GEJ adenocarcinoma at 1 or more dose levels with at least 1 dose level showing 
evidence of anti-tumor activity. 
Sponsor Name: 
 Amgen Inc. 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 15 of 175 
CONFIDENTIAL  
 
 
1.2 
Study Schema 
Figure 1.  Study Schema 
 
 
Enrollment 
 
Treatmentb (Day 1) 
 
Once  
MTD/RP2D  
is selected 
 
 
 
 
      (a) 
        End of Treatment 
 
 
 
 
           End of Treatment 
Screening (≤21 days) 
AMG 910 DOSE EXPLORATION 
(n=34) 
AMG 910 DOSE EXPANSION 
(n=36) 
 
Single Subject 
Dose Cohorts 
Multiple Subject 
Dose Cohorts (n=3-4) 
Safety Follow-up (SFU) 
(30 [+3] days after last dose 
of AMG 910) 
Long-term Follow-up (LTFU) 
(Conducted every 6 months 
up to 2 years from first dose 
of AMG 910) 
Safety Follow-up (SFU) 
(30 [+3] days after last dose 
of AMG 910) 
 
Long-term Follow-up (LTFU) 
(Conducted every 6 months 
up to 2 years from first dose 
of AMG 910) 
END OF STUDY 
 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 16 of 175 
CONFIDENTIAL  
 
 
CT = computed tomography; IV = intravenous; LTFU = long-term follow-up; MRI = magnetic resonance imaging; MTD = maximum tolerated dose; RP2D = 
recommended phase 2 dose; SCR = screening; SFU = safety follow-up 
a Multiple-subject cohorts will enroll at a dose level where specific safety and/or efficacy criteria were met in a single-subject cohort or per planned dose level from 
Table 6-2.  For subsequent dose level cohorts, 3-4 total subjects will be enrolled. 
b For cohorts 1b onwards, AMG 910 is administered as extended IV infusion over 96 hours in cycle 1 week 1 and as short-term IV infusions weekly (or twice 
weekly) starting cycle 1 day 8 onwards in cycle 1 through 6 of 28-day cycles with scheduled 2-week breaks after cycles 2 and 4 (see Section 6).   
Note:  For SCR CT and/or MRI, allowing 30 days from C1D1. 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 17 of 175 
CONFIDENTIAL  
 
 
1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities 
  
SCRa 
Treatment Cycle 1 
Week 
  
1 
2 
3 
4 
Cycle Day 
1 
2 
3 
4 
5 
8 
9 
10 
11 
15 
  16 
17 
18 
22 
23 
24 
25 
Hour (relative to EOIb) 
PRE 0 6 
24 
48 
72 
96 
EOI PRE 0 
EOI 4 
24 
48 PRE 0 EOI 4 24 PRE 0 EOI 4 24 PRE 0 EOI 4 24 PRE 0 EOI 4 24 PRE 0 EOI 4 24 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical evaluationc 
X 
X 
  
 
X 
X 
X 
X 
X 
  
  
  
X 
X 
Xo 
  
  
  Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
Vital signs, pulse oximetry 
X 
X 
Xd 
X 
 
X 
X 
Xd 
 
Xo 
Xd,o 
X 
Xd 
Xo 
Xd,o 
X 
Xd 
Xo 
Xd,o 
12-lead ECGe triplicate 
X 
X 
  
 
 
X 
  
  
X 
  
X 
  
  
 
Xo 
  
Xo 
  
  
 
  
X 
  
  
 
  Xo    
  
 
  
X 
  
  
 
  
Xo 
  
  
Adverse events review 
Continually throughout study 
Serious adverse events review 
Continually throughout study 
Prior/concomitant medication 
Continually throughout study 
LOCAL LABORATORY ASSESSMENTS 
Pregnancy testf 
X 
X 
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HIV, Hepatitis B and C screening 
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC with differential 
X 
X 
  
 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
Xo 
  
  
Xo Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
Coagulation 
X 
X 
  
 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
Xo 
  
  
Xo Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
Chemistry panel 
X 
X 
  
 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
Xo 
  
  
Xo Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
X 
  
  
  X 
Xo 
  
  
  Xo 
Urinalysis 
X 
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
OTHER ASSESSMENTS/PROCEDURES 
Gastroscopyg 
Xg 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CENTRAL LABORATORY ASSESSMENTS 
STUDY TREATMENT AND OTHER ASSESSMENTS / PROCEDURES 
Imaging 
See Table 1-3 - imaging assessments 
AMG 910 extended IV (eIV) 
infusion 
  
X 
  
 
  
  
  
  
 
 
  
  
  
  
 
  
  
  
  
 
  
  
  
  
 
  
    
  
   
    
AMG 910 short-term IV infusion 
  
 
  
X 
  
  
  
  
 
Xo 
  
  
  
  
X 
  
  
  
  
Xo 
  
  
  
  
X 
  
    
  
Xo   
    
Hospital stay 
  
From day 1 until 4 hours after EOI on 
day 5. 
Until 48 hours after EOI on day 8.  -OR- 
Until 48 hours after EOI on day 8 and until 
24 hours after EOI on day 10o.  
Until 24 hours after 
EOI on day 15. 
Until 24 hours after 
EOI on day 17o. 
Until 24 hours after 
EOI on day 22. 
Until 24 hours after 
EOI on day 24o. 
Abbreviations and footnotes defined on last page of table 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 5 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 18 of 175 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities 
  
 
Treatment Cycle 2l 
Week 
1 
2 
3 
4 
Cycle Day 
1 
3 
8 
10 
15 
17 
22 
24 
Hour (relative to EOIb) 
PR
E 
0 EOI 
4 
PRE 0 EOI 4 PRE 0 EOI 4 PRE 
0 EOI 4 
PRE 0 EOI 4 PRE 0 EOI 4 PRE 0 EOI 4 PRE 0 EOI 4 
GENERAL AND SAFETY ASSESSMENTS 
Clinical evaluationc 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
Vital signs, pulse oximetry 
X 
Xd 
Xo 
Xd,o 
X 
Xd 
Xo 
Xd,o 
X 
Xd 
Xo 
Xd,o 
X 
Xd 
Xo 
Xd,o 
12-lead ECGe 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events review 
Continually throughout study 
Serious adverse events review 
Continually throughout study 
Prior/concomitant medication 
Continually throughout study 
LOCAL LABORATORY ASSESSMENTS 
Pregnancy testf 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC with differential 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
Coagulation 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
Chemistry panel 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
X 
  
  
X 
Xo 
  
  
Xo 
Urinalysis 
  
  
  
  
Xo 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
OTHER ASSESSMENTS/PROCEDURES 
Gastroscopyg 
  
  
  
  
  
  
  
  
  
  
  
  
Xg 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CENTRAL LABORATORY ASSESSMENTS 
STUDY TREATMENT AND OTHER ASSESSMENTS / PROCEDURES 
Imaging 
See Table 1-3 - imaging assessments 
AMG 910 short-term IV infusion 
 
X 
  
  
  
Xo 
  
  
  
X 
  
  
  
Xo 
  
  
  
X 
  
  
  
Xo 
  
  
  
X 
  
    
Xo   
  
Observation 
Until 4 hours after  
EOI on day 1 
Until 4 hours after  
EOI on day 3o 
Until 4 hours 
after  
EOI on day 8 
Until 4 hours after  
EOI on day 10o 
Until 4 hours 
after  
EOI on day 15 
Until 4 hours after  
EOI on day 17o 
Until 4 hours 
after  
EOI on day 22 
Until 4 hours after 
EOI on day 24o 
Page 2 of 5 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 19 of 175 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities 
  
Treatment Cycle 3 
Week 
1 
2 
3 
4 
Cycle Day 
1 
2 
8 
15 
22 
Hour (relative to EOIb) 
PRE 
0 
EOI 
4 
24 
PRE 
0 
EOI 
8 
PRE 
0 
EOI 
4 
PRE 
0 
EOI 
4 
GENERAL AND SAFETY ASSESSMENTS 
Clinical evaluationc 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Vital signs, pulse oximetry 
X 
Xd 
X 
Xd 
X 
 
 
X 
X 
 
 
X 
12-lead ECGe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events review 
Continually throughout study 
Serious adverse events review 
Continually throughout study 
Prior/concomitant medication 
Continually throughout study 
LOCAL LABORATORY ASSESSMENTS 
Pregnancy testf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Coagulation 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Chemistry panel 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
CENTRAL LABORATORY ASSESSMENTS 
STUDY TREATMENT AND OTHER ASSESSMENTS / PROCEDURES 
Imaging 
See Table 1-3 - imaging assessments 
AMG 910 short-term IV infusion 
  
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Hospital Stay (Day 1 only) 
Until 24 hours after 
EOI on day 1 
 
 
 
 
 
 
 
 
 
 
 
 
Observation 
 
 
Until 8 hours after  
EOI on day 8 
Until 4 hours after  
EOI on day 15 
Until 4 hours after  
EOI on day 22 
Page 3 of 5 
Abbreviations and footnotes defined on last page of table 
 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 20 of 175 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities 
  
Treatment Cycles 4 through 6l 
EOTj 
SFU 
LTFU 
Week 
1 
2 
3 
4 
 
 
 
Cycle Day 
1 
8 
15 
22 
28 
 
 
Hour (relative to EOIb) 
PRE 
0 
EOI 
4 
PRE 
0 
EOI 
4 
PRE 
0 
EOI 
4 
PRE 
0 
EOI 
4 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Clinical evaluationc 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
Vital signs, pulse oximetry 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
12-lead ECGe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events review 
Continually throughout study 
 
Serious adverse events review 
Continually throughout study 
X 
Prior/concomitant medication 
Continually throughout study 
 
Survival Status and/or subsequent cancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LOCAL LABORATORY ASSESSMENTSn 
Pregnancy testf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CBC with differential 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
Coagulation 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
Chemistry panel 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY ASSESSMENTS 
STUDY TREATMENT AND OTHER ASSESSMENTS / PROCEDURES 
Imaging 
See Table 1-3 - imaging assessments 
AMG 910 short-term IV infusion 
  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Observation 
Until 4 hours after 
EOI on day 1 
Until 4 hours after  
EOI on day 8 
Until 4 hours after 
EOI on day 15 
Until 4 hours after 
EOI on day 22 
 
 
 
Page 4 of 5 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 21 of 175 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities 
 
Treatment-free Intervals after Cycles 2 and 4 (2 weeks)m 
Week 
1 
2 
Dayk (out of 14-day treatment-free interval) 
1 
8 
GENERAL AND SAFETY ASSESSMENTS 
Clinical evaluationc 
X 
X 
Vital signs, pulse oximetry 
X 
X 
Adverse events review 
Continually throughout study 
Serious adverse events review 
Continually throughout study 
Prior/concomitant medication 
Continually throughout study 
LOCAL LABORATORY ASSESSMENTS 
CBC with differential 
X 
X 
Coagulation 
X 
X 
Chemistry panel 
X 
X 
Urinalysis 
X 
 
OTHER ASSESSMENTS / PROCEDURES 
Imaging 
See Table 1-3 - imaging assessments 
Page 5 of 5 
AE = adverse event; CBC = complete blood count; ECG = electrocardiogram; EOI = end of infusion; EOT = end of treatment; IV = intravenous; LTFU = long-term follow-up; MRI = magnetic resonance 
imaging; PK = pharmacokinetic; Pre = pre-infusion; SAE = serious adverse event; SCR = screening; SFU = safety follow-up; ctDNA = circulating tumor DNA; PB = peripheral blood 
a All screening procedures should be performed within 21 days prior to cycle 1 day 1 dosing if not stated differently in Section 8.1.1. 
b End of Infusion (EOI) is considered as the end of the controlled rate post-infusion flush. 
c Clinical evaluation including physical exam, ECOG, weight, and neurological examination (as described in Section 8.2.1.5).  Performed at Screening only:  demographics, medical history, 
and height. 
d Refer to Section 8.2.3.1 and Section 8.2.3.2 for additional vital sign and pulse oximetry collection time points.   
e Triplicate ECGs to be collected at Screening and in cycle 1 only.  Single ECGs will be collected per time point for cycle 2 and beyond.  Refer to Section 8.2.3.3. 
f Pregnancy testing is required for all female subjects of childbearing potential.  Serum pregnancy test at Screening and within 48 hours prior to first dose of AMG 910.  Beginning with 
cycle 2 and beyond, within 48 hours of start of each following cycle during treatment with protocol-required therapies or at monthly intervals thereafter until 75 days after the last dose of 
protocol-required therapies. 
j EOT visit will take place on cycle 6 day 28 (± 2 days) for subjects that completed 6 cycles or on the day that subject is unable to continue study treatment (early termination). 
k Visits during the 14-day treatment-free intervals will be completed on the first day of each week (± 2 days). 
l After cycles 2 and 4, refer to page 3 of Table 1-1 for assessments performed during the 2-week treatment-free intervals. 
m There will be planned treatment-free intervals of 2 weeks after cycles 2 and 4.  This may be extended up to 3 weeks for reasons described in Section 4.1.  If there is a third week of 
observation, the same assessments are to be performed on day 15 as on days 1 and 8 of the treatment-free interval. 
n Laboratory assessments that were done within 24 hours prior to infusion do not need to be repeated. 
o Only applies to twice weekly dosing schedule. 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 22 of 175 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Pharmacokinetic Samplesa 
Pre-infusion 
Hours after start of infusion 
1 
2 
4 
24 
48 
72 
96 
120 
144 
Cycle 1 (day 1 to day 7) 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Xb 
  
Pre-infusion 
End of infusion (EOIc) 
Hours after end of infusion 
 
 
2 
4 
24 
 
 
 
 
Cycle 1 (days 8 and 10d) 
X 
X 
 
X 
X 
 
 
 
 
Cycle 1 (days 15, 17d, and 22) 
X 
X 
 
 
 
 
 
 
 
Cycle 1 (day 24)d 
X 
X 
X 
X 
X 
 
 
 
 
Cycle 2 (days 1, 3d, 8, 10d, 15, 17d, and 22) 
X 
X 
 
 
 
 
 
 
 
Cycle 2 (day 24)d 
X 
X 
X 
X 
 
 
 
 
 
Cycle 3 (day 1) 
X 
X 
X 
X 
X 
 
 
 
 
Cycle 3 (days 8, 15, and 22) 
X 
X 
 
 
 
 
 
 
 
Cycle 4, 5, and 6 (day 1) 
X 
X 
 
 
 
 
 
 
 
a Pharmacokinetic (PK) samples should be collected at the exact nominal time point as noted.  If unable to collect a PK sample at the specified nominal time point 
collect it as close as possible to the nominal time point and record the actual collection time.  Pharmacokinetic samples collected  15 minutes from planned nominal 
time point will not be considered protocol deviations.  Sample collection should be peripheral access (collection from central line/port should be avoided). 
b This sample will only be collected if the patient is hospitalized at the time. 
c End of Infusion (EOI) is considered as the end of the controlled rate post-infusion flush. 
d Only applies to twice-weekly dosing schedule when AMG 910 weekly dosing demonstrates acceptable safety and tolerability in subjects with gastric or 
gastroesophageal junction (GEJ) adenocarcinoma at 1 or more dose levels with at least 1 dose level showing evidence of anti-tumor activity. 
 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 23 of 175 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Imaging Assessments (Cycle Independent) 
  
SCR 
Treatment Period 
EOT 
SFU 
LTFU 
Notes 
MRI brain 
X 
  
  
  
  
All subjects must have MRI of the brain 
performed within 21 days prior to the first dose 
of AMG 910.  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 
Contrast enhanced CT and 
tumor burdena assessmentb  
X 
 Every 6 weeks for first 
12 weeks 
 Every 8 weeks thereafter 
X 
X 
Xa 
Radiologic imaging (CT) is required at the EOT 
or SFU visit if the subject has not had radiologic 
imaging performed within 8 weeks of the visit. 
CT  computed tomography; EOT  end of treatment; ICF  Informed Consent Form; LTFU  long-term follow-up; MRI  magnetic resonance imaging; 
RECIST  Response Evaluation Criteria in Solid Tumors; iRECIST  immune Response Evaluation Criteria in Solid Tumors; SCR  screening; SFU  safety 
follow-up 
a Optional tumor marker collection in line with imaging and local standards. 
b For subjects who discontinued treatment for any reason other than confirmed disease progression, every effort should be made to perform radiographic imaging (CT) 
of the chest, abdomen, pelvis, and all other known sites of disease every 3 months until documentation of confirmed disease progression per RECIST 1.1 and 
iRECIST, clinical progression, start of new anticancer therapy, or up to 2 years after the first dose of AMG 910, whichever occurs first. 
Notes:  If CT and/or MRI is done prior to ICF signature results can be used if the subjects allows its use and assessments are done within 30 days of C1 day 1, as 
outlined in Section 8.1.1. 
There is a tolerability window of  1 week for the imaging assessments.  
 
 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 24 of 175 
CONFIDENTIAL  
 
 
2. 
Introduction 
2.1 
Study Rationale 
Combining a highly selective therapeutic target with a T cell-mediated killing mechanism 
has been shown to constitute an effective anticancer treatment.  AMG 910 is an HLE 
BiTE® molecule designed to direct T cells towards Claudin-18 isoform 2 
(CLDN18.2)-expressing cells.  The pharmacological effect of AMG 910 is mediated by 
redirection of cytotoxic CD8+ or CD4+ T lymphocytes to kill CLDN18.2-expressing cells 
and the cytotoxic potency was demonstrated in in vitro and in vivo experiments.  Based 
on its mechanism of action, nonclinical data, and clinical experience, both with 
CLDN18.2-targeting drugs and with an approved BiTE therapy, AMG 910 may address 
an unmet need for patients with gastric and GEJ cancer.   
This is a first-in-human study in adult subjects with CLDN18.2-positive gastric 
adenocarcinoma or GEJ adenocarcinoma, collectively referred to as “gastric cancer” in 
this clinical investigation to assess the safety, tolerability, pharmacokinetic (PK), and 
anti-tumor activity of AMG 910, with additional exploratory objectives to assess 
 
2.2 
Background 
2.2.1 
Disease 
Gastric Cancer 
Gastric cancer is the third most common cause of cancer-related death 
worldwide (Torre, et al., 2015).  Treatment remains challenging because the majority of 
patients are diagnosed at an advanced stage and limited opportunities for targeted, 
personalized treatment strategies exist.  Most of the gastric cancers (> 90%) are 
adenocarcinomas, which are histologically subdivided into diffuse (undifferentiated) and 
intestinal (well-differentiated) types according to the Lauren classification.  
Approximately one third of patients present with metastatic disease at initial diagnosis 
and there is a shift in the site of gastric cancer towards disease of the proximal stomach 
and esophagogastric junction (Giacopuzzi, Bencivenga, Weindelmayer, Verlato, & de 
Manzoni, 2017).  Patients with inoperable locally advanced and/or metastatic disease 
should be considered for systemic chemotherapy.  Current standard of care for first line 
treatment is a platinum/fluoropyrimidine based doublet or triplet (c) chemo-combination 
therapy depending on fitness of patients.  However, prognosis remains poor with median 
OS around 12 months (De Mello, et al., 2018).  Median OS in second line treatment is 


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even shorter, eg, 9.6 months for patients treated with ramucirumab and paclitaxel in the 
RAINBOW trial (Wilke, et al., 2014). 
Claudin 18.2 
Claudins are a family of tight junction proteins establishing paracellular barriers which 
control flow of molecules between cells (Furuse, Fujita, Hiiragi, Fujimoto, & Tsukita, 
1998).  Depending on tissue type, different family members with their highly  
tissue-specific splice variants have been identified.  CLDN18.2 has been found to be an 
epithelial surface marker for a range of malignancies including gastric, esophageal, 
pancreatic, lung and ovarian cancers (Sahin, et al., 2008).  As expression of CLDN18.2 
in normal tissue is confined to differentiated epithelial cells of the gastric mucosa, it was 
identified as an optimal anticancer target leading to the development and clinical 
evaluation of the chimeric monoclonal antibody zolbetuximab (Singh, Sudhamshi, & 
Huang, 2017).  Completed phase 1 and 2 studies show tolerability and a phase 2b study 
shows clinically relevant benefit in PFS and OS to patients with CLDN18.2 positive 
tumors with zolbetuximab administered in first line combination with chemotherapy 
(Sahin, et al., 2019).  The antibody is currently in phase 3 evaluation in combination with 
chemotherapy in patients with advanced gastric cancer (Clinical trial information:  
NCT01630083).   
2.2.2 
Amgen Investigational Product Background:  AMG 910 
AMG 910 is an HLE BiTE antibody construct designed to direct T cells (via CD3 binding) 
towards CLDN18.2-expressing cells.  In AMG 910, the binding arms for CLDN18.2 and 
CD3 are genetically fused to the N-terminus of a single chain IgG Fc (fragment 
crystallizable; scFc) region.  The fusion to a 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).  The extended half-life of Fc fusion proteins is due to their interaction with the 
neonatal Fc receptor, which results in a protected intracellular protein reservoir that is 
recycled to the extracellular space (Rath, et al., 2015). 
A detailed description of the chemistry, pharmacology, nonclinical PK, and toxicology of 
AMG 910 is provided in the AMG 910 Investigator’s Brochure (IB). 


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2.2.2.1 
Nonclinical Pharmacology 
The activity of AMG 910 requires the simultaneous binding to both target cells and 
T cells.  The pharmacological effect of AMG 910 is mediated by redirection of previously 
primed cytotoxic CD8 or CD4 T lymphocytes to kill CLDN18.2-expressing cells. 
As part of the T-cell activation process, BiTE antibody constructs, such as AMG 910, 
cause the formation of a cytolytic synapse between T cells and target cells.  The 
subsequent release of the pore-forming protein perforin and the apoptosis inducing 
proteolytic enzyme granzyme B by T cells results in the induction of apoptosis in the 
target cells. 
AMG 910-mediated T-cell activation not only induces the directed release of cytotoxic 
proteins to target cells, but also results in a transient production of cytokines such as 
tumor necrosis factor (TNF), interferon gamma (IFN-), interleukin-2 (IL-2), interleukin-6 
(IL-6), and interleukin-10 (IL-10). 
AMG 910 monotherapy significantly prevented the development and inhibited the growth 
of established subcutaneous GSU luciferase (luc) tumors in mouse xenograft studies 
with reconstituted human T cells. 
2.2.2.2 
Nonclinical Pharmacokinetics 
In an exploratory toxicology study in male cynomolgus monkeys, AMG 910 was 
administered at 30, 60, or 90 g/kg on days 1 and 8 by IV bolus injection.  The Cmax and 
the AUClast were dose proportional with a 20 increase in Cmax for animals between 
doses on days 1 and 8.   
AMG 910 toxicokinetic (TK) parameters were also assessed in a repeat-dose 1-month 
Good Laboratory Practice (GLP) toxicology study in the cynomolgus monkey.  This study 
evaluated the potential toxicity and TK of AMG 910 when administered once a week by 
IV bolus injection over 30 days.  Cynomolgus monkeys (3/sex/group) received AMG 910 
at 3, 10, or 30 g/kg.  For days 1 and 22, the exposure was described by the 
concentration at time 0 (C0) and the AUClast.  No differences (within 2-fold) in exposure, 
as assessed by estimating C0 and AUClast, were observed between male and female 
animals.  AMG 910 exposure remained similar between day 1 and day 22 for anti-drug 
antibody (ADA) negative animals. 


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2.2.2.3 
Toxicology 
In a 1-month GLP toxicology study with a 1-month recovery period in cynomolgus 
monkeys, AMG 910 administered once a week at 3, 10, or 30 g/kg by IV bolus injection 
was well tolerated up to 10 g/kg with no clinical signs noted.  At 30 g/kg, 1 female was 
euthanized on day 15 with body weight loss and poor body condition score; cause of 
death was attributed to microscopic observations of marked degeneration/necrosis of the 
glandular epithelium in the stomach.  AMG 910-related changes at all doses that were 
attributable to the BiTE antibody mode of action were transient and included:  cytokine 
release; increases in white blood cells (WBC) including neutrophils; an increase in 
c-reactive protein (CRP) and decreases in total protein, albumin, and cholesterol 
indicative of an acute phase response.  Minimal to mild decreases in globulin may have 
been indicative of gastrointestinal loss.  Stomach and duodenum were identified as 
target organs of toxicity.  AMG 910-related microscopic changes included epithelial 
degeneration/necrosis and subtotal mucosal loss in the stomach as well as 
degeneration/necrosis of Brunner’s glands in the duodenum in 1 animal.   
In the stomach, AMG 910-related degeneration and necrosis of glandular epithelium was 
minimal in males at  10 g/kg and minimal to moderate in females at  3 g/kg.  This 
change is consistent with the anticipated T cell-mediated redirected lysis of target 
expressing cells.  Degeneration and necrosis of glandular epithelium was characterized 
by:  variable dilatation of gastric glands, often containing cellular debris; attenuation of 
the glandular epithelium; epithelial degeneration and necrosis; mucosal erosion and 
ulceration; and/or variable mixed cell inflammation with fibroplasia within the lamina 
propria/submucosa.  Although these changes extended to the submucosal layer of the 
stomach, the adjacent muscular layer and serosa were unaffected, and there was no 
associated perforation of the gastric wall.  The additional observation of glandular 
epithelial hypertrophy and hyperplasia in females at  10 g/kg was considered a 
reparative response to the adjacent injured mucosa.  No AMG 910-related macroscopic 
or microscopic changes were observed in animals at the end of the recovery period, 
indicating complete reversibility.  Based on these results, the highest non-severely toxic 
dose (HNSTD) was considered to be 10 g/kg. 
Definitive conclusions regarding a gender effect cannot be made at this time.  Groups 
comprised only 3 animals per sex (2 per sex for recovery groups) and therefore, it 
cannot be tested if there is a statistical difference between the sexes.  There is no known 
difference in Claudin18.2 expression between female and male monkey GI tissues.  


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Also, no differences in exposure or in animal characteristics (weight, age) were 
observed.  However, it cannot be ruled out that individual female human subjects may 
react more strongly to AMG 910 than male subjects.  The study protocol provides very 
detailed and comprehensive instructions on the management of adverse events tailored 
to the individual patient situation, regardless of the subject’s susceptibility to the effects 
of AMG 910 and/or possible gender differences (see Table 6-3 of the study protocol).  A 
careful assessment at each visit including a detailed history, physical examination, and 
investigations for causes of observations also by endoscopic evaluations, should be 
performed and the management of adverse events and symptoms should be tailored to 
the individual subject’s clinical situation. 
2.3 
Benefit/Risk Assessment 
Treatment of gastric cancer remains challenging as most patients are diagnosed at an 
advanced stage.  Thus far, immunotherapies have shown modest activity in advanced 
gastric cancer, and prognosis remains poor.  There is a high unmet medical need for 
effective treatment options for patients with advanced gastric cancer.   
Expression of CLDN18.2 in normal tissue is confined to differentiated epithelial cells of 
the gastric mucosa.  The target was identified as an optimal anticancer target leading to 
the development and clinical evaluation of the chimeric monoclonal antibody 
zolbetuximab (Singh, Sudhamshi, & Huang, 2017).  The antibody is currently in phase 3 
evaluation in combination with chemotherapy in patients with advanced gastric cancer 
after observation of tolerability and clinically relevant benefit in tumors expressing 
CLDN18.2.   
AMG 910 is a novel HLE BiTE molecule designed to direct T cells towards CLDN18. 
2-expressing cells.  The pharmacological effect of AMG 910 is mediated by redirection of 
cytotoxic CD8 or CD4 T lymphocytes to kill CLDN18.2-expressing cells and the 
cytotoxic potency was demonstrated in in vitro and in vivo experiments.   
Our animal data in association with human PK simulations to predict the potentially 
efficacious dose range clearly indicate that anticancer efficacy-related effects are 
expected at similar doses as assumed for on-target/off-tumor effects.  In line with target 
expression in normal tissue, the expected on-target/off-tumor toxicity is confined to 
stomach mucosal toxicity.  Due to the highly regenerative capacity of the stomach 
mucosa, recovery in the normal tissue is expected since full recovery was also observed 
in the GLP toxicology study at least up to the HNSTD.  Careful dose escalation is 
therefore required to reach the predicted pharmacodynamic active dose ranges.  


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Moreover, detailed safety monitoring rules need to be implemented to avoid continuation 
of dose escalation with non-tolerable dose levels. 
Based on its mechanism of action, nonclinical data, and clinical experience, both with 
CLDN18.2-targeting drugs and with an approved BiTE therapy, AMG 910 may address 
an unmet need for patients with gastric cancer.  The anticipated benefit/risk profile favors 
the first-in-human clinical development of AMG 910 for subjects with CLDN18.2-positive 
gastric and GEJ cancer. 
Amgen has been closely monitoring the evolving SARS-CoV-2 Coronavirus Disease 
2019 (COVID-19) pandemic around the globe.  As part of this effort, Amgen has 
performed a rigorous assessment, in discussion with study investigators, considering the 
study design, patient safety, public health risk, risk-benefit ratio, as well as the burden on 
country healthcare systems.  Given the safety concerns around COVID-19 and the 
associated risk to maintaining normal clinical study operations, Amgen is making 
decisions on a study-by-study and country-by-country basis to minimize risk to patients 
and avoid undue burden on healthcare facilities and accordingly, is allowing enrollment 
to continue in studies where the potential for significant benefit in a serious or life-
threatening condition exists and where site resources allow new patients to be safely 
enrolled and appropriately monitored. 
The lack of therapeutic options available to patients with advanced gastric cancer 
provides a strong rationale for treatment in a clinical study with AMG 910.  Potential risks 
associated with study participation, in particular with added challenges due to 
COVID-19, may be outweighed by anticipated benefits associated with the study 
treatment. 
There are no Amgen data to inform the incidence or severity of COVID-19 infections in 
patients receiving AMG 910.  Patients who display symptoms consistent with COVID-19 
infections or who have tested positive for COVID-19 should urgently contact their site 
medical monitor to ensure appropriate care as well as documentation and management 
of study activities, which may include but are not limited to temporarily withholding 
investigational product. 
Amgen considers that it is important to continue the proposed development of AMG 910 
in this study in order to advance potential therapy options for patients as rapidly as 
possible, while balancing this with appropriate measures to monitor and mitigate the 
potential impact of COVID-19. 


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Reference should be made to the Investigator’s Brochure for further data on AMG 910. 
2.3.1 
Therapeutic Context 
Although a modest success was noted with the anti-human epidermal growth factor 
receptor 2 (HER2) targeting antibody trastuzumab, the median OS of 13.8 months 
reported for the combination of trastuzumab with standard chemotherapy in the 
Trastuzumab for Gastric Cancer (ToGA) trial represents only an incremental increase 
over standard of care and treatment is associated with an increased risk for a drop in left 
ventricular ejection function 
 (Bang, et al., 2010; Chen, et al., 2011).  Newer HER-2 targeting approaches 
(trastuzumab-DM1, T-DM1 or lapatinib) have not been able to show improvements in 
OS, either in the naïve or in the pre-treated patient population (Lopez, Harada, Mizrak 
Kaya, & Ajani, 2018).   
With immune checkpoint inhibition coming of age, another modest improvement in 
prognosis for patients with advanced gastric cancer was seen.  Evaluation of the PD-1 
targeting antibody nivolumab, revealed an improvement in OS from 4.1 months in the 
standard of care group to 5.3 months, observed with nivolumab in patients with 
unresectable advanced or recurrent disease and failure after 2 or more previous 
chemotherapies (Kang, et al., 2017).  Results, however, were not interpreted in 
correlation with programmed death-ligand 1 (PD-L1) expression status. 
In the KEYNOTE-059 trial, impressive objective response (OR) results were reported 
for patients receiving monotherapy with pembrolizumab after failure of 2 or more 
previous chemotherapy lines if tumors were positive for PD-L1 expression and belonged 
to the subset of microsatellite instability-high (MSI-H) tumors (Bang, et al., 2017).  
However, although some of the observed responses were durable, in total it is only a 
small subfraction of the patients responding to the treatment.  The OR rate was 11.6% 
for all patients and 15.5% for patients with PD-L1 positive tumors (Fuchs, et al., 2018).  
In KEYNOTE-061, a study comparing front-line pembrolizumab monotherapy versus 
combination of pembrolizumab with chemotherapy versus chemotherapy alone in 
patients with unresectable locally advanced or metastatic gastric cancer, an OR rate of 
57.1% was observed with pembrolizumab monotherapy and OR rate of 64.7% was 
observed for the combination of pembrolizumab with chemotherapy in the MSI-H 
subpopulations (Shitara, Van Cutsem, & Bang, 2019). 


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In light of numerous failures of studies evaluating targeted treatment strategies in 
advanced upper gastrointestinal malignancies directed against VEGFR, mesenchymal 
epidermal transition (c-MT) or epidermal growth factor receptor (EGFR), the search for 
and evaluation of new targets and therapeutic approaches is of utmost interest.   
The combination of a highly selective therapeutic target with a T cell-mediated killing 
mechanism has been shown to constitute an effective anticancer treatment. 
Clinical experience with other BiTE antibody molecules in other tumor indications 
provides a therapeutic context for clinical exploration of AMG 910 (Hummel, et al., 2019; 
Klinger, Benjamin, Kischel, Stienen, & Zugmaier, 2016). 
2.3.2 
Key Benefits 
This study is the first-in-human trial of AMG 910.  Key benefits in humans will be 
investigated and will be described when data become available.  Potential benefits may 
include reduction or regression of gastric cancer disease burden and improvement of 
symptoms as seen with other CLDN18.2-targeting agents (Sahin, et al., 2018; Sahin, et 
al., 2019). 
2.3.3 
Key Risks 
Available clinical data are summarized in the most recent version of the IB.  The 
key safety risks for AMG 910, summarized in Table 2-1 below, are based on the 
biological mechanism of action and the potential for off-tumor effects in the 
gastrointestinal tract. 


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Table 2-1.  Key Risks for AMG 910 
Safety Risk 
Description 
Cytokine Release 
Syndrome (CRS) / 
Infusion-Related 
Reactions 
CRS is a systemic inflammatory response characterized by a 
release of cellular cytokines.  Clinical signs and symptoms of CRS 
may include the following: 
 
Constitutional – fever, rigors, fatigue, malaise 
 
Neurologic – headache, mental status changes, 
dysphasia, tremors, dysmetria, gait abnormalities, seizure 
 
Respiratory – dyspnea, tachypnea, hypoxemia 
 
Cardiovascular – tachycardia, hypotension 
 
Gastrointestinal – nausea, vomiting, transaminitis, 
hyperbilirubinemia 
 
Hematology – bleeding, hypofibrinogenemia, elevated 
D-dimer 
 
Skin – rash 
Infusion reactions may be clinically indistinguishable from 
manifestations of CRS. 
Gastrointestinal Toxicity 
Stomach and duodenum were identified as target organs of toxicity 
in the cynomolgus monkey.   
Potential gastrointestinal associated adverse events may include: 
 
Constitutional – decreased appetite, decreased food 
intake, weight decreased, anorexia, malnutrition, fatigue, 
and asthenia. 
 
Gastrointestinal – nausea, vomiting, gastritis, enteritis, 
abdominal pain, diarrhea, constipation, hematemesis, 
blood in stool, gastrointestinal ulcer, gastrointestinal 
hemorrhage, gastrointestinal perforation, and 
gastrointestinal fistula. 
Other safety considerations for this study are described below.   
 
Neurologic Events:  A wide range of commonly observed neurological symptoms has 
been associated with the use of another BiTE molecule, blinatumomab (anti-CD19 
BiTE antibody construct) in patients with acute lymphoblastic leukemia (ALL).  
However, the full spectrum of neurologic events has not been observed in clinical 
trials for other BiTE molecules, and the neurotoxicity may in part be associated with 
targeting CD19.  No neurologic events were observed in the AMG 910 1-month GLP 
toxicology study in cynomolgus monkeys.  Although AMG 910 binds CLDN18.2 and 
is a different construct from CD19 T cell engagers, the potential for neurologic events 
will be monitored as a precautionary measure in these patients. 
 
Tumor Lysis Syndrome (TLS):  While rare in gastric cancer, TLS is a severe, 
life-threatening disorder that can occur in highly proliferative malignancies or with 
debulking of extensive tumor burden.  Signs and symptoms may include 
hyperkalemia, hyperphosphatemia, hyperuricemia, hyperuricosuria, and 
hypocalcemia, potentially causing lethal cardiac arrhythmias, seizures, and/or renal 
failure.  There is possible occurrence of TLS in patients with high tumor load, hence 
TLS will be monitored in these patients. 
 
Sucrose Toxicity:  The drug product AMG 910 contains sucrose.  Renal toxicity 
following IV administration of sucrose can occur secondary to high solute load 
resulting in osmotic damage (Haskin, Warner, & Blank, 1999).  Cases of renal 
dysfunction have been reported with IV administration of some marketed products 
containing sucrose (Orbach, Tishler, & Shoenfeld, 2004). 


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Refer to the AMG 910 Investigator’s Brochure for further description of key safety risks. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of AMG 910 in adult 
subjects 
 
To determine the maximum 
tolerated dose (MTD) and/or 
recommended phase 2 dose 
(RP2D) 
 
Dose-limiting toxicities (DLT) 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs, 
electrocardiogram (ECG), and 
clinical laboratory tests 
 
Objectives 
Endpoints 
Secondary 
 
To characterize the PK of 
AMG 910 
 
PK parameters for AMG 910 
following short-term intravenous 
(IV) and extended IV (eIV) 
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 following 
multiple dosing, and, if feasible, 
half-life (t1/2) 
 
To evaluate preliminary anti-tumor 
activity of AMG 910 
 
Objective response (OR) per 
Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 and 
iRECIST 
 
Duration of response (DOR) 
 
Time to progression 
 
Progression-free survival (PFS), 
6-month and 1-year PFS 
 
Overall survival (OS), 1 and 
2-year OS 
 
 
Exploratory 


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4. 
Study Design 
4.1 
Overall Design 
This is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 910 in 
subjects with CLDN18.2-positive gastric adenocarcinoma.  The study will consist of: 
 
Dose-exploration phase 
 
Dose-expansion phase 
The dose-exploration phase of the study will estimate the MTD of AMG 910 using a 
Bayesian logistic regression model (BLRM).  A RP2D may be identified based on 
emerging safety, efficacy, and pharmacodynamic data prior to reaching an MTD.  
Following the dose-exploration phase, a dose-expansion phase will be conducted to 
confirm safety, PK, and pharmacodynamics at the MTD or RP2D and to obtain further 
safety and efficacy data and enable correlative biomarker analysis. 
Because of the observation of cytokine release syndrome (CRS) events in 
cohort 1, the dosing of AMG 910 and the dose escalation schedule will be adapted 
and AMG 910 will be administered in cycle 1 week 1 as an extended intravenous 
(IV) infusion (eIV) for 96 hours starting on day 1 followed by weekly short-term IV 
infusions (approximately 60 minutes) for all cycles of subjects enrolled in next 
cohorts (cohorts 1b and beyond). 
Furthermore, the following modifications may be recommended by the Dose Level 
Review Team (DLRT) depending on the observed safety and efficacy observed in 
all prior cohorts: 
 
To adapt duration of eIV administration during cycle 1 week 1 within a range of 
3 to 7 days 
 
To switch to the twice weekly dosing schedule after cycle 1 week 1 and 
administer AMG 910 as follows: 
o For cycles 1 and 2, twice a week at days 1 and 3 of each week in a 28-day cycle, 
starting with cycle 1 day 8 dose and 
o For cycles 3 to 6, weekly, ie, days 1, 8, 15, and 22 in a 28-day cycle 
There will be treatment-free intervals of 2 weeks after cycles 2 and 4.   


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The treatment-free intervals may be extended up to 3 weeks to allow for recovery in 
case of adverse events.  The treatment-free interval after cycle 4 may also be extended 
to 3 weeks for logistical reasons. 
The maximum treatment duration will be 6 cycles.  Subjects who have shown no disease 
progression and no worsening of performance status at the end of cycle 6 may continue 
treatment for an additional 2 cycles if there are no unresolved grade 3 or 4 toxicities and 
if the investigator and the Amgen Medical Monitor agree that continued treatment may 
likely provide benefit for the subject.  Further extensions of the treatment are to be 
agreed upon in the same manner at the end of each second cycle of extended 
treatment.   
Subjects who have derived sustained benefit from treatment, meaning at least stable 
disease and no worsening of performance status, for at least 3 months after the end of 
treatment but experience relapse or progression thereafter, and have not received any 
other systemic anti-cancer therapy since their last AMG 910 treatment, may be retreated 
in a separate retreatment group.  Treatment will be administered at the highest dose 
level assessed as safe at the time of retreatment initiation. 
The DLRT may explore 2 different AMG 910 dosing schedules in cohorts running 
in parallel. 
The safety, tolerability, and preliminary anti-tumor activity of AMG 910 in combination 
with other therapeutic agents may potentially be explored and subject to future protocol 
amendment(s).  After review of emerging data on the safety, tolerability, PK and 
preliminary anti-tumor activity of AMG 910, the protocol may be amended to include 
additional cohorts.  The rationale for amending and the data supporting the rationale will 
be included in the amended protocol(s). 
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 70 subjects will be enrolled in the study, with approximately 34 subjects in 
the dose escalation cohort and 36 subjects in the dose expansion cohort. 
Patients in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 9.2. 


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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 will be replaced by an additional 
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 3 evaluable 
subjects in a multi-subject cohort). 
4.2.2 
Number of Sites 
Approximately 30 investigative sites in North America, Europe, and Asia will be included 
in the study.  Sites that do not enroll subjects within 4 months of site initiation may be 
closed. 
4.3 
Justification for Investigational Product Dose 
The PK of AMG 910 in humans was estimated using allometric scaling of PK parameters 
obtained from nonclinical studies in cynomolgus monkeys at doses ranging between 3 to 
30 g/kg.   


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As recommended by the ICH S9 guidance (ICH S9) the selection of the starting dose for 
this first-in-human study was based on the Minimum Anticipated Biological Effect Level 
(MABEL).  Consistent with the acceptable approaches for FIH dose selection of CD3 
bispecific constructs highlighted by Saber et al. (Saber, Del Valle, Ricks, & Leighton, 
2017), the starting dose is based on the half maximal effective AMG 910 concentration 
(EC50) of the most sensitive in vitro parameter of AMG 910 activity in the most sensitive 
cells, which was T cell redirected cell lysis on co-cultured of gastric carcinoma GSU 
tumor cells. 
A starting dose of 6.5 g was selected based on human PK prediction and is predicted 
to generate first dose maximum serum concentrations (Cmax) to approximate the 
MABEL.  
 
The starting dose and dosing regimen are also supported by the GLP toxicology study in 
cynomolgus monkeys.  The HNSTD in cynomolgus monkeys was determined to be 


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10g/kg.  The predicted human steady state exposure after a starting dose of 6.5 g is 
approximately 19-fold and 59-fold lower for area under the concentration-time curve 
(AUC) and Cmax, respectively, compared to the exposure in cynomolgus monkeys at the 
HNSTD.   


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4.4 
End of Study 
An individual subject is considered to have completed the study if he/she has completed 
the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA).  
The total study duration for an individual subject is up to 2 years. 
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), including any additional parts in the study (eg, long-term follow-up, additional 
antibody testing), as applicable. 
4.5 
Patient Input on Study Design 
There was no patient input on study design. 
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 (see Section 8.1). 
102 
Age ≥ 18 years (or  legal adult age within the country if it is older than 
18 years) at time of signing the informed consent. 
103 
Subjects with histologically or cytologically confirmed metastatic or locally 
advanced unresectable gastric adenocarcinoma or GEJ adenocarcinoma positive 
for CLDN18.2 as defined by the test described herein (Section 8.2.10.1).  Prior 
treatment with any CLDN18.2-targeting product requires testing of a tissue 
sample obtained after the treatment with the CLDN18.2-targeting product (not 
applicable for re-treatment).  


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104 
Subjects should not be eligible for curative surgery and should have been 
refractory to or have relapsed after 2 or more prior lines of standard systemic 
therapy that included a platinum, a fluoropyrimidine, either a taxane or irinotecan, 
and an approved VEGFR antibody/TKI and depending on country-specific 
standards and approvals. 
105 
For subjects eligible for HER2 directed therapy, prior therapy should have 
included an approved HER2 targeting antibody.   
106 
Subjects may also be included if the aforementioned therapeutic options were 
medically not appropriate for them.  In these cases, the reason(s) why required 
prior therapies for gastric cancer were medically not appropriate should be 
documented in the subject’s eCRF. 
107 
For dose expansion only:  Subjects with at least 1 measurable lesion ≥ 10mm 
which has not undergone biopsy within 3 months of screening scan.  This lesion 
cannot be biopsied at any time during the study.   
108 
Subject agrees to gastroscopic evaluations during screening and at least once 
during the treatment period, and is an appropriate candidate for a tumor biopsy, if 
applicable. 
109 
Subject has ECOG performance status 0 to 1. 
110 
Life expectancy  3 months, in the opinion of the investigator. 
111 
Adequate organ function, defined as follows: 
 
hematological function: 
absolute neutrophil count  1 x 109/L (without growth factor support within 
7 days from screening assessment) 
platelet count  75 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) 
 
renal function: 
calculated or measured creatinine clearance  50 mL/min using: 
the MDRD formula (Levey, et al., 2006) OR 
via 24-hour urine collection with plasma and urine creatinine 
concentrations  
 
hepatic function: 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
 3 x ULN (or  5 x ULN for subjects with liver involvement) 


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total bilirubin (TBL)  1.5 x ULN (or  2 x ULN for subjects with liver 
metastases) 
albumin > 2.5 g/dL (25 g/L) 
 
coagulation function: 
Prothrombin time (PT) or international normalized ratio (INR) and partial 
thromboplastin time (PTT) or activated partial thromboplastin time 
(aPTT) ≤ 1.5 x ULN (for subjects receiving anticoagulation therapy 
 2.0 x ULN) 
112. 
Subjects with stable condition and anti-coagulative therapy ongoing for at least 
1 month, no obvious signs and symptoms of bleeding, and coagulation 
parameters as defined in inclusion criteria 111 are fulfilled. 
113. 
Subjects should be able to use proton pump inhibitors. 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Any anticancer therapy or immunotherapy within 4 weeks of start of first dose 
(14 days for palliative radiation). 
202 
Untreated or symptomatic central nervous system (CNS) metastases, 
leptomeningeal disease, or spinal cord compression.   
Other Medical Conditions 
203 
Prior major surgery within 4 weeks of first dose.   
NOTE:  Biopsy or long line insertion are not considered a major surgery. 
204 
Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials 
or antivirals 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. 
205 
Positive test for Human Immunodeficiency Virus (HIV). 
206 
Exclusion of hepatitis infection based on the following results and/or criteria: 
 
Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B). 


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 
Negative HBsAg and positive for hepatitis B core antibody:  Hepatitis B virus 
(HBV) DNA by polymerase chain reaction (PCR) is necessary.  Detectable 
HBV DNA suggests occult hepatitis B (subjects with positive hepatitis B 
core antibody and/or hepatitis B surface antibody accompanied by a 
negative HBV-DNA can be enrolled into the study, but HBV-DNA needs 
to be monitored every 2 months). 
 
Positive Hepatitis C virus antibody (HCVAb):  Hepatitis C virus RNA by PCR 
is necessary.  Detectable hepatitis C virus RNA suggests chronic hepatitis C. 
207 
History of arterial thrombosis (eg, myocardial infarction, stroke, or transient 
ischemic attack) within 12 months of first dose of AMG 910 
208 
History or presence of clinically relevant CNS pathology such as uncontrolled 
epilepsy or seizure disorder, non-traumatic paresis, aphasia, stroke, severe brain 
injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain 
syndrome, and psychosis 
209 
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 and grade 2 peripheral neuropathy, which has 
been unchanged within the last 2 months AND there is agreement to allow by 
both the investigator and sponsor 
210 
History of other malignancy within the past 2 years, with the following 
exception(s): 
 
Malignancy treated with curative intent and with no known active disease 
present for ≥ 2 years before enrollment and felt to be at low risk for 
recurrence by the treating physician. 
 
Adequately treated non-melanoma skin cancer or lentigo malignant without 
evidence of disease. 
 
Adequately treated cervical carcinoma in situ without evidence of disease. 
 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer. 
 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ. 
211 
Autoimmune disorders requiring chronic systemic steroid therapy or any other 
form of immunosuppressive therapy while on study, eg, ulcerative colitis or 
Crohn’s disease, or any other gastrointestinal autoimmune disorder causing 
chronic nausea, vomiting, or diarrhea.  Recent or current use of inhaled steroids 
or physiological substitution in case of adrenal insufficiency is not exclusionary. 


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212 
Evidence or history within last 3 months of gastrointestinal inflammatory 
conditions not associated with the underlying cancer disease including 
gastrinomas, duodenitis, proven gastric ulcer, duodenal ulcer, pancreatitis, or 
subject with recent gastric bleeding.  Subjects may be included if the 
symptomatic/immunosuppressive treatment is discontinued more than 4 weeks 
prior to the first dose of AMG 910, symptoms have resolved, and gastroscopy 
does not indicate signs of active disease. 
213 
Subjects in need of long-term antiplatelet treatment (aspirin, dosage > 300 mg/d; 
clopidogrel, dosage > 75 mg/d). 
214 
Subject has gastric outlet syndrome or persistent recurrent vomiting. 
225 
Subjects with inherited bleeding disorders (eg, Willebrand’s disease, hemophilia 
A and other clotting factor deficiency) and subjects with known heparin-induced 
thrombocytopenia. 
226 
Subjects requiring non-steroidal anti-inflammatory drugs (NSAIDs) during study 
treatment.  The NSAID(s) should be stopped within 7 days prior to start of 
treatment. 
Prior/Concurrent Clinical Study Experience 
215 
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(ies).  Other investigational procedures while participating in this study 
are excluded. 
Other Exclusions 
216 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 75 days after the last dose of 
AMG 910.   
217 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 75 days after the 
last dose of AMG 910.  Refer to Section 11.5 for additional contraceptive 
information. 
219 
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 5 months after the last dose 
of AMG 910.  Refer to Section 11.5 for additional contraceptive information. 


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220 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional 5 months after the last dose 
of AMG 910. 
221 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 5 months after the last dose of AMG 910. 
222 
Subject has known sensitivity to any of the components of AMG 910 to be 
administered during dosing. 
223 
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. 
224 
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. 
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 (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
Due to multiple sites participating in the dose escalation part, a close communication is 
necessary between Amgen and local study teams to allow parallel screening of subjects.  
The Amgen representative communicates when treatment slots become available.  
When a site identifies a potential subject, the local study team sends an email to Amgen 
with the planned consent date, planned screening date, planned treatment date, and a 
statement with respect to urgency of treatment need for this potential subject.  The 
Amgen representative will confirm slot reservation for screening back to the local study 
team.  Subjects may be eligible to enroll once all screening tests and procedures are 
completed and results indicate that all eligibility criteria are met.  The local study team 
will complete and send the enrollment eligibility documentation to the sponsor or 
designee.  The Amgen representative will acknowledge receipt and send confirmation of 
cohort and dose level assignment for the subject.  The start of patient dosing will be 
staggered by at least 72 hours as described in Section 6.2.1.1.2. 


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The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as the point 
when the subject signs the ICF) receives a unique subject identification number before 
any study-related activities/procedures are performed.  The subject identification number 
will be assigned manually.  This number will be used to identify the subject throughout 
the clinical study and must be used on all study documentation related to that subject. 
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, medical history, prior therapies, 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. 
6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 


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Table 6-1.  Study Treatments 
Study Treatment 
Name 
Amgen Investigational Producta: 
AMG 910 
Dosage 
Formulation 
AMG 910 is supplied as a sterile, preservative-free lyophilized powder for 
IV administration after reconstitution with sterile water for injection (WFI).  
After reconstitution with 1.2 mL of sterile WFI, the 1.0 mg/mL AMG 910 
drug product is formulated with L-glutamic acid, sucrose, and polysorbate 
80, pH 4.2.  The final container is a single-use, 6cc glass vial and 
contains deliverable dose of 1 mg AMG 910. 
Unit Dose 
Strength(s)/ 
Dosage Level(s) 
and Dosage 
Frequency 
This is a dose-exploration/dose-expansion study (dose range:  6.5 to 
2000 µg).  See Sections 6.2.1.1 and 6.2.1.2 for further details regarding 
dose exploration and expansion.   
AMG 910 will be administered once or twice a week in a 28-day cycle. 
There will be treatment-free intervals of 2 weeks after cycles 2 and 4.   
For details of the dosing schedule, see Section 4.1. 
Route of 
Administration 
eIV infusion for 4 days starting on cycle 1 day 1 (may be modified to 
3 to 7 days per DLRT recommendation)  
Short-term IV infusion (approximately 60 minutes) 
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 
CRF(s). 
Dosing 
Instructions 
AMG 910 will be delivered using infusion pumps approved for use by the 
appropriate regulatory authority for the country in which the subject is 
undergoing treatment.   
AMG 910 may be administered through a peripheral venous line or a 
central venous access if available.  To ensure delivery of the total dose, a 
sufficient flush volume will be infused at a controlled rate after the dose 
has been administered.  The drug should not be administered as a bolus. 
For eIV infusion, a reliable venous access like a central venous line, 
a venous access port, or equivalent is required to ensure 
continuous administration over 96 hours (eg, port-a-cath or PICC 
line).   
The dosing schedule for an individual subject will not change 
throughout the treatment period. 
See IPIM for more detailed information regarding the storage, 
preparation, destruction, and administration of AMG 910. 
Page 1 of 2 
Footnotes defined on next page of the table 


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Table 6-1.  Study Treatments 
Study Treatment 
Name 
Amgen Investigational Producta: 
AMG 910 
Hospitalization 
Guidance 
All subjects will be hospitalized for intensive monitoring for the times 
given below.  The subjects may be discharged after these hospitalization 
periods if there are no grade ≥ 2 adverse events at least possibly related 
to AMG 910.  Minimum hospitalization times for subjects will be as 
follows: 
 
cycle 1:   
 
during eIV infusion for a minimum of 4 days 
 
48 hours after dosing on day 8 
 
24 hours after dosing on days 15 and 22 with weekly dosing 
(on days 10, 17, and 24 in cohorts with twice weekly dosing) 
 
cycle 3: 
 
24 hours after dosing on day 1 
 
for cycles 1 and 3:  study sites must have immediate access to a 
medical intensive care unit staffed by critical care providers 
 
cycles 2, 3, 4, 5, and 6:  subject should be monitored intensely in 
hospital or outpatient clinic for at least 4 hours after end of each 
infusion (except cycle 3 after dosing on day 1, see above) and for 
8 hours after end of infusion on cycle 3 day 8 
 
cycles 2, 4, 5 and 6:  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:  Refer 
to Table 6-3 
in case of retreatment the same hospitalization guidance applies as for 
initial treatment at the dose level and schedule to be administered. 
Page 2 of 2 
DLRT = Dose Level Review Team; eIV = extended intravenous; IV = intravenous; PICC = peripherally 
inserted central catheter. 
a AMG 910 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
6.1.2 
Non-investigational Products 
In some regions, such as the European Union, the protocol-required therapies described 
in Section 6.1.4 are administered to prevent/reduce the severity of infusion-related 
reactions or CRS, or to treat CRS (eg, IV glucocorticoids and tocilizumab) or proton 
pump inhibitors (PPIs) for prophylactic/concomitant treatment of gastric symptoms, are 
considered to be rescue medications, a category of non-investigational medicinal 
products.   


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6.1.3 
Medical Devices 
A diagnostic test will be used to select subjects for treatment based on subject samples 
collected retrospectively or prospectively during the study.  The diagnostic test is 
intended to measure CLDN18.2 in tumor tissue, as further described in Section 8.2.10.   
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-Amgen 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, proton pump inhibitors 
and tocilizumab, 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. 
Prophylactic/concomitant treatment with a proton pump inhibitor starting approximately 
1 hour prior to start of AMG 910 infusion is recommended.  
 
 
 
 
All sites will ensure that CRS rescue medications are available on-site, including 
corticosteroids and 2 doses of tocilizumab per study subject. 
After observation of a grade ≥ 2 CRS in the study, mandatory premedication with 
dexamethasone will be introduced according to the following instructions:   
 
Dexamethasone 8 mg orally (or equivalent dose of other corticosteroids) to be 
administered 6 to 16 hours prior to all doses of AMG 910 during the first 2 weeks 
of dosing. 
 
Additionally, dexamethasone 8 mg IV (or equivalent dose of other 
corticosteroids) to be administered within 1 hour prior to all doses of AMG 910 
during the first 2 weeks of dosing. 


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 
After 2 weeks of premedication, dexamethasone administration can be at the 
discretion of the investigator. 
 
The same pretreatment regimen should be administered for 1 week of dosing 
after any treatment interruption longer than 5 days. 
 
For subsequent cycles, dexamethasone may be administered prior to AMG 910 
per investigator discretion after consultation with the Amgen medical monitor. 
The DLRT may modify premedication dosing regimen based on emerging safety data. 
6.1.5 
Other Treatment Procedures 
There are no other treatment procedures in this study. 
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(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any investigational product(s) provisioned and/or repackaged/modified by 
Amgen (ie, AMG 910). 
Any product complaint(s) associated with an investigational product(s) 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 (until safety follow-up): 
 
Any antitumor therapy other than AMG 910, such as: 
Cytotoxic and/or cytostatic drugs 
Radiation therapy (with the exception of radiotherapy for palliative care 
such as bone pain; this is only permitted after discussion with Amgen 
Medical Monitor) 
Immunotherapy 
 
Exception:  recommended preventive vaccinations may be administered in the 
treatment-free intervals (such as anti-flu or other anti-infective vaccinations); 
however, such vaccinations should not be given during the DLT period of 
an individual subject. 


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 
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).  
Recent or current use of inhaled steroids or physiological substitution in case of 
adrenal insufficiency is not exclusionary.   
 
Long-term antiplatelet treatment (aspirin, dosage > 300 mg/d; clopidogrel, 
dosage > 75 mg/d) 
 
Any other investigational agent 
 
Any major surgery 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
6.2.1.1 
Dose-exploration Phase 
The dose-exploration phase of the study will enroll up to 34 subjects with gastric cancer.  
Table 6-2 describes the planned dose levels for investigation.  Dose exploration will be 
conducted in 2 stages:  single-subject cohort(s) followed by multiple-subject cohort(s) 
(3 to 4 subjects per cohort). 
Table 6-2.  Planned AMG 910 Target Doses per Dose Cohort Level 
Cohort number 
Number of subjectsa 
Dose (g) Route 
(-1) 
(3 to 4) 
2.5 IV 
1 
3 to 4 
6.5b IV 
1b 
3 to 4 
6.5b eIV 
2b 
3 to 4 
15 eIV 
3b 
3 to 4 
30 eIV 
4b 
3 to 4 
60 eIV 
5b 
3 to 4 
150 eIV 
6b 
3 to 4 
300 eIV 
7b 
3 to 4 
600 eIV 
8b 
3 to 4 
1000 eIV 
9b 
3 to 4 
2000 eIV 
Routes of administration:  eIV  extended intravenous; IV  short-term intravenous. 
a Switching from a single subject cohort to a multiple-subject cohort will occur with cohort 3 or sooner if 
specific safety criteria are observed as described in Section 6.2.1.1.1. 
b If a dose reduction is needed according to instructions provided in Table 6-3, treatment will be continued at 
a dose of 2.5 g as specified in Section 6.2.2.3.5. 
Note:  The “b” cohort numbers are used to differentiate cohorts 1 through 10 denoted in previous 
versions of the protocol. 


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6.2.1.1.1 
Single-subject Cohorts 
The starting dose will be based on the MABEL (Saber, Del Valle, Ricks, & Leighton, 
2017).  Dose exploration will begin with single-subject cohort(s).  The starting dose is 
expected to have the first dose Cmax below the MABEL.  Serum concentrations to be 
achieved with first 3 to 4 dose level cohorts are expected to be lower than those at which 
pharmacodynamic activity translating into treatment-related adverse events or efficacy is 
predicted to be observed.  Therefore, the first 2 cohorts are pre-planned single subject 
cohorts.   
If a subject in the first single-subject cohort does not experience a grade 2 or higher 
adverse event at least possibly related to AMG 910 or DLT (Section 6.2.1.3) during the 
initial 28 days of treatment (DLT window for single-subject cohorts), then the next 
subject may be dosed at the next higher dose level(s) per Table 6-2.   
In consequence, switching from a single subject cohort to a multiple-subject cohort will 
occur with cohort 3 or sooner if any of the following safety criteria are observed during 
the DLT window: 
 
DLT (Section 6.2.1.3), or 
 
Grade  2 adverse events based on CTCAE version 5.0, at least possibly related to 
AMG 910, with the exception of lymphopenia or lymphocyte count decreased. 
NOTE:  See Table 6-3 for CRS and TLS grading criteria.   
The DLRT will convene to review the safety data and recommend the appropriate dose 
to be implemented.  The recommended dose will not exceed the levels recommended by 
the BLRM in the dose escalation portion and the next pre-defined dose level listed in 
Table 6-2.  The DLRT may also convene ad hoc meetings any time to review safety data 
if deemed necessary. 
Determination of whether a subject is evaluable for DLT assessment will be made by 
DLRT in accordance with the following rules: 
 
Subjects who receive study treatment (at least 80 of the planned dose for cycle 1) 
and remain on study through the DLT assessment window will be considered 
DLT-evaluable. 
 
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 subject at that same dose level. 


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6.2.1.1.2 
Multiple-subject Cohorts 
Dose escalation in multiple-subject cohorts (3 to 4 subjects per cohort) will begin as 
described in Section 6.2.1.1.1 and follow the planned schedule shown in Table 6-2.  
Sequential dosing of subjects by at least 72 hours should be employed to all subjects 
within a dose escalation cohort.  The DLRT will convene to review the safety data and 
recommend the appropriate dose to be implemented.  The recommended dose will not 
exceed the levels recommended by the BLRM in the dose escalation portion and the 
next dose level listed in Table 6-2.  The DLRT may recommend enrolling more subjects 
for safety reasons at any point during the study. 
For dose escalation with eIV dosing schedule, the DLRT will in addition to the 
considerations above evaluate the eIV administration and the short-term IV 
administrations separately for the occurrence of first-dose effects (eg, CRS and 
TLS).  The DLRT will review the safety data and may recommend to only escalate 
the dose for either the eIV administration or the short-term infusion 
administrations for the next cohort.  The recommended dose will not exceed the 
levels recommended by the BLRM in the dose escalation portion and the next 
dose level listed in Table 6-2.  For subsequent dose escalation decisions, the dose 
for the eIV administration and the short-term IV administrations may be again 
escalated in parallel while maintaining the relative dose difference or the dose for 
the not escalated administration may be kept constant. 
For multiple-subject cohorts, the DLRT will not recommend dose escalation decisions 
until each of the following occurs: 
 
All subjects in the cohort have been followed for safety events for a minimum of 
28 days from the first dose of AMG 910 (except if a subject experienced a DLT) or 
have been followed for a minimum of 72 hours after the seventh dose with treatment 
interruption not constituting a DLT, whatever is longer. 
 
At least 3 of the subjects can be evaluated for DLT assessment 
Determination of whether a subject is evaluable for DLT assessment will be made by 
DLRM in accordance with the following rules: 
 
Subjects who receive study treatment (at least 80 of the planned dose for cycle 1) 
and remain on study through the DLT assessment window will be considered 
DLT-evaluable. 
 
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 subject at that same dose level. 


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Dose Level Determination 
A recommendation to escalate to a higher dose level will only occur when the previous 
dose level has been found to be reasonably tolerated based on available study data and 
upon unanimous agreement of the DLRT members.  Available data from previous 
cohorts will also be considered.  Dose level recommendations will be made on a 
treatment cohort basis (not on an individual basis).  After receiving the DLRT 
recommendation, Amgen will issue a written notification of the dose change decision to 
investigators.  Further information on dose level review meetings is provided in 
Appendix 3 (Section 11.3). 
Dose Cohort Stopping Rules 
Dose escalation will follow the pre-defined dose levels in Table 6-2 until a subject 
experiences a DLT.  Then the dose for the subsequent cohorts will be decided by the 
DLRT after evaluating all available safety, laboratory, and PK data as well as the 
recommendation from the BLRM.  Dose escalation/de-escalation decisions in 
multiple-subject cohorts will be guided by the BLRM model of dose toxicity.  The MTD for 
BLRM is the dose level predicted to have the highest probability of a DLT rate within the 
target interval of 20 to 33, subject to overdose control.  To control the risk of 
overdose, the MTD must have less than a 40 predicted probability of overdosing 
(DLT rate  33). 
If late onset adverse events (ie, after the 28-day DLT period) occur or late findings from 
endoscopic evaluations are reported during a cohort, the DLRT may adaptively 
re-consider the doses evaluated within a cohort for subsequent dosing and/or possibly 
trigger a de-escalation or withholding of additional doses in subsequent cohorts.  Based 
on the BLRM model and after reviewing all available safety and tolerability data, the 
DLRT may recommend dosing at intermediate dose levels between the planned dose 
levels in Table 6-2. 
The Amgen Medical Monitor may suspend dosing and convene a dose level review 
meeting (DLRM) at any time based on emerging safety data.   
Dose escalations will end once any of the following events occur: 
 
Highest planned dose level is determined to be safe and tolerable (minimum of 
6 treated subjects on this dose level). 
 
The MTD is identified. A dose level is considered the MTD when the BLRM 
recommends treatment at this dose level and 6 or more evaluable subjects have 
already been treated at this dose level. 


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 
On the basis of a review of real-time safety data and available preliminary PK 
data, dose escalation may be halted or modified by the Sponsor as deemed 
appropriate.  A re-evaluation of the risk/benefit for the study will be necessary 
after the following observations: 
 
Gastrointestinal events of CTCAE grade 3 in 2 subjects, with the exemption of 
nausea, vomiting, and abdominal pain, and gastrointestinal events of CTCAE 
grade 4 in 2 subjects if events are at least possibly related to AMG 910 
 
Gastrointestinal event of CTCAE grade 5 in 1 subject, at least possibly related to 
AMG 910 
To acquire additional safety and pharmacodynamic data to better inform the RP2D, 
additional subjects may be enrolled at a dose level that has been shown to not exceed 
the MTD based on the dose-escalation criteria described above, and at which there is 
evidence of anti-tumor activity and/or pharmacodynamic biomarker modulation.  Up to 
approximately 3 additional subjects per dose level may be enrolled. 
6.2.1.2 
Dose-expansion Phase 
Upon completion of the dose exploration part of the study, up to approximately 
36 additional subjects will be enrolled in the dose expansion part to gain further clinical 
experience, safety and efficacy data for AMG 910 in subjects with gastric 
adenocarcinomas.  The dose to be evaluated will be at or below the MTD estimated in 
the dose exploration cohorts.  A final estimate of the MTD and RP2D will be evaluated 
and confirmed utilizing all DLT-evaluable subjects from the dose exploration and the 
dose expansion cohorts.  This final estimate of the MTD and RP2D will not exceed the 
MTD identified in the dose escalation portion of the study and will not exceed the MTD 
identified in the dose escalation portion of the study by the BLRM.  Efficacy data will be 
reviewed in the dose expansion part of the study after the first 15 subjects are enrolled 
and have had the opportunity to receive at least 8 weeks of treatment and received the 
first response assessment (with recruitment ongoing).  Dose expansion may be 
discontinued early; the guidelines for early stopping due to insufficient efficacy and the 
guidelines for early stopping due to excessive toxicity are detailed in Section 9.4.1.1.  
The DLRT may also convene ad hoc meetings any time to review safety data if deemed 
necessary.  A final BLRM estimate of the MTD will use all data from dose exploration 
and dose expansion. 
6.2.1.3 
Dose-limiting Toxicity 
The adverse event grading scale to be used for this study will be the CTCAE version 5.0 
and is described in Section 11.4, with the exception of CRS, which will be graded using 


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the criteria referenced in the publication by Lee et al (2014) (see Section 11.13) and 
TLS, which will be graded according to the Cairo Bishop criteria referenced in the 
publication by Coiffier et al (2008) (see Section 11.14). 
Dose-limiting toxicities are defined as any adverse events at least possibly related to 
AMG 910 with an onset within the first 28 days following first dose for single-subject 
cohorts and within the safety observation period for multiple-subject cohorts as defined 
in Section 6.2.1.1.2 with any of the following criteria: 
 
grade 2 gastric perforation or fistula 
 
grade  3 non-hematologic adverse events including laboratory abnormalities 
with the exceptions as stated below: 
o grade 3 fever (not associated with any other 
CRS/infusion-related reaction symptoms) that does improve to 
grade  1 within 72 hours  
o grade 3 nausea, vomiting, or diarrhea that does improve to grade 
 1 or baseline within 72 hours with optimal medical support.   
o grade 3 asymptomatic liver enzyme elevations including AST, 
ALT, GGT with AST improving to grade  2 within 72 hours and 
ALT and GGT, which have long half-lives, improving to grade  2 
within 7 days except those meeting Hy’s Law 
 
re-challenge with AMG 910 after treatment interruption due to any stomach 
toxicity results in at least same stomach toxicity and is of CTCAE grade  3 or 
grade 2 and ongoing for more than 3 days despite optimal supportive treatment 
 
grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding 
 
grade 4 neutropenia lasting longer than 28 days 
 
febrile neutropenia of any grade 
 
anemia requiring transfusion per local or international guidelines in the absence 
of bleeding 
 
grade 5 toxicity (eg, death not due to disease progression) 
 
any other toxicity related to AMG 910 considered significant enough to be 
qualified as DLT in the opinion of the investigator, and confirmed by the DLRT, 
will be reported as DLT 
6.2.1.4 
Extension of Treatment Duration 
Subjects who have shown no disease progression and no worsening of performance 
status at the end of cycle 6 may continue treatment for an additional 2 cycles if there are 
no unresolved treatment related grade 3 or 4 toxicities and if the investigator and the 
Amgen Medical Monitor agree that continued treatment may likely provide benefit for the 
subject.  Further extensions of the treatment are to be agreed in the same manner at the 


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end of each second cycle of extended treatment.  Treatment schedule and schedule of 
activities will be conducted as described for cycle 6. 
6.2.1.5 
Retreatment Group 
Subjects who have derived sustained benefit from treatment, meaning at least stable 
disease and no worsening of performance status, for at least 3 months after the end of 
treatment but experience relapse or progression thereafter, and have not received any 
other systemic anti-cancer therapy since their last AMG 910 treatment, may be retreated 
in a separate retreatment group for a total of up to 2 rounds of retreatment (up to 
6 cycles each).  Retreatment will be offered to such subjects upon agreement of the 
investigator and the Amgen Medical Monitor that retreatment is medically appropriate 
and likely to provide benefit for the subject.  Subjects must meet all protocol defined 
inclusion and exclusion criteria and provide written consent for the retreatment 
(exemption:  no additional test for CLDN18.2 expression in tumor tissue is required).  
Retreatment will be administered at the highest dose level and currently used schedule 
that has been assessed as safe by the DLRT at the time of retreatment initiation.  
Treatment schedule and schedule of activities will be conducted as described for 
cycles 1 through 6 in the dose exploration and expansion cohorts. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  AMG 910 
The reason for any dose change of AMG 910 is to be recorded on each subject’s CRF. 
6.2.2.2 
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 910 should not be interrupted, 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: 


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 
investigational product stability is sufficient to administer the remaining infusion 
or  
 
a new infusion can be administered or  
 
the dose should be withheld  
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 
(Table 1-1) for the cycle day on which the original (interrupted) infusion was 
administered.  If the infusion will need to be withheld, follow the instructions for re-start 
after interruptions due to adverse events described below for the next infusion. 
For eIV infusions, if an infusion interruption occurs due to reasons other than 
adverse events (eg, technical or logistic reasons) and does not exceed 24 hours, 
the infusion can be restarted at the same dose without additional measures and 
infusion duration will not change.  If the interruption exceeds 24 hours, the restart 
of the infusion should be performed under the supervision of the investigator or 
designee and premedication as described in Section 6.1.4 should be administered 
if implemented for start of eIV infusion.  If the interruption exceeds 48 hours and 
less than 75 of the planned 96-hour infusion has been administered, treatment 
with eIV infusion should be restarted following the dosing schedule and SoA for 
cycle 1 starting with day 1 and completion after 96 hours.  If the interruption 
exceeds 48 hours and at least 75 of the planned 96-hour infusion has been 
administered, treatment will resume with the cycle 1 day 8 short-term infusion.  
Refer to IPIM for details of handling, preparation, and administration of eIV 
infusions. 
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 infusions should 
then be administered in same dosing intervals as planned during cycles 1 and 2 or in 
intervals of 7 ( 1) days in case of all later dosing events; eg, if the cycle 3 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 17 ( 1 day) rather than the regular day 15.  
The  1-day window for dosing events after cycle 1 day 8 is allowed until the original 
dosing schedule is met again. 


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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. 
6.2.2.3 
Infusion Interruptions/Delays/Withholding and Re-start due to 
Adverse Events 
6.2.2.3.1 
General Guidelines 
Subjects should be assessed for toxicity before each infusion of AMG 910.  The severity 
of the toxicity will be graded using the CTCAE version 5.0 (Section 11.4), with the 
exception of CRS, which must be graded using the criteria referenced in the publication 
by Lee et al.  (Lee, et al., 2014), (see Table 6-3) and TLS, which must be graded 
according to the Cairo Bishop criteria referenced in the publication by Coiffier et al.  
(Coiffier, Altman, Pui, Younes, & Cairo, 2008), (see Table 6-3).  Infusion modification 
and dose reduction due to a toxicity will be performed according to the instructions 
described below and outlined in Table 6-3. 
6.2.2.3.2 
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 electronic CRF (eCRF) and provide the start and stop 
date/time of the infusion.   
Events requiring an infusion interruption are listed in Table 6-3. 
For eIV infusions, the following adverse events should not lead to infusion 
interruption or delayed dosing of a next scheduled dose:  
 
grade 1 or 2 CRS (including transient fever and/or vomiting [ 72 hours]) 
 
grade 3 transaminitis 
 
grade 3 hypotension manageable with IV fluids or low dose vasopressor 
 
grade 3 or 4 lymphopenia resolving to grade  2 within 7 days or considered 
not clinically relevant 
 
isolated 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 
 
hemoglobin  7.0 to  8.0 g/dL if observed  7 days in the absence of bleeding 
signs 


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6.2.2.3.3 
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. 
6.2.2.3.4 
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, if not already specified differently in the sections above.  The 
following assessments should be performed as for days 1, 2, and 3 per the Schedule of 
Activities for the interrupted cycle (Table 1-1): 
 
vital signs, pulse oximetry 
 
physical examination 
 
clinical evaluation 
 
weight 
 
ECOG Performance Status Scale 
 
safety labs (hematology, chemistry, coagulation, urinalysis) 
The subject should be hospitalized for at least 48 hours after re-start of the infusion. 
In case the interruption/delay occurred before cycle 1, day 8 and was  72 hours, 
treatment restart should follow the dosing schedule and SOA for cycle 1 starting with 
day 1.   
For eIV infusion administration:  In case the interruption exceeds 48 hours and 
less than 75 of the planned 96-hour infusion has been administered, treatment 
with eIV infusion should be restarted following the dosing schedule and SoA for 
cycle 1 starting with day 1 and completion after 96 hours.  If the interruption 
exceeds 48 hours and at least 75 of the planned 96-hour infusion has been 
administered, treatment will resume with the cycle 1 day 8 short-term infusion.  
Refer to IPIM for details of handling, preparation, and administration of eIV 
infusions. 


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Any premedication earlier implemented for specific dosing time points should be 
administered at the equivalent dosing timepoints of the treatment re-start.   
6.2.2.3.5 
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: 
For required dose reductions, follow instructions as outlined in Table 6-3. 
In case more than 2 dose de-escalations are required for any reason (including but not 
limited to de-escalations due to the same adverse event, 2 separate adverse events, 
etc.), permanently discontinue treatment. 
For any subject treated in cohort 1 who does not experience a DLT and who requires a 
dose reduction below the 6.5 g starting dose, treatment can resume at a lower dose of 
2.5 g. 
Background:  The lower dose to manage patients within cohort 1 was endorsed by 
DLRM after the observation of a grade 2 CRS in 1 subject shortly after administration of 
the day 1 infusion.  The subject received the C1D1 infusion at a dose of 6.5 g 
according to protocol.  Approximately 10 hours after the infusion the subject presented 
with nausea, headache, tachycardia, and liver transaminases increased up to grade 3.  
Also, the subject had grade 2 abdominal pain.  The events recovered within 3 to 4 days 
with 1 dose of tocilizumab, dexamethasone, and other symptomatic treatments.  The 
observation has not changed the benefit-risk assessment for the study and enrollment is 
continuing in line with treatment specifications as provided in Section 6. 
 


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Table 6-3.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation* and Management of Adverse Events 
Including Dose Reductions for Short-term Intravenous Infusions 
Grade 
Description of Severity 
Interruption/ 
Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Infusion-related Reaction (Short-term IV only; for eIV see Table 6-4) 
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 
Consider slowing infusion rate to deliver the dose over 
90 minutes for next dose 
Monitoringd following a grade 2 event of IRR: 
 
the subject must be monitored for all subsequent 
dose administrations for a duration of time that is at 
least as long as the time it took for the onset of the 
last IRR plus 4 hours or per the protocol monitoring 
instructions, whichever is longer.  
 also, considering the 2-week treatment free period 
after cycles 2 and 4, the subject must be monitored 
for a duration of time that is at least as long as the 
time it took for the onset of the last IRR plus 4 
hours or per the protocol monitoring instructions, 
whichever is longer independent of non-occurrence 
of events in the prior treatment 
This monitoring requirement should be followed until 
there is no reoccurrence of IRR, at which time 
monitoring for subsequent doses should follow per 
protocol post-infusion monitoring. 
If a subsequent IRR occurs, then the event should be 
managed and monitored as per protocol, i.e., until it 
resolves to grade 1. 
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 
Immediate 
interruption/delay 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 or administer delayed 
infusion. 
 
Delay of the next infusion: 
 
 72 hours:  follow the SoA for 
the cycle day on which the 
infusion was originally planned.  
The next infusions should then 
be administered in line with the 
planned dosing schedule.   
 
 72 hours:  Starting with the 
cycle 1 day 8 infusion and later 
dosing time points skip the 
infusion (twice weekly dosing 
schedule only) and resume 
SoA for the next scheduled 
infusion. 
 
Hospitalization:  at least 48 hours 
(see also Monitoringd in the Specific 
Management section) 
 
Dose modification:  resume at the 
same dose  
 
Additional measures:  additional 
assessments as indicated in 
Section 6.2.2.3.4 
If not improved to 
 grade 1 in 
 14 days  
Page 1 of 17 
Abbreviations and footnotes defined on last page of table 


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Grade 
Description of Severity 
Interruption/ 
Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Infusion-related Reaction (Short-term IV only; 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. 
 
Consider slowing infusion rate to deliver the dose 
over 90 minutes for next dose. 
 
Monitoringd following a grade 3 event of IRR: 
 the subject must be monitored for all subsequent 
dose administrations for a duration of time that is 
at least as long as the time it took for the onset of 
the last IRR plus 4 hours or per the protocol 
monitoring instructions, whichever is longer.  
 also, considering the 2-week treatment free period 
after cycles 2 and 4, the subject must be 
monitored for a duration of time that is at least as 
long as the time it took for the onset of the last 
IRR plus 4 hours or per the protocol monitoring 
instructions, whichever is longer independent of 
non-occurrence of events in the prior treatment 
This monitoring requirement should be followed until 
there is no reoccurrence of IRR, at which time 
monitoring for subsequent doses should follow per 
protocol post-infusion monitoring. 
If a subsequent IRR occurs, then the event should be 
managed and monitored as per protocol, i.e., until it 
resolves to grade 1. 
As for grade 2 
infusion-related reaction, 
with the exception of 
mandatory dose 
modification:  reduce to next 
lower dose level in Table 6-2  
 
Reoccurrence:  discuss 
restarting with Amgen 
Medical Monitor 
If not improved to 
 grade 1 in  14 days  
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 910 
therapy 
Page 2 of 17 
Abbreviations and footnotes defined on last page of table 


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Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndromec (see Section 11.13 for additional guidance and grading scale details) (Short-term IV only; for eIV see Table 6-4) 
1 
Symptoms are not life 
threatening and require 
symptomatic treatment 
only, eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
n/a 
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 
 Oxygen requirement 
 40, OR 
  Hypotension 
responsive to fluids 
or low dose of 1 
vasopressor, OR 
 Grade 2 organ 
toxicity or grade 3 
transaminitis per 
CTCAE criteria 
Immediately 
interrupt/ delay 
AMG 910 until 
event improves 
to CRS 
grade  1. 
 
eIV infusion: 
Avoid 
treatment 
interruption 
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. 
 If hypoxia or hypotension lasts  24 hours manage as 
grade 3 CRS 
Monitor for CRS symptoms including vital signs and pulse 
oximetry at least Q2 hours for 12 hours and until resolution to 
CRS grade  1. 
Investigators should consider use of tocilizumabc as an 
additional therapy in this setting at a dose of 8 mg/kg as a 
single dose. 
For subjects with extensive co-morbidities or poor 
performance status, manage per grade 3 CRS guidance 
below. 
Monitoringd following an event of CRS: 
 
the subject must be monitored for all subsequent dose 
administrations for a duration of time that is at least as 
long as the time it took for the onset of the last CRS plus 
4 hours or per the protocol monitoring instructions, 
whichever is longer.  
 
also, considering the 2-week treatment free period after 
cycles 2 and 4, the subject must be monitored for dose 1 
cycle 3 and dose 1 cycle 5 for a duration of time that is at 
least as long as the time it took for the onset of the last 
CRS plus 4 hours or per the protocol monitoring 
instructions, whichever is longer independent of 
non-occurrence of events in the prior treatment 
This monitoring requirement should be followed until there is 
no reoccurrence of CRS, at which time monitoring for 
subsequent doses should follow per protocol post-infusion 
monitoring. 
If a CRS occurs, then the event should be managed and 
monitored as per protocol, i.e., until it resolves to grade  1. 
 
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 or 
administer delayed infusion.  For eIV infusion 
administration:  In case the interruption does not 
exceed 24 hours, the infusion can be restarted at the 
same dose without additional measures.  If the 
interruption exceeds 24 hours, the restart of the 
infusion should be performed under the supervision 
of the investigator or designee and premedication as 
described in Section 6.1.4 should be administered if 
implemented for start of eIV infusion. 
 
Delay of next infusion: 
 
 72 hours:  follow the SoA for the cycle day on 
which the infusion was originally planned.  The next 
infusions should then be administered in line with 
the planned dosing schedule.   
 
 72 hours:  For the cycle 1 day 8 infusion and later 
dosing time points skip the infusion (twice weekly 
dosing schedule only) and resume SoA for the 
next scheduled infusion. 
 
Hospitalization:  at least 48 hours (see also Monitoringd in 
the Specific Management section) 
 
Dose modification:   
 
After eIV infusion interruption  24 hours restart 
at same or at lower dose after discussion with 
Amgen Medical Monitor.  Refer to 
Section 6.2.2.3. 
 
After IV interruption reduce to next lower dose level in 
Table 6-2 or discuss with Amgen Medical Monitor.  For 
cohort 1, follow instructions of Section 6.2.2.3.5. 
 
Additional measures:  additional assessments as indicated 
in Section 6.2.2.3.4 
If there is no 
improvement to 
CRS  grade 1 
within 7 days. 
 
OR 
 
Occurrence of 
grade  3 CRS with 
any subsequent 
dose 
Page 3 of 17 


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Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 11.13 for additional guidance and grading scale details) (Short-term IV only) 
3  
Symptoms require and 
respond to aggressive 
intervention 
 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 910 until 
event improves 
to CRS 
grade  1. 
Admit to intensive care unit for close clinical and 
vital sign monitoring per institutional guidelines. 
Administer dexamethasone (or equivalent) IV at a 
dose maximum of 3 doses of 8 mg (24 mg/day).  
The dose should then be reduced step-wise. 
Additionally, tocilizumabc should be administered at 
a dose of 8 mg/kg as a single dose and may be 
repeated once within 24 to 48 hours based on 
clinical assessment. 
Monitoringd following an event of CRS: 
 the subject must be monitored for all 
subsequent dose administrations for a duration 
of time that is at least as long as the time it took 
for the onset of the last CRS plus 4 hours or per 
the protocol monitoring instructions, whichever 
is longer.  
 also, considering the 2-week treatment free 
period after cycles 2 and 4, the subject must be 
monitored for dose 1 cycle 3 and dose 1 cycle 5 
for a duration of time that is at least as long as 
the time it took for the onset of the last CRS 
plus 4 hours or per the protocol monitoring 
instructions, whichever is longer independent of 
non-occurrence of events in the prior treatment 
This monitoring requirement should be followed 
until there is no reoccurrence of CRS, at which 
time monitoring for subsequent doses should 
follow per protocol post-infusion monitoring. 
If a CRS occurs, then the event should be 
managed and monitored as per protocol, i.e., until 
it resolves to grade  1. 
 
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 or administer 
delayed infusion.  For eIV infusion 
administration:  Treatment initiation 
with eIV infusion should be restarted 
following the dosing schedule and SoA 
for cycle 1 day 1.  This should be done 
at the earliest after 48 hours and under 
the supervision of the investigator or 
designee and premedication as 
described in Section 6.1.4 should be 
administered.  Refer to Section 6.2.2.3. 
 
Delay of next infusion: 
 
 72 hours:  follow the SoA for the 
cycle day on which the infusion was 
originally planned.  The next 
infusions should then be 
administered in line with the 
planned dosing schedule.   
 
 72 hours:  Starting with the cycle 1 
day 8 infusion and later dosing time 
points skip the infusion (twice weekly 
dosing schedule only) and resume 
SoA for the next scheduled infusion. 
 
Hospitalization:  at least 48 hours after 
resolution to  grade 2 (see also 
Monitoringd in the Specific Management 
section) 
 
Dose modification:  reduce to next lower 
dose level in Table 6-2  
 
Additional measures:  additional 
assessments as indicated in 
Section 6.2.2.3.4 
If there is no 
improvement to CRS 
 grade 2 within 
5 days and CRS 
 grade 1 within 
7 days. 
 
OR 
 
If subject is still febrile 
or still on 
vasopressors within 
8 hours after initiation 
of corticosteroid and 
tocilizumab 
 
OR 
 
In case of 2 separate 
grade 3 CRS events. 
Page 4 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 65 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 11.13 for additional guidance and grading scale details) (Short-term IV only) 
4 
Life-threatening 
symptoms 
 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 dexamethasone (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 should be 
administered at a dose of 8 mg/kg as a 
single dose and may be repeated once 
within 24 to 48 hours based on clinical 
assessment. 
n/a 
Immediately stop 
the infusion (if 
applicable) and 
permanently 
discontinue 
AMG 910 
therapy 
Page 5 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 66 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Tumor Lysis Syndrome (TLS) – Grading according to Cairo-Bishop Criteria (see Section 11.14) 
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 with Amgen Medical Monitor first. 
 
In case of infusion interruption, continue treatment with next 
schedule infusion, do not resume prior infusion or administer 
delayed infusion.  For eIV infusion administration:  In case the 
interruption does not exceed 24 hours, the infusion can be 
restarted at the same dose without additional measures.  If 
the interruption exceeds 24 hours, the restart of the infusion 
should be performed under the supervision of the 
investigator or designee and premedication as described in 
Section 6.1.4 should be administered if implemented for start 
of eIV infusion.  Refer to Section 6.2.2.3.  Reduce to next 
lower dose level in Table 6-2.  If the interruption exceeds 
48 hours, treatment initiation with eIV infusion should be 
restarted following the dosing schedule and SoA for cycle 1 
starting with day 1.  Restarting due to any eIV infusion 
interruption should be discussed with the medical monitor. 
 
Delay of next infusion: 
 
 72 hours:  follow the SoA for the cycle day on which the infusion 
was originally planned.  The next infusions should then be 
administered in line with the planned dosing schedule.   
 
 72 hours:  Starting with the cycle 1 day 8 infusion and later 
dosing time points skip the infusion (twice weekly dosing 
schedule only) and resume SoA for the next scheduled infusion. 
 
Hospitalization:  at least 48 hours 
 
Dose modification:  reduce to next lower dose level in Table 6-2 
 
Additional measures:  additional assessments as indicated in 
Section 6.2.2.3.4 
If not improved to 
 grade 1 in  14 days 
 
OR 
 
In case of repeat 
grade 2 TLS event 
despite dose reduction. 
Page 6 of 17 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 67 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Tumor Lysis Syndrome (TLS) – Grading according to Cairo-Bishop Criteria (see Section 11.14) 
3 (clinical 
TLS) 
Immediate 
interruption/ 
delay until 
event has 
improved to 
grade  1 
TLS should be 
managed 
according to the 
local standard of 
care and 
institutional 
guidelines 
 Re-start possible if successfully managed and improvement to  grade 1 in  14 days 
 Restart should only be considered if there is agreement between the investigator and 
the Amgen Medical Monitor that the patient is very likely to benefit from continued 
treatment. 
 In case of infusion interruption, continue treatment with next schedule infusion, do not 
resume prior infusion or administer delayed infusion.  For eIV infusion 
administration:  In case the interruption does not exceed 24 hours, the infusion 
can be restarted at the same dose without additional measures.  If the 
interruption exceeds 24 hours, the restart of the infusion should be performed 
under the supervision of the investigator or designee and premedication as 
described in Section 6.1.4 should be administered.  Reduce to next lower dose 
level in Table 6-2.  If the interruption exceeds 48 hours, treatment initiation with 
eIV infusion should be restarted following the dosing schedule and SoA for 
cycle 1 starting with day 1.  Restarting due to any eIV infusion interruption 
should be discussed with the medical monitor.  Refer to Section 6.2.2.3. 
 Delay of next infusion: 
 
 72 hours:  follow the SoA for the cycle day on which the infusion was originally 
planned.  The next infusions should then be administered in line with the 
planned dosing schedule.   
 
 72 hours:  Starting with the cycle 1 day 8 infusion and later dosing time points 
skip the infusion (twice weekly dosing schedule only) and resume SoA for the 
next scheduled infusion. 
 Hospitalization:  at least 48 hours 
 Dose modification:  reduce to next lower dose level in Table 6-2  
 Additional measures:  additional assessments as indicated in Section 6.2.2.3.4 
If not improved to 
 grade 1 in 
 14 days 
 
OR 
 
In case of repeat 
grade  2 TLS event 
despite dose 
reduction 
4 (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 910 
therapy 
Page 7 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 68 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Neurological events  
 2 
Interruption/ 
delay until 
event has 
improved to 
grade  1 
Consider 
administration of 
corticosteroids 
(and tocilizumab 
if associated with 
CRS). 
 
Following a 
seizure:  
administer 
anti-seizure 
medication 
according to 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 or administer 
delayed infusion.  For eIV infusion administration:  In case the 
interruption does not exceed 24 hours, the infusion can be 
restarted at the same dose without additional measures.  If 
the interruption exceeds 24 hours, the restart of the infusion 
should be performed under the supervision of the 
investigator or designee and premedication as described in 
Section 6.1.4 should be administered.  If the interruption 
exceeds 48 hours, treatment initiation with eIV infusion 
should be restarted following the dosing schedule and SoA 
for cycle 1 starting with day 1.  Restarting due to any eIV 
infusion interruption should be discussed with the medical 
monitor.  Refer to Section 6.2.2.3. 
 Delay of next infusion: 
 
 72 hours:  follow the SoA for the cycle day on which the 
infusion was originally planned.  The next infusions should 
then be administered in line with the planned dosing 
schedule.   
 
 72 hours:  Starting with the cycle 1 day 8 infusion and later 
dosing time points skip the infusion (twice weekly dosing 
schedule only) and resume SoA for the next scheduled 
infusion. 
 Hospitalization:  at least 48 hours 
 Dose modification for grade 2:  resume at the same dose 
 Dose modification for grade  3:  resume at next lower dose 
 Additional measures:  additional assessments as indicated in 
Section 6.2.2.3.4 
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 
Page 8 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 69 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Gastrointestinal events:  Nausea 
1 to 2 
If symptomatic 
 5 days 
 
 
Treat 
symptomatically 
 
If symptoms 
 5 days, and 
symptoms 
grade 1 to 2, 
continue 
investigational 
product 
 
Resolved or improved to grade  1 or baseline in 5 days 
o 
Dose Modification:  Resume at same dose 
 
Reoccurrence:  Resolved or improved to grade  1 or baseline in 5 days 
o 
Dose Modification:  Resume at same dose 
If not returned to 
grade  1 or 
baseline in 5 days 
after interruption   
3 
Interrupt  
 
 
Consider tube 
feed/TPN 
 
Consider GI 
consult 
 
Other medical 
interventions as 
clinically 
indicated and per 
institutional 
guidelines 
 
Resolved or improved to grade  2 in 48 hours 
 
Re-start with next scheduled infusion, do not resume prior infusion or 
administer delayed infusion.  For eIV infusion administration:  In case 
the interruption does not exceed 24 hours, the infusion can be 
restarted at the same dose without additional measures.  If the 
interruption exceeds 24 hours, the restart of the infusion should be 
performed under the supervision of the investigator or designee and 
premedication as described in Section 6.1.4 should be administered 
(Table 6-2).  If the interruption exceeds 48 hours, treatment initiation 
with eIV infusion should be restarted following the dosing schedule 
and SoA for cycle 1 starting with day 1.  Restarting due to any eIV 
infusion interruption should be discussed with the medical monitor.  
Refer to Section 6.2.2.3. 
o 
Dose Modification:  Resume at same dose 
 
Second event reoccurrence:  Resolved or improved to grade  2 in 
48 hours 
o 
Dose Modification:  consider next lower dose at investigator’s 
discretion 
 
Subsequent event occurrence:  Re-start possible after discussion with 
Amgen Medical Monitor 
o 
Dose Modification:  Resume at same dose or reduce to next lower 
dose level 
 
Second event that requires TPN or feeding tube can only be re-started 
following discussion with the Amgen Medical Monitor 
If not returned to 
grade  2 in 
48 hours after 
interruption   
Page 9 of 17 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 70 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Gastrointestinal events:  Vomiting 
1 
If deemed intolerable by the 
subject or investigator and 
not responding to 
appropriate medical 
management or if 
symptomatic  5 days 
 
Treat symptomatically 
 
If symptoms persist 
 48 hours after treatment 
interruption, consider GI 
consult and discuss with 
Amgen Medical Monitor 
 
Re-start with next scheduled infusion, do not resume prior infusion or administer 
delayed infusion 
 
Dose Modification:  Resume at same dose 
Not applicable 
2 
If deemed intolerable by the 
subject or investigator and 
not responding to 
appropriate medical 
management or if 
symptomatic  5 days 
 
IV hydration  
 
Other medical interventions 
as clinically indicated and 
per institutional guidelines 
 
Reoccurrence of event:  
Same management and GI 
consult 
 
Resolved or improved to grade  1 in 48 hours 
o Dose Modification:  Resume at same dose 
 
Re-start with next scheduled infusion, do not resume prior infusion or administer 
delayed infusion 
 
Second event occurrence:  Resolved or improved to grade  1 in 48 hours  
o Dose Modification:  Consider lower dose at investigator’s discretion 
 
Subsequent event occurrence:  Re-start possible after discussion with Amgen 
Medical Monitor 
o Dose Modification:  Per discussion with Amgen Medical Monitor 
If not returned to 
grade  1 in 48 hours 
after interruption 
3 
Interrupt 
 
Tube feed/TPN 
 
Other medical interventions 
as clinically indicated and 
per institutional guidelines 
 
Reoccurrence of event:  
Same management and GI 
consult 
 
Resolved or improved to grade  1 in 48 hours 
o Dose Modification:  Resume at same dose 
 
Re-start with next scheduled infusion do not resume prior infusion or administer 
delayed infusion.  For eIV infusion administration:  In case the interruption does 
not exceed 24 hours, the infusion can be restarted at the same dose without 
additional measures.  If the interruption exceeds 24 hours, the restart of the 
infusion should be performed under the supervision of the investigator or 
designee and premedication as described in Section 6.1.4 should be 
administered.  If the interruption exceeds 48 hours, treatment initiation with 
eIV infusion should be restarted following the dosing schedule and SoA for 
cycle 1 starting with day 1.  Restarting due to any eIV infusion interruption 
should be discussed with the medical monitor.  Refer to Section 6.2.2.3. 
 
Second event occurrence:  Resolved or improved to grade 1 in 48 hours  
o Dose Modification:  Consider next lower dose at investigator’s discretion 
 
Subsequent event occurrence:  Re-start possible after discussion with Amgen 
Medical Monitor 
o Dose Modification:  Per discussion with Amgen Medical Monitor 
 
Second event that requires TPN or feeding tube can only be re-started following 
discussion with the Amgen Medical Monitor 
If not returned to 
grade  1 in 48 hours 
after interruption 
4 
Interrupt 
 
Hospitalization for tube 
feeding/ TPN 
 
Other medical interventions 
as clinically indicated and 
per institutional guidelines 
 
GI consult  
 
Re-start possible at next lower dose if resolved or improved to grade  1 in 72 hours 
following discussion with GI consult and Amgen Medical Monitor 
 
Re-start with next scheduled infusion, do not resume prior infusion or administer 
delayed infusion 
 
Second event that require TPN or feeding tube can only be re-started following 
discussion with the Amgen Medical Monitor 
If not returned to 
grade  1 in 72 hours 
after interruption  
OR  
After second occurrence 
of a grade 4 event after 
restart of investigational 
product 
Page 10 of 17 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 71 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Gastrointestinal events:  Abdominal pain 
1 to 2 
If deemed intolerable by 
the subject or 
investigator and not 
responding to 
appropriate medical 
management  
 
 
Treat as clinically 
indicated 
 
Other medical 
interventions as 
clinically indicated 
and per institutional 
guidelines 
 
If symptomatic 
 24 hours, consider 
GI consult, consider 
upper GI endoscopy 
 
Reoccurrence of 
event:  Same 
management  
 
Resolved or improved to grade  1 or baseline in 48 hours 
o 
Dose Modification:  Resume at same dose 
 
Re-start with next scheduled infusion, do not resume prior infusion 
or administer delayed infusion.  For eIV infusion administration:  
In case the interruption does not exceed 24 hours, the 
infusion can be restarted at the same dose without additional 
measures.  If the interruption exceeds 24 hours, the restart of 
the infusion should be performed under the supervision of 
the investigator or designee and premedication as described 
in Section 6.1.4 should be administered.  Refer to 
Section 6.2.2.3. 
 
Second event occurrence:  Resolved or improved to grade  1 in 
24 hours  
o 
Dose Modification:  Re-start at next lower dose in Table 6-2 
 
Subsequent event occurrence:  Re-start possible after discussion 
with Amgen Medical Monitor 
o 
Dose Modification:  Per discussion with Amgen Medical 
Monitor 
If not returned to grade  1 or 
baseline in 48 hours after 
interruption  
If abnormal GI pathology distant 
from original tumor per GI 
consult 
 
For abdominal pain indicative of 
gastritis, gastric hemorrhage, 
gastric perforation or fistula, 
refer to events listed in table for 
guidance 
3 
Interrupt 
 
 
Treat as clinically 
indicated 
 
Other medical 
interventions as 
clinically indicated 
and per institutional 
guidelines 
 
If symptomatic 
 24 hours, consider 
GI consult, consider 
upper GI endoscopy 
 
Reoccurrence of 
event:  Same 
management  
 
Resolved or improved to grade  1 or baseline in 24 hours  
o 
Dose Modification:  Re-start at next lower dose in Table 6-2 
 
Re-start with next scheduled infusion, do not resume prior infusion 
or administer delayed infusion.  For eIV infusion administration:  
In case the interruption does not exceed 24 hours, the 
infusion can be restarted under the supervision of the 
investigator or designee and premedication as described in 
Section 6.1.4 should be administered.  Reduce to next lower 
dose level in Table 6-2.   
 
Second event occurrence:  Resolved or improved to grade  1 in 
24 hours 
o 
Dose Modification:  Restart at next lower dose in Table 6-2 
 
Subsequent event occurrence:  Re-start possible after discussion 
with Amgen Medical Monitor 
If not returned to grade  1 or 
baseline in 24 hours after 
interruption  
If abnormal GI pathology distant 
from original per GI consult or 
endoscopy  
 
For abdominal pain indicative of 
gastritis, gastric hemorrhage, 
gastric perforation or fistula, 
refer to these events listed in 
table for guidance 
Page 11 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 72 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Gastrointestinal events:  Gastritis 
1 
If deemed intolerable by 
the subject or 
investigator and not 
responding to 
appropriate medical 
management  
 
Treat as clinically indicated 
 
Re-start with next scheduled infusion, do not resume prior infusion or administer 
delayed infusion 
 
Dose Modification:  Resume at same dose 
Not applicable 
2 
If deemed intolerable by 
the subject or 
investigator and not 
responding to 
appropriate medical 
management until event 
has improved to 
grade  1 
 
 
Treat as clinically indicated 
 
Other medical interventions as 
clinically indicated and per 
institutional guidelines 
 
Consider GI consult 
 
Reoccurrence of event:  Same 
management  
 
Resolved or improved to grade  1 in 72 hours, re-start at next lower dose if 
there is agreement per GI consult and following discussion with Amgen Medical 
Monitor 
 
Re-start with next scheduled infusion, do not resume prior infusion or administer 
delayed infusion.  For eIV infusion administration:  In case the interruption 
does not exceed 24 hours, the infusion can be restarted at the same dose 
without additional measures.  If the interruption exceeds 24 hours, the 
restart of the infusion should be performed under the supervision of the 
investigator or designee and premedication as described in Section 6.1.4 
should be administered.  If the interruption exceeds 48 hours, treatment 
initiation with eIV infusion should be restarted following the dosing 
schedule and SoA for cycle 1 starting with day 1.  Restarting due to any 
eIV infusion interruption should be discussed with the medical monitor.  
Refer to Section 6.2.2.3. 
 
Second event occurrence:  Re-start possible at next lower dose if resolved or 
improved to grade  1 in 72 hours, and there is agreement per GI consult and 
following discussion with Amgen Medical Monitor  
If reoccurrence of 
grade 2 event and 
symptoms 
persists 
 72 hours 
3 
Permanent 
discontinuation 
 
 
Medical evaluation, 
assessment  
 
Hospitalization 
 
Consider TPN/tube feed  
 
GI consult including upper GI 
endoscopy 
 
Reoccurrence of event:  Same 
management  
 
Not applicable 
Permanent 
discontinuation 
4 
Permanent 
discontinuation 
 
Treat as clinically indicated 
 
Hospitalization 
 
Consider TPN/tube feed 
 
GI consult including upper GI 
endoscopy 
 
Other medical interventions as 
clinically indicated and per 
institutional guidelines 
 
Not applicable 
Permanent 
discontinuation 
Page 12 of 17 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 73 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/Delay 
Specific Management 
Re-start Guidance 
Permanent Discontinuation 
Gastrointestinal events:  Gastric hemorrhage 
1 
If event reoccurs, interrupt 
 
Medical evaluation/ 
assessment, and treatment 
as clinically indicated 
 
GI consult 
 
Reoccurrence of event:  
Same management  
 
Re-start possible at next lower dose if symptoms resolved 
in 7 days (no active bleeding), and following discussion 
with Amgen Medical Monitor 
 
Re-start treatment with next scheduled infusion, do not 
resume prior infusion or administer delayed infusion 
 
Second event occurrence:  Re-start possible at next lower 
dose if symptoms resolved in 7 days (no active bleeding) 
and following discussion with Amgen Medical Monitor 
 
Third event occurrence:  Re-start possible at next lower 
dose if symptoms resolved in 7 days (no active bleeding), 
and following discussion with Amgen Medical Monitor 
If symptoms persists  7 days  
 
OR  
 
If a fourth occurrence of 
event after restart of 
investigational product 
 
OR 
 
Occurrence of grade  3 
gastric hemorrhage with any 
subsequent dose 
2 
Interrupt 
 
 
Medical evaluation/ 
assessment, and treatment 
as clinically indicated 
 
GI consult 
 
Consider endoscopy 
 
Reoccurrence of event:  
Same management  
 
Re-start possible at next lower dose if symptoms resolved 
to grade  1 in 7 days (no active bleeding), and following 
discussion with Amgen Medical Monitor 
 
Re-start with next scheduled infusion, do not resume prior 
infusion or administer delayed infusion 
 
Second event occurrence:  Re-start possible at next lower 
dose if symptoms resolved in 7 days (no active bleeding), 
and following discussion with Amgen Medical Monitor 
 
Second event that requires TPN or feeding tube can only 
be re-started following discussion with the Amgen Medical 
Monitor 
If symptoms persists  7 days  
 
OR  
 
Occurrence of grade  3 
gastric hemorrhage with any 
subsequent dose 
3 
Permanent discontinuation 
 
Medical evaluation, 
assessment 
 
Hospitalization 
 
Consider TPN/tube feed 
 
GI consult including upper GI 
endoscopy 
 
Reoccurrence of event:  
Same management 
Not applicable 
Permanent discontinuation 
4 
Permanent discontinuation 
 
Other medical interventions 
as clinically indicated and per 
institutional guidelines 
 
Endoscopy 
Not applicable 
Permanent discontinuation  
Page 13 of 17 
Abbreviations and footnotes defined on last page of table 
 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 74 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start 
guidance 
Permanent 
Discontinuation 
Gastrointestinal events:  Gastric perforation or fistula 
2 to 3 
Permanent 
discontinuation 
 
Emergent medical evaluation/ assessment, and treatment as 
clinically indicated 
 
GI consult 
 
Other medical interventions as clinically indicated and per 
institutional guidelines 
Not 
applicable 
Permanent 
discontinuation 
4 
Permanent 
discontinuation 
 
Urgent intervention indicated 
 
GI consult 
 
Other medical interventions as clinically indicated and per 
institutional guidelines 
Not 
applicable 
Permanent 
discontinuation 
Page 14 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 75 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Any other 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 
n/a 
 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 or administer 
delayed infusion.  For eIV infusion administration:  In case the 
interruption does not exceed 24 hours, the infusion can be 
restarted at the same dose without additional measures.  If the 
interruption exceeds 24 hours, the restart of the infusion 
should be performed under the supervision of the investigator 
or designee and premedication as described in Section 6.1.4 
should be administered.  If the interruption exceeds 48 hours, 
treatment initiation with eIV infusion should be restarted 
following the dosing schedule and SoA for cycle 1 starting 
with day 1.  Restarting due to any eIV infusion interruption 
should be discussed with the medical monitor. 
 Delay of next infusion: 
 
 72 hours:  follow the SoA for the cycle day on which the 
infusion was originally planned.  The next infusions should 
then be administered in line with the planned dosing 
schedule.   
 
 72 hours:  Starting with the cycle 1 day 8 infusion and later 
dosing time points skip the infusion (twice weekly dosing 
schedule only) and resume SoA for the next scheduled 
infusion. 
 Hospitalization:  at least 48 hours 
 Dose modification:  reduce to next lower dose level in Table 6-2 
 Additional measures:  additional assessments as indicated in 
Section 6.2.2.3.4 
If not improved to 
 grade 1 in  14 days. 
 
OR 
 
In case of 
reappearance of same 
event at grade 4 
 
OR 
 
In case of repeat 
grade  3 event despite 
dose reduction 
Page 15 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 76 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
Any Non-AMG 910-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 
n/a 
 
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 or administer delayed infusion.  For 
eIV infusion administration:  In case the interruption does not 
exceed 24 hours, the infusion can be restarted at the same dose 
without additional measures.  If the interruption exceeds 24 hours, 
the restart of the infusion should be performed under the 
supervision of the investigator or designee and premedication as 
described in Section 6.1.4 should be administered.  If the 
interruption exceeds 48 hours, treatment initiation with eIV infusion 
should be restarted following the dosing schedule and SoA for 
cycle 1 starting with day 1.  Restarting due to any eIV infusion 
interruption should be discussed with the medical monitor.  Refer to 
Section 6.2.2.3. 
 
Delay of next infusion: 
 
 72 hours:  follow the SoA for the cycle day on which the infusion was 
originally planned.  The next infusions should then be 
administered in line with the planned dosing schedule.   
 
 72 hours:  Starting with the cycle 1 day 8 infusion and later dosing 
time points skip the infusion (twice weekly dosing schedule only) 
and resume SoA for the next scheduled infusion. 
 
Hospitalization:  at least 48 hours 
 
Dose modification:  If AMG 910 is resumed then the AMG 910 dose will 
be reduced to the next lower dose level in Table 6-2 after discussion with 
Amgen Medical Monitor 
 
Additional measures:  additional assessments as indicated in 
Section 6.2.2.3.4 
If not improved to 
 grade 1 in 
 28 days. 
 
OR 
 
In case of 
reappearance of 
same event at 
grade 4 
Hepatotoxicity 
For Stopping and Rechallenge Rules please refer to Section 11.7. 
Page 16 of 17 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 77 of 175 
CONFIDENTIAL  
 
 
Page 17 of 17 
CRS  cytokine release syndrome; CTCAE  Common Terminology Criteria for Adverse Events; DLT  dose-limiting toxicity; eIV  extended intravenous; 
GI  gastrointestinal; IRR  infusion-related reaction; IV  intravenous; MTD  maximum tolerated dose; NSAID  non-steroidal anti-inflammatory drug; 
Q2  every 2; SoA  Schedule of Activities; TLS  tumor lysis syndrome; TPN  total parenteral nutrition. 
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 
c All sites will ensure that CRS rescue medications are available on-site, including corticosteroids and 2 doses of tocilizumab per study subject 
d Eg, If a subject experiences an IRR or CRS that started 3 days after the cycle 1 day 8 dose, this subject should be monitored for at least 3 days plus 4 hours 
post-infusion for subsequent doses until the subject no longer has IRR or CRS events.  If a subject experiences IRR or CRS that started 1 day after the cycle 1 
day 8 dose, this subject can be monitored for 48 hours post-infusion for subsequent doses until the subject no longer has IRR or CRS events.   
*Note:  In specifically defined situations, a restart at a next lower dose level can be taken into consideration but only if all additional requirements for 
restart as stated in Section 7.1 apply. 
 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 78 of 175 
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Table 6-4.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation* and Management of Infusion-related 
Reactions Including Dose Reductions During Extended Intravenous (eIV) Infusions 
Grade 
Description of Severity 
Interruption/ 
Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
 
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 
Monitoringd following a grade 2 event of IRR: 
 
the subject must be monitored for all subsequent 
dose administrations (re-start and dosing 
thereafter) for a duration of time that is at least as 
long as the time it took for the onset of the last 
IRR plus 4 hours or per the protocol monitoring 
instructions, whichever is longer.  
 also, considering initiation after the 2-week 
treatment free period after cycles 2 and 4, the 
subject must be monitored for a duration of time 
that is at least as long as the time it took for the 
onset of the last IRR plus 4 hours or per the 
protocol monitoring instructions, whichever is 
longer independent of non-occurrence of events 
in the prior treatment 
This monitoring requirement should be followed until 
there is no reoccurrence of IRR, at which time 
monitoring for subsequent doses should follow per 
protocol post-infusion monitoring. 
If a subsequent IRR occurs, then the event should be 
managed and monitored as per protocol, i.e., until it 
resolves to grade 1. 
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 
Immediate 
interruption/delay until 
event has improved to 
grade  1 
 
Re-start possible, if 
successfully managed and 
improvement to  grade 1 in 
 14 days. 
 
Delay of re-start: 
 
Re-start 7 days from 
cycle 1 day 1 at earliest 
 
Follow the SoA from 
cycle 1 day 1 onwards 
 
Hospitalization:  at least 
48 hours (see also 
Monitoring in the 
Specific Management 
section) 
 
Dose modification:  resume at 
the same dose  
 
For next short-term infusion 
after the eIV part consider 
slowing infusion rate to 
deliver the dose over 90 
minutes 
 
Additional measures:  
additional assessments as 
indicated in Section 6.2.2.3.4 
If not improved to 
 grade 1 in 
 14 days  
 
If event re-occurs 
at higher grade 
Page 1 of 5 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 79 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Description of Severity 
Interruption/ 
Delay 
Specific Management 
Re-start guidance 
Permanent 
Discontinuation 
Infusion-related Reaction (eIV; 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 
Consider supportive therapy including steroids as 
clinically indicated. 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable. 
 
Monitoring following a grade 3 event of IRR: 
 the subject must be monitored for all 
subsequent dose administrations for a duration 
of time that is at least as long as the time it took 
for the onset of the last IRR plus 4 hours or per 
the protocol monitoring instructions, whichever 
is longer.  
 also, considering the 2-week treatment free 
period after cycles 2 and 4, the subject must be 
monitored for a duration of time that is at least 
as long as the time it took for the onset of the 
last IRR plus 4 hours or per the protocol 
monitoring instructions, whichever is longer 
independent of non-occurrence of events in the 
prior treatment 
This monitoring requirement should be followed 
until there is no reoccurrence of IRR, at which time 
monitoring for subsequent doses should follow 
per protocol post-infusion monitoring. 
If a subsequent IRR occurs, then the event should 
be managed and monitored as per protocol, i.e., 
until it resolves to grade 1. 
A restart needs to be 
discussed with Amgen 
Medical Monitor and should 
only be taken into 
consideration after careful 
risk-benefit assessment 
 
Mandatory dose 
modification:  reduce to next 
lower dose level in Table 6-2  
 
All other re-start 
instructions as for grade 2 
infusion-related reaction, 
apply 
 
For short-term infusions 
after the eIV part  
 consider slowing 
infusion rate to deliver 
the next dose over 
90 minutes 
 reduce dose to next 
lower dose level in 
Table 6-2 
 
If not improved to 
 grade 1 in  14 days  
 
Re-occurrence of a 
grade 3 event 
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 910 
therapy 
Page 2 of 5 
Abbreviations and footnotes defined on last page of table 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 80 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndromec (see Section 11.13 for additional guidance and grading scale details) (eIV) 
1 
Symptoms are not 
life-threatening and 
require symptomatic 
treatment only, 
eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
n/a 
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 
 Oxygen 
requirement  40, 
OR 
  Hypotension 
responsive to fluids 
or low dose of 1 
vasopressor, OR 
 Grade 2 organ 
toxicity or grade 3 
transaminitis per 
CTCAE criteria 
Immediately 
interrupt/ 
delay 
AMG 910 until 
event 
improves to 
CRS 
grade  1. 
 
eIV infusion: 
Avoid 
treatment 
interruption 
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. 
 If hypoxia or hypotension lasts  24 hours manage as grade 3 
CRS 
Monitor for CRS symptoms including vital signs and pulse 
oximetry at least Q2 hours for 12 hours and until resolution to 
CRS grade  1. 
Investigators should consider use of tocilizumabc as an 
additional therapy in this setting at a dose of 8 mg/kg as a 
single dose. 
For subjects with extensive co-morbidities or poor performance 
status, manage per grade 3 CRS guidance below. 
Monitoringd following an event of CRS: 
 
the subject must be monitored for all subsequent dose 
administrations for a duration of time that is at least as long 
as the time it took for the onset of the last CRS plus 4 hours 
or per the protocol monitoring instructions, whichever is 
longer.  
This monitoring requirement should be followed until there is 
no reoccurrence of CRS, at which time monitoring for 
subsequent doses should follow per protocol post-infusion 
monitoring. 
If a CRS occurs, then the event should be managed and 
monitored as per protocol, ie, until it resolves to grade  1. 
 
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 or administer delayed 
infusion.  For eIV infusion administration:  In 
case the interruption does not exceed 24 hours, 
the infusion can be restarted at the same dose 
without additional measures.  If the interruption 
exceeds 24 hours, the restart of the infusion 
should be performed under the supervision of 
the investigator or designee and premedication 
as described in Section 6.1.4 should be 
administered if implemented for start of eIV 
infusion. 
 
Delay of next infusion: 
 
 72 hours:  follow the SoA for the cycle 
day on which the infusion was originally 
planned.  The next infusions should then 
be administered in line with the planned 
dosing schedule.   
 
 72 hours:  For the cycle 1 day 8 infusion 
and later dosing time points skip the 
infusion (twice weekly dosing schedule 
only) and resume SoA for the next 
scheduled infusion. 
 
Hospitalization:  at least 48 hours (see also 
Monitoringd in the Specific Management 
section) 
 
Dose modification:   
 
After eIV infusion interruption  24 hours 
restart at same or at lower dose after 
discussion with Amgen Medical Monitor 
 
After IV interruption reduce to next lower dose 
level in Table 6-2 or discuss with Amgen 
Medical Monitor.  For cohort 1, follow 
instructions of Section 6.2.2.3.5. 
 
Additional measures:  additional assessments 
as indicated in Section 6.2.2.3.4 
If there is no 
improvement to 
CRS  grade 1 
within 7 days. 
 
OR 
 
Occurrence of 
grade  3 CRS 
with any 
subsequent dose 
Page 3 of 5 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 81 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 11.13 for additional guidance and grading scale details) (eIV) 
3  
Symptoms require 
and respond to 
aggressive 
intervention 
 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 910 until 
event improves 
to CRS 
grade  1. 
Admit to intensive care unit for close clinical 
and vital sign monitoring per institutional 
guidelines. 
Administer dexamethasone (or equivalent) IV at 
a dose maximum of 3 doses of 8 mg 
(24 mg/day).  The dose should then be reduced 
step-wise. 
Additionally, tocilizumabc should be 
administered at a dose of 8 mg/kg as a single 
dose and may be repeated once within 24 to 
48 hours based on clinical assessment. 
Monitoring following an event of CRS: 
 the subject must be monitored for all 
subsequent dose administrations for a 
duration of time that is at least as long as 
the time it took for the onset of the last CRS 
plus 4 hours or per the protocol monitoring 
instructions, whichever is longer.  
This monitoring requirement should be 
followed until there is no reoccurrence of CRS, 
at which time monitoring for subsequent doses 
should follow per protocol post-infusion 
monitoring. 
If a CRS occurs, then the event should be 
managed and monitored as per protocol, i.e., 
until it resolves to grade  1. 
 
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 or 
administer delayed infusion.  For eIV 
infusion administration:  Treatment 
initiation with eIV infusion should be 
restarted following the dosing schedule 
and SoA for cycle 1 day 1.  This should 
be done at the earliest after 48 hours 
and under the supervision of the 
investigator or designee and 
premedication as described in 
Section 6.1.4 should be administered. 
 
Delay of next infusion: 
 
 72 hours:  follow the SoA for the 
cycle day on which the infusion was 
originally planned.  The next 
infusions should then be 
administered in line with the 
planned dosing schedule.   
 
 72 hours:  Starting with the cycle 1 
day 8 infusion and later dosing time 
points skip the infusion (twice 
weekly dosing schedule only) and 
resume SoA for the next scheduled 
infusion. 
 
Hospitalization:  at least 48 hours after 
resolution to  grade 2 (see also 
Monitoringd in the Specific Management 
section) 
 
Dose modification:  reduce to next 
lower dose level in Table 6-2  
 
Additional measures:  additional 
assessments as indicated in 
Section 6.2.2.3.4 
If there is no 
improvement to 
CRS  grade 2 
within 5 days and 
CRS  grade 1 
within 7 days. 
 
OR 
 
If subject is still 
febrile or still on 
vasopressors within 
8 hours after 
initiation of 
corticosteroid and 
tocilizumab 
 
OR 
 
In case of 2 
separate grade 3 
CRS events. 
Page 4 of 5 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 82 of 175 
CONFIDENTIAL  
 
 
 
Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 11.13 for additional guidance and grading scale details) (eIV) 
4 
Life-threatening 
symptoms 
 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 dexamethasone (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 should be 
administered at a dose of 8 mg/kg as 
a single dose and may be repeated 
once within 24 to 48 hours based on 
clinical assessment. 
n/a 
Immediately 
stop the 
infusion (if 
applicable) and 
permanently 
discontinue 
AMG 910 
therapy 
Page 5 of 5 
CRS  cytokine release syndrome; CTCAE  Common Terminology Criteria for Adverse Events; DLT  dose-limiting toxicity; eIV  extended intravenous; 
IRR  infusion-related reaction; IV  intravenous; NSAID  non-steroidal anti-inflammatory drug; Q2  every 2; SoA  Schedule of Activities; TLS  tumor 
lysis syndrome. 
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. 
c All sites will ensure that CRS rescue medications are available on-site, including corticosteroids and 2 doses of tocilizumab per study subject. 
*Note:  In specifically defined situations, a restart at a next lower dose level can be taken into consideration but only if all additional requirements for 
restart as stated in Section 7.1 apply. 
 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 83 of 175 
CONFIDENTIAL  
 
 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury 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 other protocol-required therapies during the study 
are provided in the IPIM. 
6.4 
Treatment Compliance 
AMG 910 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 CRF per the CRF completion 
guidelines.  Please refer to IPIM for more details on treatment compliance of AMG 910. 
6.5 
Treatment of Overdose 
As the maximum recommended dose is not assessed yet, the effects of overdose of this 
product are not known. 
The administered AMG 910 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. 
A dose of > 10% higher than the intended AMG 910 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. 


Product:  AMG 910  
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CONFIDENTIAL  
 
 
6.6 
Prior and Concomitant Treatment 
6.6.1 
Prior Treatment 
Prior therapies that were taken/used from 3 months prior to signing informed consent will 
be collected.  Collect therapy name, indication, dose, unit, frequency, route, start date 
and stop date. 
For all prior therapies taken for gastric cancer (eg, chemotherapy or treatment with TKI), 
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 
 
type of progression (radiographic, and/or symptomatic) 
 
response (resistant versus sensitive):  categorized on the basis of the 
post-therapy radiographic change pattern for agents that reduce tumor burden 
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). 
6.6.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments (including nutritional support) 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 
safety follow-up period. 
For concomitant therapies being taken for the disease under study, collect therapy 
name, indication, dose, unit, frequency, start and stop dates.  For all other concomitant 
therapies, collect therapy name, indication, dose, start and stop dates. 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 85 of 175 
CONFIDENTIAL  
 
 
6.6.2.1 
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 all patients. 
6.6.2.2 
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. 
6.6.2.3 
Tumor Lysis Syndrome 
While rare in gastric cancer, 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 lactate 
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 
Table 6-3. 
To prevent TLS, before administration of AMG 910 all subjects should receive at the 
discretion of the investigator appropriate 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 910 infusion as outlined in 
Table 6-3.  Subjects who experience TLS should be managed according to the local 
standard of care and institutional guidelines.  Supportive therapy, including rasburicase, 
may be used as clinically indicated at the investigator's discretion. 
6.6.2.4 
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, 


Product:  AMG 910  
Protocol Number:  20180292 
Date:  02 March 2021 
Page 86 of 175 
CONFIDENTIAL  
 
 
vomiting, and diarrhea should be tailored to the individual subject’s clinical situation and 
endoscopic evaluations should be taken in consideration. 
6.6.2.4.1 
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 (dexamethasone 
or prednisolone) should be considered depending on tolerability/duration of previous 
dexamethasone administration.  In case nausea and vomiting are associated with 
abdominal pain or any indication of bleeding, gastroscopy and AMG 910 interruption as 
detailed in Table 6-3 are mandated. 
6.6.2.4.2 
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 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 (budesonide, 
dexamethasone or prednisolone) should be considered depending on 
tolerability/duration of previous dexamethasone administration.  Additional work-up 
and/or GI consultation may be considered, as needed. 
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, and 7.2.1. 


Product:  AMG 910  
Protocol Number:  20180292 
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7.1 
Discontinuation of Study Treatment 
Subjects 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 Table 1-1) 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 
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 
 
Pregnancy 
 
No longer clinically benefitting (may include clinical deterioration, disease or 
therapy related) or need for a change in systemic therapy 
 
A DLT leads to permanent discontinuation unless the following criteria apply, in 
which case a restart of treatment at the next lower dose level in Table 6-2 is 
allowed or criteria per Table 6-3 apply: 
The adverse event (including relevant lab values) is reversible and improves 
to grade ≤ 1 or baseline within 7 days 
The patient is experiencing clinical benefit as assessed by the investigator 


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There is agreement between the investigator and the Amgen Medical Monitor 
that treatment may be restarted 
The subject gives written informed consent to continue treatment after the 
investigator has led an appropriate discussion of potential risks and benefits 
with the subject  
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 (Table 1-1) 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 Study 
Reasons for removal of a subject from the study are: 
 
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.   


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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 
(see Table 1-1).   
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. 
All assessments including clinical evaluation and laboratory assessments should be 
done in line with the requested observation periods after AMG 910 administrations as 
outlined in the Schedule of Activities (Table 1-1). 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment and/or Randomization 
The procedures to be completed during screening are indicated in the Schedule of 
Activities (Table 1-1).  Informed consent must be obtained before completing any 
screening procedure or discontinuation of standard therapy for any disallowed therapy.  
After the subject has signed the ICF, the site will register the subject manually and 
screen the subject in order to assess eligibility for participation.  The screening window is 
up to 21 days.  If CT and/or magnetic resonance imaging (MRI) is done prior to ICF 


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signature results can be used if the subject allows its use and assessments are done 
within 30 days of cycle 1 day 1. 
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 
rescreening 1 time.  If CLDN18.2 test results come back delayed the subject does not 
count as screen fail and all screening results are accountable to judge on subject 
enrollment if treatment can start within 30 days from ICF signature. 
Rescreen subjects must first be registered as screen failures and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 21-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening and all screening procedures, including informed 
consent, must be repeated.  If planned cycle 1 day 1 is within 21 days after the original 
signing of the ICF, only vital signs, clinical and safety lab evaluations need to be 
repeated.   
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-1).  On-study visits may be 
completed within ± 1 day during cycles 1 and 2 and within ± 3 days cycle 3 onwards.  
The date of the first dose of investigational product 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. 
8.1.3 
Safety Follow-up 
The procedures to be completed during safety follow-up are indicated in the Schedule of 
Activities (Table 1-1).  Upon permanent discontinuation from the study treatment for any 
reason, a safety follow-up visit will be performed approximately 30 (+3) days after the 
last dose of investigational product. 
8.1.4 
Long-term Follow-up 
The procedures to be completed during long-term follow-up are indicated in the 
Schedule of Activities (Table 1-1).  Long-term follow-up will be conducted every 
6 months up to 2 years from the first dose of AMG 910 for all subjects who have not 


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withdrawn consent by clinic visit, telephone or chart review to assess for survival and/or 
the commencement of subsequent cancer therapy.  Subjects who remain on the 
treatment for more than 2 years do not need to have additional long-term 
follow-up (LTFU).  They will complete the study 30 (+3) days following 
discontinuing treatment. 
8.1.5 
End of Study 
The end of study visit is defined as the date of the final study visit (eg, final LTFU 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 must sign and personally date the IRB/IEC 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 the protocol-required therapies.   
8.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
starts 5 years prior to screening through the time of signing of informed consent.  
Medical history will include information on the subject's concurrent medical conditions.  
Record all findings on the medical history CRF. 
In addition to the medical history above, gastric cancer history must date back to the 
original diagnosis.  The current toxicity grade will be collected for each condition that has 
not resolved. 
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). 


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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 predose 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. 
should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.6 
Gastroscopy 
Endoscopic evaluation of the upper digestive system including esophagus, stomach and 
first part of the small intestine according to local standards will be done as scheduled in 
Table 1-1 and after occurrence of toxicity observations as detailed in Table 6-3 (eg, pain 
in the upper abdomen, vomiting, bleeding).  In addition, non-tumor stomach tissue 
obtained by biopsy during the gastroscopy will be evaluated by the local pathologist for 
abnormal findings (eg, unusual redness, ulcerative lesions, bleeding, blockages or other 
abnormalities).  The macroscopic and microscopic examinations reports will provide 
characterization of the findings as either normal or abnormal.  Abnormal findings found 
predose 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. 
8.2.1.7 
Physical Measurements 
Height (in centimeters) and weight (in kilograms) should be measured without shoes. 
8.2.1.8 
Performance Status  
The subject’s performance status will be assessed using the ECOG Performance Status 
Scale (see Section 11.10). 
8.2.2 
Efficacy Assessments 
Efficacy will be determined by both clinical laboratory values and radiographic 
assessments (as outlined in Section 3). 


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Radiographic Assessments 
Radiographic assessments will be obtained as scheduled in Table 1-3 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 contrast-enhanced CT of the chest, abdomen, pelvis, 
and all other known sites of disease.  The assessment should include MRI of the brain if 
a subject has signs or symptoms suggestive of CNS metastases.  The assessment can 
be conducted 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 RECIST 1.1 and iRECIST.  
RECIST 1.1 criteria will be used to determine eligibility based on the investigator’s 
review of the radiographic data.  Although tumor assessments following RECIST 1.1 will 
continue through the first disease progression (PD), iRECIST will be used and 
documented in eCRF to account for unique tumor response characteristics observed 
with immunotherapies and enable treatment decisions beyond progression (per 
RECIST 1.1).  Tumor burden assessment performed at sites for decisions on treatment 
continuation will be based on iRECIST only and will continue until immune Confirmed 
Progression Disease (iCPD).  Tumor burden assessments by the central core laboratory 
will be based on RECIST 1.1 and iRECIST.  To confirm disease progression, a second 
CT scan must be performed 4-8 weeks after the first detection of radiographical 
progression.  Responses (partial response [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 (Table 1-1). 
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate/pulse, 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 


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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 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
After each AMG 910-infusion for the first 2 cycles and after the first 2 infusions of cycle 3 
and after start of eIV infusion on cycle 1 day 1, but only while the patient is 
hospitalized or under observation post AMG 910 infusion, vital signs should be assessed 
accordingly during the following timepoints: 
Short-term IV infusion: 
 
every 15 minutes during infusion and during first 2 hours after end of infusion 
(EOI) 
 
every 30 minutes from 2 to 4 hours EOI 
 
every hour from 4 to 8 hours EOI 
 
every 2 hours from 8 to 12 hours EOI 
 
every 6 hours from 12 to 24 hours EOI 
 
after 24 hours EOI, vital signs should be assessed per institutional standards 
 
Extended IV infusion: 
 
15 minutes after start of eIV infusion 
 
every 30 minutes thereafter during the first 2 hours after start of eIV infusion 
 
every 1 hour during hours 3 to 6 after start of eIV infusion 
 
every 2 hours during hours 7 to 12 after start of eIV infusion 
 
every 6 hours during hours 13 to 24 after start of eIV infusion 
 
after 24 hours after start of eIV 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.  After each AMG 910 infusion for the first 2 cycles and after the first 
2 infusions of cycle 3 and after start of eIV infusion on cycle 1 day 1, but only while 
the patient is hospitalized or under observation post AMG 910 infusions, pulse oximetry 
should be assessed accordingly during the following timepoints: 


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Short-term IV Infusion: 
 
Every 15 minutes during infusion and during first 2 hours after end of infusion 
(EOI)  
 
Every 30 minutes from 2 to 4 hours after EOI 
 
Every hour from 4 to 8 hours after EOI 
 
Every 2 hours from 8 to 12 hours after EOI 
 
Every 6 hours from 12 to 24 hours after EOI 
 
After 24 hours EOI, pulse oximetry should be assessed per institutional 
standards 
 
Extended IV infusion: 
 
15 minutes after start of eIV infusion 
 
every 30 minutes thereafter during the first 2 hours after start of eIV 
infusion  
 
every 1 hour during hours 3 to 6 after start of eIV infusion 
 
every 2 hours during hours 7 to 12 after start of eIV infusion 
 
every 6 hours during hours 13 to 24 after start of eIV infusion 
 
after 24 hours after start of eIV infusion vital signs should be assessed per 
institutional standards 
 
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 most recumbent position as possible.  ECGs should be 
performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs 
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.  If it is 
necessary to schedule blood draws for the predose timepoints (see Section 1.3, 
Schedule of Activities) before the ECG to allow for timely administration of 
investigational product, blood draws should be performed at least 60 minutes before the 
ECG.  Each ECG must include the following measurements:  QRS, QT, QTc, RR, and 
PR intervals. 
 
For screening:  triplicate ECGs 
 
For cycle 1:  ≥ 3 baseline ECGs collected ≥ 30 minutes apart, with each baseline 
ECG in triplicate run consecutively (all 3 ECGs should be completed within a total 
of five minutes from the start of the first to the completion of the third) (total 
9 ECGs) 


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 
For cycle 1:  triplicate ECGs at time points after dosing 
 
For cycle 2 and beyond:  single ECGs may be collected per time point 
Baseline is defined as the pre-dose assessment on cycle 1 day 1.  The investigator or 
designated site clinician will review all ECGs.  Electrocardiograms may be transferred 
electronically to an ECG central reader for analysis 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.  
Standard ECG machines should be used for all study-related ECG requirements. 
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  
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 Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 and is described in 
Section 11.14, with the exception of CRS, which will be graded using the criteria 
referenced in the publication by Lee et al (2014) (see Section 11.13) and TLS, which will 
be graded according to the Cairo Bishop criteria referenced in the publication by 
Coiffier et al (2008) (see Section 11.14). 
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 investigational 
product(s)/study treatment/protocol-required therapies through the safety follow-up visit 
(30 [+3] days after the last dose of investigational product/study 
treatment/protocol-required therapies) are reported using the Events 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 


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consent through the LTFU visit or End of Study Visit (whichever occurs later) are 
reported using the Events 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 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period (as defined in Section 8.2.4.1.2) or after end of 
study.  However, these serious adverse events should be reported to Amgen 
(regardless of causality) if the investigator becomes aware of them.  Per local 
requirements in some countries, investigators are required to report serious adverse 
events that they become aware of after end of study.  If serious adverse events are 
reported, the investigator is to report them to Amgen within 24 hours following the 
investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.   
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. 
8.2.4.1.4 
Reporting a Safety Endpoint as a Study Endpoint 
Safety endpoints that are study endpoints are reported on the Events 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).   


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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 follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events 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. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.   
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
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. 


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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 will be collected after the 
start of study treatment and until 75 days after the last dose of AMG 910 or in a male 
subject’s female partner through 5 months after the last dose of AMG 910.   
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. 
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 (Table 1-1) 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 Events 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 
(Table 1-1).   
8.2.5.1 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening and 
within 48 hours of initiation of investigational product for all females of childbearing 
potential (see Section 11.5 for details).   


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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 (urine or serum) should be performed within 48 hours of 
start of each following cycle during treatment with protocol-required therapies or at 
monthly intervals thereafter until 75 days 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. 
Blood samples of approximately 2.5 mL will be collected for measurement of serum 
concentrations of AMG 910 as specified in the Schedule of Activities (Table 1-1).  A 
maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor.  Instructions for 
the collection and handling of biological samples will be provided by the sponsor.  The 
actual date and time (24-hour clock time) of each sample will be recorded.   
PK samples should be collected at the exact nominal time point as noted.  If unable to 
collect a PK sample at the specified nominal time point collect it as close as possible to 
the nominal time point and record the actual collection time.  PK samples not collected at 
the exact nominal time point will not be considered protocol deviations 
8.2.7 
Pharmacodynamic Assessments 
Venous blood samples will be collected for measurement of pharmacodynamic 
biomarkers at time points specified in the Schedule of Activities (Table 1-1). 
8.2.8 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of gastric and 
gastroesophageal adenocarcinoma and/or to identify subjects who may have positive or 
negative response to AMG 910.  Pharmacogenetic samples are collected for this part of 


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the study.  For subjects who consent to this/these analysis/analyses, DNA may be 
extracted. 
The final disposition of samples will be described in Section 11.6.   
8.2.10 
Biomarkers 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
8.2.10.1 
Biomarker Assessment to Determine Eligibility 
In order to determine eligibility, expression of CLDN18 in tumor tissue will be 
determined.   
Tumor Tissue 
For a subject with unknown CLDN18.2 expression status or with prior CLDN18.2 
targeting therapy to be eligible for study participation, tumor tissue is required prior to 
enrollment to establish CLDN18 positivity.  Tumor sample(s) need(s) to be collected 
after informed consent is obtained, but prior to enrollment.  Archival tissue samples 


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may be used for CLDN18.2 testing if available.  If fresh tissue samples need to be 
collected, these samples should be obtained as part of patient standard of care or from 
endoscopic procedures, following local standard of care procedures that are not 
expected to present any additional significant risk to the health, safety, and welfare of 
the subject.  Screening for CLDN18 will be conducted using either an approved or an 
investigational in vitro diagnostic (IVD) at a central laboratory as described in 
Section 11.2.  Investigational devices will follow regional regulatory requirements.  
Timing of sample collection is described in the Schedule of Activities (Table 1-1). 
Subjects previously tested positive for tumor expression of CLDN18 as participants of 
the Amgen study 20180293 or Amgen study 20180290 are considered CLDN18 
positive for screening purposes of the present study as long as no other 
CLDN18.2-targeting agent has been received in the interim. 
The assay uses an immunohistochemistry-based detection of CLDN18.  The assay is an 
investigational IVD± that will be used to prospectively inform subject selection for 
subjects with CLDN18-positive tumors for the enrollment phase of this study. 
±The IVD described is CE marked to detect the biomarker in the EU. 
8.2.10.2 
Optional Tumor Biopsies 
 
  The timepoint of this biopsy may be changed 
for all future cohorts based on emerging PK, pharmacodynamic and response data.  In 
case a fresh biopsy is not required for screening purposes and archival tissue from a 
biopsy after the last therapy for gastric cancer is not available, an additional optional 
biopsy should be obtained if feasible during the screening period.  Archival tissue 
samples should be collected and analyzed in addition where feasible.  The comparison 
of the pre-treatment and the on-treatment tumor samples will allow for assessment of 
biomarkers on tumor cells and infiltrating T cells.   
If subjects undergo a diagnostic or invasive intervention or surgery during the trial as per 
the investigator’s discretion, subjects may consent to donate a portion of their tumor 
and/or associated tissues (eg, malignant effusion) to this study.  The corresponding 
pathology report must be submitted for any biopsy provided for the study. 
Eligible subjects who provide consent for a tumor biopsy must have tumor tissue that is 
accessible by endoscopic biopsy or by core biopsy using minimally invasive procedures. 


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8.2.10.3.1 
Biomarker Development/Future Research 
Biomarker Development/Future Research refers to using samples collected for 
Biomarker Discovery research. 
In oncology, there is particular interest in the molecular changes underlying the 
oncogenic processes that may identify cancer subtypes, stage of disease, assess the 


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amount of tumor growth, or predict disease progression, metastasis, and responses to 
investigational product(s) or protocol-required therapies.   
If consent is provided by subjects, biomarker discovery samples collected at the time 
points specified in the Schedule of Activities will be retained for future biomarker 
development as described in Appendix 6 (Section 11.6).  No additional samples will be 
collected for biomarker development/future research.   
Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to AMG 910 to investigate 
and further understand gastric cancer. 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
AMG 910 will demonstrate acceptable safety and tolerability in subjects with gastric or 
GEJ cancer at 1 or more dose levels with at least 1 dose level showing evidence of 
anti-tumor activity. 
9.2 
Sample Size Determination 
It is anticipated that approximately 70 subjects will be enrolled in this study.  Up to 
34 subjects will be enrolled in the dose-exploration cohorts and up to 36 additional 
subjects will be enrolled in the dose-expansion cohort. 
The sample size in the dose-escalation phase is based on practical consideration and is 
consistent with conventional oncology studies with the objective to estimate the MTD.  
With 3 subjects in a cohort, there is a 27% to 70% 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. 
In the dose-expansion cohort, a subject number of 36 will provide an 84% 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 36 subjects and 19% overall 
response rate, the expected 95% CI would be 8% to 36%.  Under certain circumstances, 
the sample size in dose expansion will be smaller due to early stopping; see 
Section 9.4.1.1 for details. 


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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 910. 
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 910 with an evaluable DLT 
endpoint.  See Section 6.2.1.1.2 for definition of DLT evaluable. 
The analysis of objective response will be conducted on the RECIST and iRECIST 
Evaluable Analysis set defined as all subjects that are enrolled and receive at least 
1 dose of AMG 910 with at least 1 tumor lesion that is measurable in contrast-enhanced 
computed tomography (CT) as defined by RECIST 1.1. 
9.3.2 
Covariates 
If the number of responders is sufficient (eg, 10 or more) then the relationship of 
covariates to efficacy endpoints will be explored. 
9.3.3 
Subgroups 
Biomarker data may be incorporated in additional exploratory subgroup or multivariate 
analyses.  The analyses of biomarkers may be performed after collection of all samples 
during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoints. 
9.3.4 
Handling of Missing and Incomplete Data 
The handling of missing and incomplete data is described in the 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. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  Based on accumulating toxicity 
information, BLRM will be used to make dosing recommendations.  In DLRMs, Amgen, 


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in consultation with the site investigators, will review the BLRM recommended dose level 
and will review all available cumulative data by cohort prior to making dose escalation 
recommendations.  As a sensitivity analysis, a 1-parameter Continual Reassessment 
Method model may be used to estimate the dose-toxicity relationship and to estimate the 
dose level closest to a 25% DLT rate in order to help make dose escalation decisions.  
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, futility will be assessed after treating 15 and 25 subjects for at 
least 8 weeks of treatment.  If the observed rate of responses is consistent with a lower 
than 15% response rate, enrollment may be terminated due to futility.  As appropriate, 
enrollment to dose expansion may continue during the period of first 8 weeks follow up 
for response.  For purposes of assessing futility, a response is defined as an objective 
response per RECIST 1.1.  The guidelines for early termination due to futility are as 
follows: 
Number of Treated Subjects 
Futility Termination Guideline 
15 
1 or fewer responders 
25 
4 or fewer responders 
36 
Enrollment to dose expansion complete 
If the true response rate is 15% then these termination guidelines result in a 69.4% 
probability of terminating dose expansion early with an expected sample size of 
25 subjects.  If the true response rate is 30% then there is a 90% probability of 
continuing enrollment to n = 36 total subjects. 
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 1 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 premedication) 
3) Continue dose expansion without any changes 
The stopping rules use a Bayesian approach proposed by Thall, Simon, and Estey 
(Thall, Simon, & Estey, 1995) to terminate the study if the posterior probability that the 


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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 9-1 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%.  Also, if same CTCAE grade 4 stomach toxicity has been observed 
in > 2 subjects, the risk/benefit of the study needs to be re-evaluated. 
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 this many grade 4 or higher 
treatment-related adverse events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
36 
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% 
35.6 
0.15 
9.7% 
34.0 
0.20 
25.8% 
30.9 
0.25 
47.7% 
26.7 
0.30 
69.2% 
22.2 
9.4.1.2 
Primary Analysis 
The primary analysis for the safety endpoints, PK endpoints, and OR endpoints will 
occur when enrollment is complete, and each subject has had the opportunity to receive 
at least 6 cycles of treatment.  The primary analysis for time to event endpoints (duration 
of response, time to progression, PFS, 6-month and 1-year PFS, OS, 1 and 2-year OS) 
will occur when enrollment is complete, and each subject has had the opportunity to be 
on study for at least 2 years. 


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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.  Primary and final analysis may be combined in case all 
subjects have ended study close to the time point of the primary analysis. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Unless otherwise specific, all described analyses will be conducted on the Safety 
Analysis Set.  Descriptive statistics will be provided for selected demographics, safety, 
PK, pharmacodynamic, and biomarker data by dose, dose schedule, and time as 
appropriate.  Descriptive statistics on continuous data will include means, medians, 
standard deviations, and ranges, while categorical data will be summarized using 
frequency counts and percentages.  Graphical summaries of the data may also be 
presented. 
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Pearson (Clopper & Pearson, 1934).  Kaplan-Meier methods will 
be used to estimate the median and percentiles for time to event endpoints with CI 
calculated using the Brookmeyer and Crowley method (Brookmeyer & Crowley, 1982).  
Kaplan-Meier methods will be used to estimate landmarks for time to event endpoints 
(eg, 1-year OS) with the Greenwood formula (Kalbfleisch & Prentice, 1980) used to 
estimate the standard error used in CI calculation. 
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Listings of secondary efficacy endpoints will be produced for all subjects in 
the dose-escalation cohorts and the dose-expansion cohorts.   
 
The proportion of subjects with an objective response (per RECIST 1.1 and 
per iRECIST) and 95% CI will be tabulated by planned dose level using the 
RECIST Evaluable Analysis Set. 
 
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 (RECIST 1.1 and 
iRECIST) 2) time to progression 3) PFS 4) OS.  For all subjects treated at the 
MTD and/or RP2D, Kaplan-Meier methods will be used to estimate 6-month 
and 1-year PFS, 1-year and 2-year OS with 95% CI. 


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Exploratory 
Will be described in the statistical analysis plan finalized before database 
lock. 
 
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 910.   
The analysis of DLTs will be conducted on the DLT Analysis Set.  Subject 
incidence of DLT will be tabulated by planned dose level.  A table of DLT will 
be provided.  The probability of a subject having a DLT by dose level will be 
estimated using a 2-parameter BLRM model. 
The statistical analysis methods for other safety endpoints are described in 
Section 9.4.2.3.2-9.4.2.3.6. 
 
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.  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.  Subject incidence of device-related events, if applicable, will be tabulated 
by system organ class and preferred term. 
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. 


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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 group will be summarized.  Subjects' 
maximum post baseline values will also be categorized and the number and percentage 
of subjects in each group will be summarized.  All on-study ECG data will be listed and 
select parameters of interest plotted. 
9.4.2.3.8 
Exposure to Investigational Product 
Details of AMG 910 administration will be listed for every subject. 
9.4.2.3.9 
Exposure to Concomitant Medication 
All medication will be coded using the World Health Organization drug dictionary.  A 
subject listing of all prior and concomitant medications will be presented. 
9.4.2.4 
Other Analyses 
For AMG 910, PK parameters, including but not limited to Cmax, minimum serum 
concentration (Cmin), area under the concentration-time curve (AUC) over the dosing 
interval, accumulation following multiple dosing, and, if feasible, half-life (t1/2), will be 
determined from the time concentration profile using standard non-compartmental 
approaches and considering the profile over the complete sampling interval.  Based on 
the review of the data, analyses to describe the relationship between AMG 910 exposure 
and either pharmacodynamic effect and/or clinical outcome may also be performed. 


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Clopper, C. J., & Pearson, E. S. (1934). The use of confidence or fiducial limits 
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cells to fight cancer with BiTE® antibody constructs–past developments and future 
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Lee, D. W., Gardner, R., Porter, D. L., Louis, C. U., Ahmed, N., Jensen, M., et al. 
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Lente, F. (2006). Using standardized serum creatinine values in the modification of diet 
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gastric and gastro-oesophageal junction cancer. European Journal of Cancer, 100, 
17-26. 
Sahin, U., Tureci, Ö., Manikhas, G. M., Lordick, F., Rusyn, A., Vynnychenko, I., & 
Dhaene, K. (2019). Zolbetuximab combined with EOX as first-line therapy in advanced 
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Without Chemotherapy vs Chemotherapy in Patients With Advanced G/GEJ Cancer 
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11. 
Appendices 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADA 
Anti-drug antibody 
ALL 
Acute lymphoblastic leukemia 
aPTT 
activated partial thromboplastin time 
AUC 
Area under the concentration-time curve 
BiTE 
Bi-specific T cell engager 
BLRM 
Bayesian logistic regression model 
C0 
Concentration at time 0 
CBC 
Complete blood count 
CFR 
U.S. Code of Federal Regulations 
CLDN18.2 
Claudin-18 isoform 2 
Cmax 
Maximum serum concentration 
Cmin 
Minimum serum concentration 
c-MT 
Mesenchymal epidermal transition 
CNS 
Central nervous system metastases 
COVID-19 
SARS-CoV-2 Coronavirus Disease 2019 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
ctDNA 
Circulating tumor DNA 
CTCAE 
Common Terminology Criteria for Adverse Events 
DES 
Amgen data element standard 
DILI 
Drug induced liver injury 
DLRM 
Dose level review meeting 
DLRT 
Dose level review team 
DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
DOR 
Duration of response 
DRT 
Data review team 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 


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Abbreviation or Term 
Definition/Explanation 
EDC 
Electronic data capture 
 


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Abbreviation or Term 
Definition/Explanation 
EGFR 
Epidermal growth factor receptor 
eIV 
Extended intravenous 
Electronic Source Data 
(eSource)  
Source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
EOI 
End of Infusion is considered as the end of the controlled rate 
post-infusion flush. 
EOT 
End of treatment 
Exposure-Response  
Analysis 
Mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic (PK) exposure 
(eg, population PK modeling) and response, which may include 
biomarkers, pharmacodynamic effects, efficacy and safety 
endpoints. 
End of Follow-up 
Defined as when the last subject completes the last protocol-
specified assessment in the study   
End of Study for Individual 
Subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
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), including any additional parts in the 
study (eg, long-term follow-up, additional antibody testing), as 
applicable 
End of Treatment 
Defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
Fc 
Fragment crystallizable 
GEJ 
Gastroesophageal junction 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HBV 
Hepatitis B virus 
HER2 
Human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HLE 
Half-life extended 
HNSTD 
Highest non-severely toxic dose 
IB 
Investigator’s Brochure 
IBG 
Independent Biostatistics Group 
ICF 
Informed consent form 


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Abbreviation or Term 
Definition/Explanation 
ICH 
International Conference on Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IFN- 
Interferon gamma 
IL-2 
Interleukin-2 
IL-6 
Interleukin-6 
IL-10 
Interleukin-10 
INR 
International normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
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 
IUS 
Intrauterine hormonal-releasing system 
IV 
Intravenous 
IVD 
In vitro diagnostic 
lu 
Luciferase 
LTFU 
Long-term follow-up 
LVEF 
Left ventricular ejection fraction 
MMR 
Mismatch repair 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MSI-H 
Microsatellite instability-high 
MTD 
Maximum tolerated dose 
MUC17 
mucin-17 
NCT 
National Clinical Trials 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Objective response 
OS 
Overall survival 
PB 
Peripheral blood 
PD 
Disease progression 
PD-L1 
programmed death-ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 


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Abbreviation or Term 
Definition/Explanation 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PRE 
Pre-dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose 
SAT 
Safety assessment team 
scFc 
Single chain fragment crystallizable 
SCR 
Screening 
SFU 
Safety follow-up 
SoA 
Schedule of Activities 
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 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Half-life 
TBL 
Total bilirubin 
TIL 
tumor infiltrating lymphocytes 
TK 
Toxicokinetic 
TKI 
Tyrosine kinase inhibitor 
TLS 
Tumor Lysis Syndrome 
TMB 
Tumor mutation burden 
TMF 
Trial master file 
TNF 
Tumor necrosis factor 
ToGA 
Trastuzumab for Gastric Cancer 
ULN 
Upper limit of normal 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 and Table 11-2 will be performed by the local laboratory 
and/or by the central laboratory.   
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.  Local Laboratory Analyte Listing 
Chemistry 
Coagulation 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Adjusted 
calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
Amylase 
Lipase 
CRP 
Ferritin 
PTT or aPTT 
PT or INR 
Fibrinogen 
D-dimer 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Nucleated RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Bands/stabs 
• Segmented 
neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Total neutrophils 
 
Serum or Urine 
Pregnancy 
Hep B surface 
antigen 
Hep C antibody 
HIV 
Optional tumor 
markers as 
appropriate and 
in line with local 
standards 
 
ACTH = adrenocorticotropic hormone; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; ANC = absolute neutrophil 
count; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CRP = C-reactive protein; GFR = glomerular filtration rate; INR = international normalized 
ratio; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell count; 
SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; 
WBC = white blood cell count. 
a Creatinine clearance will be calculated using the MDRD formula   


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Table 11-2.  Central Laboratory Analyte Listing 


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11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Team 
A 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); and evaluating safety signals for purposes of applying Dose 
Cohort Stopping Rules.  The required Dose Level Review Team (DLRT) members are 
the Amgen Medical Monitor, Global Safety Officer (GSO), and Site Investigators.  The 
DLRT will include only actively screening and enrolling Site Investigators.  The Amgen 
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, and/or PK scientist. 
The Amgen 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 Amgen 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, ECG, vital signs, and 
laboratory results will be reviewed.  Data to be reviewed will be queried.   
DLRM voting will occur as follows:  there will be a total of 3 votes, 1 for the Amgen 
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 


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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 Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval 
must be sent to Amgen 
 
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 


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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 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 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. 
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 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.   


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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.   
If a potential subject is illiterate or visually impaired, 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 21 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 
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 


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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 
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 


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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 
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, 


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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. 
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 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 


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inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study 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 SAP. 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
For situations when an adverse event or serious adverse event is due to gastric 
cancer, 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. 
 


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A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
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 Events case report form (CRF). 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to first dose of investigational product, other 
protocol-required therapies; 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product (AMG 910), other 
protocol-required therapies, and/or study-mandated activity and/or 
procedures; 
o Action taken; and 
o Outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Events CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor in lieu of completion of the Events 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. 
with the exception of cytokine release syndrome (CRS), which must be graded using 
the criteria referenced in the publication by Lee et al (2014) (see Section 11.13) and 
tumor lysis syndrome (TLS), which must be graded according to the Cairo Bishop 
criteria referenced in the publication by Coiffier et al (2008) (see Section 11.14). 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies, and/or study-mandated procedure and each 
occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure 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 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 


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 
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 Events 
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.   
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper Serious Adverse Event Contingency 
Report Form (also referred to as the electronic Serious Adverse Event [eSAE] 
Contingency Report Form) (see Figure 11-1) within 24 hours of the investigator’s 
awareness of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line 
to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on a 
paper-based Serious Adverse Event Contingency Report Form (see Figure 11-1). 
 
Once the study has ended, serious adverse event(s) should be reported to Amgen 
(regardless of causality) if the investigator becomes aware of a serious adverse 


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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 Report Form 
  


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
 


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 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 75 days for females and 5 months for males after the last 
dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment 


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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of <1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Contraception Methods for Male Subjects 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject)  
 
Use a condom during treatment and for an additional 5 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) 
 
Spermicides only 
 
Lactational amenorrhea method 


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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 an additional 75 days 
after discontinuation of the study drug. 
 
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 consent 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 an additional 
75 days after discontinuation 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 11.2.  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). 


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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 
5 months after discontinuing protocol-required therapies, the information will be 
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). 
 
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 an additional 75 days after 
discontinuation of the study drug. 
 
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 216. 
 
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 an additional 75 days after 
discontinuing protocol-required therapies. 


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Figure 11-2.  Pregnancy and Lactation Notification Forms 
  


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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, tumor, biomarker, or pharmacokinetic (PK) sample collected according to the 
Schedule of Activities (Table 1-1) 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.   
 
 
 
 
  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 pharmacogenetic, biomarker development or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
sample types (eg, blood, tumor) samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 


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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 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then AMG 910 is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 11-3) 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, Events 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 11-3 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:   
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


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 
A more detailed history of:   
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain,  
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.   
 


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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 20180292 
Weight decreased 
Decreased appetite 
Fatigue 
Anaemia 
Gastric obstruction 
Helicobacter infection 
Pernicious anaemia 
Barrett’s oesophagus 
Dyspepsia 
Gastrooesophageal reflux disease 
Nausea 
Vomiting 
Abdominal pain 
Gastritis 
Gastric hemorrhage 
Gastric perforation 
For metastatic site-related adverse events, events will be evaluated for ASAEs on a case by case basis (eg, 
intestinal obstruction for intestinal metastatic disease state, increase in transaminase for liver metastatic 
disease present at baseline). 
 


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11.9 
Appendix 9.  Operating Characteristic for 2-parameter BLRM Design 
The operating characteristics of the 2-parameter Bayesian logistic regression model 
(BLRM) design were evaluated via simulation using EAST software version 6.4.1.  A 
bi-variate normal prior distribution (parameters “a” and “b”) is used for the BLRM model.  
The prior distribution is specified such that probability of dose-limiting toxicity (DLT) is 
0.05 for the starting dose (6.5 µg) and 0.3 for the reference dose (3500 µg), where the 
probability that the true DLT rate is ≤ 0.40 at the lowest planned dose is 0.90 and the 
probability the true DLT rate is ≤ 0.05 at the reference dose is 0.05.  In particular, the 
parameters of the bi-variate normal prior are as follows:  the mean natural log (ln) of “a” 
ln(a) = -0.847, standard deviation (SD) of “a” SD(a) = 1.275, mean ln(b) = -1.098, 
SD(b) = 1.981 and correlation = 0. 
The planned cohort size for the initial 2 cohorts is n=1 subject and the cohort size for 
subsequent cohorts is fixed to 3 or 4 subjects; based on observed toxicity in the initial 
2 cohorts, the cohort size for any or all of the initial 2 cohorts may be increased to n = 3  
to 4 subjects.  Planned dose levels are 6.5, 20, 65, 200, 400, 650, 1000, 1500, 2300 and 
3500 µg.  After simulated enrollment of the initial cohort at the initial dose level, 
simulations selected the subsequent dose levels based on the following rules:   
 
After each cohort, the next dose was the 1 with the highest probability of the target 
toxicity probability interval (TPI), but with a less than 0.40 probability of an excessive 
or unacceptable TPI. 
 
Skipping a planned dose level was not allowed. 
Dose exploration was stopped when either of the following occurred: 
 
The model recommended a dose level where at least 6 subjects had already 
received treatment at this recommended level. 
 
A maximum number of 34 subjects were treated. 
Operating characteristics are described below. 
Operating characteristics 
The design was evaluated for 4 possible dose-response scenarios:  “Low”, “Mid”, and 
“High” maximum tolerated dose (MTD) and an “Extreme” scenario where every planned 
dose level was excessively toxic.  Table 11-4 shows the dose level and true probability 
of dose-limiting toxicity (DLT) for each scenario used in the simulated studies.  Since the 
timing of initiation of the multiple subject cohorts impacts the design operating 
characteristics, the operating characteristics were calculated separately for each 
possible timing for starting the multiple subject cohorts:  at cohort 1, cohort 2 and at 


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cohort 3.  Overall operating characteristics are reported after weighting the 
3 timing-specific operating characteristics by the probability that a specific cohort is the 
initial multiple subject cohort.  Table 11-5 shows the dose level and true probability of a 
DLT or a grade 2 related adverse event for each scenario used in the simulated studies.  
Using the toxicity rates described in Table 11-5, the probability by cohort for initiating the 
multiple subject cohorts are shown in Table 11-6.  Table 11-7 reports the operating 
characteristics from 1000 simulated studies estimating the MTD when the target TPI is 
(0.20, 0.33].  The rate of MTD selected and the average number of subjects assigned to 
each dose level are presented in Table 11-8. 
 


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Table 11-4.  True Probability of DLT by Scenario 
Dose level (µg) 
6.5 
20 
65 
200 
400 
650 
1000 
1500 
2300 
3500 
MTD scenario 
 
 
 
 
 
 
 
 
 
 
 High 
0.01 
0.04 
0.08 
0.10 
0.12 
0.15 
0.20 
0.30 
0.40 
0.50 
 Mid 
0.08 
0.10 
0.12 
0.15 
0.20 
0.30 
0.40 
0.50 
0.60 
0.70 
  Low 
0.12 
0.15 
0.20 
0.30 
0.40 
0.50 
0.60 
0.70 
0.80 
0.90 
 Extreme 
0.35 
0.40 
0.45 
0.55 
0.60 
0.65 
0.70 
0.75 
0.80 
0.95 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose 
Table 11-5.  True Probability of DLT or Grade 2 Related Adverse Event by Scenario 
Dose level (µg) 
6.5 
20 
65 
200 
400 
650 
1000 
1500 
2300 
3500 
MTD scenario 
 
 
 
 
 
 
 
 
 
 
 High 
0.06 
0.09 
0.13 
0.15 
0.17 
0.25 
0.30 
0.40 
0.50 
0.60 
 Mid 
0.13 
0.15 
0.17 
0.25 
0.30 
0.40 
0.50 
0.60 
0.70 
0.80 
 Low 
0.17 
0.25 
0.30 
0.40 
0.50 
0.60 
0.70 
0.80 
0.90 
0.95 
 Extreme 
0.45 
0.50 
0.55 
0.65 
0.70 
0.75 
0.80 
0.85 
0.90 
0.99 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose 


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Table 11-6.  Probability by Planned Dose Level for Initiating Multiple Subject Cohorts by Scenario 
Dose level (µg) for initiating multiple subject cohorts 
 
6.5 
20 
65 
MTD scenario 
 
 
 
 
 High 
 
0.06 
0.08 
0.86 
 Mid 
 
0.13 
0.13 
0.74 
 Low 
 
0.17 
0.21 
0.62 
 Extreme 
 
0.45 
0.27 
0.27 
Table 11-7.  Operating Characteristics by Scenario 
MTD scenario 
High 
Mid 
Low 
Extreme 
Number of subjects per cohort 
4 
3 
4 
3 
4 
3 
4 
3 
Average number of subjects on study 
30.1 
25.2 
26.2 
20.8 
19.5 
16.1 
9.3 
8.1 
Average number of DLTs on study 
5.2 
4.8 
5.9 
5.0 
5.4 
4.7 
3.9 
3.4 
Percentage of studies by actual DLT probability of estimated MTD: 
 
 
 MTD below lowest planned dose 
3.1 
1.7 
6.4 
6.2 
19.8 
16.7 
79.9 
68.8 
 DLT probability at estimated MTD 
    10%  
1.3 
2.1 
0.1 
0.2 
0 
0 
0 
0 
   10% and  20% 
17.6 
18.5 
17.3 
19.4 
5.2 
5.7 
0 
0 
   20% and  33% 
56.1 
54 
51.4 
46.5 
52.9 
49.5 
0 
0 
   33% 
18.3 
19 
24.7 
27.7 
22 
28.3 
19.1 
30.1 
  15% and  33% 
66.2 
64.6 
63.4 
58.7 
57.3 
53.7 
0 
0 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose 


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Table 11-8.  The Rate of MTD Selected and the Number of Subjects Assigned at Each Dose Level by Scenario 
MTD scenario 
High 
Mid 
Low 
Extreme 
Number of subjects per cohort 
4 
3 
4 
3 
4 
3 
4 
3 
Rate of MTD selected at each dose level (%): 
Below lowest dose 
3.1 
1.7 
6.4 
6.2 
19.8 
16.7 
79.9 
68.8 
6.5 µg 
0 
0 
0.1 
0.2 
0.8 
1.5 
4.7 
8.4 
20 µg 
0 
0.1 
0.6 
1.1 
4.4 
4.2 
6.7 
8.6 
65 µg 
1.3 
2 
4.7 
6.1 
22.4 
21.6 
6 
9.5 
200 µg 
2.8 
3.4 
12 
12.2 
30.5 
27.9 
1.5 
3.1 
400 µg 
4.7 
4.5 
22.8 
19.7 
16.5 
20 
0.2 
0.4 
650 µg 
10.1 
10.6 
28.6 
26.8 
4.8 
6.9 
0 
0.1 
1000 µg 
23.7 
22.3 
18.6 
18.7 
0.6 
1.3 
0 
0 
1500 µg 
32.4 
31.7 
5.6 
8 
0.1 
0.1 
0 
0 
2300 µg 
18.3 
19 
0.5 
1 
0 
0 
0 
0 
3500 µg 
3.7 
4.7 
0 
0.1 
0 
0 
0 
0 
Average number of subjects at each dose level 
6.5 µg 
0.2 
0.2 
0.7 
0.5 
1.2 
1 
2.8 
2.2 
20 µg 
0.7 
0.6 
1.3 
1.1 
2.5 
1.9 
2.9 
2.4 
65 µg 
4.4 
3.4 
4.7 
3.6 
5.5 
4.2 
2.6 
2.3 
200 µg 
4.5 
3.4 
5 
3.6 
5.1 
3.9 
0.8 
0.9 
400 µg 
4.5 
3.4 
5.2 
3.8 
3.4 
2.9 
0.2 
0.2 
650 µg 
4.7 
3.6 
4.8 
3.7 
1.4 
1.6 
0 
0.1 
1000 µg 
4.8 
3.8 
3.2 
2.8 
0.4 
0.5 
0 
0 
1500 µg 
4.1 
3.7 
1.1 
1.3 
0 
0.1 
0 
0 
2300 µg 
1.9 
2.4 
0.2 
0.4 
0 
0 
0 
0 
3500 µg 
0.3 
0.7 
0 
0 
0 
0 
0 
0 
MTD = maximum tolerated dose 
 


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11.10 
Appendix 10.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale  
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light 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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11.11 
Appendix 11.  Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 
Quick Reference 
This study utilizes RECIST 1.1 criteria.  Details of implementation of the criteria will be 
provided in the site reader web-based training. 
Definitions 
 
Measurable Lesions 
o Measurable Tumor Lesions – Non-nodal lesions with clear borders that can 
be accurately measured in at least 1 dimension with longest diameter 
≥ 10 mm in CT/MRI scan with slice thickness no greater than 5 mm.  When 
slice thickness is greater than 5 mm, the minimum size of measurable 
lesion should be twice the slice thickness. 
o Nodal Lesions - Lymph nodes are to be considered pathologically enlarged 
and measurable, a lymph node must be ≥ 15 mm in short axis when 
assessed by CT/MRI (scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed. 
▪ 
Nodal size is normally reported as 2 dimensions in the axial 
plane.  The smaller of these measures is the short axis 
(perpendicular to the longest axis). 
o Irradiated Lesions - Tumor lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy, are not measurable 
unless there has been demonstrated progression in the lesion prior to 
enrollment. 
 
Non-measurable Lesions 
o All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 mm but to < 15 mm short axis with 
CT scan slice thickness no greater than 5 mm) are considered 
non-measurable and characterized as non-target lesions. 
o Other examples of non-measurable lesions include: 
▪ 
Lesions with prior local treatment:  tumor lesions situated in a 
previously irradiated area, or an area subject to other 
loco-regional therapy, should not be considered measurable 
unless there has been demonstrated progression in the lesion. 
▪ 
Biopsied lesions 
▪ 
Categorially, clusters of small lesions, bone lesions, 
inflammatory breast disease, and leptomeningeal disease are 
non-measurable. 


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Methods of Measurement 
 
Measurement of Lesions - The longest diameter of selected lesions should 
be measured in the plane in which the images were acquired (axial plane).  
All measurements should be taken and recorded in metric notation.  All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and not more than 4 weeks before study d ay 1. 
 
Methods of Assessment - The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion 
throughout the trial. 
 
CT/MRI – Contrast-enhanced CT or MRI should be used to assess all 
lesions.  Optimal visualization and measurement of metastasis in solid tumors 
requires consistent administration (dose and rate) of IV contrast as well as 
timing of scanning.  CT and MRI should be performed with ≤ 5 mm thick 
contiguous slices. 
Baseline documentation of “Target” and “Non-target” lesions 
 
Target Lesions - All measurable lesions up to a maximum of two (2) lesions 
per organ and five (5) lesions in total, representative of all involved organs 
should be identified as target lesions and recorded and measured at 
baseline. 
o Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and suitability for accurate repeated 
measurements. 
Pathologic lymph nodes (with short axis ≥ 15 mm) may be identified as target lesions.  
All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered non-target lesions. 


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11.12 
Appendix 12.  Immune Response Evaluation Criteria in Solid Tumors 
(iRECIST) 
Immune Response Evaluation Criteria in Solid Tumors (iRECIST) (Seymour et al, 2017) 
is a modification of RECIST 1.1 (Eisenhauer, et al., 2009) for use in cancer 
immunotherapy trials.  The RECIST working group published iRECIST to address 
response patterns specific to immunotherapies, including late and durable responses 
after having met PD according to RECIST 1.1. 
The present document is not meant to be an exhaustive teaching tool on iRECIST.  
Instead it is meant to outline the concepts and differences between iRECIST and 
RECIST 1.1. 
The tumor evaluations are exactly the same for RECIST 1.1 and iRECIST, except for the 
timepoint response nomenclature, until PD has been reached.  For example, if a PR is 
identified at timepoint 2 for RECIST 1.1, this is called iPR at the same timepoint with the 
exact same measurements utilized.  Only when the patient reaches RECIST 1.1 PD do 
the timepoint assessment processes begin to differ.   
iRECIST Disease Categories 
The iRECIST criteria define measurable disease, non-measurable disease, target-
lesions, and non-target lesions using RECIST 1.1 definitions:   
 
Measurable lesions: 
o Non-nodal lesions must be ≥ 10 mm in the longest diameter 
o Nodal lesions must be ≥15 mm in the longest diameter 
 
A maximum of five measurable lesions (two per organ) can be target lesions 
 
All other disease is considered non-target (nodal lesions must be ≥ 10 mm in the 
short axis to be considered pathological) 
At baseline, disease is categorized as target or non-target per RECIST 1.1.  The same 
definitions and measurement types are applied to iRECIST assessments.  Target lesions 
are measured uni-dimensionally and non-target lesions are assessed qualitatively.   
New lesions are identified per RECIST 1.1 definitions, but are further categorized per 
iRECIST as new target lesions and new non-target lesions: 
 
New iRECIST target lesions must measure ≥ 10 mm in longest diameter (new 
nodal lesions must be ≥15 mm in the short axis) 
 
All other new iRECIST lesions are new non-target lesions (nodal lesions must be 
≥ 10 mm in short axis to be considered pathological) 


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iRECIST recommends measuring up to five new target lesions.  The requirement to 
measure new lesions starts at the time point of RECIST 1.1 PD.  Measurement of more 
than five new lesions is optional and considered exploratory. 
iRECIST Calculations 
The iRECIST criteria requires the calculation of target lesion sum of measures (SOM) 
and new target lesion sum of measures (SOM).  These are 2 distinct sums: 
 
Target lesion SOM is calculated by summing the longest diameter of target 
lesions (and/or short axis of target nodes).  Note:  This is the same calculation 
performed for RECIST 1.1 and labeled sum of diameters (SOD). 
 
New target lesion SOM is calculated by summing the longest diameter of new 
target lesions (and/or short axis of new target lesion nodes). 
Tumor Response Assessment 
The prefix “i,” meaning immune, is used to differentiate iRECIST responses from 
RECIST 1.1 responses. 
The overall response at the time point of RECIST 1.1 PD is assessed as immune 
unconfirmed progressive disease (iUPD) per iRECIST initiating application of the 
iRECIST criteria. 
After the initial iUPD assessment per iRECIST, the following guidelines apply: 
 
iUPD → followed by tumor shrinkage = iCR, iPR, or iSD 
 
iUPD → followed by worsening = iCPD 
 
iUPD → followed by no change = iUPD 
When iUPD is followed by tumor shrinkage, this is referred to as “resetting the bar” and 
is 1 of the most important concepts of iRECIST.  A subject cannot be assessed as iCPD 
at the time point immediately after “resetting the bar.” Disease must again qualify for 
iUPD, then worsen to be assessed as iCPD. 
iRECIST tumor response assessments of iCR and iPR are made with reference to the 
original baseline time point for the subject, acquired during the study screening period.  
The nadir, or a subject’s best response on study, is used as the comparator when 
assessing for iUPD.  iCPD is assessed with reference to the iUPD assessment being 
confirmed. 


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Target Lesion Assessments  
The table within this section defines target lesion assessments per iRECIST. 
Table 11-9.  iRECIST Target Lesion Assessments 
iRECIST Target Lesion 
Assessments 
Requirements 
Immune Complete Response (iCR) 
Requires disappearance of all non-nodal target 
lesions and normalization of pathological target lymph 
nodes to <10 mm in short axis 
Immune Partial Response (iPR) 
Requires ≥ 30% decrease in sum of measures of 
target lesions, taking as reference the baseline target 
lesion sum 
 
The reference time point is the subject’s original 
baseline time point acquired during the study 
screening period 
Immune Unconfirmed Progressive 
Disease (iUPD) 
Requires ≥ 20% and a ≥ 5 mm increase in the sum of 
measures of target lesions, taking as reference the 
nadir time point 
 
The nadir time point is the time point with the 
smallest target lesion sum on study, including pre 
RECIST 1.1 PD time points 
Immune Stable Disease (iSD) 
When the requirements for iCR or iPR are not met, in 
the absence of iUPD 
Immune Confirmed Progressive 
Disease (iCPD) 
A target lesion assessment of iCPD requires 
worsening of target lesions as evidenced by an 
increase of ≥ 5mm in the target lesion SOM with 
reference to an immediately prior target lesion 
assessment of iUPD.   
 


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Non-Target Lesion Assessments 
The table within this section defines non-target lesion assessments per iRECIST.   
Table 11-10.  iRECIST Non-target Assessments 
iRECIST Non-Target Lesion 
Assessments 
Requirements 
Immune Complete response (iCR) 
Requires disappearance of all non-nodal non-target 
lesions and normalization of pathological non-target 
lymph nodes to <10 mm in short axis 
Immune Unconfirmed Progressive 
Disease (iUPD) 
Requires unequivocal progression of non-target 
lesions 
Non-iCPD/non-iUPD  
Requires persistence of 1 or more non-target lesions 
and not meeting the non-target lesion requirements 
for iCR or iPD 
Immune Confirmed Progressive 
Disease (iCPD) 
Requires worsening of non-target lesions in 
comparison to an immediately prior non-target lesion 
assessment of iUPD. 
New Lesions 
New lesions that meet the RECIST 1.1 definition of a target lesion (non-nodal ≥ 10 mm 
in longest diameter or nodal ≥15 mm in the short axis) are categorized as new target 
lesions.  iRECIST recommends measuring up to five new target lesions and that other 
new lesions are categorized as new non-target lesions (nodal lesions must be ≥ 10 mm 
in short axis to be considered pathological). 
A separate sum, the SOM of new lesions, is calculated by taking the sum of new target 
lesion measurements.  After first appearance, new lesions can worsen, remain 
unchanged, or disappear.  If the SOM of new target lesions increases by ≥ 5 mm, there 
is unequivocal worsening of new non-target lesions, or appearance of additional new 
lesions this is considered worsening.  Otherwise, the persistence of new lesions is 
considered unchanged. 
Overall response 
The first table within this section defines overall response assessments per iRECIST.  
The second table provides further detail on confirmation of progressive disease ie, the 
assessment of iCPD. 


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Table 11-11.  iRECIST Overall Response 
iRECIST Target Lesion Assessments 
Requirements 
Immune Complete Response (iCR) 
 
Can only be assessed after the initial iRECIST iUPD 
time point (ie, the time point of RECIST 1.1 PD) 
 
Requires all of the following: 
 
Disappearance of all non-nodal target lesions 
and normalization of pathological target lymph 
nodes to <10 mm in short axis – if any were 
present 
 
Disappearance of all non-nodal non-target 
lesions and normalization of pathological 
non-target lymph nodes to < 10 mm in short axis 
- if any were present 
 
No new lesions can appear for the first time or 
persist.  Any previously identified new lesions 
must have disappeared. 
Immune Partial Response (iPR) 
 
Can only be assessed after the initial iRECIST iUPD 
time point (ie, the time point of RECIST 1.1 PD) 
 
Requires all of the following:   
 
≥ 30% decrease in sum of measures of target 
lesions with reference to the baseline target 
lesion sum 
▪ 
The reference time point is the subject’s original 
baseline time point acquired prior to drug 
initiation  
 
Non-target persistence without worsening or 
non-target complete resolution 
 
No new lesions can appear for the first time.  No 
worsening of new lesions.  Persistent new 
lesions can be present if unchanged. 
Immune Unconfirmed Progressive 
Disease (iUPD) 
 
Always assessed at the time point of RECIST 1.1 PD 
(ie, the initial iRECIST iUPD time point), can also be 
assessed after RECIST 1.1 PD 
 
Requires any of the following: 
 
≥ 20% and a ≥ 5 mm increase in the sum of 
measures of target lesions, with reference to 
nadir time point (ie, the time point with the 
smallest target lesion sum on study) 
▪ 
The reference time point is the time point with 
the smallest target sum since (and including) the 
original baseline 
 
Unequivocal progression of non-target lesions 
 
First appearance of new lesions 
Immune Stable Disease (iSD) 
 
Can only be assessed after the initial iRECIST iUPD 
time point (ie, the time point of RECIST 1.1 PD) 
 
Is assessed when the requirements for iCR or iPR are 
not met, in the absence of iUPD 
Immune Confirmed Progressive Disease 
(iCPD) 
See Table 11-12 


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Table 11-12.  iCPD Requirements Summary 
Immune Confirmed Progressive Disease (iCPD) Requirements 
An overall response of iCPD can only be assessed immediately after a time point with overall 
response of  iUPD1 
Cause of iUPD 
iCPD Requirements 
Target Lesion Progression 
Additional worsening of target lesions as evidence by an 
increase of ≥ 5mm in the target lesion SOM 
Non-Target Lesion Progression 
Any worsening in non-target lesions 
New Target Lesions 
Additional worsening of new target lesions as evidenced by 
an increase of ≥ 5mm in the new target lesion SOM, or 
additional new target lesions 
New Non-Target Lesions 
Any worsening in non-target lesion lesions or additional 
non-target new lesions 
Any cause 
New RECIST 1.1-assigned progression in another lesion 
category (ie, target or non-target lesions reach the definition 
of iUPD for the first time per Table 1 or Table 2, or there are 
new lesions for the first time) 
1 Or immediately after an assessment of UE, NA, or ND if the assessment immediately before was iUPD 
 
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):  Radiographic imaging was not performed at this time point to evaluate the target 
lesions 
Best Overall Response 
Immune Best Overall Response (iBOR) is determined for iBOR as follows: 
 
iBOR is the best response seen since iUPD 
 
iBOR does not require confirmation 
 
For an iBOR of progression, the time point of iUPD that turned into iCPD is the 
time point of iBOR 
Special cases 
Bone lesions, cystic lesions, lesions with prior treatment, fluid collections, merging 
lesions, and splitting lesions are given special mention within the RECIST 1.1 
publication.  These considerations should also be applied to iRECIST. 
Methods of Assessment and Image Acquisition Specifications 
For each subject at each timepoint, there is a separate RECIST 1.1 assessment and 
iRECIST assessment.  Until PD has been reached, these assessments rely on the same 
measurements and NT/new lesion assessments .  Subsequently, the assessments will 
differ as described above.  Image acquisition for a subject should be kept consistent for 
the entire time the subject is on trial, including for the post RECIST 1.1 PD time points, 
which are assessed by iRECIST. 


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11.13 
Appendix 13.  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:  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 the 
initial infusion of AMG 910.  CRS may be life threatening or fatal.  Infusion reactions may 
be clinically indistinguishable from manifestations of CRS.  Throughout the treatment 
with AMG 910, monitor subjects for clinical signs (eg, fever, tachycardia, dyspnea, 
tremors) and laboratory changes (eg, transaminase increase) which may be related to 
CRS. 
Grading and management of CRS should be performed according to the guidelines 
provided in (based on the adopted grading system referenced in Lee et al, 2014). 
Please also refer to the general guidance for re-start of infusion after 
interruptions/delay/withholding and dose modifications in Section 6.2.2, Table 6-3 and 
Table 6-4. 
For grade 3 and 4 CRS, please also see Section 6.2.1.3 for DLT considerations. 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
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11.14 
Appendix 14.  Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 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 4.0.  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 11-13) and clinical TLS (see 
Table 11-14) 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 alkalization) and use of a 
hypouricemic agent (Table 11-14). 
Table 11-13.  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 11-13).  The grade of clinical TLS is defined by the maximal 
grade of the clinical manifestations as detailed in Table 11-14. 


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Table 11-14.  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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11.15 
Appendix 15.  Protocol Amendment 2 Schedule of Activities (SoA) 
for Cohort 1 
 
 


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Product:  AMG 910 
Protocol Number:  20180292 
Date:  02 March 2021 
Page 1 of 83 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Global Phase 1 Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of the Half-life Extended Bispecific T-cell Engager 
AMG 910 in Subjects With Claudin 18.2-Positive Gastric and Gastroesophageal 
Junction Adenocarcinoma 
 
Amgen Protocol Number 20180292 
 
Amendment Date: 
02 March 2021 
 
Rationale: 
This protocol is being amended to include the following updates: 
 
To adapt duration of extended intravenous (eIV) administration during cycle 1 week 1 
within a range of 3 to 7 days. 
 
Following cycle 1 week 1, which will be eIV, dose administration will switch to once 
weekly dosing schedule starting cycle 1 day 8 
 
To update the planned target doses of AMG 910 as 6.5, 15, 30, 60, 150, 300, 600, 
1000, and 2000 g. 
 
To update the predicted pharmacokinetic (PK) profile for AMG 910 eIV Infusion from 
the planned doses. 
 
To update the inclusion criteria (102) to include the legal age within the country. 
 
To update the inclusion criteria (104) to include the standards and approvals within 
the country. 
 
To update the exclusion criteria (206) with respect to subjects with positive hepatitis 
B core antibody and/or hepatitis B surface antibody (HBsAb) accompanied by a 
negative Hepatitis B virus-DNA (HBV-DNA) can be enrolled into the study, but 
HBV-DNA needs to be monitored every 2 months. 
 
To update long-term follow-up (LTFU). 
 
To add a 48 hours column for day 8 to the Schedule of Activities (SoA) and also 
other assessment timepoint in cycle 1. 
 
To separate Table 6-3 (short-term IV) and Table 6-4 (new table added for eIV) 
 
Editorial changes (including typographical, grammatical, abbreviation, and 
formatting) have been made throughout the document. 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  14 October 2020 
Page 1 of 47 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Global Phase 1 Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of the Half-life Extended Bispecific T-cell Engager 
AMG 910 in Subjects With Claudin 18.2-Positive Gastric and Gastroesophageal 
Junction Adenocarcinoma 
 
Amgen Protocol Number AMG 910 20180292 
 
Amendment Date: 
14 October 2020 
 
Rationale: 
The protocol is being amended to harmonize content across all concerned countries 
following the separate national regulatory and ethics review processes.  In addition, this 
amendment is intended to optimize study procedures to improve the operational 
efficiency of the protocol following investigator feedback.  Furthermore, the protocol has 
been updated to reflect feedback from initial Dose Limiting Recommendation Meetings 
(DLRM) and incorporate feedback received from global regulatory authorities during the 
initial reviews for this study. 
Changes in this amendment include (but are not limited to): 
 
Clarifications relating to observation periods that should be followed during the 
study. 
 
Clarifications of pregnancy testing timelines. 
 
Updated toxicology to include additional available data. 
 
Updated Benefit/Risk Assessment to include information related to COVID-19. 
 
Streamlining of End Of Study text. 
 
Update to inclusion criteria to add definition of coagulation function status 
required for study participation and to reflect that subjects should be able to use 
proton pump inhibitors. 
 
Update to exclusion criteria to exclude subjects with inherited bleeding disorders 
and subjects with heparin-induced thrombocytopenia and subjects requiring non-
steroidal anti-inflammatory drugs during study treatment. 


Product:  AMG 910 
Protocol Number:  20180292 
Date:  14 October 2020 
Page 2 of 47 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Addition of text to reflect slot reservation process to ensure that the start of 
patient dosing will be staggered by at least 72 hours.  
 
Updates to other protocol-required therapies to reflect more detailed 
recommendations with regard to dexamethasone pretreatment. 
 
Updates to excluded treatments, medical devices and/or procedures during study 
period to reflect that recommended preventive vaccinations may be administered 
in the treatment-free intervals. 
 
Updates to multiple-subject cohorts text to include text indicating that sequential 
dosing of subjects by at least 72 hours should be employed to all subjects within 
a dose escalation cohort. 
 
Updates to include additional dose-limiting toxicity (DLT) definitions.  
 
Updates to dose adjustments and re-start at a lower dose level text to include 
addition of supplemental text and information from initial patient dosing 
experience. 
 
Addition of supplemental text to outline timings for pulse oximetry assessments. 
 
Protocol-specific anticipated serious adverse events was updated for consistency 
with Medical Dictionary for Regulatory Activities (MedDRA) coding.  Indigestion 
was removed because it is not a preferred term (PT) in MedDRA and is 
addressed as dyspepsia instead.  Similarly, chronic acid reflux was removed 
because it is not a PT in MedDRA and is addressed as gastroesophageal reflux 
disease instead. 
Finally, corrections, as well as editorial and clarifying changes have been made 
throughout the protocol.   


Product:  AMG 910 
Protocol Number:  20180292 
Date:  17 January 2020 
Page 1 of 40 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Global Phase 1 Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of the Half-life Extended Bispecific T-cell Engager 
AMG 910 in Subjects With Claudin 18.2-Positive Gastric and Gastroesophageal 
Junction Adenocarcinoma 
 
Amgen Protocol Number AMG 910 20180292 
 
Amendment Date: 
17 January 2020 
Rationale: 
The original protocol, dated 21 November 2019, was updated based on comments 
received from the FDA on the Investigational New Drug application, mainly: 
 
Clarified and added specific AE management instruction to Table 6-3 (Infusion 
Interruptions/Delays/Withholding/Permanent Discontinuation and Management of 
Adverse Events) 
 
Clarified that the Retreatment Group does not allow for any other anticancer 
therapies between stop of AMG 910 and AMG 910 re-treatment 
 
Clarified stopping rules for dose escalation 
 
Defined “active central nervous system metastases" in exclusion criterion 202 to 
mean "untreated or symptomatic active central nervous system metastases" 
 
Corrected for inconsistency in birth control language (revising time frame from  
45 days after last dose of AMG 910 to 75 days for female subjects to be 
consistent with CTFG guidance, and 5 months for male subjects) 
 
Corrected for inconsistency in urinalysis assessments in Table 1-1 (Schedule of 
Activities) 
In addition, administrative and typographical corrections were made as a result of this 
review. 

SAP_001.pdf: 
Product:  AMG 910  
Protocol Number:  20180292 
Date:  15 June 2022 
Page 1 of 29 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
Protocol Title: 
A Global Phase 1 Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of the 
Half-life Extended Bispecific T-cell Engager AMG 
910 in Subjects With Claudin 18.2-Positive Gastric 
and Gastroesophageal Junction Adenocarcinoma 
Short Protocol Title: 
A Phase 1 Study of AMG 910 in Subjects with 
CLDN18.2-Positive Gastric and Gastroesophageal 
Junction Adenocarcinoma 
Protocol Number: 
20180292 
NCT Number: 
NCT04260191 
Authors: 
 and 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
22 February 2020 
Amendment 1 (v2.0) 
15 June 2022 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
22Feb2020 
N/A 
Amendment 1 (v2.0) 
15Jun2022 
Based on Protocol Amendment 3 
 


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Date:  15 June 2022 
Page 2 of 29 
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Table of Contents 
Table of Contents ............................................................................................................ 2 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints/ Estimand(s) ....................................................... 7 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.1.1 
Dose Exploration Phase .............................................................. 8 
3.1.2 
Dose Expansion Phase ............................................................. 12 
3.1.3 
Extension of Treatment Duration ............................................... 12 
3.1.4 
Re-treatment of Subjects ........................................................... 12 
3.2 
Sample Size .............................................................................................. 14 
4. 
Covariates and Subgroups ................................................................................... 14 
4.1 
Planned Covariates ................................................................................... 14 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 15 
6. 
Analysis Sets ........................................................................................................ 18 
6.1 
Safety Analysis Set ................................................................................... 19 
6.2 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 19 
6.3 
Study Specific Analyses Set(s) .................................................................. 19 
6.3.1 
DLT Analyses Set(s) .................................................................. 19 
6.3.2 
RECIST Evaluable Analyses Set(s) ........................................... 19 
7. 
Planned Analyses ................................................................................................. 19 
7.1 
Primary Analysis ....................................................................................... 19 
7.2 
Final Analysis ............................................................................................ 20 
8. 
Data Screening and Acceptance ........................................................................... 20 
8.1 
General Principles ..................................................................................... 20 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 20 
8.3 
Handling of Missing and Incomplete Data ................................................. 20 
8.4 
Detection of Bias ....................................................................................... 20 
8.5 
Outliers ..................................................................................................... 20 
8.6 
Distributional Characteristics ..................................................................... 20 
8.7 
Validation of Statistical Analyses ............................................................... 20 
9. 
Statistical Methods of Analysis.............................................................................. 21 
9.1 
General Considerations ............................................................................. 21 
9.2 
Subject Accountability ............................................................................... 21 
9.3 
Important Protocol Deviations ................................................................... 21 


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9.4 
Demographic and Baseline Characteristics ............................................... 21 
9.5 
Efficacy Analyses ...................................................................................... 22 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 22 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 22 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 22 
9.6 
Safety Analyses ........................................................................................ 22 
9.6.1 
Analyses of Primary Safety Endpoints ....................................... 22 
9.6.2 
Adverse Events ......................................................................... 22 
9.6.3 
Laboratory Test Results ............................................................ 23 
9.6.4 
Vital Signs ................................................................................. 23 
9.6.5 
Physical Measurements ............................................................ 23 
9.6.6 
Electrocardiogram ..................................................................... 23 
............................................................... 23 
9.6.8 
Exposure to Investigational Product .......................................... 23 
9.6.9 
Exposure to Non-Investigational Product ................................... 23 
9.7 
Other Analyses ......................................................................................... 24 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 24 
10. 
Changes From Protocol-specified Analyses.......................................................... 24 
11. 
References ........................................................................................................... 24 
12. 
Prioritization of Analyses....................................................................................... 25 
13. 
Data Not Covered by This Plan............................................................................. 25 
14. 
Appendices ........................................................................................................... 26 
14.1 
Appendix A.  Handling of Dates, Incomplete Dates and Missing 
Dates ........................................................................................................ 26 
14.2 
Appendix B.  RECIST (v1.1) Criteria ......................................................... 27 
 


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List of Tables 
Table 3-1.   Planned Doses per Dose Cohort Level…………..……………………………14 
Table 14-1. BOR per RECIST 1.1………………………………………………………........27 
Table 14-2.  BOR Derivation Steps for GSP ………………………………………………..28 
List of Figures 
Figure 3-1.  Study Schema……………………………………………………………………13 
 
 


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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AUC 
Area Under the Curve 
BiTE 
bispecific T cell engager 
BLRM 
Bayesian Logistic Regression Model 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
CI 
Confidence Intervals 
Cmax 
Maximum Serum Concentration 
Cmin 
Minimum Serum Concentration 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CR 
Complete Response 
CRF 
Case Report Form 
CRM 
Continual Reassessment Method 
CT 
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DLRT 
Dose Level Review Team 
DLT 
Dose-limiting toxicities 
DMP 
Data Management Plan  
DOR 
Duration of response  
ECG 
Electrocardiogram 
GSO-DM 
Global Study Operations-Data Management 
HLE 
Half-Life extended 
IV 
intravenous 
LTFU 
Long Term Follow-Up 
MABEL 
Minimum Anticipated Biological Effect Level 
MedDRA  
The Medical Dictionary for Regulatory Activities  
mg 
milligram 
MTD 
Maximum Tolerated Dose 
Claudin 18.2 
Claudins are a family of tight junction proteins establishing 
paracellular barriers which control flow of molecules between 
cells 
NE 
Not Evaluable 
OS 
Overall survival  
PD 
Pharmacodynamic 
PFS 
Progression-free survival  


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Abbreviation or Term 
Definition/Explanation 
PK 
Pharmacokinetics 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SFU 
Safety follow-up 
t1/2 
Half-life 
TP 
Time-point 
TTR 
Time To Response 
WHO-DRUG 
World Health Organization Drug 
 
 
 


Product:  AMG 910  
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1. 
Introduction 
AMG 910 is a novel half-life extended (HLE) bispecific T cell engager (BiTE) molecule 
designed to direct T cells towards Claudin 18 isoform 2 (CLDN18.2) - expressing cells. 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20180292, AMG 910 dated 
02 March 2021.  The scope of this plan includes 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/ Estimand(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of AMG 910 in adult 
subjects 
 
To determine the maximum 
tolerated dose (MTD) and/or 
recommended phase 2 dose 
(RP2D) 
 
Dose-limiting toxicities (DLT) 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs, 
electrocardiogram (ECG), and 
clinical laboratory tests 
 
Objectives 
Endpoints 
Secondary 
 
To characterize the PK of 
AMG 910 
 
PK parameters for AMG 910 
following short-term intravenous 
(IV) and extended IV (eIV) 
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 following 
multiple dosing, and, if feasible, 
half-life (t1/2) 
 
To evaluate preliminary anti-tumor 
activity of AMG 910 
 
Objective response (OR) per 
Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 and 
iRECIST 
 
Duration of response (DOR) 
 
Time to progression 


Product:  AMG 910  
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Date:  15 June 2022 
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CONFIDENTIAL  
 
 
 
Progression-free survival (PFS), 
6-month and 1-year PFS 
 
Overall survival (OS), 1 and 
2-year OS 
 
 
Objectives 
Endpoints 
Exploratory 
 
2.2 
Hypotheses and/or Estimations 
AMG 910 will demonstrate acceptable safety and tolerability in subjects with gastric or 
GEJ cancer at 1 or more dose levels with at least 1 dose level showing evidence of 
anti-tumor activity. 
3. 
Study Overview 
3.1 
Study Design 
This is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 910 in 
subjects with CLDN18.2-positive gastric and GEJ adenocarcinoma.  The study will 
consist of 2 phases: 
 
Dose-exploration phase 
 
Dose-expansion phase 
3.1.1 
Dose Exploration Phase 
The dose-exploration phase of the study will estimate the MTD of AMG 910 using a 
Bayesian logistic regression model (BLRM) based on enrollment of 34 gastric cancer 
subjects. A RP2D may be identified based on emerging safety, efficacy, and 
pharmacodynamics data prior to reaching an MTD.  
AMG 910 will be administered as a short-term IV infusion (approximately 60 minutes) or 
as extended IV (eIV) infusion over 96 hours (in cycle 1 week 1) over six 28-day cycles 
following the doses and dosing schedule outlined in Table 3-1. 
 
For cycles 1 and 2, twice a week at days 1 and 3 of each week in a 28-day cycle, 
starting with cycle 1 day 8 dose and 


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 
For cycles 3 to 6, weekly, i.e., days 1, 8, 15, and 22 in a 28-day cycle 
Because of the observation of cytokine release syndrome (CRS) events in cohort 1, 
the dosing of AMG 910 and the dose escalation schedule will be adapted. In cycle 
1 week 1, the administration is to start with an approximately 96-hour eIV infusion 
followed by short-term weekly or twice weekly infusions (approximately 60 minutes) 
at the planned target doses of AMG 910 of 6.5, 15, 30, 60, 150, 300, 600, 1000, and 
2000 μg from cycle 1 week 2 onwards.  
For the new dosing schedule with 96-hour eIV infusion of AMG 910, day 1 and day 
3 doses of cycle 1 week 1 will be each infused over 48 hours instead of 60 minutes 
resulting in a total infusion time of 96 hours. It is hypothesized that the eIV infusion 
approach over a 96-hour period may reduce the intensity and/or frequency of the 
symptoms associated with CRS associated with the same target dose of AMG 910 
when infused twice over a 60-minute duration. The lowest AMG 910 daily dose for 
eIV administration will be 3.25 μg/day. The calculation of a next higher eIV dose will 
be based on the following calculation:  
Daily eIV dose = total AMG 910 dose, resulting from the twice weekly dosing at the 
target dose, divided by number of eIV infusion days.  
There will be treatment-free intervals of two weeks after cycles 2 and 4. The treatment-
free intervals may be extended up to three weeks to allow for recovery in case of adverse 
events.  The treatment-free interval after cycle 4 may also be extended to three weeks for 
logistical reasons. The maximum treatment duration will be 6 cycles. Subjects who have 
shown no disease progression and no worsening of performance status at the end of cycle 
6 may continue treatment for an additional two cycles if there are no unresolved grade 3 
or 4 toxicities and if the investigator and the Amgen Medical Monitor agree that continued 
treatment may likely provide benefit for the subject. 
The DLRT may recommend enrolling more subjects for safety reasons at any point 
during the study and the DLRT may explore 2 different AMG 910 dosing schedules 
in cohorts running in parallel. 
Dose exploration will be conducted in 2 stages: single-subject cohort(s) followed by 
multiple-subject cohort(s) (3 to 4 subjects per cohort) (Refer: Table 3-1). 
Single subject cohort: 


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Protocol Number:  20180292 
Date:  15 June 2022 
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CONFIDENTIAL  
 
 
Dose exploration will begin with single-subject cohort(s) and the starting dose is expected 
to have the first dose Cmax below MABEL. Serum concentrations to be achieved with first 
3 to 4 dose level cohorts are expected to be lower than those at which pharmacodynamic 
activity translating into treatment-related adverse events or efficacy is predicted to be 
observed. Therefore, the first two cohorts are pre-planned single subject cohorts. If a 
subject in the first single-subject cohort does not experience a grade 2 or higher adverse 
event at least possibly related to AMG 910 or DLT during the initial 28 days of treatment 
(DLT window for single-subject cohorts), then the next subject may be dosed at the next 
higher dose level(s) per Table 3-1. Planned doses per cohort level ranging from 2.5 μg to 
2000 μg. Switching from a single subject cohort to a multiple-subject cohort will occur with 
cohort 3 or sooner if specific safety criteria are observed as described below during the 
DLT window: 
 
DLT or  
 
Grade ≥ 2 adverse events based on CTCAE version 5.0, at least possibly related 
to AMG 910, with the exception of lymphopenia or lymphocyte count decreased.  
The DLRT will convene to review the safety data and recommend the appropriate dose to 
be implemented. The recommended dose will not exceed the levels recommended by the 
BLRM in the dose escalation portion and the next pre-defined dose level. The DLRT may 
also convene ad hoc meetings any time to review safety data if deemed necessary. 
Multiple subject cohort:  
Dose escalation in multiple-subject cohorts (3- to 4 subjects per cohort) will begin with 
single subject cohort and the dose level(s) per Table 3-1. The DLRT will convene to review 
the safety data and recommend the appropriate dose to be implemented. The 
recommended dose will not exceed the levels recommended by the BLRM in the dose 
escalation portion and the next dose level listed in Table 3-1. The DLRT may recommend 
enrolling more subjects for safety reasons at any point during the study. 
For dose escalation with eIV dosing schedule, the DLRT will in addition to the 
 
considerations above evaluate the eIV administration and the short-term IV 
administrations separately for the occurrence of first-dose effects (e.g., CRS and 
TLS). The DLRT will review the safety data and may recommend to only escalate 
the dose for either the eIV administration or the short-term infusion administrations 
for the next cohort. The recommended dose will not exceed the levels 
recommended by the BLRM in the dose escalation portion and the next dose level 


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listed in Table 3-1. For subsequent dose escalation decisions, the dose for the eIV 
administration and the short-term IV administrations may be again escalated in 
parallel while maintaining the relative dose difference or the dose for the not 
escalated administration may be kept constant.  
For multiple-subject cohorts, the DLRT will not recommend dose escalation decisions until 
each of the following occurs: 
 
All subjects in the cohort have been followed for safety events for a minimum of 28 
days from the first dose of AMG 910 (except if a subject experienced a DLT) or 
have been followed for a minimum of 72 hours after the 7th dose with treatment 
interruption not constituting a DLT  
 
At least 3 of the subjects can be evaluated for DLT assessment  
Determination of whether a subject is evaluable for DLT assessment will be made in 
accordance with the following rules: 
 
Subjects who receive study treatment (at least 80% of the planned dose for cycle 
1) and remain on study through the DLT assessment window will be considered 
DLT-evaluable. 
 
Subjects who discontinue from the study prior to completing the DLT assessment 
window for reasons other than a DLRT will be considered non-evaluable for dose-
escalation decisions and MTD determination and may be replaced by an additional 
subject at that same dose level. 
Dose escalation/de-escalation decisions in multiple-subject cohorts will be guided by 
the BLRM model of dose toxicity. The MTD for BLRM is the dose level predicted to 
have the highest probability of a DLT rate within the target interval of 20% to 33%, 
subject to overdose control. To control the risk of overdose, the MTD must have less 
than a 40% predicted probability of overdosing (DLT rate > 33%). If late onset adverse 
events (i.e., after the 28-day DLT period) occur or late findings from endoscopic 
evaluations during a cohort, the DLRT may adaptively re-consider the doses evaluated 
within a cohort for subsequent dosing and/or possibly trigger a de-escalation or 
withholding of additional doses in subsequent cohorts. Based on the BLRM model and 
after reviewing all available safety and tolerability data, the DLRT may recommend 
dosing at intermediate dose levels between the planned dose levels listed in Table 3-
1. 


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3.1.2 
Dose Expansion Phase 
Following the dose-exploration phase, a dose-expansion phase will be conducted on 36 
additional subjects approximately to confirm safety, PK, and pharmacodynamics at the 
MTD or RP2D and to obtain further safety and efficacy data and enable correlative 
biomarker analysis. The dose to be evaluated will be at or below the MTD estimated in 
the dose exploration cohorts. A final estimate of the MTD and RP2D will be evaluated and 
confirmed utilizing all DLT-evaluable subjects from the dose exploration and the dose 
expansion cohorts. This final estimate of the MTD and RP2D will not exceed the MTD 
identified in the dose escalation portion of the study and will not exceed the MTD identified 
in the dose escalation portion of the study by the BLRM. Efficacy data will be reviewed in 
the dose expansion part of the study after the first 15 subjects are enrolled and have had 
the opportunity to receive at least 8 weeks of treatment and received the first response 
assessment (with recruitment ongoing).  
A final BLRM estimate of the MTD will use all data from dose exploration and dose 
expansion. 
3.1.3 
Extension of Treatment Duration  
Subjects who have shown no disease progression and no worsening of performance 
status at the end of cycle 6 may continue treatment for an additional two cycles if there 
are no unresolved treatment related grade 3 or 4 toxicities and if the investigator and the 
Amgen Medical Monitor agree that continued treatment may likely provide benefit for the 
subject. Further extensions of the treatment are to be agreed in the same manner at the 
end of each second cycle of extended treatment. Treatment schedule and schedule of 
activities will be conducted as described for cycle 6. 
Subjects who remain on the treatment for more than 2 years do not need to have 
additional long-term follow-up. They will complete the study 30 (+3) days following 
discontinuing treatment. 
3.1.4 
Re-treatment of Subjects  
Subjects who have derived sustained benefit from treatment, meaning at least stable 
disease and no worsening of performance status, for at least 3 months after the end of 
treatment but experience relapse or progression thereafter, and have not received any 
other systemic anti-cancer therapy since their last AMG 910 treatment, may be retreated 
in a separate retreatment group for a total of up to 2 rounds of retreatment (up to 6 
cycles each). Retreatment will be administered at the highest dose level and currently 
used schedule that has been assessed as safe by the DLRT at the time of retreatment 


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initiation. Treatment schedule and schedule of activities will be conducted as described 
for cycles 1 through 6 in the dose exploration and expansion cohorts. 
Figure 3-1.  Study Schema 
 
LTFU = long-term follow-up; MTD = maximum tolerated dose; RP2D = recommended phase 2 dose  
SFU = safety follow-up  
a Multiple-subject cohorts will enroll at a dose level where specific safety and/or efficacy criteria were met in a single-subject cohort or per 
planned dose level from Table 3-1. For subsequent dose level cohorts, 3-4 total subjects will be enrolled.  
b For cohorts 1b onwards, AMG 910 is administered as extended IV infusion over 96 hours in cycle 1 week 1 and as short-term IV 
infusions weekly (or twice weekly) starting cycle 1 day 8 onwards in cycle 1 through 6 of 28-day cycles with scheduled 2-week 
breaks after cycles 2 and 4.  


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Table 3-1. Planned Doses per Dose Cohort Level 
 
Routes of administration: eIV  extended intravenous; IV  short-term intravenous. 
a Switching from a single subject cohort to a multiple-subject cohort will occur with cohort 3 or sooner if specific safety criteria are observed 
as described in Section 6.2.1.1.1 in the protocol.  
b If a dose reduction is needed according to instructions provided in Table 6-3 as in the protocol, treatment will be continued at a dose of 
2.5 g as specified in Section 6.2.2.3.5 as in the protocol. 
Note: The “b” cohort numbers are used to differentiate cohorts 1 through 10 denoted in previous versions of the protocol 
 
3.2 
Sample Size 
It is anticipated that approximately 70 subjects will be enrolled in this study.  Up to 
34 subjects will be enrolled in the dose-exploration cohorts and up to 36 additional 
subjects will be enrolled in the dose-expansion cohort. 
The sample size in the dose-escalation phase is based on practical consideration and is 
consistent with conventional oncology studies with the objective to estimate the MTD.  
With 3 subjects in a cohort, there is a 27% to 70% 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. 
In the dose-expansion cohort, a subject number of 36 will provide an 84% 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 36 subjects and 19% overall response 
rate, the expected 95% CI would be 8% to 36%.  
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable. 


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4.2 
Subgroups 
Not applicable. 
5. 
Definitions 
Adverse events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject  
irrespective of a causal relationship with the study treatment. 
Age at enrollment 
Subject age at enrollment will be determined using the age in years reported in the  
clinical database. 
 
Area under the Curve (AUC) 
The area under the serum drug concentration-time curve (AUC) reflects the actual body 
exposure to drug after administration of a dose of the drug. 
 
Baseline 
For any variable, unless  otherwise  specified,  the  baseline  is  the  last  non-missing 
assessment taken prior to the first administration of AMG 910. 
For parameters/assessments not scheduled to be performed (or scheduled but  not  
performed) on the same day as the first administration of AMG 910, the baseline value is 
the value from the screening period measured closest to the day of first administration  
of AMG 910.  
Baseline ECG values in triplicate 
The mean of values in a triplicate should be calculated for Baseline.  Baseline triplicate 
value is the mean of all pre-dose assessments. For all post- baseline ECG, the mean  
value for measurements taken 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  
time point.  
Best Overall Response (BOR) - using RECIST v1.1 criteria 
BOR is defined as the best response in the following order: CR, PR, SD, PD, or NE, where 
CR  and  PR  require  confirmation  by  a  repeat  consecutive  assessment at  least 4 
weeks after the first detection of radiographical response or progressive disease. 
Confirmation of SD, minimum 6 weeks duration from the baseline scan is required. The 
details of derivation of BOR is described in Appendix B. 
Complete response (CR) per RECIST v1.1 criteria 


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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.  
Objective Response Rate (ORR) per RECIST v1.1 criteria 
Objective response rate is defined as the proportion of patients with a BOR of CR or PR. 
Partial Response (PR) per RECIST v1.1 criteria  
Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum diameters. Non target lesions must 
be non-Progressive Disease (non-PD). 
BMI 
Body Mass Index should be calculated using the following formula: 
BMI (kg/m2) = weight (kg) / [height (cm)/100]2 
Change from Baseline 
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline value.  
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value) 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value) /Baseline 
Value] x 100 
Cmax 
Maximum observed drug concentration. 
Cmin 
Minimum observed drug concentration. 
Dose Limiting Toxicity  
Dose limiting toxicities are defined  as  any  adverse  events  at  least  possibly  related  to 
AMG 910  with  an  onset  within  the  first  28  days  following  first  dose  for  single-
subject cohorts and within the safety observation period for multiple-subject cohorts as 
defined in section 6.2.1.1.3   of the protocol. 
Additional information on DLTs are given in the section 6.2.1.1.2 of the protocol. 
End of study (End of trial) 


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It is defined as the date when the last subject across all sites is assessed or receives an 
intervention for evaluation in the study (i.e., last subject last visit), following any additional 
parts in the study (e.g., long-term follow-up), as applicable. 
Fridericia-corrected QT intervals (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows: 
QTcF=QT/(RR/1000)1/3 
Investigational product (IP)  
The term ‘investigational product’ is used in reference to AMG 910.  
Last investigational product dose date 
The last IP date for each subject is defined as the latest date IP administered. 
Long term follow-up (LTFU) 
Subjects will be followed for every 6 months up to 2 years from the first dose of AMG 910 
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. Subjects 
who remain on the treatment for more than 2 years do not need to have additional 
long-term follow-up (LTFU). They will complete the study 30 (+3) days following 
discontinuing treatment. 
Maximum Tolerated Dose (MTD) 
A final estimate of the MTD will be made based on a Bayesian Logistic Regression Model 
(BLRM) utilizing all DLT-evaluable subjects from the dose exploration and dose expansion 
cohorts. The MTD for BLRM is the dose level predicted to have the highest probability of 
a DLT rate within the target interval of 20% to 33%, subject to overdose control. To control 
the risk of overdose, the MTD must have less than a 40% predicted probability of 
overdosing (DLT rate >33%). 
Primary completion 
The primary completion date  is  the  date  when  data  for  the  primary  endpoint  are  last 
collected for the purposes of conducting the primary analysis. It is the date when the last 
subject is assessed or receives AMG 910 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 or was terminated early. 


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Safety follow-up 
It is defined as the subject visit at least 30 (+3) days after last dose of AMG 910 is received 
to assess the risk of delayed adverse events.  
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.  
 
Requires in-patient hospitalization or prolongation of existing hospitalization.  
 
Results in persistent or significant disability/incapacity. 
 
Other medically important serious event. 
 
Is a congenital anomaly/birth defect. 
Study day 
Post-study day: study day= (date – date of Study Day 1) + 1. 
Pre-study day: study day= (date –   date of Study Day 1). 
Study day 1 
It is defined as the first day that AMG 910 is administered to the subject. 
Treatment emergent adverse event 
A  treatment - emergent  adverse  event (TEAE)  is  any  adverse  event  starting  on  or  
after  the  first  administration  of  investigational  product,  as  determined  by  the  flag  
indicating  if  the  adverse event started prior to the first dose on the Events CRF, and up 
to and including 30  days  after  the  last  IP  dose  date.  The severity of each adverse  
event  will  be  graded  using the CTCAE version 5.0.  Adverse events will be coded using 
MedDRA. 
Treatment related adverse event 
A treatment-related AE is any treatment-emergent AE that per investigator review has a 
reasonable possibility of being caused by AMG 910. 
6. 
Analysis Sets 
The following sub-sections describe the analysis sets to be used. 


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6.1 
Safety Analysis Set 
Safety analysis set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 910. As per the protocol, all endpoints, unless noted otherwise, will be conducted on 
the safety analysis set. Hence, full analysis set, primary analysis set are same as safety 
analysis set.  
6.2 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
 The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected. A subject with insufficient 
number of data points to meet analysis requirements, or where significant protocol 
deviations have affected the data, or if key dosing or sampling information is missing will 
not be used to perform PK analysis.  
6.3 
Study Specific Analyses Set(s) 
6.3.1 
DLT Analyses Set(s) 
Dose limiting toxicity will be performed on the DLT Analysis set. DLT Analysis set is 
defined as all subjects that are enrolled and receive at least 1 dose of AMG 910 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 within the DLT window in effect for the dose level cohort of the 
subject.  
A non-evaluable subject may be replaced by an additional subject at the same dose level 
for dose-escalation and MTD determination. 
6.3.2 
RECIST Evaluable Analyses Set(s) 
The analysis of objective response will be conducted on the RECIST Evaluable Analysis 
 Set. It is defined as all subjects that are enrolled and receive at least 1 dose of AMG  
910 with at least one tumor lesion that is measurable in contrast-enhanced computed  
tomography (CT) as defined by RECIST 1.1 at baseline.  
Objective response will be performed through Tumor burden assessments based on 
RECIST 1.1 criteria. 
7. 
Planned Analyses 
7.1 
Primary Analysis 
Because the sponsor decided to early terminate this study, primary analysis and 
final analysis will be combined as one final analysis as part of study close-up 
activities. 


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7.2 
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 on-going 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 
Incomplete adverse event, and death dates missing data will be imputed as described in 
Appendix A.  
8.4 
Detection of Bias 
Lack of protocol  compliance  and  the  potential  for  biased  statistical  analyses  will  be  
examined by assessing the incidence of important protocol deviations in each cohort. The 
clinical study team will identify and document the criteria for important protocol deviations. 
8.5 
Outliers 
Pharmacokinetic (PK) serum concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance with 
current risk-based quality control procedures.   


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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 
Unless otherwise specific, all described analyses will be conducted on the Safety Analysis 
Set.  Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamic, and biomarker data by dose, dose schedule, and time as appropriate.  
Descriptive statistics on continuous data will include means, medians, standard 
deviations, and ranges, while categorical data will be summarized using frequency counts 
and percentages.  Graphical summaries of the data may also be presented. 
Exact method proposed by Clopper-Pearson will be used for the estimation of confidence 
intervals (CI) for proportion. 
9.2 
Subject Accountability 
The number and percent of subjects who were enrolled, screened but not enrolled 
(screen failures), enrolled but not treated, received investigational product, discontinued 
from AMG 910 (including reasons for discontinuing), completed study, discontinued the 
study (including reasons for discontinuing) will be summarized. Key study dates for the 
first subject enrolled, last subject enrolled, and last subject’s end of study will be 
presented. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, subcategory codes, and descriptions 
will be used during the study. The final IPD list is used to produce the list of Subjects with 
IPDs. In addition, a separate listing of all inclusion and exclusion deviations will be 
provided.  
9.4 
Demographic and Baseline Characteristics 
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.  
Descriptive statistics for selected demographics, baseline characteristics, safety, PK, PD 
will be provided by dose, dose schedule, and time as appropriate. Descriptive statistics on 


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continuous data will include mean, median, standard deviation, and range, while 
categorical data will be summarized using frequency count and percentage. Graphical 
summaries of the data may also be presented.  
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
No efficacy parameter is considered in primary endpoints. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The number and percent of subjects with best overall response of complete response, 
partial response, stable disease, and progressive disease as determined will be tabulated. 
The proportion of subjects with an objective response (per RECIST 1.1) and 95% CI will 
be tabulated by planned dose level using the RECIST Evaluable Analysis Set.   
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
Not applicable. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoints 
Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the Safety Analysis Set, which includes subjects that are enrolled and 
received at least 1 dose of AMG 910.  
The analysis of DLTs will be conducted on the DLT Analysis Set. The probability of a 
subject having a DLT by planned dose level will be estimated using a two-parameter 
BLRM 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.  
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to drug interruption, withdrawal of investigational product, fatal 
adverse events and subject incidence of AEs by PT will be listed, summarized and 
tabulated by system organ class and preferred term in decreasing frequency order. 
Summaries of treatment-emergent, serious adverse events will be tabulated by system 
organ class, preferred term, grade (3 or higher) and dose/cohort.   
In addition, separate descriptive tables will be tabulated for all treatment emergent AE, 
all treatment related AEs, all serious AEs, related serious AEs, treatment emergent AEs 


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by grade, all fatal AEs, will be tabulated and presented by cohort and dose. Partial / 
missing date imputation rules are given in Appendix A. 
9.6.3 
Laboratory Test Results 
Summaries of the absolute value and/or changes from baseline at each scheduled 
assessment will be provided for selected laboratory parameters. Shifts in grades of safety 
laboratory values from baseline for selected laboratory values will also be provided. 
9.6.4 
Vital Signs 
Summary statistics of systolic/diastolic blood pressure, heart rate, respiratory rate, and 
temperature will be provided for baseline and each scheduled post-baseline 
assessment. Depending on the size and scope of changes, summaries of changes from 
baseline over time may be provided. 
9.6.5 
Physical Measurements 
Summary of physical measurement data will be provided for weight, height, BMI. 
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 QTc 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. 
9.6.8 
Exposure to Investigational Product 
Investigational product exposure will be summarized for number of cycles started, 
number of doses, cumulative dose and average dose administered. Summaries of 
the of subjects with dose modifications, interruptions and reasons for modifications, 
interruptions will be provided. In addition, a listing of the unique manufacturing lot 
numbers, and a listing of the subjects administered each manufacturing lot number will 
be provided. 
9.6.9 
Exposure to Non-Investigational Product 
There are no non-investigational products in this study. 


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9.7 
Other Analyses 
For AMG 910, PK parameters, including but not limited to Cmax, minimum serum 
concentration (Cmin), area under the concentration-time curve (AUC) over the dosing 
interval, accumulation following multiple dosing, and, if feasible, half-life (t1/2), will be 
determined from the time concentration profile using standard non-compartmental 
approaches and considering the profile over the complete sampling interval.  Based on 
the review of the data, analyses to describe the relationship between AMG 910 exposure 
and either pharmacodynamic effect and/or clinical outcome may also be performed. 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Descriptive statistics for pharmacokinetic parameters, 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 following 
multiple dosing, and, if feasible, half-life (t1/2), will be provided from the time concentration 
profile using standard non-compartmental approaches and considering the profile over the 
complete sampling interval. Individual concentration-time data will be tabulated and 
presented graphically. 
Nominal sampling times will be used for individual concentration-time plots and tables. 
Actual dose administered, and actual sampling times will be used for the calculation of PK 
parameters for each subject. The reasons for excluding any sample from the analyses will 
be provided.  
Summary of PK concentration over time and PK parameters will be provided. Mean 
concentration-time profiles for each dose will be provided. Based on the review of the 
data, analyses to describe the relationship between AMG 910 exposure and either 
pharmacodynamic effect and/or clinical outcome may also be performed. Above analyses 
will be conducted by Amgen Clinical Pharmacology Modeling and Simulation (CPMS). 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
References 
Eisenhauer  EA, P Therasse, J Bogaerts, LH Schwartz, D Sargent, R Ford, et al., 2009, 
New Response Evaluation Criteria in Solid Tumours: Revised RECIST guideline (version 
1.1), Eur J Cancer, 45(2):228-247.  
Seymour L, Bogaerts J, Perrone A, et al, on behalf of the RECIST working group. 
iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. 
Lancet Oncol 2017; 18: e143–52  


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Fuchs, C. S., Doi, T., Jang, R. W., Muro, K., Satoh, T., Machado, M., Garrido, M. (2018). 
Safety and efficacy of pembrolizumab monotherapy in patients with previously treated 
advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 
trial. JAMA oncology, 4(5), e180013-e180013.  
Bang, Y. J., Van Cutsem, E., Feyereislova, A., Chung, H. C., Shen, L., Sawaki, A., 
Aprile, G. (2010). Trastuzumab in combination with chemotherapy versus chemotherapy 
alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction 
cancer (ToGA): a phase 3, open-label, randomised controlled trial. The lancet, 
376(9742), 687-697.  
Bergstrom, K. S., & Xia, L. (2013). Mucin-type O-glycans and their roles in intestinal 
homeostasis. Glycobiology, 23(9), 1026-1037.  
Brookmeyer, R., & Crowley, J. (1982). A confidence interval for the median survival time. 
Biometrics, 29-41. 
Saber, H., Del Valle, P., Ricks, T. K., & Leighton, J. K. (2017). An FDA oncology analysis 
of CD3 bispecific constructs and first-in-human dose selection. Regulatory toxicology 
and pharmacology, 90, 144-152. 
 
12. 
Prioritization of Analyses 
No analysis is prioritized. 
13. 
Data Not Covered by This Plan 
Not applicable. 


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14. 
Appendices 
14.1 
Appendix A.  Handling of Dates, Incomplete Dates and Missing 
Dates 
Imputation Rules for Partial or Missing Start Dates 
The reference date for the following rules is the date of first dose of AMG 910. 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
 1st 
dose 
 1st 
dose 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyy 
 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
 1st dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
 1st dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1Impute the date of first dose; 2Impute the first of the month; 3Impute January 1 of the year; 4Impute 
January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date. 
Imputation Rules for Partial or Missing Death Dates 
If death year and month are available but day is missing: 
 
If yyyymm for the date last known to be alive equals yyyymm for death date, set 
death date to the day after the date last known to be alive. 
 
If yyyymm for the date last known to be alive is less than the yyyymm for death date, 
set death date to the first day of the death month. 


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 
If yyyymm for the date last known to be alive is greater than yyyymm for death date, 
assume death date is in error, do not impute and censor the subject survival time. 
If month and day are missing and year of death is known: 
 
If yyyy for the date last known to be alive equals yyyy for death date, set death date 
to the day after last known to be alive date. 
 
If yyyy for the date last known to be alive is less than yyyy for death date, set death 
date to the first day of the death year. 
 
If yyyy for the date last known to be alive is greater than yyyy for death date, assume 
death date is in error, do not impute and censor the subject survival time. 
If a death date is totally missing: 
Do not impute and censor the subject survival time. 
14.2 
Appendix B.  RECIST (v1.1) Criteria 
BOR will need to be derived based on timepoint response collected on RECIST 1.1 CRF. 
Table 14-1 provides the BOR determination per RECIST 1.1 for trials where response 
confirmation is required. That means in the case of confirming CR or PR, a confirmation is 
required by a repeat assessment at least 4 weeks after the first detection and assessments 
of NE may occur between timepoint T1 and timepoint T2. For example, BL, CR, NE, NE, NE, 
CR – then CR at post baseline 1 is confirmed at post baseline 5.  A BOR determined by Table 
14-1 is considered a Confirmed_BOR. At interim analysis, an unconfirmed response rate 
may be reported in addition to the confirmed response rate. The unconfirmed rate includes 
subjects who achieved a PR or CR and are awaiting a confirmative scan (i.e., unconfirmed 
responders). If these subjects have disease progression or death before the confirmative 
scan, then they are no longer considered as unconfirmed responder awaiting confirmative 
scan. Timepoint response “NON-CR/NON-PD” will be considered as “SD” in the algorithm 
of confirmation. Interim_BOR is defined to include these subjects in addition to 
Confirmed_BOR. Table 14-2 outlines the steps to derive Confirmed_BOR and Interim_BOR 
given the timepoint assessments.  
Table 14-1. BOR per RECIST 1.1 
Criterion 
Timepoint 
T1 
Response 
T1 ≥ 35* 
days after 
Baseline? 
Timepoint 
T2 
Response 
T2 ≥ 35* 
days after 
Baseline? 
T2 ≥ 28 
days after 
T1? 
BOR at 
time point 
T1 
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 


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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.  
*CR and PR need to be confirmed, which requires a repeat assessment at least 4 weeks after the first 
detection. Notice an unlimited number of intermittent assessments of NE can occur between the initial 
response and the confirmation. For example, CR, NE, NE, NE, CR – then CR at post baseline 1 is 
confirmed at post baseline 5.  Both first detection and repeat assessment can be unscheduled visit and the 
4 weeks apart rule needs to be met. For SD, a duration of at least 6 weeks after baseline scan is required. 
The threshold of 35 days accounts for the earliest available assessment by RECIST 1.1, as for tumor 
assessment per scheduling of imaging assessment. 
**If a CR is truly met at timepoint T1, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes progressive disease at that time point (i.e., disease must 
have re-appeared after CR). Best overall response would depend on whether minimum duration for SD 
was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the patient had PR, not CR at timepoint T1. Under this circumstances, the 
original CR should be changed to PR and the best response is PR. 
Table 14-2. BOR Derivation Steps for GSP 
Step 1. Derive Confirmed_BOR at each visit 
Derive Confirmed_BOR at each visit:  
i)       At Visit 1: Using the Visit 1 scan result and refer to Table 14-1 to derive Confirmed_BOR. 
ii)     At Visit 2 onward: 


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(a)   If current visit is CR or PR: Find last scan that is not NE or SD and at least 28 days 
before current visit. Derive BOR_temp as below: 
Last scan 
Current 
BOR_temp 
CR 
CR 
CR 
PR 
CR 
PR 
PR 
PR 
PR 
(b)   If none of above fits, find last scan that is not NE, reference Table 14-1 to derive 
BOR_temp. 
iii)    Current visit Confirmed_BOR = best of (BOR_temp, last visit confirmed_BOR). Use rule 
CR > PR > SD > PD > NE 
Step 2. Derive Interim_BOR at last visit prior to analysis data cutoff 
For subjects who discontinue tumor 
assessment (ie, had PD, death, next 
therapy, withdraw consent, or end of 
study): 
  
Assign Interim_BOR = Confirmed_BOR 
For subjects with potential for more assessment 
(ie, no PD, death, next therapy, withdraw consent, 
or end of study), unconfirmed PR/CR can be 
considered responders.   
 
If any scan is CR and no PD/death, then 
Interim_BOR = CR. 
 
If any scan is PR and no CR or PD/death, then 
Interim_BOR = PR.  
 
Else, Interim_BOR = Confirmed_BOR at the 
latest scan.