Clinical trial NCT04885998
Conditions: Small Cell Lung Cancer
Keywords: Small Cell Lung Cancer SCLC Lung Cancer AMG 757 AMG 404 Tarlatamab
Sponsor: Amgen
Start date: 2021-09-27; Completion date: 2024-09-11
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to evaluate the safety, tolerability, and recommended phase 2 target dose of tarlatamab in combination with AMG 404.

Detailed description:

Arms: arm 1: The recommended phase 2 target dose (RP2D) of tarlatamab in combination with AMG 404 will be estimated using a modified toxicity probability interval (mTPI-2) design. A combination RP2D may be identified based on emerging safety, efficacy, and pharmacodynamic data prior to reaching an maximum tolerated dose (MTD). arm 2: Participants will receive the RP2D of tarlatamab in combination with AMG 404 identified in Phase 1 (dose exploration) of the study.
Interventions: intervention 1: Tarlatamab intervention 2: AMG 404
Intervention descriptions: intervention 1: Tarlatamab will be administered as an intravenous (IV) infusion. intervention 2: AMG 404 will be administered as an intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 1 of 173 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Phase 1b Study Evaluating the Safety and 
Efficacy of AMG 757 in Combination with 
AMG 404 in Subjects with Small Cell Lung 
Cancer (SCLC) 
Short Protocol Title: 
AMG 757 and AMG 404 in Subjects with Small 
Cell Lung Cancer (SCLC) 
Protocol Number: 
20200439 
Investigational Product: 
Tarlatamab (AMG 757), AMG 404  
Trade Name: 
Not Applicable 
Sponsor 
Name of Sponsor: 
Amgen, Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA, 91329, USA 
Telephone Number: 
+1 805-447-1000 
Protocol 
Approver 
Name: 
 MD 
Function: 
Vice President Early Development, TA Head 
Oncology 
 
Key 
Sponsor 
Contact 
Name: 
MD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA, 91329, USA 
Telephone Number: 
Email Address: 
 
EudraCT Number: 
2020-005957-26 
NCT Number: 
NCT04885998 
Protocol Version Date: 
Document Version 
Date 
Original 
10 February 2021 
Amendment 1 
26 July 2021 
Amendment 2 
28 January 2022 
Amendment 3 
04 April 2023 
Amendment 4 
10 November 2023 
Data Elements Standards 
Version: 
8 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 2 of 173 
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:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 3 of 173 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1b Study Evaluating the Safety and 
Efficacy of AMG 757 in Combination with AMG 404 in Subjects with Small Cell Lung 
Cancer (SCLC), dated 10 November 2023, 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 
sub-investigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator 
Date (DD Month YYYY) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 
 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 4 of 173 
CONFIDENTIAL  
 
 
Table of Contents  
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 11 
1.1 
Synopsis ................................................................................................... 11 
1.2 
Study Schema ........................................................................................... 16 
1.3 
Schedule of Activities (SoA) ...................................................................... 18 
2. 
Introduction ........................................................................................................... 23 
2.1 
Study Rationale ......................................................................................... 23 
2.2 
Background ............................................................................................... 24 
2.2.1 
Disease ..................................................................................... 24 
2.2.2 
Amgen Investigational Product Background:  
Tarlatamab ................................................................................ 25 
2.2.2.1 
Pharmacology ......................................................... 25 
2.2.2.2 
Toxicology ............................................................... 26 
2.2.2.3 
Background Clinical Experience With 
Tarlatamab .............................................................. 26 
2.2.3 
Amgen Investigational Product Background:  
AMG 404 ................................................................................... 29 
2.2.3.1 
Nonclinical Pharmacology ....................................... 29 
2.2.3.2 
Toxicology ............................................................... 30 
2.2.3.3 
Nonclinical Pharmacokinetics .................................. 31 
2.2.3.4 
Clinical Experience .................................................. 31 
2.3 
Benefit/Risk Assessment ........................................................................... 33 
2.3.1 
Therapeutic Context .................................................................. 33 
2.3.2 
Key Benefits .............................................................................. 33 
2.3.3 
Key Safety Information .............................................................. 33 
2.3.3.1 
Tarlatamab .............................................................. 33 
2.3.3.2 
AMG 404 ................................................................. 35 
2.3.3.3 
Key Risks for Tarlatamab in Combination 
with AMG 404.......................................................... 37 
3. 
Objectives and Endpoints/Estimands .................................................................... 39 
4. 
Study Design ........................................................................................................ 39 
4.1 
Overall Design .......................................................................................... 39 
4.2 
Patient Input into the Study Design ........................................................... 45 
4.3 
Justification for Dose ................................................................................. 45 
4.4 
Justification for Investigational Product Dose ............................................ 45 
4.4.1.1 
Tarlatamab .............................................................. 45 
4.4.1.2 
AMG 404 ................................................................. 46 
4.5 
End of Study ............................................................................................. 47 
5. 
Study Population .................................................................................................. 47 
5.1 
Inclusion Criteria ....................................................................................... 47 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 5 of 173 
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5.2 
Exclusion Criteria ...................................................................................... 49 
5.3 
Subject Enrollment .................................................................................... 52 
5.4 
Screen Failures ......................................................................................... 52 
6. 
Study Intervention ................................................................................................. 53 
6.1 
Study Interventions Administered .............................................................. 53 
6.1.1 
Investigational Products ............................................................ 53 
6.1.2 
Non-investigational Products ..................................................... 55 
6.1.3 
Medical Devices ........................................................................ 55 
6.1.4 
Other Protocol-required Therapies ............................................ 55 
6.1.5 
Other Intervention Procedures ................................................... 55 
6.1.6 
Product Complaints ................................................................... 56 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 56 
6.2 
Dose Modification ...................................................................................... 57 
6.2.1 
Dose Cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 57 
6.2.1.1 
Dose-Exploration ..................................................... 57 
6.2.1.2 
Dose Level Review Team........................................ 57 
6.2.1.3 
Step Dosing ............................................................ 57 
6.2.1.4 
Dose-limiting Toxicities ............................................ 57 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 58 
6.2.2.1 
Amgen Investigational Product:  
Tarlatamab .............................................................. 58 
6.2.2.2 
Amgen Investigational Product:  AMG 404 .............. 61 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 71 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 71 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 71 
6.4.1 
Method of Treatment Assignment .............................................. 71 
6.4.2 
Blinding ..................................................................................... 71 
6.5 
Treatment Compliance .............................................................................. 71 
6.6 
Treatment of Overdose ............................................................................. 71 
6.7 
Prior and Concomitant Treatment ............................................................. 72 
6.7.1 
Prior Treatment ......................................................................... 72 
6.7.2 
Concomitant Treatment ............................................................. 72 
6.8 
Support Care and Potential Risk Management Guidelines for 
Tarlatamab ................................................................................................ 73 
6.8.1 
Cytokine Release Syndrome ..................................................... 73 
6.8.2 
Neurologic Events ..................................................................... 77 
6.8.3 
Pituitary Dysfunction .................................................................. 77 
6.8.4 
Neutropenia ............................................................................... 80 
6.8.5 
Tumor Lysis Syndrome .............................................................. 82 
6.8.6 
Vaccines .................................................................................... 82 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 6 of 173 
CONFIDENTIAL  
 
 
6.8.7 
Management of SARS-CoV-2 Infection and COVID-19 
Disease ..................................................................................... 82 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 85 
7.1 
Discontinuation of Study Treatment........................................................... 85 
7.2 
Continuation on Study Treatment After Radiologic Disease 
Progression ............................................................................................... 86 
7.3 
Subject Discontinuation/Withdrawal from the Study .................................. 86 
7.3.1 
Reasons for Removal from Study .............................................. 87 
7.4 
Lost to Follow-up ....................................................................................... 87 
8. 
Study Assessments and Procedures .................................................................... 88 
8.1 
General Study Periods .............................................................................. 88 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 88 
8.1.2 
Treatment Period ....................................................................... 88 
8.1.3 
Safety Follow-up ........................................................................ 89 
8.1.4 
Long-term Follow-up .................................................................. 90 
8.1.5 
End of Study .............................................................................. 90 
8.2 
General Assessments ............................................................................... 90 
8.2.1 
Informed Consent ...................................................................... 90 
8.2.2 
Demographics ........................................................................... 90 
8.2.3 
Medical History .......................................................................... 91 
8.2.4 
Physical Examination ................................................................ 91 
8.2.5 
Physical Measurements ............................................................ 91 
8.2.6 
Substance Abuse History .......................................................... 91 
8.2.7 
Performance Status ................................................................... 91 
8.3 
Efficacy Assessments ............................................................................... 91 
8.3.1 
Radiologic Imaging Assessment ................................................ 91 
8.4 
Safety Assessments .................................................................................. 93 
8.4.1 
Vital Signs and Pulse Oximetry ................................................. 93 
8.4.2 
Neurological Examination .......................................................... 94 
8.4.3 
Writing Test ............................................................................... 94 
8.4.4 
Mini-Mental Status Examination ................................................ 94 
8.4.5 
Electrocardiograms (ECGs) ....................................................... 94 
8.4.6 
Clinical Laboratory Assessments ............................................... 95 
8.4.7 
Vital Status ................................................................................ 95 
8.4.8 
Other Safety .............................................................................. 95 
8.4.8.1 
Echocardiogram (ECHO)/Multigated 
Acquisition (MUGA) Scan ........................................ 95 
8.4.9 
Adverse Events and Serious Adverse Events ............................ 96 
8.4.9.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 96 
8.4.9.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 97 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 7 of 173 
CONFIDENTIAL  
 
 
8.4.9.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 97 
8.4.9.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 97 
8.4.9.5 
Safety Monitoring Plan ............................................ 98 
8.4.9.6 
Pregnancy and Lactation ......................................... 98 
8.5 
Pharmacokinetic Assessments .................................................................. 99 
9. 
Statistical Considerations .................................................................................... 102 
9.1 
Statistical Hypotheses ............................................................................. 102 
9.2 
Sample Size Determination ..................................................................... 102 
9.3 
Populations for Analysis .......................................................................... 103 
9.3.1 
Covariates ............................................................................... 104 
9.4 
Statistical Analyses ................................................................................. 104 
9.4.1 
Planned Analyses .................................................................... 104 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................. 104 
9.4.1.2 
Primary Analysis ................................................... 107 
9.4.1.3 
Final Analysis ........................................................ 107 
9.4.2 
Methods of Analyses ............................................................... 107 
9.4.2.1 
General Considerations ......................................... 107 
9.4.2.2 
Efficacy Analyses .................................................. 107 
9.4.2.3 
Safety Analyses .................................................... 108 
9.4.2.4 
Other Analyses ...................................................... 109 
9.4.2.5 
Adaptive Design .................................................... 109 
10. 
References ......................................................................................................... 111 
11. 
Appendices ......................................................................................................... 114 
11.1 
Appendix 1.  List of Abbreviations ........................................................... 115 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 120 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 123 
Dose Level Review Meetings (DLRM) ..................................................... 123 
Regulatory and Ethical Considerations .................................................... 124 
Informed Consent Process ...................................................................... 125 
Data Protection/Subject Confidentiality ................................................... 127 
Publication Policy .................................................................................... 128 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 8 of 173 
CONFIDENTIAL  
 
 
Investigator Signatory Obligations ........................................................... 129 
Data Quality Assurance ........................................................................... 129 
Source Documents .................................................................................. 130 
Study and Site Closure............................................................................ 131 
Compensation ......................................................................................... 132 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 133 
Definition of Adverse Event ..................................................................... 133 
Definition of Serious Adverse Event ........................................................ 134 
Recording Adverse Events and Serious Adverse Events ........................ 135 
Evaluating Adverse Events and Serious Adverse Events ........................ 136 
Reporting of Serious Adverse Event ........................................................ 137 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 142 
Definition of Females of Childbearing Potential ....................................... 142 
Collection of Pregnancy Information ........................................................ 143 
Collection of Lactation Information .......................................................... 145 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 148 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 150 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-
required Therapies Due to Potential Hepatotoxicity ................. 150 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 151 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 152 
11.8 
Appendix 8.  Performance Status According to Eastern 
Cooperative Oncology Group (ECOG) .................................................... 154 
11.9 
Appendix 9.  Modified Response Evaluation Criteria in Solid 
Tumors Version 1.1 (Modified RECIST 1.1) ............................................ 155 
11.10 Appendix 10.  Schedule of Activities: ....................................................... 159 
 
List of Tables 
Table 1-1.  Summary of Single Step Dosing Schedule of Tarlatamab to 
Mitigate  Cytokine Release Syndrome (CRS) During Cycle 1 ................. 18 
Table 1-2.  Schedule of Activities:  Tarlatamab Monotherapy ........................................ 19 
Table 2-1.  Key Safety Risk of Tarlatamab .................................................................... 34 
Table 2-2.  Key Safety Risks of AMG 404 ...................................................................... 36 
Table 2-3.  Potential Safety Concerns Based on Drug Class Effects, 
Biological Mechanism of Action, and Nonclinical Studies ........................ 37 
Table 4-1.  Planned Target Doses per Dose Cohort Level ............................................. 40 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 9 of 173 
CONFIDENTIAL  
 
 
Table 4-2.  Guideline for Escalation/De-escalation ........................................................ 43 
Table 6-1.  Investigational Products ............................................................................... 54 
Table 6-2.  AMG 404 Dose Modification and Toxicity Management Guidelines 
for Immune-Related Adverse Events ...................................................... 62 
Table 6-3.  Management of Infusion-Related Reactions With AMG 404 ........................ 69 
Table 6-4.  Grading and Management of Cytokine Release Syndrome.......................... 74 
Table 6-5.  Management of Adverse Events Related to Neurologic Events ................... 77 
Table 6-6.  Monitoring and Management of Pituitary Gland Dysfunction 
(González-Rodríguez and Rodríguez-Abreu, 2016; Brahmer et 
al, 2018) ................................................................................................. 79 
Table 6-7.  Tarlatamab Dose Modification Guidelines for Neutropenia .......................... 81 
Table 6-8.  Infusion Interruptions/Delays/Withholding/Permanent 
Discontinuation and Management of SARS-CoV-2 Infection 
and COVID-19 Disease .......................................................................... 83 
Table 9-1.  Probability of Observing at Least 1 DLT..................................................... 103 
Table 9-2.  Stopping Boundary for Dose Expansion with Posterior Probability 
of 80 and Grade 4 or Higher Treatment-related Adverse 
Event Limit of 20 ................................................................................ 105 
Table 9-3 Operating Characteristics with Batch Size of 
 Subjects ............................ 105 
Table 9-4.  The Criteria for Evaluating the Use of Siltuximab ....................................... 106 
Table 11-1.  Analyte Listing ......................................................................................... 121 
Table 11-2.  DILI Potential Analyte Listing ................................................................... 122 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 151 
Table 11-4.  List of Schedule of Activities Tables ......................................................... 159 
Table 11-5.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only 
(AMG 404 Administered 
 ............................................................ 160 
Table 11-6.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only 
(AMG 404 Administered 
 ............................................................ 163 
Table 11-7.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only 
(AMG 404 Administered 
 .......................................................... 166 
Table 11-8.  Schedule of Activities:  Cycle 2 and Beyond (If AMG 404 was 
Administered on 
 in Cycle 1) ................................................. 168 
Table 11-9.  Schedule of Activities:  Cycle 2 and Beyond (If AMG 404 was 
Administered on 
 in Cycle 1) ...................................................... 170 
 
 
List of Figures 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 10 of 173 
CONFIDENTIAL  
 
 
Figure 1-1.  Study Schemac ........................................................................................... 16 
Figure 4-1.  Part 1 Tarlatamab and AMG 404 Planned Dose Levels .............................. 42 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) ...................................................................... 139 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 146 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 11 of 173 
CONFIDENTIAL  
 
 
1. 
Protocol Summary  
1.1 
Synopsis  
Protocol Title:  A Phase 1b Study Evaluating the Safety and Efficacy of AMG 757 in 
Combination with AMG 404 in Subjects with Small Cell Lung Cancer (SCLC) 
Short Protocol Title:  AMG 757 and AMG 404 in Subjects with Small Cell Lung Cancer 
(SCLC) 
Study Phase:  1b 
Indication:  Small cell lung cancer (SCLC) 
Rationale 
Delta-like protein 3 (DLL3), a non-canonical Notch ligand, is a promising target for the 
development of T-cell directed therapies due to its high expression on the cell surface of 
neuroendocrine tumor cells, and minimal, mainly cytoplasmic localization in normal 
tissues (Owen et al, 2019).  Tarlatamab (International Nonproprietary Name 
[INN]; AMG 757) is a half-life extended (HLE) bi-specific T-cell engager (BiTE®) molecule 
combining the binding specificities for DLL3 and CD3 genetically fused to the N-terminus 
of a single chain immunoglobulin G (IgG) Fc (fragment crystallizable; single chain 
fragment crystallizable [scFc]) region.  Currently, tarlatamab is being evaluated in a 
phase 1 study (Study 20160323) of subjects with small cell lung cancer (SCLC). 
AMG 404 is a fully human antibody that binds human programmed cell death-1 (PD-1) 
with high affinity and blocks the ability of this receptor to interact with its ligands, 
programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2).  
AMG 404 has been evaluated as a monotherapy agent in a phase 1 study 
(Study 20180143) of subjects with advanced or metastatic solid tumors. 
Pembrolizumab (Keytruda) and nivolumab (Opdivo), both antibodies blocking human 
PD-1, were approved by the US FDA under the accelerated approval program for 
treatment of patients with metastatic SCLC who have progression after platinum-based 
chemotherapy and at least 1 other line of therapy (Keytruda USPI, 2020; Opdivo USPI, 
2019), based on relatively low response rates (19 with pembrolizumab and 12 with 
nivolumab; Keytruda USPI, 2020; Opdivo USPI, 2019).  However, both approvals were 
subsequently withdrawn after confirmatory studies did not meet their primary endpoint of 
overall survival (OS) (Merck, 2021; Bristol Myers Squibb, 2020).  These data suggest 
that immune checkpoint inhibition may need to be combined with other therapies in 
second line or later. 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 12 of 173 
CONFIDENTIAL  
 
 
The combination of tarlatamab and anti-PD-1 antibodies increases T-cell mediated 
redirected lysis of tumor cells that express DLL3 in vitro as compared to tarlatamab 
alone.  In addition, upregulation of PD-1/PD-L1 in the tumor microenvironment is a 
mechanism of resistance to BiTE therapy that treatment with anti-PD-1 therapy may 
mitigate (Friberg and Reese, 2017; Köhnke et al, 2015).  These data support testing the 
combination of tarlatamab and AMG 404 in patients with SCLC. 
Objective(s) and Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety, tolerability, 
and recommended phase 2 dose 
of tarlatamab in combination with 
AMG 404 
 
Dose-limiting toxicities (DLTs), 
treatment-emergent and 
treatment-related adverse events, 
changes in vital signs, 
electrocardiograms (ECGs), and 
clinical laboratory tests 
Secondary 
 
To evaluate anti-tumor activity of 
tarlatamab in combination with 
AMG 404 
 
Objective response (OR) per 
modified response evaluation 
criteria in solid tumors (RECIST) 
v1.1, duration of response (DOR), 
disease control rate (DCR), 
progression-free survival (PFS), 
and overall survival (OS).   
 
To characterize the 
pharmacokinetics (PK) of 
tarlatamab in combination with 
AMG 404 
 
PK parameters including, but not 
limited to, maximum serum 
concentration (Cmax), minimum 
serum concentration (Cmin), and 
area under the concentration-time 
curve (AUC) over the dosing 
interval 
 
Overall Design 
This is a phase 1b, multicenter, open-label study evaluating the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of tarlatamab in 
combination with AMG 404 in subjects with SCLC.  The study will consist of dose 
exploration (Part 1) and dose expansion (Part 2). 
   
Part 1 (Dose Exploration)  


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 13 of 173 
CONFIDENTIAL  
 
 
The dose exploration part of the study will estimate the recommended phase 2 dose 
(RP2D) of tarlatamab in combination with AMG 404 using a modified toxicity probability 
interval (mTPI-2) design.  A combination RP2D may be identified based on emerging 
safety, efficacy, and pharmacodynamic data prior to reaching an MTD. 
Part 2 (Dose Expansion) 
Upon completion of Part 1 of the study, enrollment will commence in Part 2 to confirm 
the safety and tolerability of the selected dose and to further evaluate the efficacy of 
tarlatamab in combination with AMG 404. 
Number of Subjects 
Study enrollment ended in 
.  A total of 
 subjects were enrolled in this 
study including 
 subjects in Part 1, and  subjects in Part 2. 
Summary of Subject Eligibility Criteria 
Adult subjects (≥ 18 years of age) with small cell lung cancer (SCLC) are eligible to 
enroll.  Subjects must have histologically or cytologically confirmed SCLC and have 
progressed or recurred following at least 1 platinum-based regimen.  Subjects must have 
measurable disease per modified Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria, have an Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤ 1, and adequate organ function (refer to inclusion criteria 107). 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
Tarlatamab is an Amgen investigational product used in this study.  Tarlatamab will be 
manufactured and packaged by Amgen Inc. and distributed using Amgen clinical study 
drug distribution procedures.  Tarlatamab will be administered as a short-term 
intravenous (IV) infusion (approximately 60 minutes [ 10 minutes] followed by a flush) 
on 
 and 
 in a 
 cycle beginning in cycle 2.  The starting dose of 
tarlatamab will be a target dose of 
 mg with 1-step dosing.  The highest planned target 
dose of tarlatamab will not exceed 
 mg using 
 regimen 
(see Section 4.1 for details on the starting dose).  To reduce the risk of cytokine release 
syndrome (CRS), premedication with dexamethasone  mg IV (or equivalent dose of 
other corticosteroids) will be administered within 1 hour prior to all cycle 1 doses.  
Intravenous hydration (1L normal saline over 4 to 5 hours) will also be administered 
following administration of tarlatamab in cycle 1.  In addition, 1-step-dosing will be 
implemented in cycle 1 with  mg administered on cycle 1 
  Sites are required to 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
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CONFIDENTIAL  
 
 
have tocilizumab or siltuximab (if tocilizumab not available) on site for potential treatment 
of CRS. 
AMG 404 is an Amgen investigational product used in this study.  AMG 404 will be 
manufactured and packaged by Amgen Inc. and distributed using Amgen clinical study 
drug distribution procedures.  AMG 404 will be administered as a short-term IV infusion 
(30 minutes [ 5 minutes]) 
 (± 3 days) at a dose of 
 mg (note if 
AMG 404 is initially administered on cycle 1 
 there will be a 
 interval 
between the 
 mg cycle 1 
 and 
 mg cycle 2-
 dose).  Since treatment 
initiation with tarlatamab may result in CRS, the first dose of AMG 404 will be 
administered on either 
 in cycle 1, and subsequently 
 
 beginning on cycle 2 
 or cycle 2 
 
 
Statistical Considerations 
A total of approximately 
 subjects were anticipated to be enrolled in the study (up to 
 subjects in a dose exploration phase and the remaining subjects enrolled in a dose 
expansion phase).  Up to  planned dose cohorts may be examined during dose 
exploration.  Each cohort will enroll 
 subjects.  Additional subjects can be enrolled if 
more data are needed.  Up to 
 subjects can be enrolled in dose exploration part.  At 
least  DLT- evaluable subjects need to be treated at a selected dose level.  For the 
Dose Exploration phase, the sample sizes are empirically decided and consistent with 
conventional early oncology studies with the objective to estimate the RP2D and to 
evaluate safety and tolerability.  Formal safety interim analyses will be performed for 
every 
 subjects who have had opportunity to have at least 
 of follow up since 
first dose of tarlatamab.  If the sample size in the dose expansion phase of 10 (or 20), 
there is 65 (88) probability of observing at least 1 adverse event with 10 incidence 
rate and the exact 95 confidence interval for 20 objective response (OR) is 3 to 
56 (6 to 44).  Study enrollment ended in 
.  A total of 
 subjects were 
enrolled including 
 subjects in Part 1, and  subjects in Part 2.   
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
No formal statistical hypotheses will be tested. 
 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 15 of 173 
CONFIDENTIAL  
 
 
Sponsor Name: 
 Amgen, Inc. 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
 
Date:  10 November 2023 
Page 16 of 173 
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1.2 
Study Schema  
Figure 1-1.  Study Schemac  
 
C  cycle;
 DLT  dose level toxicity; FIH  first-in-human; IV  intravenous; PD  pharmacodynamics; Ph1  phase 1; PK  pharmacokinetics; 
a The starting dose and associated dosing schedule of tarlatamab will be a target dose of 
 mg with 1-step dosing  
b If the combination is not tolerated (based on target DLT rate > 30), AMG 404 may be administered on cycle 1
  Based upon emerging PK, PD, and safety 
data in the current study as well as the ongoing FIH study (20160323), alternative (intermediate) dose cohort levels,
 
 as part of the de-escalation recommendations may be explored (see Section 4.1 and Figure 4-1 for study 
design details pertaining to footnote b) 
Study Periods: 
 Screening:  up to 
 before enrollment 
 Treatment:  treatment continues until confirmed radiographic progression or disease progression* 
 End of treatment:  should occur as soon as possible (within 
) after the last dose of investigational product 
 Safety follow-up:  approximately 
 after the end of the last dose of tarlatamab and approximately 
 after the last dose of AMG 404 
 Long-term follow-up:  every 3 months ( 2 weeks) up to 1 year from the first dose of tarlatamab 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 only 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
 
Date:  10 November 2023 
Page 17 of 173 
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*Note: Subjects with confirmed disease progression per modified RECIST 1.1 criteria who have clinical benefit in the investigator’s judgment may be 
allowed to continue treatment after approval by the Medical Monitor as per Section 7.2.   
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
 
Date:  10 November 2023 
Page 18 of 173 
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1.3 
Schedule of Activities (SoA)  
Table 1-1.  Summary of Single Step Dosing Schedule of Tarlatamab to Mitigate  
Cytokine Release Syndrome (CRS) During Cycle 1  
Tarlatamab 
Step Dosing 
One-step 
First step dose 
N/A 
Step dose 
(equal to Target 
dose) 
Target dose 
N/A  not applicable 
 
 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
 
Page 19 of 173 
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Table 1-2.  Schedule of Activities:  Tarlatamab Monotherapy  
STUDY PERIOD/ TREATMENT CYCLE 
Every Cyclebb 
Every Other Cycle 
EOTii 
SFU-1ee,hh 
SFU-2ff,hh 
LTFUaa 
WEEKb 
1 
3 
1 
 
 
 
 
DAYb 
HOUR (relative to infusion)d 
Pre 757 
EOI 757 
Pre 757 
EOI 757 
Pre 757 
EOI 757 
 
 
 
 
General/Safety Assessments 
Clinical Evaluatione 
X 
 
X 
 
 
 
X 
X 
X 
 
Vital signs, pulse oxf 
X 
 
X 
 
 
 
X 
X 
X 
 
12-lead ECGg 
Xcc 
 
Xcc 
 
 
 
 
 
 
 
ECHO or MUGA 
 
 
 
 
 
 
 
 
 
 
Adverse event review 
=========================================================➔ 
 
Serious adverse event review 
=========================================================➔ 
Prior/concomitant medication 
=========================================================➔ 
Local Laboratory Assessments 
CBC with differential 
X 
 
X 
 
 
 
X 
X 
X 
 
Coagulation 
X 
 
 
 
 
 
X 
X 
X 
 
Chemistry panelh 
X 
 
X 
 
 
 
X 
X 
X 
 
Lipase and Amylase 
X 
 
 
 
 
 
 
X 
 
 
Urinalysis 
 
 
 
 
X 
 
 
 
 
 
Serum/urine pregnancy Testi 
X 
 
 
 
 
 
 
X 
X 
 
Safety endocrine panelj 
X 
 
 
 
 
 
X 
X 
 
 
CRP  
X 
 
 
 
 
 
X 
X 
 
 
Ferritin 
X 
 
 
 
 
 
X 
X 
 
 
Central and Biomarker Laboratory Tests 
Study Drug Administration 
Tarlatamab IV infusiont 
Hospital stayw 
 
 
 
 
 
 
 
 
 
 
 
MRI Brainx 
 
 
 
 
 
 
 
 
 
 
Radiological imaging and tumor burden 
assessmenty 
 
 
 
 
X 
 
Xz 
Xz 
 
Xdd 
Survival Status and subsequent cancer 
therapyaa 
 
 
 
 
 
 
 
 
 
X 
Page 1 of 1 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
 
Page 20 of 173 
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Abbreviations used:  0  Hour zero; when Tarlatamab is infused; ACTH  adrenocorticotropic hormone; BP  blood pressure; C  cycle; C1
  cycle 1 
 
CBC  complete blood count; CNS  central nervous system; CRP  C-reactive protein; CT  computed tomography;
ECG  electrocardiogram; ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic case report form; 
EOI  end of infusion; EOT  end of treatment; FFPE  formalin-fixed paraffin-embedded; FSH  follicle stimulating hormone; FT4  free thyroxine; 
HBcAb  anti-hepatitis B antibody; HBsAg  hepatitis B antigen; HCV  hepatitis C; HIV  human immunodeficiency virus; HR  heart rate; IGF-1  insulin-like growth 
factor 1; IV  intravenous; LH  luteinizing hormone; MUGA  multigated acquisition; LDH  lactate dehydrogenase; LTFU  long-term follow-up; MRI  magnetic 
resonance imaging;
 PD  progressive disease; PK  pharmacokinetic; Pre  pre-infusion; Q cyc  every cycle; Q2 
Cyc  every 2 cycles; RECIST  response evaluation criteria in solid tumors; RR  respiratory rate; SCR  screening; SFU  safety follow-up; SOI  start of infusion; 
TLS  tumor lysis syndrome; TSH  thyroid stimulating hormone 
a 
All screening procedures should be performed within 
 prior to cycle 1 
 dosing.   
b 
Each visit week and day is relative to 
 of each cycle.  Cycle 1 and 2 visits have a  1-day window from designated time point unless otherwise specified.  
All subsequent visits beginning in cycle 3 will have a  3-day window. 
c 
See Section 6.2.1.3 for more details regarding Step Dosing. 
d 
 
End of infusion (EOI) assessments or procedures are to be completed immediately after infusion of tarlatamab.  EOI indicates the time when the 
investigational product infusion and saline flush is completed.  Assessments after EOI indicate the time relative to EOI.  Investigational product infusions are 
marked in the EOI column. 
 
Assessments are done pre-infusion unless specified.  
 
Laboratory assessments that were done within 24 hours prior to infusion do not need to be repeated (except for cycle 1 
 dosing where laboratory 
assessments that were done within 48 hours prior to infusion do not need to be repeated). 
 
All assessments and procedures should be collected at the exact nominal time point as noted in the Schedule of Assessments.  If unable to perform a 
procedure at the specified nominal time point, collect it as close as possible to the nominal time point and record the actual collection time. 
e 
Clinical evaluation including physical exam, ECOG, weight and neurological exams, writing test, and mini-mental status exams (neurology specialty consultation 
service as clinically indicated).  Mini mental status exams and writing test are required on days 
(if 
 clinical evaluation required per dosing 
regimen),
 (may be performed if clinically indicated on days 
) in cycle 1.  Mini mental status exam and writing test may be 
performed in cycle 2 and beyond at the investigator’s discretion.  Performed at screening only:  demographics, medical history, and height.  Clinical evaluation 
should be completed within 6 hours prior to the first dose of tarlatamab. 
f 
Vital signs (BP, HR, RR, temp) and pulse oximetry will be assessed.  Vitals will be taken pre-AMG 404 infusion and at AMG 404 EOI.  
 
 For each 
tarlatamab-infusion for the first 2 cycles (during the hospitalization period) vital signs should be assessed as detailed in Section 8.4.1. 
g 
ECGs will be collected once and considered safety ECGs.  ECGs should be collected prior to blood draws when assessments are conducted at the same 
nominal time point (pre-infusion timepoints for tarlatamab and AMG 404 may be collected 15 minutes prior to infusion, post-infusion time points for tarlatamab 
may be collected ± 15 minutes of indicated time point).  See Section 8.4.5. 
h 
For cycles 1 and 2 only, please collect LDH, phosphorus, and uric acid along with the chemistry panel for TLS monitoring. 
i 
Serum pregnancy test at screening; serum or urine pregnancy test monthly until 
 from the last investigational product (tarlatamab or AMG 404) dose.  
Additionally, a pregnancy test at 
 after last dose of AMG 404. 
j 
Safety endocrine panels:  ACTH, cortisol, TSH, and FT4 will be evaluated at screening, 
 of every cycle starting with cycle 2, EOT, and SFU-1.  Prolactin, 
FSH, LH, testosterone (in males) and estradiol (in females) will be evaluated only at screening, EOT, and as clinically indicated. 
m 
A tumor biopsy is required at screening if patient has received any treatment prior to participating into this study and biopsy can be performed safely as 
determined by the investigators.  Tumor tissue (archival or fresh biopsy) must be available.  Subjects must consent to allow the acquisition of FFPE material 
(block or unstained slides) by study personnel.   


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
 
Page 21 of 173 
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r 
AMG 404 PK samples to be collected at pre-infusion and end of infusion in cycles 3, 5, 7, 9, and 11 and at pre-infusion in cycles 4, 6, 8, 10, and 12. 
u 
Dexamethasone  mg IV (or equivalent dose of other corticosteroids) will be administered within 1 hour prior to all tarlatamab doses, in week 1 and step doses 
of tarlatamab in cycle 1 only. 
v 
Refer to Section 6.1.4 for administration details. 
w 
x 
All subjects must have MRI/CT of the brain performed within 
 prior to the first dose of tarlatamab.  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. 
y 
 
 
Tumor burden assessments will be performed based on modified RECIST 1.1 guidelines (see Section 11.9). 
 
 
 
z 
 
aa 
LTFU will be conducted every 3 months ( 2 weeks) for 1 year from the first dose of tarlatamab on 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 only.  If the investigator becomes aware of serious 
adverse events suspected to be related to investigational product or any fatal adverse event (regardless of causality) after the protocol-required reporting 
period (as defined in Section 8.4.9.1.3) is complete, then these serious adverse events will be reported to Amgen immediately and no later than 24 hours 
following the investigator’s awareness of the event on the Event eCRF. 
bb 
Assessments to be completed at specified timepoint beginning with cycle 3 and at each subsequent cycle unless otherwise specified. 
cc 
For cycles 3 and 4 only:  please collect ECG post-tarlatamab infusion.  No further ECG’s are collected after cycle 4.   


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
 
Page 22 of 173 
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dd 
For subjects who discontinued treatment for any reason other than confirmed PD, every effort should be made to perform radiographic imaging (CT/MRI) of the 
chest, abdomen, pelvis, and all other known sites of disease every 3 months until documentation of confirmed PD per modified RECIST 1.1, clinical 
progression, start of new anticancer therapy, or up to 12 months after the first dose of tarlatamab, whichever occurs first.   
ee 
The first safety follow-up visit should be completed
from the last dose (tarlatamab or AMG 404). 
ff 
The second safety follow-up visit should be completed
after the last dose of AMG 404 or prior to initiation of other therapy, whichever occurs first. 
hh 
Subjects who discontinue AMG 404 but remain on treatment with AMG 757 will continue to have safety event collection at regularly scheduled study visits.  The 
second safety follow-up visit need only occur if 
 has not elapsed from the end of AMG 404 treatment at the time of end of study treatment. 
ii 
After end of study, serious adverse events suspected to be related to investigational product will be reported to Amgen.  Please refer to 
Section 8.4.9.1.3 for additional details. 
 
 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 23 of 173 
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2. 
Introduction  
2.1 
Study Rationale  
Delta-like protein 3 (DLL3), a non-canonical Notch ligand, is a promising target for the 
development of T-cell directed therapies due to its high expression on the cell surface of 
neuroendocrine tumor cells, and minimal, mainly cytoplasmic localization in normal 
tissues (Owen et al, 2019).  Tarlatamab is a half-life extended (HLE) bi-specific T-cell 
engager (BiTE®) molecule combining the binding specificities for DLL3 and CD3 
genetically fused to the N-terminus of a single chain immunoglobulin G (IgG) Fc 
(fragment crystallizable; single chain fragment crystallizable [scFc]) region.  Currently, 
tarlatamab is being evaluated in a phase 1 study (Study 20160323) of subjects with 
small cell lung cancer (SCLC). 
AMG 404 is a fully human antibody that binds human programmed cell death-1 (PD-1) 
with high affinity and blocks the ability of this receptor to interact with its ligands, 
programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2).  
AMG 404 has been evaluated as a monotherapy agent in a phase 1 study 
(Study 20180143) of subjects with advanced or metastatic solid tumors. 
Pembrolizumab (Keytruda) and nivolumab (Opdivo), both antibodies blocking human 
PD-1, were approved by the US FDA under the accelerated approval program for 
treatment of patients with metastatic SCLC who have progression after platinum-based 
chemotherapy and at least 1 other line of therapy (Keytruda USPI, 2020; Opdivo USPI, 
2019), based on relatively low response rates (19 with pembrolizumab and 12 with 
nivolumab; Keytruda USPI, 2020; Opdivo USPI, 2019).  However, both approvals were 
subsequently withdrawn after confirmatory studies did not meet their primary endpoint of 
overall survival (OS) (Merck, 2021; Bristol Myers Squibb, 2020).  These data suggest 
that immune checkpoint inhibition may need to be combined with other therapies in 
second line or later. 
The combination of tarlatamab and anti-PD-1 antibodies increases T-cell mediated 
redirected lysis of tumor cells that express DLL3 in vitro as compared to tarlatamab 
alone.  In addition, upregulation of PD-1/PD-L1 in the tumor microenvironment is a 
mechanism of resistance to BiTE therapy that treatment with anti-PD-1 therapy may 
mitigate (Friberg and Reese, 2017; Köhnke et al, 2015).  These data support testing the 
combination of tarlatamab and AMG 404 in patients with SCLC. 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 24 of 173 
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2.2 
Background  
2.2.1 
Disease  
Small cell lung cancer (SCLC), accounting for 10 to 15 of lung cancer 
(Rudin et al, 2015), is an aggressive lung cancer subtype with neuroendocrine 
differentiation and strongly associated with smoking (Koinis et al, 2016).  It displays a 
distinct natural history characterized by a high growth fraction, rapid doubling time and 
early establishment of widespread metastatic lesions (Gustafsson et al, 2008).  While 
30 of patients present with disease confined to one hemithorax (limited disease [LD]), 
the majority of cases have disease not encompassed by one radiotherapy field 
(extensive disease [ED]).  Small cell lung cancer is exquisitely sensitive to first-line 
chemotherapy (approximately 60 to 70 response rates) and to radiation which is 
stark contrast to subsequent resistance to second line and subsequent therapies after 
disease recurrence (Byers and Rudin, 2015).  Patients with ED develop drug resistance 
and die as a result of disease at a median time of 10 to 12 months from diagnosis 
(Rudin et al, 2015).  For patients with ED SCLC, first-line treatment is platinum-based 
chemotherapy.  Most patients in the United States receive platinum-etoposide (EP) 
chemotherapy (with either carboplatin or cisplatin), and some patients receive 
platinum-irinotecan as an alternative, especially outside the United States.  In 
March 2019, atezolizumab was approved by the United States Food and Drug 
Administration (US FDA) in combination with carboplatin and etoposide for the first-line 
treatment of adult patients with ED-SCLC (TECENTRIQ United States Prescribing 
Information [USPI], 2019).  In March 2020, durvalumab, in combination with 
standard-of-care chemotherapy, etoposide, and carboplatin or cisplatin, was approved 
by the FDA as a frontline treatment for adult patients with extensive stage SCLC 
(IMFINZI® USPI).  Similar approvals for these molecules have also now been received in 
EU and other geographic regions, although levels of adoption remain variable globally. 
After relapse, topotecan is approved by the US FDA for relapses that occur after 45 days 
from the completion of chemotherapy.  However, despite its indication in this setting, 
topotecan has produced disappointing response rates (Byers and Rudin, 2015).  Based 
on the results of an open-label study of 105 patients with SCLC after failure of first-line 
therapy, lurbinectedin recently received accelerated approval by the US FDA following 
progression on or after platinum-based chemotherapy (Trigo et al, 2020). 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 25 of 173 
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2.2.2 
Amgen Investigational Product Background:  Tarlatamab  
Tarlatamab (International Nonproprietary Name [INN]; AMG 757) is an HLE BiTE® 
antibody construct combining the binding specificities for delta-like ligand 3 (DLL3) and 
CD3 genetically fused to the N-terminus of a single chain IgG Fc (fragment 
crystallizable; scFc) region and is being developed with the intent to treat patients with 
SCLC. 
Refer to the specific section of the Investigator Brochure for additional information 
related to the physical, chemical, and pharmaceutical properties and formulation(s).  A 
detailed description of the chemistry, pharmacology, efficacy, and safety of tarlatamab is 
provided in the Investigator’s Brochure. 
2.2.2.1 
Pharmacology  
The activity of tarlatamab requires the simultaneous binding to both target cells and 
T cells.  The pharmacological effect of tarlatamab is mediated by specific redirection of 
previously primed cytotoxic CD8+ or CD4+ T lymphocytes to kill DLL3+ cells.  
Tarlatamab is a potent molecule showing mean half-maximal lysis of human tumor cell 
lines by human effector cells in vitro over a range of 
 
As part of the T cell activation process, BiTE® antibody constructs, such as tarlatamab, 
cause the formation of a cytolytic synapse between T cells and target cells.  This has 
been exemplified using an epithelial cell adhesion molecule (EpCAM)-specific BiTE® 
antibody construct (Offner et al, 2006). 
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. 
Tarlatamab-mediated T cell activation not only induces the directed release of cytotoxic 
proteins to target cells, but also results in a transient production of inflammatory 
cytokines such as tumor necrosis factor (TNF), interferon gamma (IFN-) and 
interleukin 2 (IL-2) by T cells.  In vitro studies demonstrated that cytokine release by 
tarlatamab-activated T cells is attenuated by corticosteroids, but this can be 
accompanied by a slight reduction in cytotoxic potency 
 
Tarlatamab monotherapy induced regression of established SCLC primary tumors and 
liver metastases in orthotopic mouse models, with evidence for BiTE® target 
engagement and increased T cell infiltration and proliferation in tumors 
 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 26 of 173 
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2.2.2.2 
Toxicology  
The cynomolgus monkey was chosen to evaluate the nonclinical safety of tarlatamab 
because both the CD3 and DLL3 binding moieties of tarlatamab cross-reacted with 
similar high affinities to the analogous human and cynomolgus monkey antigens.  The 
potential toxicity of tarlatamab was evaluated in a Good Laboratory Practice (GLP) 
compliant 
 cynomolgus monkey toxicology studies.  In the 
 
study, tarlatamab was administered once weekly by intravenous (IV) infusion at 
 
 and 
 g/kg.  Tarlatamab-related changes were limited to a minor decrease in 
lymphocyte populations (detected after the second dose only) at 
 µg/kg, a slightly 
increased heart rate (HR) (on 
 but not at 
) at 
 g/kg, and a minimal to 
mild mixed inflammatory cell infiltrate in the pituitary at 
 and 
 g/kg.  There was no 
evidence of tissue injury associated with the infiltrate.  A dose-related increase in 
incidence of anti-drug antibodies (ADAs) was detected.  One animal had vascular 
injury-associated changes in the heart and lung that were consistent with secondary 
effects likely mediated by ADA-related immune complexes (ADA-IC).  It is important to 
note that the production of ADAs in animals is not predictive of a potential for antibody 
formation in humans.  All tarlatamab-related effects exhibited full or partial reversibility 
and all changes were considered not adverse.  In the 
 study, tarlatamab-related 
clinical pathology changes were limited to a minimal decrease in lymphocytes at 
 µg/kg.  In addition, tarlatamab-related changes were observed in the pituitary gland 
at 
 µg/kg, characterized as a minimal to mild mononuclear cell infiltrate composed 
primarily of lymphocytes, with no evidence of tissue injury.  The Highest Non-Severely 
Toxic Dose (HNSTD) was determined to be 
 g/kg in both the 
 
studies based on the absence of any tarlatamab-related adverse findings. 
2.2.2.3 
Background Clinical Experience With Tarlatamab  
As of 29 September 2021 data cut, 
 subjects were enrolled in the tarlatamab first in 
human (FIH) Study 20160323, 120 (96.8) of whom received at least 1 dose of 
tarlatamab.  
 subjects received monotherapy in Part A1 (cohorts 1 to 10, 
cohort 23, and cohort 26 in the dose exploration phase):   subject each was assigned 
 and 
 mg of tarlatamab; 
 subjects were assigned 
 mg; 
 subjects were assigned  mg;
 subjects were assigned 
 mg (i.e.,  mg starting 
cycle 1 
 after an initial step dose of  mg at cycle 1 
 subjects were 
assigned 
 mg; 
subjects were assigned 
 mg; 
 subjects were assigned 
 mg;
 subjects were assigned 
 mg (i.e., 
 mg starting cycle 1 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 27 of 173 
CONFIDENTIAL  
 
 
following two step dose of  mg at cycle 1 
 and 
 mg at cycle 1 
 of 
tarlatamab monotherapy administered IV 
; and  subjects were 
assigned 
 mg of extended IV dosing.  Overall, all subjects (100) in Part A1 had 
treatment-emergent adverse events; the most commonly reported adverse events were 
cytokine release syndrome (CRS) (
 subjects [44.4]); pyrexia (
 subjects 
[33.3]); fatigue (
 subjects [28.4]); constipation (
 subjects [24.7]); nausea 
(
 subjects [25.9]); decrease appetite (
 subjects [23.5]); anaemia and headache 
(
 subjects [17.3]); and dysgeusia (
 subjects [19.8]).  Serious adverse events 
were reported for 
 subjects (49.4), treatment-related adverse events leading to 
withdrawal from tarlatamab were reported for  subjects (3.7), and grade ≥ 3 
treatment-emergent adverse events were reported for 
 subjects (53.1).  
 subject 
(1.2), who received 2 doses of tarlatamab at 
 mg IV 
, had a 
treatment-emergent fatal adverse event of pneumonitis, which was considered to be a 
dose-limiting toxicity (DLT) event. 
Among subjects who received tarlatamab in Part A1 (i.e., cohorts 1 to 10, cohort 23, and 
cohort 26), CRS is the most frequently reported adverse event occurring in 
 subjects 
(44.4) with grade  2 CRS occurring in  subjects (9.9) and grade  3 CRS occurring 
in  subject (1.2).  No grade 4 or higher CRS has been reported at the time of the data 
cutoff date.  Cytokine release syndrome presented mainly as fever, tachycardia, nausea, 
and fatigue  hypotension and was reversible.  In 
 subjects (13.6), CRS was 
reported as a serious adverse event, 1 event of which led to treatment discontinuation.  
Cytokine release syndrome occurred predominantly following the first 2 doses of 
tarlatamab in cycle 1 (CRS typically did not recur in subsequent cycles following cycle 1) 
and was managed with supportive care and corticosteroids. 
As of 29 September 2021, preliminary efficacy data was available for 
 subjects who 
received monotherapy in Part A1.  Overall, a confirmed partial response (PR) was 
observed starting at a dose level of 
 through 
 mg in a total of 
 subjects for an 
overall ORR (95 CI) of 19.5 (11.3, 30.1).  The disease control rate (95 CI) was 
49.4 (37.8, 61.0). 
As of 29 September 2021, data cut, 
 subjects (100.0) receiving monotherapy in 
Part A2 (i.e., cohort 30) had treatment-emergent events.  Grade  3 adverse events 
were reported in  subjects (35.3).  Serious adverse events were reported in 
 subjects (52.9).  No adverse events were fatal or led to discontinuation of tarlatamab.  


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 28 of 173 
CONFIDENTIAL  
 
 
Adverse events by preferred term reported for  20.0 of subjects were CRS 
(
 subjects [76.5]); dysgeusia and pyrexia (each  subjects [47.1]); decreased 
appetite, headache, and vomiting (each  subjects [29.4]); and arthralgia, fatigue, and 
nausea (each  subjects [23.5]). 
Among subjects who received tarlatamab in Part A2, CRS was grade  2 in  subjects 
(11.8); no grade  3 events were reported.  In  subjects (41.2), CRS was reported 
as a serious adverse event.  No CRS (AMQN) adverse events were fatal or led to 
discontinuation of tarlatamab. 
Neutropenia was grade  2 in  subjects (23.5) and grade  3 in  subjects (11.8).  
Neutropenia was reported as a serious adverse event in  subject (5.9).  No 
neutropenia adverse events were fatal or led to discontinuation of tarlatamab. 
As of the data cut-off,  subjects received 
 in 
Part C of the ongoing FIH Study 20160323 with  subjects assigned 
 mg and 
 subjects assigned 
 mg of tarlatamab.  Cohort 16 with 
 mg of tarlatamab 
administered over 1-hour 
 in 
 administered at 
 mg 
 has been deemed safe and tolerable by the dose level 
review team (DLRT).  As of 29 September 2021,  (100) subjects had 
treatment-emergent adverse events,  (37.5) subjects had serious treatment-emergent 
adverse events,  (37.5) subjects had grade  3 treatment-emergent adverse events, 
 (0) subjects had treatment-emergent adverse events that led to treatment 
discontinuation.  The most common adverse events include:  fatigue (  subjects 
[62.5]), nausea (  subjects [37.5]), decreased appetite (  subjects [37.5]), vomiting 
(  subjects [37.5]), constipation (  subjects [25]), contusion (  subjects [25]), 
dyspnea (  subjects [25.0]), headache (  subjects [25]), myalgia (  subjects 
[25.0]), and pyrexia (  subjects [25]).  Cytokine release syndrome was reported in 
 subject (12.5); the event was grade 2, nonserious, and did not lead to 
discontinuation of treatment. 
 subjects received a CRS mitigation strategy in Part D of the ongoing FIH 
Study 20160323 consisting of 
 mg tarlatamab plus dexamethasone.  All 
 subjects (100.0) reported a treatment-emergent adverse event.  Grade  3 adverse 
events were reported for  subjects (57.1).  A fatal adverse event was reported in 
 subject (7.1); the preferred term was small cell lung cancer.  Adverse events by 


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preferred term reported for  20.0 of subjects were CRS (  subjects [64.3]), pyrexia 
(  subjects [50.0]), dysgeusia (  subjects [42.9]), constipation (  subjects [35.7]), 
and fatigue, headache, hypomagnesemia, hypotension, and nausea (each  subjects 
[21.4]).  Reported CRS of grade ≥ 2 was reported in  subjects (28.6).  No grade  3 
CRS adverse events were reported.  Serious CRS was reported in  subjects (28.6).  
Cytokine release syndrome led to discontinuation of tarlatamab in  subject (7.1). 
As of 29 September 2021, with a total of 
 subjects (
 subjects in Study 20160323, 
 subject in Study 2020040, and  subject in Study 20200439) exposed to tarlatamab, 
grade  2 neutropenia was observed in 
 subjects (11.7), and  subjects (4.1) 
experienced grade 4 or higher neutropenia events.  There were no fatal neutropenia 
events.  Serious adverse events of neutropenia were reported for  subjects (1.7).  
tarlatamab was interrupted in  subjects (3.3) due to neutropenia and discontinued in 
 subjects (1.7) (interrupted in  subject prior to discontinuation).  There were no cases 
of febrile neutropenia. 
As of 26 February 2021, preliminary PK data for tarlatamab were available for 
 subjects (
 subjects from monotherapy cohorts and  subjects from the 
 cohorts). 
Within the evaluated target dose range of 
 to 
 mg 
 (with or without one 
step dosing paradigm), the serum tarlatamab exposures increased in an approximate 
dose-proportional manner with mean estimated t1/2 at steady state ranging from 
 
  Approximate steady state in serum tarlatamab exposures was achieved within 
4 weeks of every other week target regimen initiation. 
Refer to the AMG 757 Investigator’s Brochure for additional information. 
2.2.3 
Amgen Investigational Product Background:  AMG 404  
2.2.3.1 
Nonclinical Pharmacology  
AMG 404 is a fully human antibody that binds human and cynomolgus monkey PD-1 
with high affinity and blocks the ability of these receptors to interact with human ligands, 
PD-L1 and PD-L2.  The ligand blocking activity of AMG 404 was evaluated in 3 different 
assays using 3 different readouts and both cell-expressed, as well as recombinant, 
soluble ligands.  In each assay, AMG 404 demonstrated the expected dose-dependent 
activity, indicating it is a potent inhibitor of human and cynomolgus monkey PD-1 
binding. 


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AMG 404 blocks the interaction between cynomolgus monkey PD-1 and human PD-L1 
with a similar half maximal inhibitory concentration (IC50) as human PD-1 and human 
PD-L1, suggesting that cynomolgus monkey is an appropriate species for nonclinical 
safety evaluation. 
AMG 404 is an IgG1 antibody; however, the Fc region has been modified to eliminate 
undesired interactions with Fc gamma receptors.  The absence of Fc-binding to Fc 
gamma receptors was demonstrated in a functional assay where AMG 404 induced little 
to no antibody-dependent cellular cytotoxicity (ADCC) as compared to a positive control 
anti-CD38 antibody.  These results demonstrate that the Fc region of AMG 404 does not 
interact with Fc gamma receptors. 
2.2.3.2 
Toxicology  
The potential for AMG 404 to cause acute release of cytokines from human peripheral 
blood leukocytes (PBL) in the presence of human endothelial cells (HUVECs) was 
evaluated in vitro.  Human PBL were cultured in autologous Platelet Poor Plasma (PPP) 
in the presence of HUVECs with AMG 404 (
 µg/mL) for 24 hours, and 
supernatants from the cultures were subsequently assessed for the presence of 
cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, and TNFα).  Under the 
conditions tested in this assay, AMG 404 did not induce cytokine release above 
background levels. 
AMG 404 was evaluated in a 
 GLP toxicology study in cynomolgus monkeys.  
Doses of 
 or 
 mg/kg were administered by slow IV bolus, and doses of  or 
 mg/kg were administered subcutaneously (SC) (3 animals/sex/group).  Animals 
were dosed once weekly (4 total doses).  There were no AMG 404-related clinical signs 
or effects on body weight, food consumption, respiratory rate (RR), body temperature, 
organ weights, or urinalysis parameters and no AMG 404-related ocular, 
electrocardiographic, neurologic, or macroscopic findings.  AMG 404-related clinical 
pathology changes were limited to mild decreases in lymphocytes for females at all dose 
levels on day 
that were generally similar to control and/or baseline values on 9 and 
throughout the remainder of the study, and mildly increased C-reactive protein in some 
animals.  AMG 404-related microscopic findings included an increased incidence and/or 
severity of mononuclear cell infiltration in the brain (minimal to mild) and/or spinal cord 
(minimal) of animals given 
 mg/kg IV or 
 mg/kg SC and at the administration site 
(minimal to mild) of males given 
 mg/kg SC.  The increased incidence and/or severity 
of mononuclear cell infiltration in the brain and/or spinal cord observed in this study may 


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represent an exacerbation of this background finding in cynomolgus monkeys, while the 
mononuclear cell infiltration at the administration site was considered an expected 
reaction to the administration of an exogenous protein.  In conclusion, administration of 
AMG 404 by once weekly IV bolus or SC injection was well tolerated in cynomolgus 
monkeys at levels of 
 mg/kg IV and 
 mg/kg IV and SC. 
2.2.3.3 
Nonclinical Pharmacokinetics  
The PK of AMG 404 was characterized after single IV bolus injection at 
 and  mg/kg 
and single SC injection at  mg/kg to male cynomolgus monkeys.  Serum concentrations 
of AMG 404 declined in a biphasic manner for the first 168 hours post dose followed by 
a more rapid decrease, most likely because of the formation of anti-AMG 404 antibodies 
which were observed in all animals at 336 hours post dose. 
The toxicokinetics of AMG 404 were characterized in a GLP study after weekly IV 
administration of 
 or 
 mg/kg or SC administration of 
 mg/kg for 4 consecutive 
weeks.  Following repeat dose administration, AMG 404 exposure increased 
approximately dose-proportionally from 
 to 
 mg/kg as measured by maximum 
serum concentration (Cmax) and area under the concentration-time curve (AUC) over 
 days.  AMG 404 exposures were similar between male and female animals. 
2.2.3.4 
Clinical Experience  
As of the 30 April 2021 data cutoff date, preliminary safety data were available for 
 subjects with advanced or metastatic solid tumors who had received at least 1 dose 
of AMG 404 IV 
 in monotherapy Study 20180143.  These subjects 
were dosed at 1 of 3 dose levels:   subjects were dosed at the 
 mg dose level, 
 subjects at the 
 mg dose level, and 
 subjects at the 
 mg 
 dose level 
(the highest dose level studied to date). 
Among the 
subjects treated with at least 1 dose of AMG 404 in Study 20180143, the 
treatment emergent adverse events, any grade, with a subject incidence of at least 10 
by preferred term were:  fatigue (n  
, 33.8), nausea (n  
, 26.9), decreased 
appetite (n  
, 23.1), vomiting (n  
, 16.9), pyrexia (n  
, 16.2), diarrhea 
(n  
, 15.4), constipation (n  
, 14.6), anemia (n 
, 13.8), arthralgia, 
abdominal pain, and rash (n 
, 11.5 each), and aspartate aminotransferase 
increased, hypothyroidism, and dyspnea (n  
, 10.0 each).  Treatment-emergent 
adverse events with a worst grade ≥ 3, with a subject incidence of at least  were:  
anemia (n  
 5.4), sepsis (n  
 3.8), fatigue (n  , 3.1), seizure (n  , 2.3), 


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and abdominal pain, aspartate aminotransferase increased, back pain, decreased 
appetite, disease progression, dyspnea, hyponatremia, postoperative wound infection, 
urinary tract infection, colorectal cancer metastatic, metastases to spine, malignant 
neoplasm of thymus, and pancreatic cancer (n  
 1.5 each).  In  subjects (6.2), 
reported treatment emergent adverse events led to AMG 404 discontinuation and the 
adverse events were:  brain edema, diarrhea, dysarthria, hemorrhage, 
immune-mediated enterocolitis, malignant neoplasm of thymus, porocarcinoma, and 
tumor hemorrhage (n  
 0.8 each).  
subjects reported treatment emergent 
fatal adverse events, of which 
 (11.5) came under the System Organ Class, 
neoplasms benign, malignant, and unspecified (incl cysts and polyps) and the remaining 
4 treatment emergent fatal adverse events were:  disease progression, coronavirus 
disease 2019 (COVID-19), hemorrhage, and (uncoded) recurrent undifferentiated 
hepatic sarcoma (n  
 0.8 each). 
Hypothyroidism, colitis, and myasthenia gravis are identified adverse drug reactions 
(ADRs) to AMG 404.  In Study 20180143, administration of AMG 404 has been 
associated with the reported events of hypothyroidism (
 subjects [10.0], all subjects 
experienced an event grade ≤ 2) or blood thyroid stimulating hormone (TSH) increased 
(  subjects [3.1], 
subject experienced a grade 3 event, 
subjects experienced a 
grade ≤ 2 event).  In total, 
subjects (13.1) experienced an event associated with an 
underactive thyroid.  
 hypothyroidism event was serious.  No event of 
hypothyroidism or blood TSH increased led to AMG 404 discontinuation.  Administration 
of AMG 404 has been associated with noninfectious colitis in  subjects (1.5).  
 
subject experienced the adverse events colitis (grade 2, nonserious), immune-mediated 
enterocolitis (grade 3, serious), and diarrhea (grade 2, nonserious).  The 
 subject 
experienced the adverse event immune-mediated enterocolitis (grade 2, 
nonserious).  Both subjects with noninfectious colitis discontinued AMG 404 due to 
colitis/diarrhea.  Administration of AMG 404 has been associated with the serious 
adverse event myasthenia gravis in  subject.  This was a study subject in a phase 1b/2 
combination study of AMG 404 and AMG 160 (Study 20190505 Subprotocol C).  Both 
study drugs were permanently discontinued because of the event.  As of 30 April 2021, 
study subjects had been exposed to this investigational product combination.  The 
myasthenia gravis event was reported in  subject, between the ages of 60 and 
70 years, with stage 4 prostate cancer. 


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As of 30 April 2021, preliminary efficacy data were available for 
 subjects dosed with 
AMG 404 who had an objective response value recorded.  Among all cohorts, 
 subjects (9.5) had a confirmed partial response, and 
 subjects (43.1) had stable 
disease.  Among cohorts 6, 7, 8, and 9, there were 
 subjects with a response value 
who were dosed with AMG 404 
 mg IV 
.  Of these 
subjects,  subjects 
(13.4) had a confirmed partial response, and 
 subjects (44.8) had stable disease. 
Refer to the AMG 404 Investigator’s Brochure for additional information. 
2.3 
Benefit/Risk Assessment  
2.3.1 
Therapeutic Context  
The combination of tarlatamab and AMG 404 will be investigated in subjects with SCLC. 
2.3.2 
Key Benefits  
Key benefits of the combination of tarlatamab and AMG 404 will be investigated and will 
be described when the data become available.  Potential benefits include reduction or 
regression of SCLC disease burden. 
2.3.3 
Key Safety Information  
2.3.3.1 
Tarlatamab  
Based on experience with tarlatamab in the phase 1 FIH Study 20160323 for the 
indication of SCLC, the key safety information for tarlatamab includes CRS and 
neutropenia as identified risks.  The additional potential safety concerns of neurological 
events, pituitary dysfunction and tumor lysis syndrome (TLS) are summarized in the 
sections below and are based on the biological mechanism of action, experience with 
other BiTE molecules, and on the potential for on target, off-tumor effect. 


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 Table 2-1.  Key Safety Risk of Tarlatamab  
Safety Risk  
Description  
CRS 
CRS is an adverse drug reaction of tarlatamab administration based on 
safety data from tarlatamab phase 1 FIH Study 20160323 for the 
indication SCLC. 
CRS is a systemic inflammatory response characterized by a release of 
cellular cytokines.  CRS is risk of T-cell directed therapies.  CRS is a risk 
associated with therapy with the approved BiTE molecule, blinatumomab 
(anti-CD19 BiTE antibody construct) in patients with ALL and is 
associated also with other BiTE molecules currently in development for 
treatment of solid and hematologic cancers. 
Clinical signs and symptoms of CRS may include the following:  
• 
Constitutional:  fever  rigors, malaise, fatigue, anorexia, myalgias, 
arthralgias, nausea, vomiting, headache 
• 
Neurologic:  headache, mental status changes, confusion, delirium, 
world finding difficulty or frank aphasia, hallucinations, tremor, 
dysmetria, altered gait, seizures  
• 
Respiratory:  dyspnea, tachypnea, hypoxemia 
• 
Skin:  rash 
• 
Gastrointestinal:  nausea, vomiting, diarrhea  
• 
Cardiovascular:  tachycardia, widened pulse pressure, hypotension, 
increased cardiac output (early), potentially diminished cardiac output 
(late)  
• 
Coagulation:  elevated D-dimer, hypofibrinogenemia  bleeding,  
• 
Renal:  azotemia 
• 
Hepatic:  transaminitis, hyperbilirubinemia 
Infusion reactions may be clinically indistinguishable from manifestations 
of CRS.  Specific recommendations for the management of CRS, and 
infusion interruption and stopping rules are found in Table 6-4 
Neutropenia 
Neutropenia has been observed in patients receiving tarlatamab.  The risk 
mitigation plan includes monitoring of laboratory parameters (including, 
but not limited, to white blood cell count and absolute neutrophil count) 
which will be evaluated at baseline and monitored throughout the study.  
Specific recommendations for the management of neutropenia, and 
infusion interruption and stopping rules are found in Table 7. 
ALL  acute lymphoblastic leukemia; BiTE  bi-specific T-cell engager; CD-19  cluster of differentiation 19; 
CRS  cytokine release syndrome; FIH  first-in-human; GLP  Good Laboratory Practices; SCLC  small 
cell lung cancer 
2.3.3.1.1 
Additional Potential Safety Concerns for Tarlatamab  
2.3.3.1.1.1 
Neurological Events  
There exists the risk of neurotoxicity with administration of tarlatamab.  Very low levels of 
DLL3 expression have been detected in the brain.  In addition, a wide range of 
commonly observed neurological symptoms have been associated with the use of the 
approved BiTE molecule, blinatumomab (anti CD19 BiTE antibody construct) in 
patients with acute lymphoblastic leukemia (ALL).  The spectrum of neurologic events 
associated with blinatumomab has not been observed in clinical trials for other BiTE 
molecules, and the neurotoxicity may in part be associated with targeting CD19. 


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Neurological events have been observed with tarlatamab administration in the 
tarlatamab phase 1 FIH Study 20160323 for the indication SCLC.  No neurologic events 
were observed in the tarlatamab 
 GLP toxicology studies in 
cynomolgus monkeys. 
2.3.3.1.1.2 
Pituitary Dysfunction  
There exists the risk of pituitary dysfunction with administration of tarlatamab.  The target 
DLL3 protein is expressed in the pituitary and there were observations of a tarlatamab 
related mixed inflammatory cell infiltrate in the pituitary in the 
 GLP 
cynomolgus monkey toxicology studies. 
2.3.3.1.1.3 
Tumor Lysis Syndrome  
Tumor lysis syndrome, a severe, life-threatening disorder that can occur in highly 
proliferative malignancies or with debulking of extensive tumor burden, is characterized 
by a group of metabolic disorders caused by the massive and abrupt release of cellular 
metabolites into the blood after lysis of the malignant cells (Coiffier et al, 2008).  The 
metabolic complications predispose patients with cancer to various clinical 
complications, including renal failure, seizures, cardiac arrhythmias, and even sudden 
death.  Tumor lysis syndrome occurs primarily during treatment of neoplasms which are 
rapidly proliferating such as aggressive lymphomas and acute leukemias.  It has been 
reported to occur rarely in solid tumors.  With the introduction of more effective 
therapeutic agents, the possible occurrence of TLS in patients with bulky, 
treatment-sensitive solid tumors must be recognized.  Therefore, there is a risk of TLS in 
humans with administration of tarlatamab. 
2.3.3.2 
AMG 404  
AMG 404 has been evaluated as a monotherapy agent in a FIH, phase 1 study 
(Study 20180143) of subjects with advanced or metastatic solid tumors. Based on the 
available clinical data with AMG 404, hypothyroidism, colitis, and myasthenia gravis are 
identified risks of AMG 404. (Table 2-2). 


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Table 2-2.  Key Safety Risks of AMG 404  
Safety Risk 
Description 
Hypothyroidism 
Administration of AMG 404 has been associated with hypothyroidism or 
blood thyroid stimulating hormone increased.  Signs and symptoms that 
may be associated with hypothyroidism include fatigue, increased 
sensitivity to cold, constipation, dry skin, weight gain, hoarseness, muscle 
weakness, myalgia, arthralgia, menstrual disturbance, alopecia, 
bradycardia, hypercholesterolemia, depression, impaired memory, and 
enlarged thyroid gland (goiter).  
Hypothyroidism or blood thyroid stimulating hormone increased reported 
events did not lead to AMG 404 discontinuation or AMG 404 treatment 
interruption.  Subjects should be monitored for laboratory values of thyroid 
stimulating hormone and Free T4, and signs and symptoms of 
hypothyroidism during AMG 404 treatment.  Subjects should continue to 
be monitored after discontinuation of AMG 404 due to the risk of late 
onset hypothyroidism.  Requirements for monitoring and management of 
hypothyroidism are provided in the clinical study protocol.  
Colitis 
Administration of AMG 404 has been associated with colitis. Signs and 
symptoms that may be associated with colitis include diarrhea, abdominal 
pain, abdominal cramping, and blood or mucus in the stool.  
Colitis events have led to AMG 404 discontinuation.  Subjects should be 
monitored for signs and symptoms of colitis during AMG 404 treatment.  
Subjects should continue to be monitored after discontinuation of 
AMG 404 due to the risk of late onset colitis.  Requirements for monitoring 
and management of colitis are provided in the clinical study protocol(s). 
Myasthenia Gravis 
Administration of AMG 404 has been associated with the serious 
myasthenia gravis in 
 subject in a combination study of AMG 404 and 
AMG 160 for prostate cancer. 
Signs and symptoms that may be associated with myasthenia gravis 
include diplopia, ptosis, muscle weakness and fatigability, difficulty with 
speech, swallowing, and/or breathing.  Myasthenia gravis event led to 
permanent discontinuation of the study drugs.  Subjects should be 
monitored for signs and symptoms of myasthenia gravis during AMG 404 
treatment. 
 
2.3.3.2.1 
AMG 404 Potential Safety Concerns  
Additional key safety information (Table 3), which are based on the mechanism of 
action, the nonclinical safety pharmacology and toxicology studies for AMG 404, 
available data from the ongoing clinical study, and class effects of approved 
anti-PD-1/PD-L1 checkpoint inhibitors, but for which a causal association with AMG 404 
has not been established, are summarized below.   
 


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Table 3.  Potential Safety Concerns Based on Drug Class Effects, Biological 
Mechanism of Action, and Nonclinical Studies  
Safety Risk  
Description 
Immune-related toxicities  
Immune-related adverse effects associated with PD-1 blocking agents 
include pneumonitis, hepatitis, endocrinopathies, nephritis and renal 
dysfunction, skin reactions, encephalitis, and other immune-related 
adverse reactions (including the identified risks of hypothyroidism, colitis 
and myasthenia gravis).  
Infusion-related reactions  
Severe and life-threatening infusion-related reactions have been 
observed with other anti-PD-1 therapies and may occur with the 
administration of AMG 404.  Signs and symptoms may include pyrexia, 
chills, rigors, flushing, urticaria, hypotension, dyspnea, wheezing, 
headache, back pain, and abdominal pain.  
Embryofetal toxicity  
Based on its mechanism of action, AMG 404 may cause fetal harm if 
administered during pregnancy. Animal studies published in the 
literatures have demonstrated that inhibition of the PD-1/PD-L1 pathway 
can lead to increased risk of immune-mediated rejection of the 
developing fetus resulting in fetal death. However, the risk to a fetus 
following conception by an AMG 404 exposed male, or the risk to a fetus 
from an AMG 404 exposed male sexual partner of a pregnant woman, is 
uncharacterized.  
PD-1  programmed cell death 1; PD-L1  programmed death ligand 1 
Clinical signs and symptoms of immune-related toxicities and infusion-related reactions, 
along with safety laboratory parameters, will be monitored during the study to ensure 
subjects’ safety.  To mitigate embryofetal toxicity risk, study subject contraception will be 
required, and pregnancy status will be monitored.  Refer to Section 6.2.2.2.1 for specific 
recommendations regarding the mitigation and management of immune-related toxicities 
and infusion-related reactions. 
Refer to the AMG 404 Investigator’s Brochure for further description of key safety 
information. 
2.3.3.3 
Key Risks for Tarlatamab in Combination with AMG 404  
To date, there is limited safety data with BiTE molecules in combination with PD-1 
inhibitors.  However, in a phase 1 study, the combination of the BiTE molecule 
blinatumomab with the PD-1 inhibitor nivolumab was reported to be safe and tolerable in 
a small number of subjects with acute lymphoblastic leukemia (ALL) 
(Webster et al, 2018).  No clinical or preclinical safety information is available for the 
combination of tarlatamab with AMG 404.  In the ongoing tarlatamab FIH study 
(20160323), a
 is being conducted 
(tarlatamab dose level of 
 mg in 
 deemed safe and 
tolerable).  Based on biological mechanism of action and initial clinical safety information 
from the monotherapy study with tarlatamab (20160323), the key safety information and 
additional risks described for monotherapy would also be expected along with the key 


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risks described for AMG 404.  Moreover, with combination treatment, adverse events 
may be more severe and occur at different time points and/or dose levels in comparison 
to monotherapy.  In particular, synergistic activation of T cells is expected and may 
contribute to more severe immune-related toxicities.  Pneumonitis is an immune 
mediated toxicity for the PD-1 inhibitor class of drugs and has been observed in 
tarlatamab.  Refer to Section 6.8 for specific recommendations regarding the mitigation 
and management of CRS and infusion-related reactions.  Key safety risks for the 
combination of tarlatamab and AMG 404 include:  
 
exacerbated CRS and/or infusion reactions  
 
exacerbated pituitary dysfunction  
 
exacerbated neurologic events 
The available data thus far with BiTE® molecules in combination with anti-PD-1 suggests 
that the combination is tolerable.  Additionally, given the overall low incidence of grade 2 
or higher CRS (preferred term, 11, with only 1 G3 CRS reported) with a reported 
incidence of grade 2 or higher CRS following cycle 1 
 administration of 6 
(preferred term) with tarlatamab monotherapy along with the low risk of reported 
infusion-related reactions (preferred term) reported thus far with AMG 404 monotherapy, 
the likelihood of the combination developing intolerable CRS or infusion-related 
reactions appears to be sufficiently low to merit the administration of both investigational 
products initially on cycle 1 
  To further mitigate this risk, a 1-week stagger in 
enrollment of Subject 1 and Subject 2 in each dose cohort will take place to monitor for 
potential first dose effects associated with the combination therapy given on cycle 1 
  If de-escalation is necessary, the study design incorporates the possibility that 
first dose effects, such as CRS, may be exacerbated with the combination on cycle 1 
 by adjusting the dosing schedule to allow for AMG 404 to be administered initially 
on cycle 1
 or cycle 1 
 based on emerging safety data and the 
recommendations of the dose level review meeting (DLRM). 
Initially, subjects will be hospitalized after administration of tarlatamab and AMG 404 to 
monitor for these safety risks (refer to Section 8.1.2).  Clinical signs and symptoms, 
along with safety laboratory parameters, will be monitored during study treatment cycles 
to ensure subjects’ safety.  Refer to the National Comprehensive Cancer Network 
(NCCN) Clinical Practice Guideline 2019 for specific recommendations regarding the 
mitigation and management of immune-related toxicities. 


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3. 
Objectives and Endpoints/Estimands  
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety, tolerability, 
and recommended phase 2 dose 
of tarlatamab in combination with 
AMG 404 
 
Dose-limiting toxicities (DLTs), 
treatment-emergent and 
treatment-related adverse events, 
changes in vital signs, 
electrocardiograms (ECGs), and 
clinical laboratory tests 
Secondary 
 
To evaluate anti-tumor activity of 
tarlatamab in combination with 
AMG 404 
 
Objective response (OR) per 
modified response evaluation 
criteria in solid tumors (RECIST) 
v1.1, duration of response (DOR), 
disease control rate (DCR), 
progression-free survival (PFS), 
and overall survival (OS).   
 
To characterize the 
pharmacokinetics (PK) of 
tarlatamab in combination with 
AMG 404 
 
PK parameters including, but not 
limited to, maximum serum 
concentration (Cmax), minimum 
serum concentration (Cmin), and 
area under the concentration-time 
curve (AUC) over the dosing 
interval 
 
 
  
 
Exploratory 
4. 
Study Design  
4.1 
Overall Design  
This is a phase 1b, multicenter, open-label study evaluating the safety, tolerability, PK, 
pharmacodynamics (PD), and efficacy of tarlatamab in combination with AMG 404 in 
subjects with SCLC.  The study will consist of dose exploration (Part 1) and dose 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 40 of 173 
CONFIDENTIAL  
 
 
expansion (Part 2).  Study enrollment ended in 
.  A total of 
 subjects 
were enrolled including 
 subjects in Part 1, and  subjects in Part 2. 
 
 
. 
Part 1 (Dose Exploration): 
The dose exploration part of the study will estimate the recommended phase 2 dose 
(RP2D) of tarlatamab in combination with AMG 404 using a modified toxicity probability 
interval (mTPI-2) design.  A combination RP2D may be identified based on emerging 
safety, efficacy, and pharmacodynamic data prior to reaching an MTD. 
AMG 404 will be administered (Table 6-1) as a short-term IV infusion (30 minutes) every 
 ( 3 days) (note if AMG 404 is initially administered on cycle 1 
 there will 
be a 
 interval between the cycle 1 
 and cycle 2 
 dose).  AMG 404 will 
be administered at the recommended phase 2 dose of 
 mg throughout the study.  
The starting dose of tarlatamab will be 
 mg with 1-step dosing (  mg on cycle 1 
 
followed by 
 mg on cycle 1 
 mg on cycle 1 
 and 
 mg 
 
thereafter).  Thus far in the ongoing FIH study (Study 20160323), the highest target dose 
deemed safe and tolerable is 
 mg.  Planned dose levels in Study 20160323 are 
shown in Table 4-1.  The highest planned target dose of tarlatamab will not exceed 
 mg in this study using the 
 regimen. 
Table 4-1.  Planned Target Doses per Dose Cohort Level  
Dose Cohort Levels 
Dose (mg) IV 
 
-1 
1 
2 
3 
IV  intravenous 
Footnotes are referenced from first-in-human study (Study 20160323) 
To mitigate the risk of CRS and to potentially optimize the PD activity of tarlatamab, a 
step dosing approach with 1-step dosing will be implemented as part of the dosing 
schedule.  Based on emerging safety data and the recommendations of the DLRM, the 
dosing schedule may be adjusted to allow for AMG 404 to be administered initially on 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
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CONFIDENTIAL  
 
 
cycle 1 
 or cycle 1 
  Depending on which day AMG 404 is administered on 
in cycle 1, beginning in cycle 2, AMG 404 will be administered 
 beginning on 
cycle 2 
 or cycle 2 
 (see Table 11-8 and Table 11-9 for more details).  
Part 1 may include one or more of the following planned dose levels of tarlatamab in 
combination with a fixed dose of AMG 404 (design in Figure 4-1): 
 
Dose Cohort Level 1:  tarlatamab at a target dose of 
 mg administered IV 
 
(with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 
 beginning on cycle 1 
 
 
Dose Cohort Level 2:  tarlatamab at a target dose of 
 mg administered IV 
 
(with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 beginning 
on cycle 1 
 
 
Dose Cohort Level 3:  tarlatamab at a target dose of 
 mg administered IV 
 (with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 
beginning on cycle 1 
 
 
Dose Cohort Level -1:  tarlatamab at a target dose of 
 mg administered IV 
 (with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 (in 
case Dose Cohort Level 1 is not well tolerated) beginning on cycle 1 
 
 
Dose Cohort Level -2:  tarlatamab at a target dose of 
 mg administered IV 
 (with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 (in 
case Dose Cohort Level -1 is not well tolerated) beginning on cycle 1 
 
 
Dose Cohort Level -3:  tarlatamab at a target dose of  mg administered IV 
 
(with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 (in case 
Dose Cohort Level -2 is not well tolerated) beginning on cycle 1 
 


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Figure 4-1.  Part 1 Tarlatamab and AMG 404 Planned Dose Levels  
 
D  de-escalation; E  escalation 
Based upon emerging PK, PD, and safety data in the current study as well as the 
ongoing FIH study (20160323), alternative (intermediate) dose cohort levels, 
 
 
 as part of the de-escalation recommendations per the DLRM may be explored. 
Step Dosing 
Due to its known mechanism of action, subjects are at an increased risk for CRS during 
initiation of tarlatamab treatment.  To mitigate this risk, tarlatamab will be administered 
with 1-step dosing.  One-step dosing involves a first step dose on 
 mg), followed 
by a step dose on 
 (equal to the target dose) and the target dose on 
 then 
 
Dose exploration will begin with 
 subjects treated at Dose Cohort Level 1.  The 
study DLT period is 
  Once all subjects enrolled at a certain Dose Cohort Level 
are DLT evaluable, a DLRT meeting will be convened.  Depending on observed safety 
data, the following may occur:  1) dose de-escalation to the next lowest Dose Cohort 
Level, 2) additional enrollment to the current Dose Cohort Level, or 3) dose escalation to 
the next highest Dose Cohort Level or initiation of enrollment in Part 2.  Re-escalation to 
the next higher Dose Level may be allowed, as appropriate.  If re-escalation occurs, 
alternative (intermediate) dose levels may be explored per the recommendations of the 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
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CONFIDENTIAL  
 
 
DLRM, 
 
 
Dose escalation/de-escalation recommendations will be guided by a mTPI-2 model 
(Guo et al, 2017) with a target toxicity probability of 30, equivalence toxicity interval of 
(25, 33) and probability of overdosing of 95.  Beta (1, 1) is used as a prior 
distribution. 
The detailed information of escalation/de-escalation rules are defined in Table 4-2.  The 
DLT decision starts from the 
 subject. 
Table 4-2.  Guideline for Escalation/De-escalation  
Number of 
Evaluable Subjects 
Number of DLTs 
Decision 
0 
E 
1-2 
D 
3 
DU 
0 
E 
1 
S 
2 
D 
≥ 3 
DU 
0-1 
E 
2-3 
D 
≥ 4 
DU 
0-1 
E 
2-3 
D 
≥ 4 
DU 
0-1 
E 
2 
S 
3-4 
D 
≥ 5 
DU 
≤ 2 
E 
3-4 
D 
≥ 5 
DU 
≤ 2 
E 
3 
S 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
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Number of 
Evaluable Subjects 
Number of DLTs 
Decision 
4-5 
D 
≥ 6 
DU 
D  de-escalate to the next lower dose level; DLT  dose-limiting toxicity; DU  the current dose is 
unacceptably toxic; E  escalate to the next higher dose; S  stay at the current dose 
If late onset adverse events occur during a cohort, the DLRT may adaptively re-consider 
the doses evaluated within a cohort for subsequent dosing and/or possibly trigger a 
de-escalation or withholding of additional doses in subsequent cohorts.  Additionally, if 
dose de-escalation occurs and based on emerging PK, PD and safety data, alternative 
(intermediate) dose levels may be explored per the recommendations of the DLRM, 
 
  The recommended phase 2 dose will be estimated using 
isotonic regression (Ji et al, 2010) and the recommended phase 2 dose will be the dose 
level with the estimated DLT rate closest to 0.30.  In order to consider a certain dose 
level as the recommended phase 2 dose at least  DLT evaluable subjects must be 
enrolled at that dose level. 
Dose exploration phase will end once any of the following events occur: 
 
Highest planned dose level is determined to be safe and tolerable (minimum of 
 evaluable subjects overall). 
 
One of dose levels is determined to be safe and tolerable (minimum of 
 evaluable subjects) and the next higher dose level is determined to be unsafe 
and intolerable.  
 
All planned dose levels (including any intermediate doses or alternate dosing 
schedules) are determined to be unsafe and intolerable. 
To minimize the number of subjects treated at potentially toxic dose levels, the first 
 subjects in each cohort will be enrolled sequentially with a minimum of  days between 
the first dose of these subjects. 
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. 
Part 2 (Dose Expansion): 
Upon completion of Part 1 of the study, enrollment will commence in Part 2 to confirm 
the safety and tolerability of the selected dose and to further evaluate the efficacy of 
tarlatamab in combination with AMG 404.  Formal safety interim analyses will be 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
Page 45 of 173 
CONFIDENTIAL  
 
 
performed for every 
 subjects who have had opportunity to have at least 
 of 
follow-up since first dose of tarlatamab.  The details are provided in Section 9.4.1. 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 9.2. 
4.2 
Patient Input into the Study Design  
Patient input was not obtained for this study. 
4.3 
Justification for Dose  
4.4 
Justification for Investigational Product Dose  
4.4.1.1 
Tarlatamab  
The proposed starting dose and associated dosing schedule for this study is a target 
dose of 
 mg administered with 1-step dosing (  mg on cycle 1 
 followed by 
 mg on cycle 1 
 mg on cycle 1 
 and 
 mg 
 thereafter).  The 
selection of this starting dose and dosing schedule is based on the safety, tolerability, 
and preliminary efficacy data from the ongoing FIH study (20160323). 
As of 29 September 2021, 
 subjects (96.8%) out of 
 enrolled in Study 20160323 
had received at least 1 dose of tarlatamab given as monotherapy in subjects with 
relapsed/refractory SCLC (Study 20160323).  Subjects were enrolled across doses 
ranging from 
 to 
 mg tarlatamab administered IV 
  In cohort 8 with a target 
dose of 
 mg with 1-step dosing (  mg on cycle 1 
 followed by 
 mg on cycle 1 
 mg on cycle 1 
 and 
 mg 
 thereafter), 
 subjects were 
enrolled and received at least 1 dose of tarlatamab.  In these 
 subjects, all subjects 
(100) reported treatment related adverse events of any grade, of which grade 3 or 
higher treatment related adverse events were reported in 
 subjects (70.6) and 
serious adverse events were reported in  subjects (47.1).  Cytokine release syndrome 
of any grade was reported in  subjects (52.9).  No treatment-related adverse events 
leading to discontinuation of tarlatamab were reported in cohort 8.  In cohort 10 with a 
target dose of 
 mg with 1-step dosing (  mg on cycle 1 
 followed by 
 mg on 
cycle 1 
 mg on cycle 1 
 and 
 mg 
 thereafter), 
 subjects were enrolled and received at least 1 dose of tarlatamab.  In these 
 subjects, 
 subjects (100) reported treatment-related adverse events of any grade, 
of which grade 3 or higher treatment related adverse events were reported in  subjects 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439  
Date:  10 November 2023 
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CONFIDENTIAL  
 
 
(46.2) and serious adverse events were reported in  subjects (46.2).  Cytokine 
release syndrome of any grade was reported  subjects (46.2), with grade 2 CRS 
reported in  subject (8).  No grade 3 or higher CRS was reported in cohort 10.  
Treatment-related adverse events leading to withdrawal of tarlatamab were reported in 
 subjects (15) in Cohort 10.  
As a conservative approach, due to the mechanism of action, the starting dose and 
dosing schedule of tarlatamab in combination with AMG 404 will be 2 dose levels below 
the highest target dose deemed safe and tolerable for tarlatamab as determined in the 
ongoing monotherapy FIH study (Study 20160323).  Additionally, the potential doses 
proposed in this study will not exceed a target dose of 
 mg, a dose which has been 
deemed safe and tolerable with a manageable toxicity profile as monotherapy in the 
ongoing FIH study (Study 20160323). 
The selected starting dose and dosing schedule as well as the potential doses that may 
be used of tarlatamab in combination with AMG 404 is expected to show clinical activity 
in subjects with SCLC based on the preliminary evidence of efficacy of tarlatamab when 
administered alone in subjects with SCLC (see Section 2.2.2.3 for additional details). 
4.4.1.2 
AMG 404  
The AMG 404 dose to be used in this study is 
 mg IV 
 which is the RP2D for 
monotherapy in subjects with advanced solid tumors.  This dose was selected based on 
the safety, tolerability, PK, and PD of AMG 404 at dose levels of 
, and 
 mg 
in subjects with advanced solid tumors in Study 20180143.  As of the 14 February 2020 
data cut-off date, AMG 404 was safe and well tolerated across the 
 and 
-mg 
dose range with no dose-related increases in frequency or severity of adverse events in 
subjects and no DLTs.  Preliminary PK results were consistent with those for other 
therapeutic anti-PD-1 monoclonal antibodies.  An approximately dose-proportional 
increase was observed over the dose range of 
 to 
 mg IV 
 preliminary PD 
results at the 
 and 
-mg dose levels were consistent with the expected 
saturation of receptor occupancy (RO) for these doses given the potent inhibition of 
PD-1/PD-L1 interactions in vitro with low nanomolar IC50 values and preliminary 
observed AMG 404 exposures in human subjects.  Taking into consideration the 
cumulative preliminary safety, PK, and PD data, the AMG 404 RP2D for monotherapy is 
 mg IV 
 in subjects with advanced solid tumors. 


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4.5 
End of Study  
An individual subject is considered to have completed the study if he/she has completed 
the last visit shown in the Schedule of Activities.  The total study duration for an 
individual subject is approximately 24 months.  The actual duration for individual 
subjects will vary depending upon tolerability of tarlatamab and AMG 404, evidence of 
clinical and/or radiological disease progression, and willingness to participate in the 
study. 
The end of study date is defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (ie last subject last visit), 
including any additional parts in the study (eg, long-term follow-up, 
 
), as applicable. 
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 the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Age ≥ 18 years. 
103 
Subjects with histologically or cytologically confirmed SCLC who progressed or 
recurred following at least 1 platinum-based regimen  
Note:  In countries where standard of care first line systemic treatment includes 
platinum containing chemotherapy in combination with PD(L)1 inhibitor, it is 
required that patients have failed PD(L)1 inhibitor therapy as part of their first 
systemic treatment or have no access to PD(L)1 inhibitors. 
Note:  If patients progress or relapse within 6 months from receiving platinum 
containing-systemic treatment for limited stage disease, they are eligible for 
study regardless of receiving PD(L)1 containing regimen. 
Note:  Subjects with a diagnosis of combined small cell carcinoma with 
predominant small cells (as determined by the local pathologist) may be 


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considered for inclusion based on investigator discretion and after discussion 
with the medical monitor. 
104 
Subjects with disease measurable by modified Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1  
105 
Subjects with treated brain metastases are eligible provided they meet the 
following criteria: 
106 
Eastern Cooperative Oncology Group (ECOG) 0 to 1 
107 
Adequate organ function per local laboratory, defined as follows:  
 
absolute neutrophil count  1 x 109/L  
 
platelet count  75 x 109/L  
 
hemoglobin  9 g/dL (90 g/L)  
 
Estimated glomerular filtration rate based on Modification of Diet in Renal 
Disease (MDRD) calculation > 45 mL/min/1.73 m2  
 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
 3 x upper limit of normal (ULN) (or  5 x ULN for subjects with liver 
involvement). 
 
total bilirubin (TBL)  1.5 x ULN (or  2 x ULN for subjects with liver 
metastases). 
 
Prothrombin time (PT)/international normalized ratio (INR) and partial 
thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) 
 1.5 x institutional ULN (subjects on stable anticoagulation are permitted) 
108 
Pulmonary function: 
 
No clinically significant pleural effusion. Treatment of pleural effusions to 
meet eligibility is permitted. 
 
Baseline oxygen saturation > 90 on room air 
109 
Cardiac function: 
 
Cardiac ejection fraction ≥ 50,  
 
No evidence of clinically significant pericardial effusion as determined by an 
echocardiogram (ECHO) or multigated acquisition (MUGA). 
 
No clinically significant electrocardiogram (ECG) findings  


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110 
Minimum life expectancy of 12 weeks. 
5.2 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
Other Medical Conditions 
201 
History of other malignancy within the past 2 years, with the following exceptions: 
 
Malignancy treated with curative intent and with no known active disease 
present for ≥ 2 years before enrollment and felt to be at low risk for 
recurrence by the treating physician. 
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
 
Adequately treated cervical carcinoma in situ without evidence of disease. 
 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer. 
 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma 
in situ. 
202 
Major surgery within 28 days of first dose of tarlatamab. 
203 
Untreated (includes new lesions or progression in previously treated lesions) or 
symptomatic brain metastases and leptomeningeal disease. 
204 
Subject who experienced recurrent grade 2 pneumonitis or severe or 
life-threatening immune-mediated adverse events or infusion-related reactions 
including those that lead to permanent discontinuation while on treatment with 
immuno-oncology agents  
205 
Subject with evidence of interstitial lung disease or active, non-infectious 
pneumonitis  
206 
History of any immune-related colitis.  Infectious colitis is allowed if evidence of 
adequate treatment and clinical recovery exists and at least 3 months interval 
observed since diagnosis of colitis. 
207 
History of allergic reactions or acute hypersensitivity reactions to antibody 
therapies. 
208 
Positive/non-negative test for Human Immunodeficiency Virus (HIV). 
209 
Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, 
indwelling Foley catheter, biliary drain, or peritoneal/pericardial catheter). 
 
Note:  a pleural catheter or dedicated central venous access catheters such 
as a Port-a-Cath or Hickman catheter are permitted 
210 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose 
of tarlatamab. 
211 
Presence of fungal, bacterial, viral, or other infection requiring oral or IV 
antimicrobials for management within 7 days of first dose tarlatamab. 


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Note:  Simple UTI and uncomplicated bacterial pharyngitis are permitted if 
responding to active treatment and after consultation with sponsor.  Subjects 
requiring oral antibiotics who have been afebrile > 24 hours, have no 
leukocytosis or have any clinical signs of infection are eligible.  Subjects who 
meet these criteria and who were previously on IV antimicrobials should have 
been off IV antimicrobials for > 48 hours. 
212 
Unresolved toxicity from prior anti-tumor therapy, defined as not having resolved 
to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
grade 1, or to levels dictated in the eligibility criteria with the exception of 
alopecia or toxicities from prior anti-tumor therapy that are considered irreversible 
(defined as having been present and stable for > 21 day) which may be allowed if 
they are not otherwise described in the exclusion criteria AND there is agreement 
to allow by both the investigator and Amgen  
213 
History of hypophysitis or pituitary dysfunction 
214 
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). 
 
Negative HBsAg and positive for hepatitis B core antibody:  
hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary.  
Detectable hepatitis B virus DNA suggests occult hepatitis B. 
 
Positive Hepatitis C virus antibody (HCVAb):  hepatitis C virus RNA by PCR 
is necessary.  Detectable hepatitis C virus RNA suggests chronic hepatitis C. 
215 
History of arterial thrombosis (eg, stroke or transient ischemic attack) within 
12 months of first dose of tarlatamab. 
216 
Myocardial infarction and/or symptomatic congestive heart failure (New York 
Heart Association > class II) unstable angina, or cardiac arrhythmia requiring 
medication within 12 months of first dose of tarlatamab. 
217 
Active autoimmune disease that has required systemic treatment (except 
replacement therapy) within the past 2 years or any other diseases requiring 
immunosuppressive therapy while on study.  Subjects with Type I diabetes, 
vitiligo, psoriasis, hypo- or hyper-thyroid disease not requiring 
immunosuppressive treatment are permitted. 
Prior/Concomitant Therapy 
218 
Prior anti-cancer therapy, including anti-PD-1 or anti-PD(L)1 antibody therapy:  at 
least 28 days must have elapsed between any prior anti- cancer therapy and the 
first planned dose of tarlatamab 
233 
Subjects who have received prior tarlatamab therapy or prior DLL3 x CD3 
bispecific therapy are not eligible. 


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219 
History of solid organ transplantation. 
220 
Live vaccine therapy within 4 weeks prior to study drug administration. 
Prior/Concurrent Clinical Study Experience 
221 
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 
222 
Subject has known sensitivity to any of the products or components 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. 
225 
Female subjects of childbearing potential unwilling to use protocol specified 
method of contraception (see Section 11.5) during treatment and for an 
additional: 
 
 following the last dose of tarlatamab 
 
 following the last dose of AMG 404 
226 
Female subjects who are breastfeeding or who plan to breastfeed while on study 
through: 
 
 following the last dose of tarlatamab 
 
 following the last dose of AMG 404 
227 
Female subjects planning to become pregnant while on study through  
 
 following the last dose of tarlatamab 
 
 following the last dose of AMG 404 
228 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at Screening by a highly sensitive serum pregnancy test. 
229 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use 
contraception during treatment and for an additional: 
 
 following the last dose of tarlatamab 
 
 following the last dose of AMG 404  
230 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional: 
 
 following the last dose of tarlatamab 
 
 following the last dose of AMG 404  


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231 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional: 
 
 following the last dose of tarlatamab 
 
 following the last dose of AMG 404 
232 
Evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection.  If history of SARS-CoV-2: 
 
Acute symptoms of COVID-19 within 
 prior to first dose of 
investigational product (counted from day of positive test for asymptomatic 
subjects). 
5.3 
Subject Enrollment  
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or the subject’s legally acceptable representative 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 Subject 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. 
Sites that do not enroll subjects within 6 months of site initiation may be closed. 
5.4 
Screen Failures  
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 


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Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened. 
6. 
Study Intervention  
Study intervention is defined as any investigational product(s), non-investigational 
product(s), placebo, combination product(s), 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. 
A summary of the dosing and administration of each treatment is shown in Table 6-1 
below. 
6.1 
Study Interventions Administered  
6.1.1 
Investigational Products  
 


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Table 6-1.  Investigational Products  
Study Treatment Name 
Amgen Investigational Product:a 
Tarlatamab 
Amgen Investigational Product:a 
AMG 404 
Dosage Formulation 
Tarlatamab is supplied as a sterile, single use, preservative free 
lyophilized drug product containing 
 mg of tarlatamab 
per vial.  Tarlatamab is intended for reconstitution with sterile water 
for injection and dilution in an intravenous (IV) bag with normal 
saline (
 sodium chloride) and an IV solution stabilizer.  The 
drug product is formulated with 
 mM L-glutamic acid,  (w/v) 
sucrose,
 (w/v) polysorbate 80, at a final pH of 
. 
AMG 404 is supplied in a 3 mL Type 1 glass 
tubing vial containing 1 mL deliverable volume of 
 mg/mL.  The drug product is formulated with 
 mM acetate (sodium counterion), 
 (w/v) 
sucrose, 
 (w/v) polysorbate 80, pH 
and 
will be prepared for IV administration by dilution. 
Unit Dose Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
The starting dose and dosing schedule of tarlatamab will be 
 mg 
as the target dose with 1-step dosing.  Tarlatamab will be 
administered 
 after the target dose is reached.  If the 
combination of tarlatamab and AMG 404 is not tolerated (based on 
target DLT rate > 30), tarlatamab dose level will be further dose 
reduced or the day of administration of AMG 404 in combination 
with tarlatamab will be adjusted. 
 mg 
 
Route of Administration 
IV 
IV 
Accountability 
The total volume of preparation, dose, start date/time, stop 
date/time, and lot number are to be recorded on each subject's 
CRF(s). 
The total volume of preparation, dose, start 
date/time, stop date/time, and lot number are to 
be recorded on each subject's CRF(s). 
Dosing Instructions 
Tarlatamab will be administered as a short-term IV infusion for 
60 minutes ( 10 minutes) followed by a flush 
 
(except in cycle 1 where 1-step-dosing will be implemented).   
 
 
AMG 404 will be delivered using infusion pumps 
approved for use by the appropriate regulatory 
authority for the country in which the subject is 
undergoing treatment.  
AMG 404 solution for infusion will be prepared in 
bags for IV infusion and delivered through 
infusion lines.    
The drug will be administered as a short-term IV 
infusion at a constant flow rate over 30 minutes 
( 5 minutes) every 
 (± 3 days).   
CRF  case report form; DLT  dose limiting toxicity; IV  intravenous;
a Tarlatamab and AMG 404 will be manufactured and packaged by Amgen Inc. and distributed using Amgen clinical study drug distribution procedures. 


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6.1.2 
Non-investigational Products  
No non-investigational products will be administered in this study. 
6.1.3 
Medical Devices  
No medical devices will be used in this study. 
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, dexamethasone and tocilizumab 
(siltuximab may be used if tocilizumab is not available), 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. 
Dexamethasone  mg IV (or equivalent dose of other corticosteroids) will be 
administered within 1 hour prior to all cycle 1 doses of tarlatamab including all step 
doses.  Dexamethasone dose and schedule may be changed based on emerging safety 
data.  
Additionally, prophylaxis with IV hydration (1L normal saline over 4 to 5 hours) will be 
administered: 
 
immediately following all tarlatamab doses in cycle 1 
Additionally, based upon emerging PK, PD, and safety data in the current study as well 
as the ongoing FIH study (20160323), the premedication regimen may be modified 
(including with additional prophylactic therapies) as per the recommendations of the 
DLRT. 
To mitigate the risk of CRS, sites are required to have tocilizumab or siltuximab (if 
tocilizumab is not available) on site. 
6.1.5 
Other Intervention Procedures  
There are no other treatment procedures in this study. 


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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 all components distributed with the drug, such as packaging drug 
containers, delivery systems, labeling, and inserts. 
This includes any investigational/non-investigational product(s), device(s) or combination 
product(s) provisioned and/or repackaged/modified by Amgen (i.e., tarlatamab and 
AMG 404) for which Amgen wants to collect complaints. 
Any product complaint(s) associated with an investigational product supplied by Amgen 
are to be reported. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period  
The following treatments and/or procedures are excluded within the timeframes specified 
during the study: 
 
Other investigational agents 
 
Concurrent experimental or approved anti-tumor therapies other than study drugs 
 
Radiation therapy 
Exception:  radiation therapy for symptom control (eg, bone metastasis) or brain may be 
allowed after discussion with the Medical Monitor.  The radiation therapy should not 
include the thoracic field and must have been completed at least 
 before the 
subsequent dose of tarlatamab. 
 
Immunosuppressive agents with the exception of those required by protocol, 
treatment for adverse events, CNS metastases, corticosteroid replacement therapy 
or unless agreed upon by the Principal Investigator and Medical Monitor. 
 
Any live vaccine therapies.  Examples of live vaccines include, but are not limited to, 
the following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, bacille 
Calmette-Guerin (BCG), and typhoid (oral) vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed.  However, intranasal 
influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed. 
 
Subjects must not schedule any major elective surgery during the treatment period 
and for at least 
 days after the last administration of study drugs.  If a subject 
undergoes any unexpected surgery during the course of the study, all study 
treatments must be withheld, and the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.  A subject may be allowed to resume 
study drugs if both the investigator and sponsor’s medical monitor agree to restart 
study therapy. 


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6.2 
Dose Modification  
6.2.1 
Dose Cohort Study Escalation/De-escalation and Stopping Rules  
6.2.1.1 
Dose-Exploration  
The dose-exploration part of the study will estimate the recommended phase 2 dose of 
tarlatamab in combination with AMG 404 using an mTPI2 design.  The starting dose and 
dosing schedule of tarlatamab will be 
 mg as the target dose with 1-step dosing.  The 
planned dose levels are shown in Table 4-1. 
6.2.1.2 
Dose Level Review Team  
For the dose exploration phase, a DLRT will convene to review the safety data before 
recommendations to dose escalate.  The required DLRT voting members include the 
Medical Monitor, Global Safety Officer (GSO), and Site Investigator or designee.  The 
DLRT members are responsible for dosing recommendations, which may include 
implementing step dosing, escalation to the next dose, de-escalation to a lower dose, 
exploring intermediate dose levels; continuation, delay, or termination of dosing; or 
repetition or expansion of a cohort; or determination of recommended phase 2 dose.  
The DLRT will not make dose escalation recommendations until at least 3 subjects 
enrolled at the dose level are deemed DLT-evaluable.  Cumulative adverse events 
profile will be taken into consideration when making recommendations on dose 
escalation or de-escalation.  See Section 11.3 for more details regarding the DLRT. 
Dose Cohort Stopping Rules 
For details on dose escalation and stopping rules, refer to Section 4.1. 
6.2.1.3 
Step Dosing  
Due to its known mechanism of action, subjects are at an increased risk for CRS during 
initiation of tarlatamab treatment.  To mitigate this risk, tarlatamab will be administered 
with the following dosing schedule:  
 
One-step dosing involving a first step dose on 
 mg), followed by a step dose 
on 
 (equal to the target dose) and the target dose on 
 then 
 
6.2.1.4 
Dose-limiting Toxicities  
Dose-limiting toxicities are defined as any adverse event with an onset within first 
 following first dose of tarlatamab with any of the following criteria unless clearly 
related to causes other than tarlatamab: 
 
All grade 3 adverse events except 


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 
Fatigue lasting less than 7 days 
 
Grade 3 non-febrile neutropenia that improves to  grade 1 within 3 weeks 
including the use of growth factor support per neutropenia management 
guidelines (see Section 6.8.4) 
 
Endocrinopathies, if manageable with replacement therapy 
 
Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate 
antiemetic and other supportive care 
 
Grade 3 amylase or lipase values that are not associated with symptoms or 
clinical manifestations of pancreatitis 
 
Grade 3 hematologic lab abnormalities that are not considered clinically 
relevant 
 
Grade 3 electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions 
 
Grade 4 adverse event regardless of duration, except: 
 
Grade 4 non febrile neutropenia lasting less than or equal to 7 days including 
the use of growth factor support per neutropenia management guidelines (see 
Section 6.8.4) 
 
Grade 4 electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions 
 
Grade 4 amylase or lipase values that are not associated with symptoms or 
clinical manifestations of pancreatitis 
 
Grade 4 hematologic lab abnormalities that are considered not clinically 
relevant 
 
Grade 5 adverse events 
 
Recurrent grade 2 or higher pneumonitis 
 
Without exception, any other toxicity requiring permanent discontinuation of 
AMG 404 per Table 6-2.   
The following adverse events will NOT be adjudicated as DLT regardless of the grade or 
duration: 
 
Lymphopenia 
 
Fever 
 
Tumor lysis syndrome including associated manifestations attributable to TLS (eg, 
electrolyte abnormalities, renal dysfunction, hyperuricemia) 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
6.2.2.1 
Amgen Investigational Product:  Tarlatamab  
The reason for dose change of tarlatamab is to be recorded on each subject’s CRFs. 


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6.2.2.1.1 
Dosage Adjustment  
Subjects should continue on the same target dose of tarlatamab (not including the initial 
first step dose and step doses) throughout the study with the exception of subjects who 
experienced a DLT or other intolerable tarlatamab-related adverse events but show 
evidence of clinical benefit.  These subjects will have the option to reduce the dose to 
the immediate next lower dose level shown to be safe and tolerable in the dose 
exploration part of the study (Section 4.1).  The study drug can be resumed once the 
adverse events recover to grade  1, and the reintroduction of tarlatamab is deemed 
safe and tolerable by the investigator, Medical Monitor, and GSO.  The subject must be 
informed of the risk of continuing on therapy.  Each subject is allowed one dose 
reduction.  For adverse events related to CRS, neurological events, and pituitary 
dysfunction, please see Sections 6.8.1, 6.8.2, and 6.8.3, respectively, for guidelines for 
dose adjustments. 
If restarting tarlatamab due to adverse events, dose reductions would occur with 
tarlatamab (as described in Section 6.8).  The study drug can be resumed once the 
adverse events recover to grade 0 to 1 and the reintroduction of tarlatamab is deemed 
safe by the investigator, Medical Monitor, and GSO. 
6.2.2.1.2 
Dose Delays  
During the first 
 DLT observation period, if the dosing of tarlatamab is delayed for 
more than 72 hours for reasons other than DLT during the DLT evaluation period, a 
replacement subject may be enrolled and assigned to the same dose level.  The subject 
may continue on study only after discussion with the Medical Monitor. 
After the 
 DLT observation period, if the dosing of tarlatamab is delayed for 
 2 weeks, the subject should resume the treatment as soon as possible if deemed safe 
by the investigator.  If the dosing of tarlatamab is delayed between 2 to 4 weeks due to 
severe or life-threatening treatment-related adverse events, the subject can resume 
treatment if the toxicities resolve to grade  1 or return to subjects’ baseline values within 
3 weeks and restarting of therapy has been deemed safe by the investigator and 
medical monitor. 
If the dosing of tarlatamab is delayed for more than 4 weeks due to severe or 
life-threatening treatment-related adverse events, the subject will be discontinued from 
investigational product.  If the dosing delay occurred under other conditions, the case will 
be reviewed by the sponsor to determine whether and when the subject will be allowed 
to resume tarlatamab. 


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For adverse events related to CRS, neurological events, and pituitary dysfunction, 
please see Sections 6.8.1, 6.8.2, and 6.8.3 respectively for guidelines for dose delays.  
6.2.2.1.3 
Rules for Withholding or Restarting  
Tarlatamab should be withheld for any of the following: 
 
DLT 
 
Symptomatic hypophysitis (See Section 6.8.3) 
 
Criteria for conditional withholding of tarlatamab due to potential hepatotoxicity 
(Section 11.7) 
Tarlatamab dosing can be resumed if the toxicities resolve to grade  1 or return to 
subjects’ baseline values within 3 weeks.  The restarting of therapy should be deemed 
safe by the investigator and medical monitor.  
Subjects should not be restarted with tarlatamab if the following treatment-related 
adverse events occur: 
 
Criteria for permanent withholding of tarlatamab due to potential hepatotoxicity 
(Section 11.7) 
 
Any grade  4 adverse events except those not considered DLT as described in 
Section 6.2.1.4 
 
Grade 3 adverse event(s) that do not recover to grade  1 within 3 weeks 
 
Any grade 3 adverse events that recur (with the exception of grade 3 laboratory 
parameters not considered clinically relevant or recurrent non-febrile grade 3 
neutropenia which resolves with supportive care to grade  1 or returns to 
subjects’ baseline values within 3 weeks) 
For adverse events related to CRS, neurological events and pituitary dysfunction, please 
see Sections 6.8.1, 6.8.2, and 6.8.3 respectively for guidelines for dose adjustment. 
6.2.2.1.4 
Criteria to Pause Enrollment  
At any point during the study, enrollment will be paused at the occurrence of 2 or more 
of the same grade 4 or one or more grade 5 investigational product-related adverse 
events.  The DLRT will be reconvened to review the safety data and determine 
appropriate next step that may include but not limited to implementing safety/toxicity 
management, informing health authorities, voluntarily putting the clinical trial on hold, or 
proceeding with enrollment.  (Note: following occurrence of an enrollment pause and 
DLRT review, a subsequent enrollment pause will occur at the occurrence of 2 or more 
new grade 4 or 1 more grade 5 investigational product-related adverse events; 
additionally, if a pause and a DLRT has already occurred and the appropriate 


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safety/toxicity management for grade 4 adverse events have already been implemented 
a subsequent enrollment pause may not occur.) 
6.2.2.2 
Amgen Investigational Product:  AMG 404  
6.2.2.2.1 
Immune-related Adverse Reactions  
Adverse events following the administration of AMG 404 may represent an immunologic 
etiology.  Based on clinical experience with other anti-PD-L1 therapies, these 
immune-related toxicities may occur shortly after the first dose to several months after 
the last dose of treatment and may affect more than 1 body system simultaneously.  
Early recognition and management are critical to reduce complications. 
Most immune-related adverse events require adequate evaluation to confirm etiology or 
exclude other causes.  Additional procedures or tests, such as bronchoscopy, 
endoscopy, or skin biopsy, may be included as part of the evaluation. 
Based on the type and severity of the immune-related adverse event, withholding or 
permanent discontinuation of AMG 404 may be required, in addition to treatment with 
corticosteroids and/or other therapies.  Dose modification and toxicity management 
guidelines for immune-related adverse reactions are provided in Table 6-2. 
6.2.2.2.2 
Infusion-related Reactions  
Infusion-related reactions may occur with the administration of AMG 404.  Subjects 
should be monitored for signs and symptoms of infusion-related reactions, including 
pyrexia, chills, rigors, flushing, urticaria, hypotension, dyspnea, wheezing, headache, 
back pain, and abdominal pain.  If an infusion-related reaction is suspected, perform a 
physical examination, monitor vital signs, monitor pulse oximetry, and perform and ECG 
if the patient is experiencing chest pain or sustained tachycardia. 
For mild or moderate infusion-related reactions, interrupt or slow the rate of infusion.  For 
severe or life-threatening infusion-related reactions, permanently discontinue AMG 404.  
Treatment guidelines for infusion reactions associated with the administration of 
AMG 404 are provided in Table 6-3.


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Table 6-2.  AMG 404 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events  
Immune-Related 
Adverse 
Reactions 
Severity or Specific Conditions 
AMG 404 Dose 
Modification 
Management with 
Corticosteroids and/or Other 
Therapies 
Monitor & Follow-up 
Pneumonitis 
Grade 2 (symptomatic; medical intervention indicated; 
limiting instrumental ADL) 
Withhold 
Administer corticosteroids at 
an initial dose of 1 to 
 mg/kg/d prednisone (or 
equivalent) followed by taper.  
Consider additional 
immunosuppressive agent 
(eg, infliximab, 
mycophenolate, 
cyclophosphamide) if 
refractory to corticosteroids. 
Monitor subjects for signs and 
symptoms of pneumonitis.  
Evaluate subjects with 
suspected pneumonitis with 
radiographic imaging.  Add 
prophylactic antibiotics for 
opportunistic infections. 
Recurrent grade 2 
Permanently 
discontinue 
Grade 3 (severe symptoms, limiting self-care ADL, 
oxygen indicated) 
Grade 4 (life-threatening respiratory compromise, 
urgent intervention indicated [eg, tracheotomy or 
intubation]) 
Colitis/Diarrhea 
Grade 2 (increase of 4 to 6 stools per day over 
baseline; moderate increase in ostomy output 
compared to baseline) 
Withhold 
Administer corticosteroids at 
an initial dose of 1 to 
 mg/kg/d prednisone (or 
equivalent) followed by taper.  
Consider infliximab if 
symptoms refractory to 
corticosteroids within 2 to 
3 days. 
Monitor subjects for signs and 
symptoms of enterocolitis (eg, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(eg, peritoneal signs and ileus).  
For subjects with grade  2 
diarrhea suspecting colitis, 
consider GI consultation and 
endoscopy to rule out colitis. 
Grade 3 (increase of 7 or more stools per day over 
baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared with 
baseline; limiting self-care ADL) 
Grade 4 (life-threatening consequences; urgent 
intervention indicated) 
Permanently 
discontinue 
Page 1 of 6 
Footnotes defined on last page of this table


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Table 6-2.  AMG 404 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Immune-Related 
Adverse 
Reactions 
Severity or Specific Conditions 
AMG 404 
Dose 
Modification 
Management with Corticosteroids and/or Other 
Therapies 
Monitor & Follow-up 
Hepatotoxicity 
When applicable, refer to Section 11.7 for managing AST and/or ALT and/or total bilirubin elevations, when other liver parameters remain 
within normal limits (eg, INR). 
Immune-mediated 
hepatitisa 
(Adapted from 
NCCN Guidelines) 
Grade 1 (AST or ALT  ULN but  3 x ULN) without 
elevated total bilirubin 
Continue 
Consider holding for concerning lab value trend. 
Monitor with liver 
function tests more 
frequently until 
returned to baseline 
or stable.  Additional 
management per 
institutional and 
professional society 
guidelines. 
Grade 2 (AST or ALT 3 to 5 x ULN) without elevated 
total bilirubin 
Withhold 
Consider corticosteroids at an initial dose of 
 to  mg/kg/d prednisone (or equivalent) 
followed by taper. 
Grade 3 (AST or ALT 5 to 20 x ULN) without 
elevated total bilirubin 
(Without a clear alternative etiology.  If a clear 
alternative etiology, then withhold, do not 
discontinue AMG 404.) 
Permanently 
discontinue 
Administer corticosteroids at an initial dose of 
 to  mg/kg/d prednisone (or equivalent) 
followed by taper.  Consider mycophenolate 
mofetil if refractory to corticosteroids or no 
improvement after 3 days. 
Grade 4 (AST or ALT  20 x ULN) without elevated 
total bilirubin 
(Without a clear alternative etiology.  If a clear 
alternative etiology, then withhold, do not 
discontinue AMG 404.) 
Administer corticosteroids at an initial dose of 
 mg/kg/d prednisone (or equivalent) followed 
by taper.  Consider mycophenolate mofetil if 
refractory to corticosteroids or no improvement 
after 3 days. 
Grade  1 (AST or ALT  3 x ULN) with total bilirubin 
 1.5 x ULN 
[Without a clear alternative etiology.  If a clear 
alternative etiology, then withhold, do not 
discontinue.  Consider holding for concerning lab 
value trend.] 
Administer corticosteroids at an initial dose of 
 mg/kg/d prednisone (or equivalent) followed 
by taper.  Consider mycophenolate mofetil if 
refractory to corticosteroids or no improvement 
after 3 days. 
Page 2 of 6 
Footnotes defined on last page of this table


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Table 6-2.  AMG 404 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Immune-Related 
Adverse Reactions 
Severity or Specific Conditions 
AMG 404 Dose 
Modification 
Management with Corticosteroids and/or Other 
Therapies 
Monitor & Follow-up 
Hypophysitis 
(Event reported as 
Endocrine 
disorders, Other, 
Hypophysitis) 
Grade 3 or 4 (Severe or 
medically significant but not 
immediately life-threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
limiting self-care ADL, or;  
Life-threatening consequences; 
urgent intervention indicated) 
Withhold 
Administer corticosteroids at an initial dose of 
 mg/kg/d prednisone (or equivalent) followed 
by taper.  In addition, initiate hormonal 
replacement therapy as clinically indicated. 
Monitor for signs and symptoms of 
hypophysitis.  Consider endocrine 
consultation. 
Adrenal 
Insufficiency 
Grade 3 or 4 (severe symptoms, 
hospitalization indicated or 
life-threatening consequences, 
urgent intervention indicated) 
Withhold 
Initiate IV stress-dose corticosteroids on 
presentation (hydrocortisone 
 mg or 
dexamethasone 
mg [if the diagnosis is not 
clear and ACTH stimulation testing will be 
needed]).  Taper stress-dose corticosteroids 
down to maintenance doses (prednisone 5 to 
 mg daily) over 1 to 2 weeks after discharge.  
Monitor for signs and symptoms of 
adrenal insufficiency.  Consider 
endocrine consultation. 
Hypothyroidism  
Grade 3 or 4 (severe symptoms, 
limiting self-care ADL; 
hospitalization indicated or 
life-threatening consequences, 
urgent intervention indicated) 
Withhold 
Initiate thyroid hormone supplementation. 
Monitor subjects for signs and 
symptoms of hypothyroidism.  
Consider endocrine consultation. 
Hyperthyroidism 
Grade 3 or 4 (severe symptoms, 
limiting self-care ADL; 
hospitalization indicated or 
life-threatening consequences, 
urgent intervention indicated)  
Withhold 
Initiate -Blocker (eg, atenolol, propranolol) for 
symptomatic relief.  For severe symptoms or 
concern for thyroid storm, initiate prednisone 
 to  mg/kg/d (or equivalent) tapered over 1 to 
2 weeks.  Consider use of SSKI or thionamide 
(methimazole or PTU). 
Monitor subjects for signs and 
symptoms of hyperthyroidism.  
Consider endocrine consultation. 
Page 3 of 6 
Footnotes defined on last page of this table


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


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Table 6-2.  AMG 404 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Immune-Related 
Adverse Reactions 
Severity or Specific Conditions 
AMG 404 
Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Skin 
Grade 3 rash or suspected 
Stevens-Johnson syndrome (SJS) 
or toxic epidermal necrolysis (TEN) 
Withhold 
Administer corticosteroids at an initial 
dose of  to  mg/kg/d prednisone (or 
equivalent) followed by taper.  Treat 
with topical emollients, oral 
antihistamines, and high-potency topical 
corticosteroids as indicated. 
Monitor subjects for suspected severe skin 
reactions and exclude other causes (eg, 
infection, an effect of another drug, a skin 
condition linked to another systemic 
disease, etc).  For signs or symptoms of 
SJS or TEN, withhold study drug and refer 
the patient for specialized care for 
assessment and treatment. 
Grade 4 rash or confirmed SJS or 
TEN 
Permanently 
discontinue 
Encephalopathy 
Grade 2 (moderate symptoms, 
limited instrumental ADL) 
Withhold 
Administer corticosteroids at an initial 
dose of  to  mg/kg/d prednisone (or 
equivalent) followed by taper.  Consider 
empirical antiviral (IV acyclovir) and 
antibacterial therapy until CSF results 
obtained and negative for aseptic 
meningitis. 
Monitor subjects for neurologic symptoms 
and exclude other etiologies (eg, 
infectious).  Evaluation of patients with 
neurologic symptoms may include, but not 
be limited to, consultation with a 
neurologist, brain MRI, and lumbar 
puncture. 
Grade 3 or 4 (Severe symptoms; 
limiting self-care ADL; or 
life-threatening consequences; 
urgent intervention indicated) 
Permanently 
discontinue 
(If event not 
attributable to 
tarlatamab) 
Page 5 of 6 
Footnotes defined on last page of this table 


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Table 6-2.  AMG 404 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Immune-Related 
Adverse Reactions 
Severity or Specific Conditions 
AMG 404 
Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-up 
Myocarditis 
Grade 1 (asymptomatic with laboratory [eg, BNP] or cardiac 
imaging abnormalities)  
Withhold 
Administer corticosteroids at an 
initial dose of  to  mg/kg/d 
prednisone (or equivalent) 
followed by taper. 
Monitor patients with 
cardiovascular 
symptoms.  Ensure 
adequate evaluation to 
confirm etiology and/or 
exclude other causes. 
Grade 2 (symptoms with mild to moderate activity or 
exertion) 
Permanently 
discontinue 
Grade 3 (severe with symptoms at rest or with minimal 
activity or exertion; intervention indicated) 
Permanently 
discontinue 
Grade 4 (life-threatening consequences; urgent intervention 
indicated [eg, continuous IV therapy or mechanical 
hemodynamic support]) 
All Other 
Immune-Related 
Adverse Reactions 
Grade 3 adverse reaction involving a major organ 
Withhold 
Based on type and severity of 
adverse reaction, administer 
corticosteroids.  Refer to ASCO 
Clinical Practice Guidelines for 
additional recommendations. 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes. 
Life-threatening or grade 4 adverse reaction involving a 
major organ 
Permanently 
discontinue 
Recurrent or 
Persistent 
Immune-Related 
Adverse Reactions 
Recurrence of same grade 3 or grade 4 adverse reaction 
Permanently 
discontinue 
Based on type and severity of 
adverse reaction, administer 
corticosteroids.  Additional 
immunosuppressive treatment 
may be required. 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes. 
Requirement for
mg/day prednisone (or equivalent) for 
more than 12 weeks 
Persistent grade 2 or 3 adverse reactions lasting 12 weeks 
or longer after last dose (ie, does not resolve to grade 0 or 1 
within 12 weeks) 
Page 6 of 6 
NOTE:  Recommendations adapted from the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines for the Management of Immune-Related 
Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy (Brahmer et al, 2018). 
General considerations: 


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 
Corticosteroid taper should be initiated upon improvement of signs/symptoms and/or laboratory values to grade 1 or less.  Continue corticosteroid taper over 
the course of at least 4 to 6 weeks.  
 
If AMG 404 has been withheld, treatment with AMG 404 may be resumed after adverse event (or associated signs/symptoms/laboratory parameters) has been 
reduced to grade 1 or less and corticosteroid has been tapered to prednisone 
mg (or equivalent).  
 
For severe and life-threatening immune-related adverse reactions, IV corticosteroids should be initiated first followed by oral corticosteroids.  Other 
immunosuppressive treatment should be initiated if the event cannot be controlled by corticosteroids. 
ACTH  adrenocorticotropic hormone; ADL  activities of daily living; ALT  alanine aminotransferase; ASCO  American Society of Clinical Oncology; AST  aspartate 
aminotransferase; BNP  B-natriuretic peptide; CSF  cerebral spinal fluid; ECG  electrocardiogram; GI  gastrointestinal; INR  international normalized ratio; 
IV  intravenous; MRI  magnetic resonance imaging; NCCN  National Comprehensive Cancer Network; PTU propylthiouracil; SJS  Stevens-Johnson syndrome; 
SSKI  saturated solution of potassium iodide; TEN  toxic epidermal necrolysis; ULN  upper limit of normal 
a Immune-mediated hepatitis guidance adapted from the NCCN Version 1.2020, Management of Immune Checkpoint Inhibitor-Related Toxicities 


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Table 6-3.  Management of Infusion-Related Reactions With AMG 404  
Severity 
AMG 404 Dose 
Modification 
Management 
Premedication at Subsequent Dosing 
Grade 1 
(mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated) 
Interrupt or slow the rate of 
the infusion to 50 or less 
of the standard rate. 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable.  
 
If the infusion is interrupted, then after all 
symptoms have resolved, consider rechallenge 
with a reduced infusion rate (50 or less of 
standard rate) and additional premedication 
(such as corticosteroids and antihistamines. 
 
Treat per institutional guidelines. 
None 
Grade 2 
(therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment [eg, 
antihistamines, NSAIDs, narcotics, IV 
fluids]; prophylactic medications 
indicated for  24 hours) 
Interrupt or slow the rate of 
the infusion to 50 or less 
of the standard rate.  
For subjects who develop 
grade 2 infusion-related 
reaction despite adequate 
premedication, 
permanently discontinue 
AMG 404. 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable.  
 
If the infusion is interrupted, then after all 
symptoms have resolved, consider rechallenge 
with a reduced infusion rate (50 or less of 
standard rate) and additional premedication 
(such as corticosteroids and antihistamines).  
 
Treat per institutional guidelines.  Additional 
appropriate medical therapy may include but is 
not limited to IV fluids, antihistamines, NSAIDs, 
acetaminophen, and narcotics. 
Subject may be premedicated 
1.5 hours ( 30 minutes) prior to 
infusion of AMG 404 with:  
 
Diphenhydramine 
 mg orally 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 
 to 
 mg 
orally (or equivalent dose of 
antipyretic). 
Page 1 of 2 
Footnotes defined on last page of this table 
 
 
 
 
 
 
 


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Table 6-3.  Management of Infusion-Related Reactions With AMG 404 
Severity 
AMG 404 Dose 
Modification 
Management 
Premedication at Subsequent Dosing 
Grade 3 
(prolonged [eg, not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion]; 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for clinical sequelae) 
OR 
Grade 4 
(life-threatening consequences; 
urgent intervention indicated) 
Permanently discontinue 
study drug. 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable.  
 
Hospitalization may be indicated. 
 
Treat per institutional guidelines.  Additional 
appropriate medical therapy may include but is 
not limited to IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, 
vasopressors, corticosteroids, and epinephrine.  
In cases of anaphylaxis, epinephrine should be 
used immediately. 
No subsequent dosing 
Page 2 of 2 
IV  intravenous; NSAIDs  non-steroidal anti-inflammatory drugs 


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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 drug accountability for the investigational product will be 
provided to the site. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding  
6.4.1 
Method of Treatment Assignment  
Subjects who meet eligibility criteria will be assigned to treatment with tarlatamab and 
AMG 404. 
6.4.2 
Blinding  
This is an open-label study; blinding procedures are not applicable. 
6.5 
Treatment Compliance  
When subjects are dosed at the site, they will receive tarlatamab and AMG 404, or 
tarlatamab monotherapy 
 directly from the investigator or 
designee, under medical supervision.  The date and time of each dose administered in 
the clinic will be recorded in the source documents and recorded in the CRF. 
6.6 
Treatment of Overdose  
The effects of overdose of these products are not known. 
The administered investigational product dose may be up to 10 lower or higher than 
specified in the protocol.  A dose of up to 10 higher than the intended dose may not 
require specific intervention. 
In any case of overdose, consultation with the Amgen medical monitor is required for 
prompt reporting of clinically apparent or laboratory adverse events possibly related to 
overdosage.  Consultation with the Amgen medical monitor is also required even if there 
are no adverse events, in order to discuss further management of the subject.  If the 
overdose results in clinically apparent or symptomatic adverse events, the subject 
should be followed carefully until all signs of toxicity are resolved or returned to baseline 
and the adverse event(s) should be recorded/reported per Section 11.4. 


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A dose of > 10 higher than the intended investigational product dose will be 
considered clinically important and classified as a serious adverse event under the 
criterion of “other medically important serious event” Section 11.4. 
6.7 
Prior and Concomitant Treatment  
6.7.1 
Prior Treatment  
Prior therapies that were being taken/used from 1 month prior to signing informed 
consent will be collected.  For all prior therapies not taken for SCLC, collect therapy 
name, indication, dose, unit, frequency, route, start and stop dates. 
All prior cancer treatment therapies will be collected. 
For all prior therapies taken for SCLC (eg, chemotherapy, immunotherapy, biological 
therapy or targeted therapy), collect (in the order they were administered):  
 
therapy name  
 
indication  
 
dose and schedule of the agent(s)  
 
unit  
 
frequency  
 
start and stop dates  
 
disease state in which it was administered  
 
reason for discontinuation (disease progression, clinical progression, toxicity, 
subject’s decision) 
 
Additionally, details of the dates, portals, and total administered dose by portal should be 
recorded for all courses of radiation therapy, including those directed at the primary and 
metastatic site(s).  Details of prior radioisotope therapy should also be recorded. 
6.7.2 
Concomitant Treatment  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary, including the use of growth factors such as 
erythropoiesis-stimulating proteins as well as granulocyte colony stimulating factor 
(G-CSF), to provide adequate supportive care except for those listed in Section 6.1.7. 
All prescription and nonprescription concomitant therapies are to be collected from 
informed consent through the end of safety follow-up (SFU) period.  Collect therapy 
name, indication, dose, unit, frequency, route, start date, and stop date and record in the 
electronic case report form (eCRF). 


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6.8 
Support Care and Potential Risk Management Guidelines for 
Tarlatamab  
6.8.1 
Cytokine Release Syndrome  
Cytokine release syndrome is clinically defined and may have various manifestations.  
There are no established diagnostic criteria.  Signs and symptoms may include 
(Lee et al, 2014): 
 
Constitutional :  fever  rigors, malaise, fatigue, anorexia, myalgias, arthralgias, 
nausea, vomiting, headache 
 
Neurologic:  headache, mental status changes, confusion, delirium, word finding 
difficulty or frank aphasia, hallucinations, tremor, dysmetria, altered gait, seizures 
 
Respiratory:  dyspnea, tachypnea, hypoxemia 
 
Skin:  rash 
 
Gastrointestinal:  nausea, vomiting, diarrhea 
 
Cardiovascular:  tachycardia, widened pulse pressure, hypotension, increased 
cardiac output (early), potentially diminished cardiac output (late) 
 
Coagulation:  elevated D-dimer, hypofibrinogenemia  bleeding  
 
Renal:  azotemia 
 
Hepatic:  transaminitis, hyperbilirubinemia 
Cytokine release syndrome is an identified risk of tarlatamab administration.  Subjects 
may be at an increased risk for CRS during the first few days following the initial infusion 
of tarlatamab and after a dose step increase.  Cytokine release syndrome may be 
life-threatening or fatal.  Infusion reactions may be clinically indistinguishable from 
manifestations of CRS.  Subjects will be hospitalized for intensive monitoring in cycle 1 
and cycle 2 as described in Section 8.1.2.  Throughout the infusion with tarlatamab and 
after the end of infusion (EOI) (as described in Section 8.1.2), monitor subjects 
intensively for clinical signs (eg, fever, hypotension, 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 Table 6-4.  For subjects with suspected CRS, samples may be collected for 
analysis after discussion with the Medical Monitor. 


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Table 6-4.  Grading and Management of Cytokine Release Syndrome  
CRS 
Grade 
Description of Severitya 
Minimum Expected 
Intervention 
Instructions for Dose 
Modifications of Tarlatamab 
1 
Symptoms are not life 
threatening and require 
symptomatic treatment only, 
eg, fever, nausea, fatigue, 
headache, myalgias, malaise 
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 
2 
Symptoms require and 
respond to moderate 
intervention 
 
Oxygen 
requirement < 40, OR  
 
Hypotension responsive 
to fluids or low dose of 
one vasopressor, OR 
grade 2 organ toxicity or 
grade 3 transaminitis per 
CTCAE criteria 
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 
(e.g., > 120 bpm) may 
also indicate the need for 
intervention for 
hypotension. 
Monitor for CRS symptoms 
including vital signs and pulse 
oximetry at least Q2 hours for 
12 hours or until resolution to 
CRS grade ≤ 1, whichever is 
earlier. 
For subjects with extensive 
co-morbidities or poor 
performance status or if CRS 
does not resolve to grade ≤ 1 
in 48 hours, manage per 
grade 3 CRS guidance below. 
If CRS occurs during 
tarlatamab treatment, 
immediately interrupt the 
infusion and delay the next 
tarlatamab dose until the 
event resolves to CRS grade 
≤ 1 for no less than 72 hours.   
 
Resume tarlatamab at same 
dose or reduce to next lower 
dose, if clinically indicated. 
(continuation with the next 
planned dose may be allowed 
after discussion with the 
medical monitor). 
 
Permanently discontinue 
tarlatamab if there is no 
improvement to CRS 
≤ grade 1 within 7 days. 
 


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Table 6-4.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of Severity a 
Minimum Expected 
Intervention 
Instructions for Dose 
Modifications of Tarlatamab 
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 
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  mg 
(
 mg/day).  The dose 
should then be reduced 
step-wise. 
 
Investigators should consider 
use of tocilizumabc  mg/kg 
over 1 hour (not to exceed 
mg).  Repeat tocilizumabc 
every 8 hours as needed if 
not responsive to IV fluids or 
increasing supplemental 
oxygen.  Maximum of 3 doses 
in a 
r period.  
Maximum total of 4 doses. 
 
Investigators may also 
consider additional 
therapy, based on clinical 
judgment. 
If CRS occurs during 
tarlatamab treatment, 
immediately interrupt 
tarlatamab and delay the next 
dose until event resolves to 
CRS grade ≤ 1 for no less 
than 72 hours. 
 
Resume tarlatamab to next 
lower dose (continuation at 
same dose with 
dexamethasone 
premedication may be 
allowed after discussion with 
the medical monitor). 
 
Permanently discontinue 
tarlatamab if there is no 
improvement to 
CRS ≤ grade 2 within 5 days 
or CRS ≤ grade 1 within 
7 days. 
Permanently discontinue or 
reduce to next lower dose of 
tarlatamab if CRS grade 
3 occurs at the initial first step 
dose.  
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  mg 
(
 mg/day).  Further steroid 
use should be discussed with 
the Amgen medical monitor. 
Investigators should consider 
use of tocilizumabc  mg/kg 
IV over 1 hour (not to exceed 
mg).  Repeat tocilizumabc 
every 8 hours as needed if 
not responsive to IV fluids or 
increasing supplemental 
oxygen.  Maximum of 3 doses 
in a 
 period.  
Maximum total of 4 doses. 
 
Investigators may also 
consider additional 
therapy, based on clinical 
judgment. 
If CRS occurs during 
tarlatamab treatment, 
immediately stop the infusion.  
Permanently discontinue 
tarlatamab therapy.   
CRS  cytokine release syndrome; CTCAE  Common Terminology Criteria for Adverse Events; 
IV  intravenous; N/A  not applicable  
a Revised grading system for CRS (Lee et al, 2014) 
b High dose vasopressors (all doses are required for ≥ 3 hours):  Norepinephrine monotherapy ≥ 20 µg/min; 
Dopamine monotherapy ≥ 10 µg/kg/min, Phenylephrine monotherapy ≥ 200 µg/min, Epinephrine 
monotherapy ≥ 10 µg/min; If on vasopressin, vasopressin + norepinephrine equivalent of ≥ 10 µg/min; If on 
combination vasopressors (not vasopressin), norepinephrine equivalent of ≥ 20 µg/min  


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c If tocilizumab is not available, siltuximab (an anti-interleukin-6 [IL-6] monoclonal antibody) may be used in 
the management of cytokine release syndrome, following the criteria outlined in Table 6-4.  The 
recommended dose of siltuximab is 
 mg/kg administered over 1 hour as an intravenous infusion, 
consistent with the prescribing information for the treatment of multicentric Castleman’s disease (Sylvant 
Prescribing Information), and the CARTOX Working Group Guidelines for CRS management (Neelapu, 
2018). Siltuximab may be repeated if needed, in the event that CRS recurs after a subsequent infusion of 
tarlatamab.  Siltuximab may not be repeated in an individual subject that develops anaphylaxis to 
siltuximab, or gastrointestinal perforation after siltuximab. 


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Re-start of treatment after CRS: 
After a grade 3 CRS event, the next infusion may be administered if all the following 
criteria are met: 
 
The Amgen medical monitor must be consulted prior to re-starting treatment 
 
If CRS occurred during tarlatamab infusion, infusion has been interrupted for at least 
72 hours 
 
The event has resolved to grade ≤ 1 prior to re-starting treatment 
If a subject experiences two separate grade 3 CRS events, tarlatamab must be 
permanently discontinued.   
6.8.2 
Neurologic Events  
Please see Table 6-5 for the management of adverse events related to neurological 
events.  For subjects with suspected neurological events, samples may be collected for 
analysis after discussion with the Medical Monitor. 
Table 6-5.  Management of Adverse Events Related to Neurologic Events  
Toxicity 
Gradea 
Instructions for Treatment Interruption and Restart 
Neurologic 
Events 
3b 
 Interrupt tarlatamab until the event improves to grade ≤ 1 and 
administer corticosteroids per local practice  
 Resume tarlatamab no less than 72 hours after the initial 
observation of the grade 3 adverse event at 1 dose level below 
 Permanently discontinue if: 
o 
Initial grade 3 neurologic event does not improve to grade 
≤ 1 within 7 days, OR 
o 
Grade 3 neurologic event reoccurs at the lower dose level 
within 7 days of re-initiation 
4 
 Permanently discontinue tarlatamab  
Seizure  
 Interrupt tarlatamab, administer corticosteroids and anti-seizure 
medication per local practice 
 For restart, refer to grade 3 neurologic events above for dose 
level rules for re-instituting infusion. 
 Do not re-initiate tarlatamab until 7 days after the last seizure and 
after therapeutic levels of anti-seizure medication are likely to 
have been achieved. 
 Permanently discontinue if a second seizure occurs with 
re-initiation of tarlatamab at any dose 
a Per Common Terminology Criteria for Adverse Events (CTCAE) Guidelines Version 4.0 
b For adverse events grade ≤ 2, please follow institutional guidelines for management. 
6.8.3 
Pituitary Dysfunction  
Based on the expression of DLL3 in the pituitary and observations in the cynomolgus 
monkey toxicology study, there is a key risk of pituitary dysfunction in humans with 
administration of tarlatamab. 


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Early recognition of signs and symptoms and prompt intervention are essential.  
Symptoms may derive from hormonal deficiencies and by the mass effect due to the 
swelling of the gland.  The most common presentation includes headaches, asthenia, 
fatigue, nausea, weakness, lethargy, erectile dysfunction, and loss of libido. 
The diagnosis and management of pituitary gland dysfunction should be performed 
according to the guidelines provided in Table 6.  Adrenocorticotropic hormone (ACTH), 
cortisol, TSH, free thyroxine (FT4) will be evaluated at screening and monitored 
throughout the study.  Prolactin and follicle stimulating hormone (FSH)/luteinizing 
hormone (LH), testosterone (in males) and estradiol (in females) will also be evaluated 
at screening, end of therapy and as clinically indicated.  After a confirmed diagnosis, 
tarlatamab will be withheld, and corticosteroids and hormone replacement administered 
if clinically indicated.  Please see Section 6.2.2.1.3 for guidelines for restarting 
tarlatamab.  This management recommendation may be revised based on emerging 
clinical data.


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Table 6.  Monitoring and Management of Pituitary Gland Dysfunction (González-Rodríguez and Rodríguez-Abreu, 2016; 
Brahmer et al, 2018)  
 
Monitor for signs and symptoms of pituitary gland dysfunction, TSH, FT4, cortisol, and ACTH throughout study (prolactin, FSH, LH, testosterone [in males] and 
estradiol [in females] will be evaluated only at screening, EOT, and as clinically indicated) 
 
Abnormal hormone monitoring result or clinical suspicion of pituitary gland dysfunction (headache, fatigue, asthenia, impaired vision, vomiting, hypotension, 
amenorrhea, impotence) 
 
Diagnostic tests:  consider brain MRI (if clinically indicated) with or without contrast with pituitary/sellar cuts in subjects with multiple endocrine 
abnormalities and/or with new headache or vision changes.  Evaluate ACTH, AM Cortisol, TSH, FT4, electrolytes and consider evaluating LH, FSH, and 
testosterone levels in males or estrogen females. 
 
Obtain endocrinology consultation for hypophysitis or if clinically indicated 
 
Once pituitary gland dysfunction is confirmed, hold further treatment with tarlatamab pending completion of evaluation.  Manage pituitary dysfunction according 
to NCCN or ASCO guidelines for Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy (NCCN 
Guidelines, 2021; Brahmer et al, 2018).  
 
Once stabilized on any replacement hormones and taking 
 mg or less of prednisone or equivalent may consider restarting tarlatamab.  If subject experienced 
grade 3 or higher pituitary dysfunction, must discuss with medical monitor prior to restarting treatment. 
 
Continue endocrinological surveillance 
ACTH  adrenocorticotropic hormone; EOT  end of treatment; FSH  follicle stimulating hormone; FT4  free thyroxine; LH  luteinizing hormone; MRI  magnetic 
resonance imaging; TSH  thyroid stimulating hormone 


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6.8.4 
Neutropenia  
Neutropenia has been observed in patients receiving tarlatamab.  The risk mitigation 
plan includes monitoring of laboratory parameters (including, but not limited, to white 
blood cell [WBC] count and absolute neutrophil count) which will be evaluated at 
baseline and monitored throughout the study.  Specific recommendations for the 
management of neutropenia, and infusion interruption and stopping rules are found in 
the Table 7. 
 


Product:  Tarlatamab (AMG 757), AMG 404 
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Table 7.  Tarlatamab Dose Modification Guidelines for Neutropenia  
Grade 
Interruption/ Delay 
Specific Management 
Re-start guidance 
Permanent Discontinuation 
Non-febrile Neutropenia 
3 
Interrupt tarlatamab until the 
event improves to grade  2 
Assess for other potential etiologies of 
neutropenia, including concomitant 
medications and underlying infection 
Consider bone marrow biopsy, anti-neutrophil 
antibodies 
Granulocyte colony-stimulating factor (G-CSF) 
administration permitted 
Resume tarlatamab no less than 
72 hours after the initial 
observation of the grade 3 
adverse event at the same dose 
level 
Initial grade 3 non-febrile 
neutropenia does not improve 
to  grade 2 in 3 weeks 
4 
Interrupt tarlatamab until the 
event improves to grade  2 
Assess for other potential etiologies of 
neutropenia, including concomitant 
medications and underlying infection 
Consider bone marrow biopsy, anti-neutrophil 
antibodies 
Consider G-CSF administration 
Resume tarlatamab no less than 
72 hours after the initial 
observation of the grade 4 
adverse event and discuss with 
medical monitor the restarting 
dose 
Initial grade 4 non-febrile 
neutropenia event that lasts 
 7 days 
G-CSF  granulocyte colony-stimulating factor 


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6.8.5 
Tumor Lysis Syndrome  
Tumor lysis syndrome, a preventable complication of cancer therapies, is a result of 
rapid tumor necrosis with release of intracellular ions into the bloodstream.  It is 
characterized by hyperuricemia, hyperkalemia, and hyperphosphatemia.  Tumor lysis 
syndrome occurs primarily in hematological malignancies and high-grade lymphomas.  
The occurrence of TLS in solid tumors is rare but is more common in highly responsive 
tumors with large tumor burdens.  Pretreatment elevation of serum lactate 
dehydrogenase (LDH) and uric acid, and pre-existing renal failure are risk factors for the 
development of TLS (Kallab and Jillella, 2001).  In light of the extremely low incidence of 
TLS in patients with solid tumors, routine prophylactic measures, such as allopurinol and 
alkaline hydration, cannot be recommended in all patients.  However, the potential for 
TLS in patients with bulky, SCLC who present with renal insufficiency, dehydration, 
hyperuricemia, and elevated serum LDH levels must be recognized, to allow for 
appropriate monitoring after treatment and early initiation of therapeutic measures if 
necessary (Kalemkerian et al, 1997).  Intravenous hydration and careful monitoring of 
fluid status is recommended.  Allopurinol or rasburicase can be considered for both 
prophylaxis and/or treatment of hyperuricemia. 
6.8.6 
Vaccines  
Every effort should be made to fully vaccinate patients prior to 
 days from first dose of 
tarlatamab.  The use of vaccines except live and live-attenuated vaccines will be allowed 
during therapy per regional and institutional standard of care.  However, SARS-CoV-2 
vaccinations should be avoided during screening (within a minimum of 
 days from first 
dose of tarlatamab) and should be also avoided in the first treatment cycle for better 
assessment of safety parameters.  Throughout the trial, SARS-CoV-2 vaccination should 
be avoided within  days after the administration of tarlatamab.  In the event where a 
patient requires steroids for treatment of adverse events, vaccination should be avoided 
while on steroids. 
6.8.7 
Management of SARS-CoV-2 Infection and COVID-19 Disease  
Management of SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) 
should be performed according to the guidelines provided in Table 8 (exceptions may be 
permitted with medical monitor approval). 


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Table 8.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of SARS-CoV-2 Infection and 
COVID-19 Disease  
Grade 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
SARS-CoV-2 infection and COVID-19 disease 
Asympto
matic 
Interruption required until 
at least 10 days since 
positive SARS-CoV-2 test 
UNLESS patient previously 
fully vaccinated against 
SARS-CoV-2.  If patient 
previously vaccinated and 
tests positive, then discuss 
with medical monitor. 
Follow local 
guidelines and 
standard of care 
for COVID-19 
treatment and 
isolation 
Contact Amgen 
Medical Monitor 
within 
1 business day 
to ensure 
appropriate 
documentation 
and 
management of 
study activities 
 
Re-start possible upon agreement between investigator and Amgen 
Medical Monitor provided: 
o 
There are no new findings on physical exam related to 
SARS-CoV-2, AND 
o 
Subject tests negative for SARS-CoV-2 by RT-PCR  
o 
Consider CT of the chest imaging, ECG, ECHO and 
cardiology assessment prior to re-start of investigational 
product.  
OR 
o 
If subject continues to test positive for SARS-CoV-2 more 
than 10 days after initial positive test, or if subject initially 
tests positive in the setting of prior COVID vaccination, 
resume investigational product only after discussion with 
patient and reassessment of individual risk/benefit and 
perform CT of chest imaging and ECG required prior to re-
start of investigational product.  Consider ECHO and 
cardiology assessment 
 
Consider hospitalization for re-start of investigational product based 
on length of treatment interruption, risk of CRS at restart, and 
amount of time since patient was last treated 
 
Dose modification:  resume at the same dose or reduce to next 
lower dose if clinically indicated 
 
Premedication and assessments:  follow guidance in SOA tables 
Immediately stop the 
infusion (if applicable) and 
permanently discontinue 
investigational product 
therapy if: 
Subject required 
treatment interruption 
greater than 28 days and 
upon discussion with 
Amgen medical monitor 
the decision is made to 
permanently discontinue 
treatment 
OR 
Initial benefit/risk 
assessment for individual 
patient is no longer 
favorable 
Page 1 of 2 
Footnotes defined on last page of this table. 


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Table 6 8.  Infusion Interruptions/Delays/Withholding/Permanent Discontinuation and Management of SARS-CoV-2 Infection 
and COVID-19 Disease 
Grade 
Interruption/ Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
SARS-CoV-2 infection and COVID-19 disease 
Symptom
atic 
Interruption required 
until at least 10 days 
since complete 
resolution of acute 
symptoms 
Follow local 
guidelines and 
standard of care for 
COVID-19 
treatment and 
isolation 
Contact Amgen 
Medical Monitor 
within 1 business 
day to ensure 
appropriate 
documentation and 
management of 
study activities 
 
Re-start possible upon agreement between investigator and Amgen 
medical monitor provided: 
o 
There are no new findings on physical exam and chest 
imaging, related to SARS-CoV-2 
o 
Subject tests negative for SARS-CoV-2 by RT-PCR 
o 
Consider CT of the chest imaging and ECG, ECHO and 
cardiology assessment prior to re-start of IP.  
OR 
o 
If subject continues to test positive for SARS-CoV-2 more 
than 10 days after initial positive test, resume investigational 
product  only after discussion with patient and reassessment 
of individual risk/benefit and perform CT of chest imaging 
and ECG required prior to re-start of investigational product.  
Consider ECHO and cardiology assessment 
 
Consider hospitalization for re-start of investigational product based 
on length of treatment interruption, risk of CRS at restart, and amount 
of time since patient was last treated 
 
Dose modification:  resume at the same dose or reduce to next lower 
dose if clinically indicated 
 
Premedication and assessments:  follow guidance in SOA tables 
Immediately stop the 
infusion (if applicable) and 
permanently discontinue 
investigational product 
therapy, if: 
Subject required 
treatment interruption 
greater than 28 days due 
to severe or 
life-threatening COVID-19 
OR 
Initial benefit/risk 
assessment for individual 
patient is no longer 
favorable 
Page 2 of 2  
COVID-19  coronavirus disease 2019; CRS  cytokine release syndrome; CT  computed tomography; ECG  electrocardiogram; ECHO  echocardiogram; RT PCR 
 real time polymerase chain reaction; SARS-CoV-2  severe acute respiratory syndrome coronavirus 2; SOA  Schedule of Activities 
 


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7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal  
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 Section 1. 
7.1 
Discontinuation of Study Treatment  
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies and/or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see 
Section 1.3) including different options of follow-up (eg, in person, by phone/mail, 
through family/friends, in correspondence/communication with other treating physicians, 
from the review of medical records) and collection of data, including endpoints, adverse 
events, and must document this decision in the subject’s medical records.  Subjects who 
have discontinued investigational product and/or other protocol-required therapies 
and/or procedures should not be automatically removed from the study.  Whenever safe 
and feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 


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 
Confirmed disease progression as defined by modified RECIST 1.1 criteria 
(Section 11.9) or disease progression accompanied by worsening of symptoms or 
deterioration of the subject’s general condition 
*Note: Subjects with confirmed disease progression per modified RECIST 1.1 
criteria who have clinical benefit in the investigator’s judgment may be allowed 
to continue treatment after approval by the Medical Monitor as per Section 7.2 
 
Requirement for alternative therapy 
 
Protocol-specified criteria: 
Subjects who require more than 1 dose reduction 
7.2 
Continuation on Study Treatment After Radiologic Disease 
Progression  
This section details the conditions necessary to allow continued treatment with 
tarlatamab after radiologic disease progression in subjects that continue to have 
clinical benefits in the investigator’s judgement, provided all of the following 
criteria are met at each occurrence:  
 
Absence of threat to vital organs or critical anatomical sites (eg, respiratory 
failure due to tumor compression, spinal cord compression) requiring urgent 
alternative medical intervention with persistent immediate threat to vital 
organs after intervention.  The presence of brain metastases may be allowed, 
provided the lesions are amenable to radiation therapy or dexamethasone (or 
corticosteroid equivalent) and the subject is clinically stable as per 
investigator’s judgment.  
 
No other treatment discontinuation criteria are met.  
 
No significant, unacceptable, or irreversible toxicities related to any dose of 
the study treatment or treatment related adverse events of CTCAE grade 4 at 
the current dose at the time of progression.  
 
The subject is willing to undergo biopsy of one of the new or progressing 
lesions. If tumor biopsy is not clinically feasible or advisable, the subject may 
continue only upon agreement with the investigator and the Amgen Medical 
Monitor.  
 
Approval for continuation from the Amgen Medical Monitor.  
 
Palliative radiation for new, progressive, or symptomatic lesions is permitted 
as per Section 6.1.7.  Tarlatamab must be held during treatment and radiation 
and must be completed at least  days before the subsequent dose of 
tarlatamab.  
 
All protocol-mandated procedures must be performed as noted in the 
Schedule of Activities (Section 1.3) (imaging, labs, and clinic visits may be 
obtained earlier per clinical judgment and if clinically indicated).  
7.3 
Subject Discontinuation/Withdrawal 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 


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will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study and must document the 
subject’s decision to withdraw in the subject’s medical records. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.3.1 
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 
7.4 
Lost to Follow-up  
A subject will be considered lost to follow-up if they repeatedly fail to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator should 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. 


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8. 
Study Assessments and Procedures  
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 1.3).  
If an enrolled subject is subsequently determined to be ineligible for the study, this must 
be discussed with the sponsor immediately upon occurrence or awareness to determine 
if the subject is to continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods  
8.1.1 
Screening, Enrollment and/or Randomization  
Informed consent must be obtained before completing any screening procedure 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 
. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 1 time. 
Rescreen subjects must first be registered as screen failures and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 
 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the ICF, all screening procedures, including informed 
consent, must be repeated. 
8.1.2 
Treatment Period  
Treatment begins on cycle 1 
 when the first IV infusion of investigational product is 
administered to a subject.  The following procedures will be completed during the 
treatment period at the times designated in the Schedule of Activities (Section 1.3).  The 
results of the cycle 1 
 laboratory tests must be available before starting treatment 
with tarlatamab.  Laboratory assessments that were done within 24 hours prior to 


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infusion do not need to be repeated (except for cycle 1 
 dosing where laboratory 
assessments that were done within 48 hours prior to infusion do not need to be 
repeated).  Clinical evaluation should be completed within 6 hours prior to the first dose 
of tarlatamab.  All assessments and procedures should be collected at the exact nominal 
time point as noted in the Schedule of Activities (Section 1.3).  If unable to perform a 
procedure at the specified nominal time point, collect it as close as possible to the 
nominal time point and record the actual collection time. 
The end of treatment (EOT) visit will occur at the end of the last treatment cycle.  For 
subjects who prematurely discontinue investigational product treatment, the EOT visit 
should occur as soon as possible (within 
) after the last dose of investigational 
product was administered. 
Hospitalization and Monitoring Guidance 
8.1.3 
Safety Follow-up  
The procedures to be completed during SFU are indicated in the Schedule of Activities 
(Section 1.3).  Upon permanent discontinuation from the study treatment for any reason, 
an SFU visit will be performed approximately 
 after the last dose 
(tarlatamab or AMG 404) or prior to initiation of other therapy, whichever occurs first.  


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The second safety follow-up visit will be performed approximately 
 after 
the end of the last dose of AMG 404 or prior to initiation of other therapy, whichever 
occurs first. 
Subjects who discontinue AMG 404 but remain on treatment with AMG 757 will continue 
to have safety event collection at regularly scheduled study visits.  The second safety 
follow-up visit need only occur if 
 has not elapsed from the end of AMG 404 
treatment at the time of end of study treatment. 
8.1.4 
Long-term Follow-up  
Long term follow-up will be conducted every 3 months ( 2 weeks) up to 1 year from the 
first dose of tarlatamab 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 only. 
For subjects who discontinued treatment for any reason other than confirmed 
progressive disease, every effort should be made to perform radiographic imaging 
(computed tomography [CT]/MRI) of the chest, abdomen, pelvis, and all other known 
sites of disease every 3 months until documentation of confirmed disease progression 
per modified RECIST 1.1, clinical progression, start of new anticancer therapy, or up to 
12 months after the first dose of tarlatamab, whichever occurs first. 
8.1.5 
End of Study  
The End of Study visit is defined as the date of the final study visit (eg, final long-term 
follow-up visit) when and assessments and/or procedures are performed.  
8.2 
General Assessments  
8.2.1 
Informed Consent  
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
8.2.2 
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. 


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8.2.3 
Medical History  
The Investigator or designee will collect a complete medical and surgical history that 
started prior to enrollment through the time of consent.  Medical history will include 
information on the subject's concurrent medical conditions.  Record all findings on the 
medical history CRF.  In addition to the medical history above, SCLC history must date 
back to the original diagnosis.  Relevant medical history, including antecedent 
hematologic or oncologic disease, other diseases/symptoms such as fatigue, bleeding, 
and infection (resolved and ongoing) will be collected.  The current toxicity grade will be 
collected for each condition that has not resolved.  Any unresolved medical history will 
be graded according to the CTCAE version 4.0 (See Section 11.4) unless specified 
otherwise. 
All prior cancer therapies will be collected. 
8.2.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.5 
Physical Measurements  
Height (in centimeters) and weight (in kilograms) should be measured without shoes. 
8.2.6 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of tobacco. 
8.2.7 
Performance Status  
The subject’s performance status will be assessed using the ECOG performance scale 
(see Section 11.8). 
8.3 
Efficacy Assessments  
8.3.1 
Radiologic Imaging Assessment  
The extent of disease will be evaluated by contrast-enhanced MRI/computed 
tomography (CT) according to modified RECIST 1.1 (Section 11.9).   
All radiological imaging will be performed as indicated in the Imaging Procedural Manual 
provided by the central imaging core laboratory.  Organ-specific imaging protocols or 
existing diagnostic guidelines should be followed whenever possible to evaluate the full 
extent of the disease appropriately.  In order to reduce radiation exposure for subjects, 
low dose CT or MRI should be applied whenever possible.  MRI/CT scans should be 
performed with contiguous slices thickness of ≤ 5 mm according to the Imaging 
Procedural Manual. 


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Due to the mechanism of action of immune-enhancing therapies, subjects may 
experience delayed response or enhanced T-cell expansion and infiltration into tumors, 
leading to an apparent enlargement of existing lesions or the appearance of new lesions 
prior to maximal clinical benefit being observed. 
  All brain scans on protocol are required to be MRI unless MRI is 
contraindicated, and then CT with contrast is acceptable. 
Determination of disease response for clinical management of subjects will be assessed 
at the clinical sites per modified RECIST 1.1.  Scans may be submitted to a central 
imaging core laboratory for archival, response assessment including modified 
RECIST 1.1, and/or 
 eg, volumetric and viable tumor measurements.  


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Detailed information regarding submission of images to the central imaging core 
laboratory is found in the Imaging Procedural Manual. 
8.4 
Safety Assessments  
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Section 1.3). 
8.4.1 
Vital Signs and Pulse Oximetry  
Vitals signs (blood pressure [BP], RR, HR, and temperature) and pulse oximetry will be 
recorded by the investigator or designee at time points specified in the Schedule of 
Assessments (Section 1.3). 
The following measurements must be performed:  systolic/diastolic BP, HR, RR, and 
temperature.  Subject must be in a rested and calm state for at least 5 minutes before 
blood pressure assessments are conducted.  The position selected for a subject should 
be the same that is used throughout the study and documented on the vital sign 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. 
In subjects with an initial blood pressure reading within the hypertensive range, a 
second reading should be taken at least 1 minute after the initial reading, with the 
two readings averaged to obtain a final blood pressure measurement.  The average 
value should be recorded in the eCRF. 
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. 
Vital signs will be taken pre-AMG 404 infusion and at AMG 404 EOI.  After each 
tarlatamab infusion for the first 2 cycles (during the hospitalization period), vital signs will 
be assessed accordingly during the following timepoints:  


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8.4.2 
Neurological Examination  
A neurological examination will be performed as outlined in the Schedule of Activities 
(Section 1.3).  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 eCRF.  Abnormal findings found after the subject is dosed 
will be reported on the Event page of the eCRF. 
A more detailed neurological assessment may be performed in subjects at selected 
sites. 
8.4.3 
Writing Test  
Subjects will be asked to provide writing tests in order to detect early cerebellar signs as 
outlined in the Schedule of Activities (Section 1.3).  Subjects will write down the current 
date, location of the clinic, and the current time in a sentence.  The sentence format 
should be repeated each time throughout the study.  Interpretation of writing sample 
results will be based solely on the investigator’s assessment. 
8.4.4 
Mini-Mental Status Examination  
The Mini Mental Status Examination (MMSE) Version 2 will be performed as outlined in 
the Schedule of Activities (Section 1.3).  The MMSE is a 30-point healthcare 
professional (including study coordinators) administered questionnaire to assess 
potential subjects for cognitive impairment.  The assessment covers 8 categories, such 
as orientation to time, orientation to place or language, with a total score that ranges 
from 0 to 30 (30 indicates the best possible outcome).  The overall total score should be 
recorded on the appropriate eCRFs. 
8.4.5 
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.  The ECG must 
include the following measurements:  Heart Rate, QRS, QT, QTc, and PR intervals.  The 


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Principal Investigator will review all ECGs.  Once signed, the original ECG tracing will be 
retained with the subject's source documents.  At the request of the sponsor, a copy of 
the original ECG will be made available to Amgen.  See Section 1.3 for timing of ECG 
assessments. 
8.4.6 
Clinical Laboratory Assessments  
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) for the timing and frequency. 
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Section 1.3). 
8.4.7 
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. 
8.4.8 
Other Safety  
8.4.8.1 
Echocardiogram (ECHO)/Multigated Acquisition (MUGA) Scan  
ECHO or MUGA will be performed to assess cardiac ejection fraction and will occur at 
time points specified in the Schedule of Activities (Section 1.3). 
Echocardiography/MUGA should include an evaluation from left ventricular ejection 
fraction (LVEF).  Additional ECHO/MUGA assessments may be performed as clinically 
indicated.  For subjects developing COVID-19 during screening period and following 
screening imaging assessments, consider repeating ECHO following resolution. 


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8.4.9 
Adverse Events and Serious Adverse Events  
8.4.9.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information  
8.4.9.1.1 
Adverse Events  
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of investigational 
products through the second safety follow-up visit are reported using the Events CRF. 
8.4.9.1.2 
Serious Adverse Events  
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through SFU-2 are reported using the Events CRF. 
All serious adverse events will be collected, recorded, and reported to the sponsor or 
designee immediately and no later than 24 hours of the investigator’s awareness of the 
event, as indicated in Section 11.4.  The investigator will submit any updated serious 
adverse event data to the sponsor immediately and no later than 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 also report these 
grade 4 abnormalities as serious adverse events.  For any adverse event that applies 
to this situation, comprehensive documentation of the event’s severity must be 
recorded in the subject medical records. 
8.4.9.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period  
During the long-term follow-up period, if the investigator becomes aware of serious 
adverse events suspected to be related to investigational product and all fatal serious 
adverse events (regardless of causality), then these serious adverse events will be 
reported to Amgen.  The investigator will report serious adverse events to Amgen 
immediately and no later than 24 hours after the investigator’s awareness of the event 
on the Events CRF. 
There is no requirement to actively monitor study subjects after the study has 
ended with regards to study subjects treated by the investigator.  However, if the 
investigator becomes aware of serious adverse events suspected to be related to 


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investigational product after the study has ended, then these serious adverse events 
will be reported to Amgen immediately and no later than 24 hours after the investigator’s 
awareness of the event. 
Serious adverse events reported after the end of study will be captured within the 
safety database as clinical trial cases and handled accordingly based on relationship to 
investigational product. 
If further safety related data is needed to fulfill any regulatory reporting requirements for 
a reportable event, then additional information may need to be collected from the 
subject’s records if the subject ends the study. 
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. 
8.4.9.2 
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. 
8.4.9.3 
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 7.4).  
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 immediately and no later than 24 hours following awareness of the new 
information.  If specifically requested, the investigator may need to provide additional 
follow-up information, such as discharge summaries, medical records, or extracts from 
the medical records.  Information provided about the serious adverse event must be 
consistent with that recorded on the Events CRF. 
8.4.9.4 
Regulatory Reporting Requirements for Serious Adverse Events  
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 


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Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met. 
The sponsor 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.    
Amgen will prepare a single Development Safety Update Report (DSUR) (also referred 
to as Annual Safety Report [ASR] in the European Union) for the Amgen Investigational 
Product.  In order to ensure that consolidated safety information for the trial is provided, 
this single DSUR will also include appropriate information on any other investigational 
products used in the clinical trial, if applicable. 
8.4.9.5 
Safety Monitoring Plan  
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.4.9.6 
Pregnancy and Lactation  
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 
 
 respectively, after the last dose of tarlatamab and 
 for female 
study subjects and 
 for female partners of male study subjects after the 
last dose of AMG 404. 
If a pregnancy is reported, the investigator is to inform Amgen immediately and no later 
than 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. 


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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. 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening and 
within  days of initiation of investigational product for females of childbearing potential. 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 11-2.  Refer to Section 11.5 for contraceptive requirements.  
A pregnancy test should be performed 
 after the last dose of tarlatamab and 
 after the last dose of AMG 404. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.5 
Pharmacokinetic Assessments  
All subjects enrolled in the study will have PK samples assessed. 
Blood samples will be collected for measurement of serum concentrations of tarlatamab, 
and AMG 404 as specified in the Schedule of Activities (Section 1.3).  Instructions for the 
collection and handling of biological samples will be provided by the sponsor.  The actual 
date and time (24-hour clock time) of each sample will be recorded. 


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9. 
Statistical Considerations  
9.1 
Statistical Hypotheses  
No formal statistical hypothesis will be tested. 
9.2 
Sample Size Determination  
Approximately 
 subjects were anticipated to be enrolled in the study (up to 
 subjects 
in a dose exploration phase, and the remaining subjects enrolled in a dose expansion 
phase).  Study enrollment ended in 
.  A total of 
 subjects were enrolled, 
including 
 subjects in Part 1, and  subjects in Part 2. 
Dose Exploration Phase: 
Up to 6 planned dose cohorts will be examined during dose exploration.  The planned 
dose levels for tarlatamab with a fixed dose of AMG 404 (
 mg IV 
) are described 
in Section 4.1. 
Dose exploration will begin with 
 subjects treated at Dose Cohort Level 1.  The 
study DLT period is 
.  Once all subjects enrolled at a certain Dose Cohort Level 
are DLT evaluable, a DLRT meeting will be convened.  Depending on observed safety 
data, the following may occur:  1) dose de-escalation to the next lowest Dose Cohort 
Level, 2) additional enrollment to the current Dose Cohort Level, or 3) dose escalation to 
the next highest Dose Cohort Level or initiation of enrollment in Part 2.  In order to 
consider a certain Dose Level as the recommended phase 2 dose, at least 
 DLT-evaluable subjects must be enrolled at that Dose Level. 
These sample sizes are based on practical considerations and are consistent with 
conventional oncology studies with the objective to estimate the recommended phase 2 
dose and to evaluate initial safety and tolerability.  The probability of observing at least 
1 DLT if the true DLT rate is 10 to 30 is provided in Table 9-1 for various number of 
subjects. 


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Table 9-1.  Probability of Observing at Least 1 DLT  
Number of Subjects 
10 DLT Rate 
30 DLT Rate 
19 
55 
27 
70 
34 
80 
47 
91 
57 
96 
65 
98 
DLT  dose-limiting toxicity 
Dose Expansion Phase: 
If the sample size in the dose expansion phase of 10 (or 20).  There is 65 (88) 
probability of observing at least 1 adverse event with 10 incidence rate, and the 95 
exact confidence interval for 20 objective response (OR) is 3 to 56 (6 to 44). 
9.3 
Populations for Analysis  
The following populations are defined: 
Population 
Description 
Enrolled 
All subjects who sign the ICF 
Safety 
The Safety Analysis Set will consist of all subjects who 
received at least 1 dose of any Investigational Products.  
The analysis of all safety and efficacy endpoints, unless 
noted otherwise, will be conducted on the Safety Analysis 
Set. 
DLT 
For the dose exploration part of the study, the analysis of 
DLT will be conducted on the DLT Analysis Set, defined as 
all subjects that are enrolled and received at least 1 dose of 
tarlatamab and AMG 404 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 and receives tarlatamab and AMG 404 treatment as 
planned in cycle 1 and has been followed for safety events 
a minimum of 
 from start of treatment. 
OR 
The OR Analysis Set will consist of all subjects in the 
Safety Analysis Set who have had the opportunity to be 
followed for at least 8 weeks starting from day 1.  
PK 
The PK Analysis Set will contain all subjects who have 
received at least 1 dose of the Investigational Product and 


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have at least 1 PK sample collected.  These subjects will 
be evaluated for PK analysis unless the number of data 
points required for analysis is not enough, or significant 
protocol deviations have affected the data, or if key dosing 
or sampling information is missing. 
 
9.3.1 
Covariates  
The relationship between covariates and efficacy endpoints may be explored if 
appropriate. 
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 4.5. 
9.4.1 
Planned Analyses  
9.4.1.1 
Interim Analysis and Early Stopping Guidelines  
Safety data will be reviewed on an ongoing basis. 
During dose exploration (Part 1) and formally during DLRMs, Amgen, in consultation 
with the site investigators, will review all available cumulative data by cohort prior to 
making dose escalation or dose de-escalation recommendation.  Adverse events and 
DLTs observed in all subjects will be evaluated continually and fully integrated into all 
DLRMs and considered in all enrolment and dosing decisions. 
During dose expansion (Part 2), Amgen will conduct evaluations of the ongoing grade 4 
or higher treatment-related TEAEs to assess if the threshold for possible early trial 
termination has been reached. The safety interim will occur for every 
 subjects 
enrolled who have had opportunity to have at least 
 of follow up since the first 
dose of tarlatamab. If this threshold is met, enrollment to dose expansion will be halted 
pending review of safety data by the DLRT.  After receiving the DLRT recommendation, 
Amgen will choose to take one of the following actions. 


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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 (Thall et al, 1995) to 
terminate the study if the posterior probability that the grade 4 or higher 
treatment-related TEAE rate is greater than 20 is > 80.  The stopping boundaries 
assume a prior distribution of Beta (0.40, 1.60) are presented in Table 9-2 and the 
operating characteristics with pre-specified batch size of 
 new subjects per batch are 
presented in Table 9-3. 
Table 9-2.  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 Subjects if Observing This Many Grade 4 or Higher 
Treatment-related Adverse Events 
≥ 4 
≥ 6 
≥ 9 
Dose Expansion Complete 
Table 9-3 Operating Characteristics with Batch Size of 
 Subjects  
True Grade 4 or Higher 
Treatment-related Adverse 
Event Rate 
Probability of Early Stopping 
of Dose Expansion 
Average Dose Expansion 
Sample Size 
0.10 
2.0 
39.5 
0.15 
9.7 
37.6 
0.20 
25.8 
33.9 
0.25 
47.7 
28.8 
0.30 
69.2 
23.4 
 
9.4.1.1.1 
Criteria for Evaluating Treatment With Siltuximab  
Amgen will conduct evaluations of the treatment and outcome of the CRS events treated 
with siltuximab on an ongoing basis to assess if the threshold for evaluating siltuximab 
treatment has been reached as outlined in the Table 4.  If these criteria are met, an 
adhoc DLRM will be triggered to review safety data and available pharmacokinetic, 
pharmacodynamics, and efficacy data.  If recommended by DLRT, the use of siltuximab 


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will resume.  The criteria to trigger an adhoc DLRM to review siltuximab treatment use a 
Bayesian approach proposed by Thall et al, 1995; an adhoc DLRM will be triggered if the 
posterior probability that the CRS progression to Grade 3 rate of greater than 20 is 
> 80 or the posterior probability that the CRS progression to Grade 4 rate of greater 
than 7.5 is >80; or observation of any grade 5 CRS after the event has been treated 
with siltuximab.  The boundaries presented below assume a prior distribution of Beta 
(0.4, 1.6) for progression to grade 3 CRS and a prior distribution of Beta (0.15, 1.85) for 
progression to grade 4 CRS.  The evaluations could occur more frequently if necessary 
to address emerging safety concerns.  If the triggered ad hoc DLRM coincide with 
regular DLRM, they may be combined. 
Table 4.  The Criteria for Evaluating the Use of Siltuximab  
Number of 
subjects treated 
with siltuximab 
Trigger DLRM if severity of any CRS event treated with siltuximab 
progresses to Grade 5   
Or this number of subjects with 
severity of CRS progressed to 
Grade 3 after being treated with 
siltuximab 
Or this number of subjects with 
severity of CRS progressed to 
Grade 4 after being treated with 
siltuximab 
≥ 3 
≥ 2 
≥ 4 
≥ 2 
≥ 5 
≥ 3 
≥ 6 
≥ 3 
≥ 7 
≥ 4 
≥ 9 
≥ 4 
≥ 10 
≥ 5 
≥ 11 
≥ 5 
CRS   cytokine release syndrome; DLRM  Dose Level Review Meeting 
9.4.1.2 
Primary Analysis  
The primary analysis for this study will occur when target enrollment is complete and 
each subject either completes at least 6 months on study or withdraws from the study. 
9.4.1.3 
Final Analysis  
The final analysis will be performed after the last subject has had an opportunity to 
complete the corresponding EOT visit/procedures. 


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9.4.2 
Methods of Analyses  
9.4.2.1 
General Considerations  
Descriptive statistics will be provided for selected demographics, safety, 
pharmacokinetic, efficacy 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 and Pearson, 1934).  Kaplan-Meier methods will 
be used to estimate the median and percentiles for time to event endpoints with CI 
calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) method.  
Kaplan-Meier methods will be used to estimate landmarks for time to event endpoints 
(eg, 1-year OS) with the Greenwood formula (Kalbfleisch and Prentice, 1980) used to 
estimate the standard error used in CI calculation. 
9.4.2.2 
Efficacy Analyses  
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
The proportion of subjects with an objective response and disease 
control (per modified RECIST v1.1) and 95 CI will be tabulated by 
planned dose level and schedule.  
 
For all subjects treated at the recommended phase 2 dose, 
Kaplan-Meier methods will be used to estimate for 1) duration of 
response (DOR), 2) OS, 3) progression-free survival (PFS) with 95 
CI.  For all subjects treated at the recommended phase 2 dose, 
Kaplan-Meier methods will be used to estimate landmarks for time to 
event events (eg, 6-month PFS and OS) with 95 CI. 
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 
The analysis of DLTs will be conducted on the DLT Analysis Set.  
Subject incidence of DLT will be tabulated by planned dose level.   
Secondary 
The statistical analysis methods for other safety endpoints are below. 
 


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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 discontinuation from investigational product or other 
protocol-required therapies, and significant treatment emergent adverse events will also 
be provided.  
 
 
9.4.2.3.3 
Laboratory Test Results  
The analyses of safety laboratory endpoints will include summary statistics at selected 
time points by treatment group.  Shifts in grades of safety laboratory values between the 
baseline and the worst on-study value will be tabulated by treatment group. 
9.4.2.3.4 
Vital Signs  
The analyses of vital signs will include summary statistics at selected time points by 
treatment group.  Shifts in vital sign values between the baseline and the worst on-study 
value will be tabulated by treatment group. 
9.4.2.3.5 
Physical Measurements  
The analyses of physical measurements will include summary statistics at baseline by 
treatment group. 
9.4.2.3.6 
Electrocardiogram  
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  No statistical analyses of ECG measurements are planned. 
9.4.2.3.8 
Exposure to Investigational Product  
Subject exposure to investigational product and combination therapy will be summarized 
using descriptive statistics.  The number of cycles of protocol-specified therapy 
administered will be summarized with an additional breakdown of the number of cycles 
started.  In addition, the duration of therapy, the cumulative dose, and the average dose 
per administration and relative dose intensity will be summarized.  The number and 
percent of subjects with dose modifications (eg, dose reductions, dose interruptions) and 


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reason for modification will be summarized as well.  Subject-level data may be provided 
instead of the summary if the subject incidence is low or single dose is given. 
9.4.2.3.9 
Exposure to Concomitant Medication  
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each treatment group as coded by the World Health Organization, 
2018. 
9.4.2.4 
Other Analyses  
Pharmacokinetic parameters will be determined from the concentration-time profile using 
standard non-compartmental approaches and considering the profile over the complete 
sampling interval.  
 
 
 
 
9.4.2.5 
Adaptive Design  
The guidelines described in Section 4.1 for dose escalation or de-escalation to the next 
dose level are determined by using a mTPI-2 algorithm (Guo et al, 2017) with one 
practical modification.  Consistent with conventional oncology phase 1 study designs 
(eg, 3+3 design) and given the imprecision with making decisions using as few as 
 subjects, in the instance of 1 DLT in the initial  subjects at a dose level then, as 
appropriate, the design allows expansion at the dose level beyond  subjects.  All other 
dose escalation or de-escalation rules are determined strictly by the mTPI-2 algorithm as 
described below.  The mTPI-2 algorithm employs a simple beta-binomial Bayesian 
model.  Let 𝑝𝑇 be the target toxicity level and (𝑝𝑇 − ϵ1, 𝑝𝑇 + ϵ2) be the equivalence toxicity 
interval denoted as EI.  The unit toxicity interval (0, 1) is divided into subintervals with 
equal length given by (ϵ1 + ϵ2).  Let the under-dosing intervals (LI) denote for a set of 
intervals below EI, and the overdosing intervals (HI) for a set of intervals above EI.  The 
3 types of dosing intervals (EI, LI, HI) are associated with 3 different dose-escalation 
decisions.  The LI correspond to a dose escalation (E), the HI correspond to a dose 
de-escalation (D), and proper dosing intervals (EI) correspond to staying at the current 
dose (S).  This study design uses a target toxicity level, 𝑝𝑇 of 30, and EI of (25, 33). 
Decision rules are based on the unit probability mass (UPM) calculated on these 
equal-length intervals.  Given an interval and a probability distribution, the UPM of that 
interval is defined as the probability of the interval divided by the length of the interval.  


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The mTPI-2 design calculates the UPMs for the each of equal-length dosing intervals.  If 
the interval with the largest UPM is from LI, EI, or HI, then the corresponding dose 
decision would be E, S, or D, respectively. 
A dose level will be considered unsafe, with no additional subjects enrolled at that dose 
level, if it has an estimated 95 or more probability of exceeding the target DLT rate 𝑝𝑇 
(ie, P [DLT > 𝑝𝑇 | data] > 95).  Based on this rule, the following instances would result 
in a dose level being considered unsafe. 
 
or more DLTs in ≤
subjects  
 
or more DLTs in ≤
subjects 
 
or more DLTs in ≤
subjects  
 
or more DLTs in 
subjects 
After the escalation phase is completed, final DLT rates at each dose level will be 
estimated by isotonic regression (Ji et al, 2010).  The weighted least squares regression 
model will assume monotonic non-decreasing DLT rates with increasing dose and use 
the empirical (observed) DLT rates at each dose level as responses and dose level 
sample sizes as weights, along with the pool adjacent violators algorithm (PAVA) to 
estimate the DLT rate at each dose level.  Given the DLT estimates for each dose level, 
the recommended phase 2 dose will be selected from all tried dose levels that have not 
been previously declared to be unsafe with a DU decision according to the mTPI 
decision table.  With this constraint, the recommended phase 2 dose will be determined 
as the dose level with the DLT estimate closest to the target toxicity level of 30. 


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10. 
References  
AMG 404 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
AMG 757 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
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Bristol Myers Squibb.  Bristol Myers Squibb Statement on Opdivo (nivolumab) Small Cell 
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Myers-Squibb-Statement-on-Opdivo-nivolumab-Small-Cell-Lung-Cancer-US-
Indication/default.aspx 
Brookmeyer R, Crowley J.  A confidence interval for the median survival time.  
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Byers LA, Rudin CM.  Small cell lung cancer:  where do we go from here?  Cancer.  
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Clopper CJ and Pearson ES.  The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial.  Biometrika.  1934;26:404-413. 
Coiffier B, Altman A, Pui C-H, et al.  Guidelines for the Management of Pediatric and 
Adult Tumor Lysis Syndrome:  An Evidence-Based Review.  J Clin Oncol.  
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Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer.  2009;45:228-247. 
Friberg G, Reese D.  Blinatumomab (Blincyto):  lessons learned from the bispecific t-cell 
engager (BiTE) in acute lymphocytic leukemia (ALL). Annals of Oncology. 2017;28:2009. 
González-Rodríguez E, Rodríguez-Abreu D; Spanish Group for Cancer Immuno 
Biotherapy (GETICA).  Immune Checkpoint Inhibitors:  Review and Management of 
Endocrine Adverse Events.  Oncologist. 2016 Jul;21(7):804-816. 
doi:10.1634/theoncologist.2015-0509. Epub 2016 Jun 15 
Guo W, Wang SJ, Yang S, Lynn H, Ji Y.  A Bayesian interval dose-finding design 
addressing Ockham’s razor:  mTPI-2.  Contemp Clin Trials. 2017;58:23-33. 
Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM.  Bronchopulmonary 
neuroendocrine tumors.  Cancer.  2008;113:5-21. 
IMFINZI United States Prescribing Information 
https://www.azpicentral.com/imfinzi/imfinzi.pdf#page1 
Ji Y, Liu P, Li Y, Bekele BN.  A modified toxicity probability interval method for 
dosefinding trials.  Clin Trials.  2010;7:653-663. 
Kalbfleisch JD, Prentice RL.  The statistical analysis of failure time data. John Wiley & 
Sons, Inc., New York, 1980. xi + 321 pp 
Kalemkerian GP, Darwish B, Varterasian ML.  Tumor lysis syndrome in small cell 
carcinoma and other solid tumors.  Am J Med.  1997 Nov;103(5):363-367. 
Kallab AM, Jillella AP.  Tumor lysis syndrome in small cell lung cancer.  Med Oncol.   
2001;18(2):149-151. 


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Keytruda United States Prescribing Information, 2020.  
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf 
Köhnke T, Krupka C, Tischer J, Knösel T, Subklewe M.  Increase of PD-L1 expressing 
B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager 
antibody blinatumomab.  J Hematol Oncol.  2015;8:111.  Published 2015 Oct 8. 
doi:10.1186/s13045-015-0213-6 
Koinis F, Kotsakis A, Georgoulias V.  Small cell lung cancer (SCLC):  no treatment 
advances in recent years.  Transl Lung Cancer Res.  2016;5:39-50 
Lee DW, Gardner R, Porter DL, et al.  Current concepts in the diagnosis and 
management of cytokine release syndrome.  Blood 2014;124(2):188-195 
Merck.  Merck Provides Update on KEYTRUDA (pembrolizumab) Indication in 
Metastatic Small Cell Lung Cancer in the US.  2021.  
https://www.merck.com/news/merck-provides-update-on-keytruda-pembrolizumab-
indication-in-metastatic-small-cell-lung-cancer-in-the-us/. 
NCCN Guidelines.  Immunotherapy.  2021.  
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 
Neelapu SS, Tummala S, Kebriaei P, et al.  Chimeric antigen receptor T-cell therapy - 
assessment and management of toxicities.  Nat Rev Clin Oncol.  2018;15(1):47-62. 
Nishino M, Giobbie-Hurder A, Gargano M, et al.  Developing a common language for 
tumor response to immunotherapy:  immune-related response criteria using 
unidimentional measurements.  Clin Cancer Res.  2013;19:3936-3943. 
Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA.  Induction of regular 
cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I 
negative tumor cells.  Mol Immunol.  2006;43:763-771. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
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J Hematol Oncol.  2019;12:61. 
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Society of Clinical Oncology endorsement of the American College of Chest Physicians 
guideline.  J Clin Oncol.  2015;33:4106-4111. 
Sylvant United States Prescribing Information, 2014. 
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TECENTRIQPrescribing Information 2019. 
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Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for single-arm 
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Trigo J, Subbiah V, Besse B, et al.  Lurbinectedin as second-line treatment for patients 
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Webster J, Luskin MR, Prince GT, et al.  Blinatumomab in combination with immune 
checkpoint inhibitors of PD-1 and CTLA-4 in adult patients with relapsed/refractory (R/R) 
CD19 positive B-Cell acute lymphoblastic leukemia (ALL): preliminary results of a 
phase I study.  Blood.  2018;132(Suppl 1):557. doi: 10.1182/blood-2018-99-111845. 
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2009;15:7412-7420. 
 
 


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11. 
Appendices  
 
 


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11.1 
Appendix 1.  List of Abbreviations  
 
Abbreviation 
Explanation 
ACTH  
adrenocorticotropic hormone  
ADA-IC 
anti-drug antibody related immune complexes 
ADAs 
anti-drug antibodies 
ADCC 
antibody-dependent cellular cytotoxicity 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
ASR 
aspartate aminotransferase 
Annual Safety Report 
AUC 
area under the concentration-time curve 
BCG 
bacille Calmette-Guerin 
BiTE® 
BNP 
bi-specific T-cell engager 
B-Natriuretic Peptide 
BP 
blood pressure 
CBC 
complete blood count 
CD3 
cluster of differentiation 3 
CFR 
Code of Federal Regulations 
CI 
confidence intervals 
Cmax 
maximum serum concentration 
Cmin 
minimum serum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
CSF 
cerebral spinal fluid 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
dose de-escalation 


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Abbreviation 
Explanation 
DCR 
disease control rate 
DILI 
drug induced liver injury 
DLL3 
delta-like ligand 3 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
DNA 
dose-limiting toxicity  
deoxyribonucleic acid 
DSUR 
DOR 
Development Safety Update Report 
duration of response 
E 
dose escalation 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ED 
extensive disease 
EI 
dosing interval 
EDC 
electronic data capture 
EOI 
end of infusion 
EOT 
End of treatment 
EP 
platinum-etoposide 
EpCAM 
epithelial cell adhesion molecule 
eSAE 
electronic Serious Adverse Event 
EU 
European Union 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GSO 
Global Safety Officer 
GLP 
Good Laboratory Practice 
HBcAb 
anti-hepatitis B antibody 
HBsAg 
hepatitis B antigen 
HCV 
hepatitis C 
HCVAb 
Hepatitis C virus antibody 


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Abbreviation 
Explanation 
HI 
overdosing intervals 
HIV 
human immunodeficiency virus 
HLE 
half-life extended 
HNSTD  
Highest Non-Severely Toxic Dose 
HR 
heart rate 
HUVECs 
human endothelial cells 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN- 
interferon gamma 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
intravenous(ly) 
LD 
limited disease 
LDH  
lactate dehydrogenase 
LH 
luteinizing hormone 
LI 
under-dosing intervals 
LVEF 
left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
MMSE 
Mini Mental Status Examination 
MRI 
magnetic resonance imaging 
mTPI 
modified toxicity probability interval 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCT 
National Clinical Trials 
ND 
not done 
NSAIDs 
non-steroidal anti-inflammatory drugs 
OR 
Objective response 
OS 
overall survival 
PAVA 
pool adjacent violators algorithm 


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Abbreviation 
Explanation 
PBL 
peripheral blood leukocytes 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PD-1 
programmed cell death-1 
PD-L1 
programmed death ligand-1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PPP 
Platelet Poor Plasma 
PR 
partial response 
Pre 
pre-infusion 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PTU 
propylthiouracil 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RO 
receptor occupancy 
RP2D 
recommended phase 2 dose 
RR 
RNA 
respiratory rate 
ribonucleic acid 
S 
current dose 
SARS-CoV-2 
severe acute respiratory syndrome-coronavirus-2 
SC 
subcutaneous 
scFC 
single chain fragment crystallizable 
SCLC 
Small Cell Lung Cancer 
SD 
stable disease 
SFU 
safety follow-up 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SJS 
Stevens-Johnson syndrome 
SLD 
sum of the longest diameters 
SOI 
start of infusion 
SSKI 
saturated solution of potassium iodide 


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Abbreviation 
Explanation 
TBL 
total bilirubin 
TEAE(s) 
treatment-emergent adverse events(s) 
TEN 
toxic epidermal necrolysis 
TLS 
tumor lysis syndrome 
TNF 
tumor necrosis factor 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
UPM 
US 
USFDA 
unit probability mass 
United States 
United States food and drug administration 
USPI 
United States Prescribing Information 
WBC 
white blood cell 
 
 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests  
The tests detailed in Table 11-1 will be performed by the central laboratory and/or by the 
local 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. 


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Table 11-1.  Analyte Listing  
LOCAL/SAFETY LABS 
CENTRAL LABS 
Chemistry 
 
Sodium 
 
Potassium 
 
Chloride 
 
Bicarbonate or 
CO2  
 
Total protein 
 
Albumin 
 
Calcium 
 
Glucose 
 
BUN (Blood Urea 
Nitrogen) or 
Serum Urea 
 
Creatinine 
 
Total bilirubin 
 
Direct bilirubin 
 
Alkaline phos 
 
AST (SGOT) 
 
ALT (SGPT) 
 
Estimated CrCl, 
GFR, MDRD 
calculation 
 
 
CBC with differential 
 
RBC 
 
Hemoglobin 
 
MCV 
 
Platelets 
 
WBC 
 
Differentials 
5-part differential: 
 
Lymphocytes 
 
Monocytes 
 
Eosinophilsa 
 
Basophilsa 
 
Total Neutrophilsa 
or (Segmented 
neutrophils and 
bands/stabs]  
3-part differential if 
unable to perform 
5-part: 
 
Lymphocytes 
 
Granulocytes 
 
Monocytes 
OR 
 
Lymphocytes 
 
Neutrophils 
 
Mid-cell fraction 
Coagulation 
 
PT/INR 
 
Partial 
Thromboplastin 
Time (PTT) or 
Activated Partial 
Thromboplastin 
Time (aPTT) 
 
Urinalysis 
 
Blood 
 
Protein  
 
Glucose 
 
Bilirubin 
 
Endocrine safety 
 
Cortisol (AM 
sample preferred) 
 
TSH 
 
FT4 
 
ACTH (AM sample 
preferred) 
Only collected at 
screening and EOT  
 
Prolactin 
 
FSH 
 
LH 
 
Estradiol (in 
females) 
 
Testosterone (in 
Males) 
 
Biomarker analysis  
 
Other Labs: 
 
Tarlatamab PK 
 
AMG 404 PK 
 
Pre-dose tumor 
tissue (archival or 
fresh tumor biopsy) 
Other safety labs 
 
 
CRP 
 
Ferritin 
 
LDH 
 
Uric Acid 
 
Phosphorus 
 
HIV antibody 
testing 
 
 
Pregnancy test 
(serum or urine) 
 
Amylase 
 
Lipase 
 
Hepatitis Serology 
Testing 
 
Hep B surface 
antigen 
 
Hep C antibody 
 
Hep B total core 
antibody 
 
a Local lab may report Granulocytes instead of Neutrophils, Eosinophils, and Basophils individually. 
ACTH  adrenocorticotropic hormone; ALT  alanine aminotransferase; AM  ante-meridiem; aPTT  
activated partial thromboplastin time; AST  aspartate aminotransferase; BUN  blood urea nitrogen; 
CBC  complete blood count; CO2  carbon dioxide; CrCL  creatine clearance; CRP  c-reactive protein; 
EOT  end of treatment; FSH  follicle stimulating hormone; FT4  free thyroxine; Hep B  hepatitis B; 
Hep C  hepatitis C; GFR  glomerular filtration rate; HIV  human immunodeficiency virus; INR  
international normalized ratio; LDH  lactate dehydrogenase; LH  luteinizing hormone; MCV  mean 
corpuscular volume; MDRD  modification of diet in renal disease; PT  prothrombin time; PTT  partial 
thromboplastin time;
 PK  pharmacokinetics; RBC  red blood 
cell; SGOT  serum glutamic-oxaloacetic transaminase; SFU  safety follow-up; SGPT  serum 
glutamic-pyruvic transaminase; TSH  thyroid stimulating hormone; WBC  white blood cell 


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If the subject is being followed for possible drug induced liver injury (DILI), the following 
analytes may be tested at the local laboratory depending on the clinical situation (see 
Section 11.7): 
Table 11-2.  DILI Potential Analyte Listing  
Chemistry 
Total bilirubin, direct bilirubin, ALP, LDH, AST (SGOT), ALT (SGPT), 
creatine kinase, ferritin, gamma-glutamyl transferase, haptoglobin 
Hematology 
Hemoglobin, Platelets, RBC Morphology, WBC Count, WBC Differential 
Coagulation 
PT, INR 
Immunology 
5 Prime Nucleotidase, Alpha-1 Antitrypsin, Antinuclear Antibodies, Anti-
Smooth Muscle Antibody, Anti-Soluble Liver Ag/Liver-Pancreas Ag, 
Cytomegalovirus IgG Antibody, Cytomegalovirus IgM Antibody, Endomysial 
IgA Antibody, Epstein-Barr Virus EDA IgG Antibody, Epstein-Barr Virus NA 
IgG Antibody, Epstein-Barr Virus VCA IgG Antibody, Epstein-Barr Virus 
VCA IgM Antibody, Hepatitis A Virus IgG Antibody, Hepatitis A Virus IgM 
Antibody, Hepatitis B Core Antibodies, Hepatitis B Core IgM Antibody, 
Hepatitis B Surface Antigen, Hepatitis B Virus DNA Genotyping, Hepatitis B 
Virus Surface Antibody, Hepatitis C Antibodies, Hepatitis C Virus RNA 
Genotyping, Hepatitis D Virus Antibody, Hepatitis E IgG Antibody, Hepatitis 
E IgM Antibody, Herpes Simplex Virus Type 1_2 IgG AB, Herpes Simplex 
Virus Type 1_2 IgM AB, Human Herpes Virus 6 DNA, Human Herpes Virus 
7 DNA, Human Herpes Virus 8 DNA, Immunoglobulin G, Liver Kidney AB 1,  
Parvovirus IgM/IgG Antibody, Serum Caeruloplasmin, Tissue 
Transglutaminase IgA Antibody, Toxoplasma IgM/IgG, Varicella Zoster 
Virus Antibody 
Toxicology 
Acetaminophen 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
Ig  immunoglobulin; INR  international normalized ratio; LDH  lactate dehydrogenase; PT  prothrombin 
time; RBC  red blood cell; SGOT  serum glutamic-oxaloacetic transaminase; SGPT  serum 
glutamic-pyruvic transaminase; WBC  white blood cell 
 
 


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11.3 
Appendix 3.  Study Governance Considerations  
Dose Level Review Meetings (DLRM)  
A dose level review meeting (DLRM) is conducted to review and interpret safety data for 
the purposes of making recommendations about dose-level escalation (either to the next 
planned dose or to an intermediate dose), dose level de-escalation, cohort continuation, 
or cohort expansion; making recommendations about non-dose escalation cohorts (eg, 
expanded, highest dose and/or final cohort); and evaluating safety signals for purposes 
of applying Dose Cohort Stopping Rules.  Based on emerging safety data, the dose level 
review team (DLRT) will make recommendations on the day of AMG 404 administration 
in cycle 1 as well as the dose of tarlatamab administered.  The DLRT will make 
recommendations on additional premedications, including the recommendation to 
implement additional corticosteroids (dexamethasone
 mg orally [PO] 6 to 16 hours 
prior to the first step dose and step dose[s] in cycle 1) based on emerging results from 
Part D in the ongoing first-in-human (FIH) study (20160323), as well as emerging data 
from the current study (20200439).  The DLRT will also make any recommendations on 
adjustments to the step-dosing schedule if necessary.  Additionally, based on emerging 
safety data, the DRLT may make recommendations on the hospitalization requirements, 
including reducing or eliminating the required hospitalization time in cycle 1 or cycle 2.  
The required DLRT members are the Medical Monitor, Global Safety Officer (GSO), and 
Site Investigators.  The DLRT will include actively screening and enrolling Site 
Investigators.  The Medical Monitor, GSO, and Site Investigators are the only voting 
DLRT members.  The following non-voting Amgen representatives may also be part of 
the DLRT:  as appropriate other functional area representatives (eg, clinical study 
manager, biostatistician, or pharmacokinetic (PK) scientist). 
The Medical Monitor must be in attendance and cannot be represented by a voting 
designee or delegate.  Voting designees can be identified as appropriate by the GSO or 
Site Investigator(s).  A Site Investigator may identify a delegate (eg, sub-Investigator) 
who is listed in the Delegation of Authority.  If a Site Investigator does this, the Site 
Investigator must provide written agreement with the designee or delegate’s vote. 
For a DLRM to occur, the Medical Monitor must attend, and the GSO or delegate must 
attend.  In addition, a quorum of Site Investigators must be present.  A quorum is defined 
as greater than or equal to 50 of the participating investigators or their qualified 
designee.  The DLRM will be rescheduled if these requirements are not met. 


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All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, electrocardiogram (ECG), 
vital signs, and laboratory results will be reviewed.  Data will not need to be source data 
verified and queries will not need to be resolved prior to the DLRM. 
DLRM voting will occur as follows:  there will be a total of 3 votes, 1 for the Medical 
Monitor, 1 for the GSO or delegate, and 1 for all the Site Investigators or delegates 
combined.  Regardless of how many Site Investigators there are, all the Site 
Investigators combined will have a total of 1 vote decided by a majority of``` the 
investigators (defined as greater than or equal to 50). 
DLRM recommendations to escalate to the next planned cohort, or to an intermediate 
cohort, must be by unanimous vote.  If the voting members of the DLRT are not able to 
reach a unanimous recommendation on whether to escalate to the next planned cohort 
or to an intermediate cohort, then this should be reflected in the DLRM Memo.  Other 
recommendations, such as expanding a cohort or lowering a dose will be made by a 
majority vote. 
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), 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 ICF 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. 


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During the course of the study, if new information becomes available that alters the 
benefit-risk of the study or the study drug, Amgen will follow applicable regulations to 
notify investigators, the IRB/IEC, and regulatory authorities, as appropriate. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process  
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample ICF are 
to be communicated formally in writing from the Amgen Trial Manager to the 
investigator.  The written informed consent form is to be prepared in the language(s) of 
the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered and answer all questions regarding the 
study. 
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 


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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 or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 1. 
If important new information becomes available that may be relevant to the subject’s 
consent during their participation in the study, subjects will be reconsented.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 30 days from the previous informed consent form signature 
date. 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  


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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. 
The 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. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study. 
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the Sponsor’s systems.  The 


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Sponsor uses access-controlled systems to house, review and analyze subject data.  
These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The Sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the Sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 
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. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be prepared in accordance with Amgen’s publications policy 
and submitted to Amgen for review.  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 


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data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations  
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
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 


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any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case report forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents  
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the 
interactive response technology (IRT) system (if used, such as subject ID and 


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randomization number) and CRF entries if the CRF is the site of the original recording 
(i.e., there is no other written or electronic record of data, such as paper questionnaires 
for a clinical outcome assessment or certain demographic information). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure  
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP. 
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by a separate protocol or as provided for by the local country’s regulatory mechanism.  


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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 [ECG], radiological scans, vital 
signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
investigator (i.e., 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 small cell 
lung cancer (SCLC) report all known signs and symptoms.  Death due to disease 
progression in the absence of signs and symptoms should be reported as the 
primary tumor type (eg, metastatic pancreatic cancer).  Note:  The term “disease 
progression” should not be used to describe the adverse event. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.  
 


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Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event  
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 


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Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Recording Adverse Events and Serious Adverse Events  
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event Case Report Form (CRF). 
 
The investigator must assign the following mandatory adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to first dose of investigational product, other protocol-
required therapies; 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product(s) and other 
protocol-required therapies.  
o Assessment of relatedness to study-required activity and/or procedures 
is only required for serious adverse events. 
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 as a single event with the worst severity on the Event CRF. 


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 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to sponsor/responsible contract research organization (CRO) in lieu of 
completion of the Event CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events  
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 4 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product(s) protocol-required therapies and each occurrence of each adverse event. 
 
The investigator is obligated to assess the relationship between 
investigational product(s) protocol-required therapies, study-required 
activity and/or procedures and each occurrence of each 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 they have reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. For sites reporting serious 
adverse events via electronic data capture (EDC), the investigator or sub 


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investigator must confirm causality in EDC within 72 hours of the serious adverse 
event being entered on the Events CRF. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. In this case, for sites reporting serious adverse events via 
EDC, the investigator or sub-investigator must reconfirm causality in the EDC 
system within 72 hours of the serious adverse event being entered on the Events 
CRF. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
immediately and no later than 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, then the site will report the information to Amgen 
using a paper-based Serious Adverse Event Contingency Report Form (also 
referred to as the electronic Serious Adverse Event (eSAE) Contingency Report 
Form) (see Figure 11-1) immediately and no later than 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. 


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 
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 system has been taken off-line, then the site can report this information on 
the paper-based Serious Adverse Event Contingency Report Form (see 
Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen immediately and not later 
than 24 hours of the investigator's awareness of the 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 
(paper-based form)  
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information  
Study-specific contraception requirements for males and females of childbearing 
potential are outlined in Section 5.2.  Contraceptive use and methods should be 
consistent with local regulations for subjects participating in clinical studies. 
Male and female subjects of childbearing potential should be advised of the pregnancy 
prevention requirements and the potential risk to the fetus if they become pregnant (or 
father a child) during treatment and for 
, respectively, after the last 
dose of tarlatamab.  Additionally, subjects will have pregnancy prevention requirements 
 following the last dose of AMG 404 (females), and an additional 
 
following the last dose of AMG 404 (males). 
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 documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Females with 
documented permanent infertility due to an alternate medical cause 
(eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), can be considered 
not of childbearing potential. 
Note:  Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of ≥ 55 years with no menses for 12 months without an alternative medical 
cause OR   
 
A woman age < 55 years with no menses for at least 12 months and with a 
follicle-stimulating hormone (FSH) level within the definition of “postmenopausal 
range” for the laboratory involved.  In the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 


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 
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 
 days following the last 
dose of tarlatamab, and 
 days following the last dose of AMG 404 
The female partner should consider using a method of contraception for female subjects 
stated above (a female condom should not be used 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. 
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 
after the last 
dose of tarlatamab, and 
 after the last dose of AMG 404. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety immediately and no 
later than 24 hours of the site’s awareness 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 
 
following the last dose of tarlatamab and 
 following the last dose of 


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AMG 404.  This information will be forwarded to Amgen Global Patient Safety.  
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an adverse event or serious adverse event.  
Abnormal pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, 
congenital anomalies) 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. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting. 
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment while pregnant (see Section 7.1 for details). 
Male Subjects with Partners Who Become Pregnant 
 
In the event a male subject fathers a child during treatment, and for an additional 
 following the last dose of tarlatamab, and 
 following the last dose 
of AMG 404 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 immediately and no later than 24 hours 
of the site’s awareness of the pregnancy.  (Note:  Sites are not required to provide 
any information on the Pregnancy Notification Form that violates the country or 
regions local privacy laws). 
 
Males whose partners become pregnant during treatment and for an additional 
 after the last dose of tarlatamab, and 
 after the last dose of 
AMG 404 must practice sexual abstinence or use a condom through 
 after 
the last dose of tarlatamab, and 
 after the last dose of AMG 404. 
 
The investigator will attempt to obtain a signed consent 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 consent 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). 


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 
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 
 after the last dose of 
tarlatamab, and 
 after the last dose of AMG 404. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety immediately and no later than 24 hours 
of the investigator’s awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 226. (See Section 5.2). 
 
With the female subjects signed consent 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 
 after the last dose of tarlatamab 
and 
 after the last dose of AMG 404. 


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Figure 11-2.  Pregnancy and Lactation Notification Forms  
 


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11.6 
Appendix 6.  Sample Storage and Destruction  
When permitted by local regulations, any blood, biomarker, pharmacokinetic (PK) 
sample collected according to the Schedule of Activities (Section 1.3) can be analyzed 
for any of the tests outlined in the protocol and for any tests necessary to minimize risks 
to study subjects.  This includes testing to ensure analytical methods produce reliable 
and valid data throughout the course of the study.  This can also include, but is not 
limited to, investigation of unexpected results, incurred sample reanalysis, and analyses 
for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
When permitted by local regulations and if informed consent is provided by the subject, 
Amgen can do additional testing on remaining samples (i.e., residual and back-up) to 
investigate and better understand the small cell lung cancer, the dose response and/or 
prediction of response to Amgen investigational product(s) or other protocol-specified 
therapy, characterize antibody response, and characterize aspects of the molecule (eg, 
mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of 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. 


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


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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines  
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity  
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 


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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.  
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 
> 3 x ULN  
at any time 
> 2 x ULN 
 
 
OR 
INR 
-- 
> 1.5 x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8 x ULN at any time 
> 5 x ULN but < 8 x ULN for ≥ 2 weeks 
> 5 x ULN but < 8 x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3 x ULN with clinical signs or symptoms
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3 x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8 x ULN at any time 
-- 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; INR  
international normalized ratio; TBL  total bilirubin; ULN  upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity  
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then tarlatamab and other protocol-required 
therapies are 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 immediately and 
no later than 24 hours of discovery or notification of the event (i.e., 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 (LDH), and peripheral 
blood smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for PK analysis if this has not already been collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  
 


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11.8 
Appendix 8.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG)  
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50 of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50 of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair 
5 
Dead 
ECOG  Eastern Cooperative Oncology Group. 
Source:  Oken et al, 1982


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11.9 
Appendix 9.  Modified Response Evaluation Criteria in Solid Tumors 
Version 1.1 (Modified RECIST 1.1)  
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) are guidelines 
for assessing tumor burden changes in response to treatment (Eisenhauer et al, 2009).  
Additional patterns of response have been observed with immune-enhancing therapies, 
including delayed clinical response, leading to criteria modifications to capture treatment 
responses more accurately (Nishino et al, 2013; Wolchok et al, 2009).  This study 
utilizes modified RECIST 1.1 criteria which applies aspects of the immune-related 
response criteria (including requiring confirmation of disease progression) to RECIST 1.1 
as outlined below. 
Modified RECIST 1.1 tumor response assessment 
 
All measurable and non-measurable lesions should be assessed at screening, all 
defined tumor assessment time points (Schedule of Assessment), and any 
unscheduled imaging visits. 
Measurable lesions: 
 
Non-nodal lesions with clear borders that can be measured accurately and 
serially in one dimension in the axial plane (longest diameter ≥ 10 mm measured 
by magnetic resonance imaging/computed tomography (MRI/CT) with scan slice 
thickness ≤ 5 mm). 
 
Nodal lesions with the longest diameter perpendicular to the long axis (short axis) 
≥ 15 mm on MRI/CT. 
 
Must exclude simple cysts, pleural/pericardial effusions and ascites. 
Non-measurable lesions: 
 
All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 mm but < 15 mm short axis) are considered 
non-measurable and characterized as non-index lesions.   
 
Other examples of non-measurable lesions include: 
 
Lesions with prior local treatment: 
▪ 
Tumor lesions situated in a previously irradiated area, or an area 
subject to other loco-regional therapy, should not be considered 
measurable unless there has been demonstrated progression in 
the lesion. 
 
Biopsied lesions 
 
Categorically, clusters of small lesions, bone lesions, inflammatory breast 
disease, and leptomeningeal disease are non-measurable.  See Imaging 
Procedural Manual provided by the central imaging core laboratory for 
additional guidance. 


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


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


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


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11.10 
Appendix 10.  Schedule of Activities:  
Table 11-4.  List of Schedule of Activities Tables  
Quick link to 
Schedule of 
Activities 
Table Title 
Table 11-5 
One-Step Dosing – Cycle 1 only (AMG 404 Administered
 
Table 11-6 
One-Step Dosing – Cycle 1 only (AMG 404 Administered 
 
Table 11-7 
One-Step Dosing – Cycle 1 only (AMG 404 Administered 
 
Table 11-8 
Cycle 2 and Beyond (AMG 404 Administered on
in Cycle 1) 
Table 11-9 
Cycle 2 and Beyond (AMG 404 Administered on 
in Cycle 1) 
 
 


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Table 11-5.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
  
STUDY PERIOD/ 
TREATMENT 
CYCLE 
SCRa 
Cycle 1 only 
WEEKb 
-3 
to -1 
1 
2 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
General/Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluatione 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Vital signs, pulse 
oxf 
X 
X 
X 
X 
X 
Xf 
 
 
X 
X 
Xf 
X 
X 
X 
Xf 
X 
X 
12-lead ECGg 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
review 
 
 
=======================================================================================================➔ 
Serious adverse 
event review 
=====================================================================================================================➔ 
Prior/concomitant 
medication  
=====================================================================================================================➔ 
Local Laboratory Assessments 
CBC with 
differential 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Chemistry panelh 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Lipase and 
Amylase 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine 
pregnancy testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety endocrine 
panelj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP  
 
X 
 
 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Ferritin 
 
X 
 
 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
HBsAg, HBcAb, 
HCV Ab, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 3 
Footnotes described after Table 11-9 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 161 of 173 
CONFIDENTIAL  
 
 
Table 11-5.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
 
STUDY PERIOD/ 
TREATMENT 
CYCLE 
SCRa 
Cycle 1 only 
WEEKb 
-3 
to -1 
1 
2 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
Central and Biomarker Laboratory Tests 
Study Drug Administration 
Tarlatamab IV 
infusiont 
AMG 404 IV 
infusiont 
Page 2 of 3 
Footnotes described after Table 11-9 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 162 of 173 
CONFIDENTIAL  
 
 
Table 11-5.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
 
STUDY PERIOD/ 
TREATMENT 
CYCLE 
SCRa 
Cycle 1 only 
WEEKb 
-3 
to -1 
1 
2 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
Study Drug Administration (continued) 
Dexamethasone or 
equivalentu  
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
IV Hydrationv 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Hospital stayw 
 
=============================➔ 
 
 
===================➔ 
 
=======================➔ 
 
 
Other Assessments 
MRI Brainx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiological 
imaging and tumor 
burden 
assessmenty 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 3 
Footnotes described after Table 11-9 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 163 of 173 
CONFIDENTIAL  
 
 
Table 11-6.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
  
STUDY PERIOD/ 
TREATMENT 
CYCLE 
SCRa  
Cycle 1 only 
WEEKb 
-3 
to -1 
1 
2c 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 757 
 EOI 757 
2 
6 
24 
48 
96 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
General/Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluatione 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Vital signs, pulse 
oxf 
X 
X 
X 
Xf 
 
 
X 
X 
X 
X 
Xf 
X 
X 
X 
Xf 
X 
X 
12-lead ECGg 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
review 
 
 
=======================================================================================================➔ 
Serious adverse 
event review 
=====================================================================================================================➔ 
Prior/concomitant 
medication  
=====================================================================================================================➔ 
Local Laboratory Assessments 
CBC with 
differential 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Chemistry panelh 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Lipase and 
Amylase 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine 
pregnancy Testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety endocrine 
panelj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP  
 
X 
 
 
X 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Ferritin 
 
X 
 
 
X 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
HBsAg, HBcAb, 
HCV Ab, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central and Biomarker Laboratory Tests 
Page 1 of 3 
Footnotes described after Table 11-9 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 164 of 173 
CONFIDENTIAL  
 
 
Table 11-6.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
 
STUDY PERIOD/ 
TREATMENT 
CYCLE 
SCRa  
Cycle 1 only 
WEEKb 
-3 
to -1 
1 
2c 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 757 
 EOI 757 
2 
6 
24 
48 
96 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
Central and Biomarker Laboratory Tests (continued) 
Study Drug Administration 
Tarlatamab IV 
infusiont 
AMG 404 IV 
infusiont 
Dexamethasone or 
equivalentu  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
IV Hydrationv 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Hospital stayw 
 
==================➔ 
 
 
=============================➔ 
 
=====================➔ 
 
 
Page 2 of 3 
Footnotes described after Table 11-9 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 165 of 173 
CONFIDENTIAL  
 
 
Table 11-6.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
 
STUDY PERIOD/ 
TREATMENT 
CYCLE 
SCRa  
Cycle 1 only 
WEEKb 
-3 
to -1 
1 
2c 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 757 
 EOI 757 
2 
6 
24 
48 
96 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
Other Assessments 
MRI Brainx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiological 
imaging and tumor 
burden 
assessmenty 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 3 
Footnotes described after Table 11-9 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 166 of 173 
CONFIDENTIAL  
 
 
Table 11-7.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
  
STUDY PERIOD/ 
TREATMENT CYCLE 
SCRa  
Cycle 1 only 
WEEKb 
-3 to -1 
1 
2c 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
General/Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluatione 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Vital signs, pulse oxf 
X 
X 
X 
Xf 
X 
X 
X 
X 
Xf 
X 
X 
X 
X 
X 
Xf 
X 
X 
12-lead ECGg 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event review 
 
 
=======================================================================================================➔ 
Serious adverse 
event review 
====================================================================================================================➔ 
Prior/concomitant 
medication  
====================================================================================================================➔ 
Local Laboratory Assessments 
CBC with differential 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
X 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
Chemistry panelh 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
Lipase and Amylase 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine 
pregnancy Testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety endocrine 
panelj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP  
 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
Ferritin 
 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
HBsAg, HBcAb, HCV 
Ab, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central and Biomarker Laboratory Tests 
Page 1 of 2 
Footnotes described after Table 11-9 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 167 of 173 
CONFIDENTIAL  
 
 
Table 11-7.  Schedule of Activities:  One-Step Dosing – Cycle 1 Only (AMG 404 Administered 
 
STUDY PERIOD/ 
TREATMENT CYCLE 
SCRa  
Cycle 1 only 
WEEKb 
-3 to -1 
1 
2c 
3 
4 
DAYb 
HOUR (relative to 
infusion)d 
 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
Pre 757 
EOI 757 
2 
6 
24 
48 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
Central and Biomarker Laboratory Tests (continued) 
Study Drug Administration 
Tarlatamab IV infusiont 
AMG 404 IV infusiont 
Dexamethasone or 
equivalentu  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
IV Hydrationv 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Hospital stayw 
 
==================➔ 
 
 
===================➔ 
 
================================➔ 
 
 
Other Assessments 
MRI Brainx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiological imaging 
and tumor burden 
assessmenty 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
Footnotes described after Table 11-9


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 168 of 173 
CONFIDENTIAL  
 
 
Table 11-8.  Schedule of Activities:  Cycle 2 and Beyond (If AMG 404 was Administered on 
 in Cycle 1)  
STUDY PERIOD/ 
TREATMENT CYCLE 
Cycle 2  
Q cycbb 
Q2 cyc 
EOThh 
SFU-1ee 
SFU-2ff 
LTFUaa 
WEEKb 
1 
2c 
3 
4 
1 
3 
1 
 
 
 
 
DAYb 
HOUR (relative to 
infusion)d 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
168 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
 
 
 
 
 
 
 
General/Safety Assessments 
Clinical Evaluatione 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Vital signs, pulse oxf 
X 
X 
X 
X 
Xf 
X 
X 
X 
X 
X 
Xf 
X 
X 
X 
X 
 
X 
X 
X 
 
12-lead ECGg 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Xcc 
Xcc 
 
 
 
 
 
ECHO or MUGA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event review 
 
========================================================================================================➔ 
 
Serious adverse event 
review 
===================================================================================================================➔ 
Prior/concomitant 
medication 
===================================================================================================================➔ 
Local Laboratory Assessments 
CBC with differential 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Coagulation 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Chemistry panelh 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Lipase and Amylase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum/urine pregnancy 
Testi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Safety endocrine panelj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
CRP  
X 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Ferritin 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Central and Biomarker Laboratory Tests 
Page 1 of 2 
Footnotes described after Table 11-9 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 169 of 173 
CONFIDENTIAL  
 
 
Table 11-8.  Schedule of Activities:  Cycle 2 and Beyond (If AMG 404 was Administered on 
 in Cycle 1) 
STUDY PERIOD/ 
TREATMENT CYCLE 
Cycle 2  
Q cycbb 
Q2 cyc 
EOThh 
SFU-1ee 
SFU-2ff 
LTFUaa 
WEEKb 
1
2c
3
4
1
3
1
 
 
 
 
DAYb 
HOUR (relative to 
infusion)d 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
168 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
 
 
 
 
 
 
 
General/Safety Assessments 
Tarlatamab PK 
collectionp 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Xq 
 
 
 
 
 
 
AMG 404 PK collectionp 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Xr 
 
 
 
 
X 
 
Study Drug Administration 
Tarlatamab IV infusiont 
AMG 404 IV infusiont 
Hospital stayw 
=============================➔ 
 
 
 
=================➔ 
 
 
 
 
 
 
 
 
 
Other Assessments 
MRI Brainx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiological imaging 
and tumor burden 
assessmenty 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xz 
Xz 
 
Xdd 
Survival Status and 
subsequent cancer 
therapyaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 2 of 2 
Footnotes described after Table 11-9 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 170 of 173 
CONFIDENTIAL  
 
 
Table 11-9.  Schedule of Activities:  Cycle 2 and Beyond (If AMG 404 was Administered on 
 in Cycle 1)  
STUDY PERIOD/ 
TREATMENT CYCLE 
Cycle 2  
Q cycbb 
Q2 cyc 
EOThh 
SFU-1ee 
SFU-2ff 
LTFUaa 
WEEKb 
1 
2c 
3 
4 
1 
3 
1 
 
 
 
 
DAYb 
HOUR (relative to 
infusion)d 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
168 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
 
 
 
 
 
 
 
General/Safety Assessments 
Clinical Evaluatione 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Vital signs, pulse oxf 
X 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xf 
X 
X 
X 
X 
 
X 
X 
X 
 
12-lead ECGg 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Xcc 
Xcc 
 
 
 
 
 
ECHO or MUGA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event review 
 
========================================================================================================➔ 
 
Serious adverse event 
review 
===================================================================================================================➔ 
Prior/concomitant 
medication 
===================================================================================================================➔ 
Local Laboratory Assessments 
CBC with differential 
X 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Coagulation 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Chemistry panelh 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Lipase and Amylase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum/urine pregnancy 
Testi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Safety endocrine panelj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
CRP  
X 
 
 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Ferritin 
X 
 
 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Central and Biomarker Laboratory Tests 
Page 1 of 2 
Footnotes described after Table 11-9 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 171 of 173 
CONFIDENTIAL  
 
 
Table 11-9.  Schedule of Activities:  Cycle 2 and Beyond (If AMG 404 was Administered on 
 in Cycle 1) 
STUDY PERIOD/ 
TREATMENT CYCLE 
Cycle 2  
Q cycbb 
Q2 cyc 
EOThh 
SFU-1ee 
SFU-2ff 
LTFUaa 
WEEKb 
1 
2c
3
4
1
3
1
DAYb 
HOUR (relative to 
infusion)d 
Pre 757 
EOI 757 
2 
6 
24 
48 
96 
168 
Pre 404 
EOI 404 
Pre 757 
EOI 757 
2 
6 
24 
48 
168 
 
 
 
 
 
 
 
Tarlatamab PK 
collectionp 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Xq 
 
 
 
 
 
 
AMG 404 PK collectionp 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Xr 
 
 
 
X 
 
Study Drug Administration 
Tarlatamab IV infusiont 
AMG 404 IV infusiont 
Hospital stayw 
===================➔ 
 
 
 
===========================➔ 
 
 
 
 
 
 
 
 
 
Other Assessments 
MRI Brainx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiological imaging 
and tumor burden 
assessmenty 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xz 
Xz 
 
Xdd 
Survival Status and 
subsequent cancer 
therapyaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 2 of 2 
Abbreviations used:  0  Hour zero; when Tarlatamab is infused; ACTH  adrenocorticotropic hormone; BP  blood pressure; C  cycle; C1
  cycle 1 
 
CBC  complete blood count; CNS  central nervous system; CRP  C-reactive protein; CT  computed tomography;
 ECG  electrocardiogram; ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic case report form; 
EOI  end of infusion; EOT  end of treatment; FFPE  formalin-fixed paraffin-embedded; FSH  follicle stimulating hormone; FT4  free thyroxine; 
HBcAb  anti-hepatitis B antibody; HBsAg  hepatitis B antigen; HCV  hepatitis C; HIV  human immunodeficiency virus; HR  heart rate; IGF-1  insulin-like growth 
factor 1; IV  intravenous; LH  luteinizing hormone; MUGA  multigated acquisition; LDH  lactate dehydrogenase; LTFU  long-term follow-up; MRI  magnetic 
resonance imaging;
 PD  progressive disease; PK  pharmacokinetic; Pre  pre-infusion; Q cyc  every cycle; Q2 
Cyc  every 2 cycles; RECIST  response evaluation criteria in solid tumors; RR  respiratory rate; SCR  screening; SFU  safety follow-up; SOI  start of infusion; 
TLS  tumor lysis syndrome; TSH  thyroid stimulating hormone 
a 
All screening procedures should be performed within 
 prior to cycle 1 
 dosing.   
b 
Each visit week and day is relative to 
 of each cycle.  Cycle 1 and 2 visits have a  1-day window from designated time point unless otherwise specified.  All 
subsequent visits beginning in cycle 3 will have a  3-day window. 
c 
See Section 6.2.1.3 for more details regarding Step Dosing. 
d 
 
End of infusion (EOI) assessments or procedures are to be completed immediately after infusion of tarlatamab.  EOI indicates the time when the 
investigational product infusion and saline flush is completed.  Assessments after EOI indicate the time relative to EOI.  Investigational product infusions are 
marked in the EOI column. 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 172 of 173 
CONFIDENTIAL  
 
 
 
Assessments are done pre-infusion unless specified.  
 
Laboratory assessments that were done within 24 hours prior to infusion do not need to be repeated (except for cycle 1 
 dosing where laboratory 
assessments that were done within 48 hours prior to infusion do not need to be repeated). 
 
All assessments and procedures should be collected at the exact nominal time point as noted in the Schedule of Assessments.  If unable to perform a 
procedure at the specified nominal time point, collect it as close as possible to the nominal time point and record the actual collection time. 
e 
Clinical evaluation including physical exam, ECOG, weight and neurological exams, writing test, and mini-mental status exams (neurology specialty consultation 
service as clinically indicated).  Mini mental status exams and writing test are required on 
 (if 
 clinical evaluation required per dosing regimen), 
 (may be performed if clinically indicated on days 
 in cycle 1.  Mini mental status exam and writing test may be performed in 
cycle 2 and beyond at the investigator’s discretion.  Performed at screening only:  demographics, medical history, and height.  Clinical evaluation should be 
completed within 6 hours prior to the first dose of tarlatamab. 
f 
Vital signs (BP, HR, RR, temp) and pulse oximetry will be assessed.  Vitals will be taken pre-AMG 404 infusion and at AMG 404 EOI. 
 
  For each 
tarlatamab-infusion for the first 2 cycles (during the hospitalization period) vital signs should be assessed as detailed in Section 8.4.1. 
g 
ECGs will be collected once and considered safety ECGs.  ECGs should be collected prior to blood draws when assessments are conducted at the same 
nominal time point (pre-infusion timepoints for tarlatamab and AMG 404 may be collected 15 minutes prior to infusion, post-infusion time points for tarlatamab 
may be collected ± 15 minutes of indicated time point).  See Section 8.4.5. 
h 
For cycles 1 and 2 only, please collect LDH, phosphorus, and uric acid along with the chemistry panel for TLS monitoring. 
i 
Serum pregnancy test at screening; serum or urine pregnancy test monthly until 
 from the last investigational product (tarlatamab or AMG 404) dose.  
Additionally, a pregnancy test at 
 after last dose of AMG 404. 
j 
Safety endocrine panels:  ACTH, cortisol, TSH, and FT4 will be evaluated at screening,
 of every cycle starting with cycle 2, EOT, and SFU-1.  Prolactin, 
FSH, LH, testosterone (in males) and estradiol (in females) will be evaluated only at screening, EOT, and as clinically indicated. 
m 
A tumor biopsy is required at screening if patient has received any treatment prior to participating into this study and biopsy can be performed safely as 
determined by the investigators.  Tumor tissue (archival or fresh biopsy) must be available.  Subjects must consent to allow the acquisition of FFPE material 
(block or unstained slides) by study personnel.   
q 
For cycles 3 and 4, collect tarlatamab PK samples at pre- and post-infusion.  For all remaining cycles beginning with cycle 5, collect at pre-infusion only.  
tarlatamab PK samples to be collected until end of cycle 12 only 
r 
AMG 404 PK samples to be collected at pre-infusion and end of infusion in cycles 3, 5, 7, 9, and 11 and at pre-infusion in cycles 4, 6, 8, 10, and 12. 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 173 of 173 
CONFIDENTIAL  
 
 
u 
Dexamethasone  mg IV (or equivalent dose of other corticosteroids) will be administered within 1 hour prior to all tarlatamab doses, in week 1 and step doses of 
tarlatamab in cycle 1 only. 
v 
Refer to Section 6.1.4 for administration details. 
w 
x 
All subjects must have MRI/CT of the brain performed within 
 prior to the first dose of tarlatamab.  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. 
y 
 
 
Tumor burden assessments will be performed based on modified RECIST 1.1 guidelines (see Section 11.9).  
 
 
z 
. 
aa LTFU will be conducted every 3 months ( 2 weeks) for 1 year from the first dose of tarlatamab on 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 only. If the investigator becomes aware of serious 
adverse events suspected to be related to investigational product or any fatal adverse event (regardless of causality) after the protocol-required 
reporting period (as defined in Section 8.4.9.1.3) is complete, then these serious adverse events will be reported to Amgen immediately and no later 
than 24 hours following the investigator’s awareness of the event on the Event eCRF. 
bb Assessments to be completed at specified timepoint beginning with cycle 3 and at each subsequent cycle unless otherwise specified. 
cc For cycles 3 and 4 only:  please collect ECG post-tarlatamab infusion.  No further ECG’s are collected after cycle 4.   
dd For subjects who discontinued treatment for any reason other than confirmed PD, every effort should be made to perform radiographic imaging (CT/MRI) of the 
chest, abdomen, pelvis, and all other known sites of disease every 3 months until documentation of confirmed PD per modified RECIST 1.1, clinical 
progression, start of new anticancer therapy, or up to 12 months after the first dose of tarlatamab, whichever occurs first.   
ee The first safety follow-up visit should be completed
 from the last dose (tarlatamab or AMG 404). 
ff 
The second safety follow-up visit should be completed
 after the last dose of AMG 404 or prior to initiation of other therapy, whichever occurs first. 
hh After end of study, serious adverse events suspected to be related to investigational product will be reported to Amgen.  Please refer to 
Section 8.4.9.1.3 for additional details. 
 
 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  10 November 2023 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
Amendment 4  
Protocol Title:  A Phase 1b Study Evaluating the Safety and Efficacy of AMG 757 in 
Combination with AMG 404 in Subjects with Small Cell Lung Cancer (SCLC)  
 
Amgen Protocol Number AMG 757, AMG 404, 20200439 
EudraCT number:  2020-005957-26 
NCT Number:  NCT04885998 
 
Amendment Date: 
10 November 2023 
 
Rationale: 
This protocol is mainly being amended to specify the conditions to be met for the 
continuation of tarlatamab treatment in subjects with radiologic disease progression, who 
continue to have clinical benefits as per the investigator’s judgement.  A new section 
(Section 7.2) has been added to elaborate the conditions to be met and language is 
being included throughout to update/clarify the protocol.  The following changes were 
also incorporated into the protocol: 
 
Updated the key sponsor contact as 
, MD and also updated the relevant 
contact details. 
 
Added language to the rationale in Section 1.1 and Section 2.1 to clarify that 
AMG 404 has been evaluated as a monotherapy agent. 
 
Added footnotes in the schedule of assessment tables (Table 1-2, Table 11-8 and 
11-9) to clarify the reporting requirements of serious adverse events. 
 
Removed sucrose-mediated renal impairment as a potential safety concern for 
tarlatamab and deleted language related to this throughout the protocol. 
 
Deleted language related to first-in-human study in Section 4.4.1.1. 
 
Clarified the requirements for recording and reporting of serious adverse events in 
Section 8.4.9.1.2 and Section 8.4.9.1.3 and changes associated with this were 
updated throughout the protocol. 
 
Clarified the timing for collecting pregnancy and lactation details for female subjects 
and female partners of male subjects after tarlatamab treatment in Section 8.4.9.6 
and associated changes were updated throughout the protocol. 
 
Administrative, grammatical and editorial changes have been made throughout the 
protocol for clarification. 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  04 April 2023 
Page 1 of 22 
 
Amendment 3 
Protocol Title:  A Phase 1b Study Evaluating the Safety and Efficacy of AMG 757 in 
Combination with AMG 404 in Subjects with Small Cell Lung Cancer (SCLC) 
 
Amgen Protocol Number Tarlatamab 20200439 
 
 
Amendment Date: 
04 April 2023 
 
Rationale: 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  28 January 2022 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
Amendment 2 
Protocol Title:  A Phase 1b Study Evaluating the Safety and Efficacy of AMG 757 in 
Combination with AMG 404 in Subjects with Small Cell Lung Cancer (SCLC) 
 
Amgen Protocol Number AMG 757, AMG 404, 20200439 
EudraCT number:  2020-005957-26 
NCT Number:  NCT04885998 
 
Amendment Date: 
28 January 2022 
 
Rationale: 
This protocol is being amended to address site shortages of tocilizumab.  Applicable 
sections of the protocol are being modified to clarify the use of siltuximab in place of 
tocilizumab for the treatment of potential cytokine release syndrome (CRS) during a 
treatment-related adverse event.  Language is being included throughout to 
update/clarify the protocol.  Changes including, but not limited to, the following were 
incorporated into the protocol: 
 
Added language to include neutropenia as a risk following study treatment 
administration and guidance for treatment of neutropenia 
 
Criteria for use of siltuximab in place of tocilizumab, justification for the proposed 
dose and schedule, and safety stopping rules were included 
 
Updated schedule of assessment (SOA) to exclude antineutrophil cytoplasmic 
antibodies (ANCA)/antinuclear antibody (ANA) testing as a clinical test; to modify 
fresh tumor biopsies language to allow biopsies on subjects who provide consent at 
the end of cycle 2 and end of treatment (EOT); and to clarify that safety endocrine 
panels are to be evaluated day 1 of every cycle starting with cycle 2 
 
Updated the SOA timepoints for the electrocardiogram (ECG), Coagulation, Lipases 
and amylase, C reactive protein (CRP), and ferritin assessments   
 
Updated AMG 757 and AMG 404 background clinical experience and key safety 
information sections, and AMG 757 toxicology section to reflect latest version of the 
Investigator’s Brochure (IB) 
 
Updated restarting AMG 757 dosing rules to allow resuming of dosing if the toxicities 
resolve to grade  1 or return to subjects’ baseline values within 3 weeks, instead of 
4 weeks  
 
Update end of study section to increase the total study duration from 12 to 
24 months 


Product:  Tarlatamab (AMG 757), AMG 404 
Protocol Number:  20200439 
Date:  28 January 2022 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
 
Update table for monitoring and management of pituitary gland dysfunction to align 
with latest approved AMG 757 protocol  
 
Updated long-term follow-up language to continue radiographic imaging for subjects 
that discontinued treatment for any reason 
 
Updated language in dosage formulation and dosing instructions in Table 6-1 of 
investigational products  
 
Updated language in vital signs and pulse oximetry section to exclude supine 
positioning as a requirement for vital signs to be measured 
 
Updated language on recording and reporting of serious adverse events. 
 
Updated contraception and pregnancy language  
 
Added vaccine and COVID-19 language  
 
Included hypothyroidism, colitis, myasthenia gravis, and other additional risks as 
potential safety risk to AMG 404 based on recent available clinical data   
 
Administrative and editorial changes have been made throughout the protocol for 
clarification 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  26 July 2021 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 1 
Protocol Title:  A Phase 1b Study Evaluating the Safety and Efficacy of 
AMG 757 in Combination with AMG 404 in Subjects with Small Cell Lung 
Cancer (SCLC) 
 
Amgen Protocol Number:  AMG 757, AMG 404 20200439  
 
Amendment Date: 
26 July 2021 
 
Rationale: 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  26 July 2021 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 

SAP_001.pdf: 
Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 1 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1b Study Evaluating the Safety and 
Efficacy of AMG 757 in Combination with AMG 404 
in Subjects with Small Cell Lung Cancer (SCLC) 
Short Protocol Title: 
AMG 757 and AMG 404 in Subjects with Small Cell 
Lung Cancer (SCLC) 
sProtocol Number: 
20200439 
NCT Number: 
NCT04885998 
Authors: 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA, 91329, USA 
SAP Date: 
Original (v1.0) 
6 September 2021 
Amendment 1 (v2.0) 
9 March 2022 
Amendment 2 (v3.0)          27 March 2023 
Amendment 3 (v4.0) 
08 May 2023 
Amendment 4 (v5.0) 
14 August 2023 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 2 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
06-September-
2021 
 
[Amendment 1 (v2.0)] 
09MAR2022 
 
Added section 7.1.1 as per the 
protocol amendment 2. 
 
Replaced AMG 757 with 
tarlatamab as per the PA2. 
 
Added the analysis sets as per 
PA2 except OR analysis set. 
 
Updated table 7 to remove 
sensitivity analysis and added 
“Analysis set”. 
 
Updated table 8 for the criteria 
37. 
[Amendment 2 (v3.0)] 
27MAR2023 
 
Updated section 5 to add the 
definitions of Duration of 
disease control, modified the 
definitions of Duration of 
response, Progression-free 
survival, Overall survival, 
TEAE, treatment-related TEAE. 
 
Updated section 6 to modify the 
definition of safety analysis set, 
interim efficacy analysis set. 
 
Updated section 9.5 efficacy 
analysis table to add a column 
“Analysis Set”. 
 
Updated 9.6.2 to include EOI 
related text. 
 
Updated appendices  
o A for the imputation of 
death dates. 
o B for the text confirmed 
BOR by investigator, 
table 14-2. 
o C to add PFS version. 
[Amendment 3 (v4.0)] 
08MAY2023 
 
Added ECG Analysis 
 
Added definition for ECG 
baseline 
 
Updated list of baseline 
characteristics parameters 
 
Updated interim efficacy 
analysis set definition 
 
Updated MedDRA version 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 3 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
 
Removed imputation rule for 
time to event end points from 
Appendix A 
[Amendment 4 (v5.0)] 
14AUGUST2023 
 
Updated ECG Analysis 
 
Updated list of baseline 
characteristics parameters 
 
Updated definition of TEAE for 
extended period 
 
Added derivation logic for Last 
known alive date. 
 
Added definition for TTR 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 4 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
 
Table of Contents 
1. 
Introduction ........................................................................................ 11 
2. 
Objectives, Endpoints and Hypotheses .............................................. 11 
2.1 
Objectives and Endpoints/Estimands ..................................... 11 
2.2 
Hypotheses and/or Estimations .............................................. 12 
3. 
Study Overview ................................................................................. 12 
3.1 
Study Design .......................................................................... 12 
3.2 
Sample Size ........................................................................... 18 
3.3 
Adaptive Design ..................................................................... 20 
4. 
Covariates
 ................................................................ 21 
4.1 
Planned Covariates ................................................................ 21 
5. 
Definitions .......................................................................................... 22 
6. 
Analysis Sets ..................................................................................... 29 
6.1 
Full Analysis Set..................................................................... 29 
6.2 
Safety Analysis Set ................................................................ 29 
6.3 
DLT Analysis Set .................................................................... 30 
6.4 
Pharmacokinetic Analyses Set(s) ........................................... 30 
6.5 
Interim Efficacy Analysis Set .................................................. 30 
7. 
Planned Analyses  ............................................................................. 30 
7.1 
Interim Analysis and Early Stopping Guidelines ..................... 30 
7.1.1 
Criteria for Evaluating Treatment With Siltuximab ... 31 
7.2 
Primary Analysis .................................................................... 32 
7.3 
Final Analysis ......................................................................... 33 
8. 
Data Screening and Acceptance ........................................................ 33 
8.1 
General Principles .................................................................. 33 
8.2 
Data Handling and Electronic Transfer of Data ...................... 33 
8.3 
Handling of Missing and Incomplete Data .............................. 33 
8.4 
Detection of Bias .................................................................... 33 
8.5 
Outliers .................................................................................. 33 
8.6 
Distributional Characteristics .................................................. 33 
8.7 
Validation of Statistical Analyses ............................................ 34 
9. 
Statistical Methods of Analysis........................................................... 34 
9.1 
General Considerations .......................................................... 34 
9.2 
Subject Accountability ............................................................ 34 
9.3 
Important Protocol Deviations ................................................ 35 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 5 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
9.4 
Demographic and Baseline Characteristics ............................ 35 
9.5 
Efficacy Analyses ................................................................... 36 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s)
 ............................................................................... 37 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s)........... 38 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) .......... 38 
9.6 
Safety Analyses ..................................................................... 38 
9.6.1 
Analyses of Dose Limiting Toxicities ....................... 38 
9.6.2 
Adverse Events ...................................................... 39 
9.6.3 
Laboratory Test Results ......................................... 40 
9.6.4 
Vital Signs .............................................................. 41 
9.6.5 
Physical Measurements ......................................... 41 
9.6.6 
Electrocardiogram .................................................. 41 
 
9.6.8 
Exposure to Investigational Product ....................... 41 
9.6.9 
Exposure to Non-investigational Product ................ 42 
9.6.10 
Exposure to Other Protocol-required Therapy ........ 42 
9.6.11 
Exposure to Concomitant Medication ..................... 42 
9.7 
Other Analyses ...................................................................... 42 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ...... 42 
9.7.2 
Analyses of Clinical Outcome Assessments ........... 42 
9.7.3 
Analyses of Health Economic Endpoints ................ 42 
9.7.4 
Analyses of Biomarker Endpoints ........................... 42 
10. 
Changes From Protocol-specified Analyses....................................... 43 
11. 
Literature Citations / References ........................................................ 43 
12. 
Prioritization of Analyses.................................................................... 43 
13. 
Data Not Covered by This Plan.......................................................... 43 
14. 
Appendices ........................................................................................ 44 
Appendix A.  Date Imputation Rules  ................................................. 44 
Appendix B. BOR Calculation Algorithm ............................................ 46 
Appendix C. PFS Calculation and Censoring Rule............................. 51 
List of Table 
Table 1. Planned Target Doses per Dose Cohort Level .............................. 11 
Table 2. Guideline for Escalation /De-escalation ........................................ 14 
Table 3.  Probability of Observing at least 1 DLT ........................................ 18 
Table 4. Stopping Boundary for Dose Expansion with Posterior Probability of 
80% and Grade 4 or Higher Treatment-related Adverse Event 
Limit of 20% ......................................................................... 28 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 6 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Table 5. Operating Characteristics with Batch Size of 
 Subjects ............. 28 
Table 6 .  The Criteria for Evaluating the Use of Siltuximab ........................ 29 
Table 7. Efficacy Endpoint Summary Table ................................................ 33 
Table 8.  BOR per Modified RECIST 1.1 .................................................... 46 
Table 9.  BOR Derivation Step ................................................................... 47 
Table 10.  PFS Censoring Rule .................................................................. 49 
 
List of Figures 
Figure 1 Study Schema .............................................................................. 17 
 
 
 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 7 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
List of Abbreviations 
 
Abbreviation 
Explanation 
ACTH  
Adrenocorticotropic hormone  
ADA-IC 
Anti-drug antibody related immune complexes 
ADAs 
Anti-drug antibodies 
ADCC 
Antibody-dependent cellular cytotoxicity 
ADL 
Activities of daily living 
ALL 
Acute lymphoblastic leukemia 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
ASR  
Annual Safety Report 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BID 
Twice daily 
BNP 
B-Natriuretic Peptide 
BP 
Blood pressure 
C 
Cycle 
CBC 
Complete blood count 
CI 
Confidence intervals 
Cmax 
Maximum serum concentration 
Cmin 
Minimum serum concentration 
CNS 
Central nervous system 
CRF 
Case report form 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CSF 
Cerebral spinal fluid 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DLL3 
Delta-like protein 3 
DLRM 
Dose level review meeting 
DLRT 
Dose level review team 
DLT 
Dose-limiting toxicity  
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 8 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Abbreviation 
Explanation 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EOI 
End of infusion 
EOT 
End of treatment 
eSAE 
Electronic Serious Adverse Event 
FFPE 
Formalin-fixed paraffin-embedded 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GSO 
Global Safety Officer 
GLP 
Good Laboratory Practice 
H 
Hour 
HBsAb 
Anti-hepatitis B antibody 
HBsAg 
Hepatitis B antigen 
HCV 
Hepatitis C 
HCVAb 
Hepatitis C virus antibody 
HIV 
Human immunodeficiency virus 
HLE 
Half-life extended 
HNSTD  
Highest Non-Severely Toxic Dose 
HR 
Heart rate 
HUVECs 
Human endothelial cells 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN- 
Interferon gamma 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL-2 
Interleukin-2 
IM 
Intramuscular 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 9 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Abbreviation 
Explanation 
INR 
International normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH  
Lactate dehydrogenase 
LH  
Luteinizing hormone 
LTFU 
Long-term follow-up 
LVEF 
Left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
MMSE 
Mini Mental Status Examination 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTPI 
Modified toxicity probability interval 
MUGA scan 
Multigated acquisition scan 
NCT 
National Clinical Trials 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OR 
Objective response 
OS 
Overall survival 
PAVA 
Pool adjacent violators algorithm 
PBL 
Peripheral blood leukocytes 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PPP 
Platelet Poor Plasma 
PR 
Partial Response 
Pre 
Pre-infusion 
PT 
Prothrombin time 
PTT 
Partial thromboplastic time 
PTU 
Propylthiouracil 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
RR 
Respiratory rate 
SAE 
Serious adverse event 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 10 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
Abbreviation 
Explanation 
SC 
Subcutaneous 
SCLC 
Small Cell Lung Cancer 
SCR 
Screening 
SFU 
Safety follow-up 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SJS 
Stevens-Johnson syndrome 
SOA 
Schedule of Assessments 
SSKI 
Saturated solution of potassium iodide 
T4 
Thyroxine 
TEN 
Toxic epidermal necrolysis 
TLS 
Tumor lysis syndrome 
TNF 
Tumor necrosis factor 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UPM 
Unit probability mass 
US 
United States 
USFDA 
United States food and drug administration 
VS 
Vital signs 
WBC 
White blood cell 
 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 11 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20200439, dated 08 May 
2023. The scope of this plan includes the interim analysis, the primary analysis and the 
final analysis that are planned and will be executed by the Amgen Global Biostatistical 
Science department unless otherwise specified. Pharmacokinetic, pharmacodynamic, 
exposure-response and biomarker analyses will be performed by Clinical Pharmacology 
Modeling and Simulation (CPMS) or biomarker group. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety, tolerability, and 
recommended phase 2 target dose of 
tarlatamab in combination with AMG 
404 
 
Dose-limiting 
toxicities 
(DLTs), 
treatment-emergent and treatment-
related adverse events, changes in 
vital 
signs, 
electrocardiograms 
(ECGs), and clinical laboratory tests 
Secondary 
 
To evaluate anti-tumor activity of 
tarlatamab 
in 
combination 
with 
AMG 404 
 
Objective response (OR) per modified 
response evaluation criteria in solid 
tumors (RECIST) v1.1, duration of 
response (DOR), disease control rate 
(DCR), 
progression-free 
survival 
(PFS), and overall survival (OS).  
 
To characterize the pharmacokinetics 
(PK) of tarlatamab in combination with 
AMG 404 
 
PK parameters including, but not 
limited 
to, 
maximum 
serum 
concentration (Cmax), minimum serum 
concentration (Cmin), and area under 
the concentration-time curve (AUC) 
over the dosing interval 
Exploratory 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 12 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
 
2.2 
Hypotheses and/or Estimations 
No formal statistical hypothesis will be tested. 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1b, multicenter, open-label study evaluating the safety, tolerability, PK, 
pharmacodynamics (PD), and efficacy of tarlatamab in combination with AMG 404 in 
subjects with SCLC. The study will consist of dose exploration (Part 1) and dose 
expansion (Part 2). Study enrollment ended in 
. A total of 
 subjects 
were enrolled including 
 subjects in Part 1, and  subjects in Part 2. 
 
 
. 
Part 1 (Dose Exploration)  
The dose exploration part of the study will estimate the recommended phase 2 dose 
(RP2D) of tarlatamab in combination with AMG 404 using a modified toxicity probability 
interval (mTPI-2) design. A combination RP2D may be identified based on emerging 
safety, efficacy, and pharmacodynamic data prior to reaching an MTD.  
AMG 404 will be administered as a short-term IV infusion (30 minutes) every 
 (± 
3 days) (note if AMG 404 is initially administered on cycle 1 
 there will be a 
 
interval between the cycle 1 
 and cycle 2 
 dose). AMG 404 will be 
administered at the recommended phase 2 dose of 
 mg throughout the study. The 
starting dose of tarlatamab will be 
 mg with 1-step dosing (  mg on cycle 1 
 
followed by 
 mg on cycle 1 
 mg on cycle 1 
 and 
 mg 
 
thereafter). Thus far in the ongoing FIH study (Study 20160323), the highest target 
dose deemed safe and tolerable is 
 mg. Planned dose levels in Study 20160323 are 
shown in Table 1. The highest planned target dose of tarlatamab will not exceed 
 
mg in this study using the 
 regimen. 
Table 1. Planned Target Doses per Dose Cohort Level 
Dose Cohort Levels 
Dose (mg) IV 
 
-1 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
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Page 13 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
1 
2 
3 
IV = intravenous 
Footnotes are referenced from first-in-human study (Study 20160323)  
To mitigate the risk of CRS and to potentially optimize the PD activity of tarlatamab, a 
step dosing approach with 1-step dosing will be implemented as part of the dosing 
schedule. Based on emerging safety data and the recommendations of the DLRM, the 
dosing schedule may be adjusted to allow for AMG 404 to be administered initially on 
cycle 1 
 or cycle 1 
. Depending on which day AMG 404 is administered on 
in cycle 1, beginning in cycle 2, AMG 404 will be administered 
 beginning on cycle 
2 
 or cycle 2 
 (refer the Table 1-6 and Table 1-7 of protocol section 1.3 for 
more details).  
Part 1 may include one or more of the following planned dose levels of tarlatamab in 
combination with a fixed dose of AMG 404: 
 
Dose cohort Level 1: tarlatamab at a target dose of 
 mg administered IV 
 
(with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 
 beginning on cycle 1 
  
 
Dose cohort Level 2: tarlatamab at a target dose of 
 mg administered IV 
 
(with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 beginning 
on cycle 1 
 
 
Dose Cohort Level 3: tarlatamab at a target dose of 
 mg administered IV 
 (with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 
beginning on cycle 1 
  
 
Dose cohort Level -1: tarlatamab at a target dose of 
 mg administered IV 
 (with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 (in 
case Dose Cohort Level 1 is not well tolerated) beginning on cycle 1 
 
 
Dose cohort Level -2: tarlatamab at a target dose of 
 mg administered IV 
 (with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 (in 
case Dose Cohort Level -1 is not well tolerated) beginning on cycle 1 
 


Product:  AMG 757, AMG 404 
Protocol Number:  20200439 
Date:  14 August 2023 
Page 14 of 51 
CONFIDENTIAL  
 
 
Confidential Clinical Trials 
 
Dose cohort Level -3: tarlatamab at a target dose of  mg administered IV 
 (with 1-step dosing) in combination with AMG 404 at 
 mg IV 
 
(in case Dose Cohort Level -2 is not well tolerated) beginning on cycle 1 
 
Based upon emerging PK, PD and safety data in the current study as well as the 
ongoing FIH study (20160323), alternative (intermediate) dose cohort levels, 
 
 
 as part of the de-escalation recommendations per the DLRM, or alternative 
dosing schedule(s), including additional step dosing strategies of tarlatamab, may be 
explored.  
Step Dosing 
Due to its known mechanism of action, subjects are at an increased risk for CRS during 
initiation of tarlatamab treatment. To mitigate this risk, tarlatamab will be administered 
with 1-step dosing. One-step dosing involves a first step dose on 
mg), followed 
by a step dose on 
 (equal to the target dose) and the target dose on 
 then 
 
Dose exploration will begin with 
 subjects treated at Dose Cohort Level 1. The 
study DLT period is 
. Once all subjects enrolled at a certain Dose Cohort Level 
are DLT evaluable, a DLRT meeting will be convened. Depending on observed safety 
data, the following may occur: 1) dose de-escalation to the next lowest Dose Cohort 
Level, 2) additional enrollment to the current Dose Cohort Level, or 3) dose escalation 
to the next highest Dose Cohort Level or initiation of enrollment in Part 2. Re-escalation 
to the next higher Dose Level may be allowed, as appropriate. If re-escalation occurs, 
alternative (intermediate) dose levels may be explored per the recommendations of the 
DLRM, 
 
 
Dose escalation/de-escalation recommendations will be guided by a mTPI-2 model 
(Guo et al, 2017) with a target toxicity probability of 30%, equivalence toxicity interval of 
(25%, 33%) and probability of overdosing of 95%. Beta (1, 1) is used as a prior 
distribution. 


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The detailed information of escalation/de-escalation rules are defined in Table 2. The 
DLT decision starts from the 
 subject. 
Table 2. Guideline for Escalation /De-escalation 
Number of 
Evaluable Subjects 
Number of DLTs 
Decision 
0 
E 
1-2 
D 
3 
DU 
0 
E 
1 
S 
2 
D 
≥3 
DU 
0-1 
E 
2-3 
D 
≥4 
DU 
0-1 
E 
2-3 
D 
≥4 
DU 
0-1 
E 
2 
S 
3-4 
D 
≥5 
DU 
≤2 
E 
3-4 
D 
≥5 
DU 
≤2 
E 


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3 
S 
4-5 
D 
≥6 
DU 
D  de-escalate to the next lower dose level; DLT  dose-limiting toxicity; DU  the current dose is 
unacceptably toxic; E  escalate to the next higher dose; S  stay at the current dose 
 If late onset adverse events occur during a cohort, the DLRT may adaptively re-
consider the doses evaluated within a cohort for subsequent dosing and/or possibly 
trigger a de-escalation or withholding of additional doses in subsequent cohorts. 
Additionally, if dose de-escalation occurs and based on emerging PK, PD and safety 
data, alternative (intermediate) dose levels may be explored per the recommendations 
of DLRM, 
 
. The recommended phase 2 target dose will be estimated 
using isotonic regression (Ji et al, 2010) and recommended phase 2 target dose will be 
the dose level with estimated DLT rate closest to 0.30. In order to consider a certain 
dose level as the recommended phase 2 target dose at least  DLT evaluable subjects 
must be enrolled at the dose level.  
Dose exploration phase will end once any of the following events occur: 
 
Highest planned dose level is determined to be safe and tolerable (minimum of 
 evaluable subjects overall). 
 
One of dose levels is determined to be safe and tolerable (minimum of  
evaluable subjects) and the next higher dose level is determined to be unsafe 
and intolerable.  
 
All planned dose levels (including any intermediate doses or alternate dosing 
schedules) are determined to be unsafe and intolerable. 
To minimize the number of subjects treated at potentially toxic dose levels, the first  
subjects in each cohort will be enrolled sequentially with a minimum of  days between 
the first dose of these subjects. 
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.  
Part 2 (Dose Expansion) 


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Upon completion of Part 1 of the study, enrollment will commence in Part 2 to confirm 
the safety and tolerability of the selected dose and to further evaluate the efficacy of 
tarlatamab in combination with AMG 404. Formal safety interim analyses will be 
performed for every 
 subjects who have had opportunity to have at least 
 of 
follow-up since first dose of tarlatamab. The details are provided in protocol Section 
9.4.1. 
The overall study design is described by the study schema in Figure 1. 


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Figure 1 Study Schemac 
 
C  cycle;
 DLT  dose level toxicity; FIH  first-in-human; IV  intravenous; PD  
pharmacodynamics; Ph1  phase 1; PK  pharmacokinetics;
a The starting dose and associated dosing schedule of tarlatamab will be a target dose of 
 mg with 1-
step dosing  
b If the combination is not tolerated (based on target DLT rate > 30), AMG 404 may be administered on 
cycle 1
Based upon emerging PK, PD, and safety data in the current study as well as the ongoing 
FIH study (20160323), alternative (intermediate) dose cohort levels,
 
 as part of the de-escalation 
recommendations may be explored. 
Study Periods: 
 Screening: up to 
 before enrollment 
 Treatment: treatment continues until confirmed radiographic progression or disease progression 
 End of treatment: should occur as soon as possible (within 
) after the last dose of 
investigational product 
 Safety follow-up: Upon permanent discontinuation from the study treatment for any reason, an SFU 
visit will be performed approximately 
 after the last dose (tarlatamab or AMG 404) or prior 
to initiation of other therapy, whichever occurs first. The second safety follow-up visit will be performed 
approximately 
 after the end of the last dose of AMG 404 or prior to initiation of other 
therapy, whichever occurs first. 
 Subjects who discontinue AMG 404 but remain on treatment with AMG 757 will continue to have safety 
event collection at regularly scheduled study visits. The second safety follow-up visit need only occur if 
 has not elapsed from the end of AMG 404 treatment at the time of end of study treatment. 
 Long-term follow-up:  every 3 months ( 2 weeks) up to 1 year from the first dose of tarlatamab 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 only 
Subjects in this clinical investigation shall be referred to as “subjects”. For the sample 
size justification, see protocol section 9.2. 
3.2 
Sample Size 
Approximately 
 subjects were anticipated to be enrolled in the study (up to 
 
subjects in a dose exploration phase, and the remaining subjects enrolled in a dose 
expansion phase). 


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Study enrollment ended in 
 A total of 
 subjects were enrolled in this 
study including 
 subjects in Part 1, and  subjects in Part 2. 
Dose Exploration Phase: 
Up to 6 planned dose cohorts will be examined during dose exploration. The planned 
dose levels for tarlatamab with a fixed dose of AMG 404 (
 mg IV 
) are 
described in protocol section 4.1. 
Dose exploration will begin with 
 subjects treated at Dose Cohort Level 1. The 
study DLT period is 
. Once all subjects enrolled at a certain Dose Cohort Level 
are DLT evaluable, a Dose Level Review Team (DLRT) meeting will be convened. 
Depending on observed safety data, the following may occur: 1) dose de-escalation to 
the next lowest Dose Cohort Level, 2) additional enrollment to the current Dose Cohort 
Level, or 3) dose escalation to the next highest Dose Cohort Level or initiation of 
enrollment in Part 2. In order to consider a certain Dose Level as the recommended 
phase 2 target dose, at least  DLT-evaluable subjects must be enrolled at that Dose 
Level. In total, there are up to 
 subjects enrolled in dose exploration phase.  
These sample sizes are based on practical considerations and are consistent with 
conventional oncology studies with the objective to estimate the recommended phase 2 
target dose and to evaluate initial safety and tolerability. The probability of observing at 
least 1 DLT if the true DLT rate is 10 to 30% is provided in Table 3 for various number 
of subjects. 
Table 3. Probability of Observing at least 1 DLT 
Number of Subjects 
10% DLT Rate 
 
30% DLT Rate 
19 
 
55 
27 
 
70 
34 
 
80 
47 
 
91 
57 
 
96 
65 
 
98 
DLT = dose-limiting toxicity 
Dose Expansion Phase: 


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If the sample size in the dose expansion phase of 
 There is 65% (88%) 
probability of observing at least 1 adverse event with 10% incidence rate, and the 95% 
exact confidence interval for 20% objective response (OR) is 3% to 56% (6% to 44%). 
3.3 
Adaptive Design 
The guidelines described in protocol section 4.1 of the protocol for dose escalation or 
de-escalation to the next dose level are determined by using a mTPI-2 algorithm (Guo 
et al, 2017) with one practical modification. Consistent with conventional oncology 
phase 1 study designs (eg, 3+3 design) and given the imprecision with making 
decisions using as few as
subjects, in the instance of 1 DLT in the initial
subjects at 
a dose level then, as appropriate, the design allows expansion at the dose level beyond 
subjects. All other dose escalation or de-escalation rules are determined strictly by 
the mTPI-2 algorithm as described below. The mTPI-2 algorithm employs a simple 
beta-binomial Bayesian model. Let 𝑝𝑇 be the target toxicity level and (𝑝𝑇 − ϵ1, 𝑝𝑇 + ϵ2) 
be the equivalence toxicity interval denoted as EI. The unit toxicity interval (0, 1) is 
divided into subintervals with equal length given by (ϵ1 + ϵ2). Let the under-dosing 
intervals (LI) denote for a set of intervals below EI, and the overdosing intervals (HI) for 
a set of intervals above EI. The 3 types of dosing intervals (EI, LI, HI) are associated 
with 3 different dose-escalation decisions. The LI correspond to a dose escalation (E), 
the HI correspond to a dose de-escalation (D), and proper dosing intervals (EI) 
correspond to staying at the current dose (S). This study design uses a target toxicity 
level, 𝑝𝑇 of 30%, and EI of (25%, 33%).  
Decision rules are based on the unit probability mass (UPM) calculated on these 
equal-length intervals. Given an interval and a probability distribution, the UPM of that 
interval is defined as the probability of the interval divided by the length of the interval. 
The mTPI-2 design calculates the UPMs for the each of equal-length dosing intervals. If 
the interval with the largest UPM is from LI, EI or HI, then the corresponding dose 
decision would be E, S, or D, respectively. 
A dose level will be considered unsafe, with no additional subjects enrolled at that dose 
level, if it has an estimated 95% or more probability of exceeding the target DLT rate 𝑝𝑇 
(ie, P [DLT > 𝑝𝑇 | data] > 95%). Based on this rule, the following instances would result 
in a dose level being considered unsafe 
 
 or more DLTs in ≤  subjects  
 
 or more DLTs in ≤  subjects 


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 
 or more DLTs in ≤  subjects  
 
 or more DLTs in 
 subjects 
After the escalation phase is completed, final DLT rates at each dose level will be 
estimated by isotonic regression (Ji et al, 2010). The weighted least squares regression 
model will assume monotonic non-decreasing DLT rates with increasing dose and use 
the empirical (observed) DLT rates at each dose level as responses and dose level 
sample sizes as weights, along with the pool adjacent violators algorithm (PAVA) to 
estimate the DLT rate at each dose level. Given the DLT estimates for each dose level, 
the MTD will be selected from all tried dose levels that have not been previously 
declared to be unsafe with a DU decision according to the mTPI decision table. With 
this constraint, the MTD will be determined as the dose level with the DLT estimate 
closest to the target toxicity level of 30%. 
4. 
Covariates 
 
4.1 
Planned Covariates 
The relationship between covariates and efficacy endpoints may be explored if 
appropriate. 
The following baseline covariates may be summarized as appropriate for each 
study part: sex, age, race, ethnicity, weight, height, BMI, ECOG, smoking history, 
sum of diameters of target lesions at baseline, presence of metastatic disease 
related to current malignancy at initial diagnosis, presence of liver metastasis at 
initial diagnosis, presence of brain metastasis at initial diagnosis, limited or 
extensive stage disease at initial diagnosis, number of prior lines of anti-cancer 
therapy, prior PD-1 or PD-L1, platinum sensitivity to first line platinum based 
treatment, prior radiotherapy treatment, prior anti-cancer therapy, prior surgery 
for current malignancy, neurological examination, writing test, mini mental status 
score, and Echo/MUGA scan result. 


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5. 
Definitions 
Adverse Event 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject. The event does not necessarily have a causal relationship with study 
treatment.  
The definition of adverse event includes worsening of a preexisting medical condition. A 
preexisting condition that has not worsened during the study, or involves an 
intervention, is not considered an adverse event.  
Age at Enrollment 
Subject age at enrollment will be determined using the age in years reported in the 
clinical database. 
Area under the concentration-time curve (AUC) 
It is defined as actual body exposure to drug after administration of a dose of the drug. 
Baseline 
Unless otherwise specified, the baseline value for parameters/assessments scheduled 
to be performed on the same day as the earliest date of first administration of 
tarlatamab or AMG 404 is the last non missing value measured before the first 
administration of tarlatamab or AMG 404 on that day. 
For parameters/assessments not scheduled to be performed (or scheduled but not 
performed) on the same day as the earliest date of first administration of tarlatamab or 
AMG 404 the baseline value is the value from the screening period measured closest to 
the day earliest date of first administration of tarlatamab or AMG 404. In the event that 
multiple assessments are done on the same day as the earliest date of first 
administration of tarlatamab or AMG 404 and there is no time associated with the 
assessments, the value associated with the last clinically planned event before the 
earliest date of first administration of tarlatamab or AMG 404 will be used as the 
baseline value. 
Baseline ECG 
Baseline ECG is the Cycle 1 
 pre-dose assessment. If Cycle 1 
 pre-
dose assessment is missing, the last non-missing assessment(s) taken prior to 


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the first administration of tarlatamab or AMG 404 treatment will be used as the 
baseline ECG.  
Best Overall Response (BOR) 
Best overall response (BOR) for a subject is the best observed post baseline disease 
response per modified response evaluation criteria in solid tumors (modified RECIST 
1.1). Overall response assessments occurring after the start of the first subsequent 
anticancer therapy will not be included.  
BOR is defined as the best response in the following order: CR, PR, SD, PD, or NE, 
where CR, PR and PD require confirmation by a repeat, consecutive scan at least 4 
weeks after the first documentation of response. A best overall response of SD requires 
an on-study imaging of SD or better no earlier than 
 days after cycle 1 
 
otherwise the best overall response will be not evaluable (NE).  
Please refer the Appendix B for more details.  
Body Mass Index (BMI) 
Body Mass Index should be calculated using the following formula 
BMI (kg/m2) = weight (kg) / [height (cm)/100]2  
Body Surface Area (BSA) 
The Body Surface Area should be calculated using the following formula 
BSA= 0.007184 × weight(kg)0.425 × height(cm)0.725 
Change from Baseline 
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline. 
Cmax 
Maximum observed serum concentration of tarlatamab.  
Cmin 
Minimum observed serum concentration of tarlatamab. 
Disease control rate (DCR) 
DCR is defined as the incidence of a BOR of a confirmed response (CR/PR) or SD 
while on study as defined by modified RECIST 1.1.  


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Duration of Disease Control (DoDC) 
The duration of disease control (in month) is defined as time from the earlier date of first 
dose of tarlatamab or AMG 404 to disease progression or death due to any cause, 
whichever occurs first. DoDC will be calculated only for subjects with a best overall 
response of CR, PR or SD. 
Subjects will be censored following the censoring strategy described in the analyses of 
PFS (Appendix C). 
Duration of Response (DOR) 
The duration of response (in months) is defined as time from first evidence of CR or PR 
to disease progression or death due to any cause, whichever occurs first. DOR will be 
calculated only for subjects who achieve a best overall response of PR or CR. 
DOR (Months)= (PD / death date - response start date + 1) ×12 / 365.25 
Subjects will be censored following the censoring strategy described in the analyses of 
PFS (Appendix C). 
Dose Limiting Toxicity (DLT) 
Dose-limiting toxicity (DLT) is defined as tarlatamab-related toxicity with an onset within 
the first 
 following first dose with the criteria defined in section 6.2.1.4 of the 
Protocol. 
End of Follow-Up 
It is defined as when the last subject completes the last protocol-specified assessment 
in the study. 
End of IP administration 
End of IP Admin for each subject is defined as the date the decision was made to end 
IP as recorded on the End of Investigational Product Administration CRF page. 
End of Study (Individual Subject) 
End of study for each subject is defined as the date when the subject completed 
protocol-specified last visit shown in the schedule of activities. The date will be recorded 
on the End of Study CRF page. 
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), including any 
additional part in the study (eg, long-term follow-up, 
), as 
applicable. 
End of Treatment (EOT) 
It is defined as the last assessment per the protocol-specified treatment phase of the 
study (i.e., end of last treatment cycle) for an individual subject. For subjects who 
prematurely discontinue investigational product treatment, the EOT should occur as 
soon as possible (within 
) after the last dose of investigational product was 
administered. 
Half-Life (t1/2) 
The time required for the observed concentration of a drug to be reduced by one-half. 
Investigational Product 
The term ‘investigational product’ is used in reference to tarlatamab and AMG 404. 
Last Investigational Product Dose Date 
The last IP date for each subject is defined as the latest date IP administered.  
Last Known Alive Date:  
 
Last known alive date is the latest date of the following dates before death date: 
 
Date of Enrollment on Subject Enrollment form 
 
Date First Taken, Date Last Taken on Concomitant Medications form, Other 
Protocol Required Therapy form, and Anti-Cancer Therapies (Subsequent) 
form 
 
Date Performed on ECOG Performance Status, Vital Signs, MUGA scan or 
Echocardiogram, Electrocardiogram and Mini Mental Status Examination 
forms 
 
Admission Date, Discharge Date on Hospitalizations form, Date of 
Examination on Physical Measurement form 
 
Date Collected on all lab forms (e.g., Pregnancy Test (Local Lab), Chemistry 
(Local Lab), Hematology (Local Lab), Coagulation (Local Lab), Urinalysis 
(Local Lab)) and in central lab data 


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 
Start Date, Stop Date on Investigational Product Administration forms. 
 
Start date and Stop date on Cytokine Release Syndrome form 
 
Date subject ended on End of Investigational Product Administration (AMG 
757), End of Investigational Product Administration (AMG 404), and End of 
Study, End of Safety Follow-up, and End of Radiographic Follow-Up forms 
where the primary reason is not death or lost to follow-up. 
 
Date Started and Date Ended but not Resulted in Death on Events form 
 
 Subject Status Date if status is Alive on Survival Status form 
 
Date Performed on ‘CT or MRI’, ‘Neurological Evaluation’, ‘Writing Test’ 
forms 
 
Date of Imaging for Index Lesions, New Lesions and Non-Index Lesions 
 
Date Scan Performed for Tumor Response Assessment 
 
Date performed for Procedure, Transfusions, Liver Biopsy Results, Liver 
Imaging Results forms 
 
Date Consent Signed, Date Consent Withdrawn from Additional 
Consents/Withdrawal of Consent form 
If death happened, then last known alive date is death date minus 1. 
Death date sources eCRF forms: 
 
End of study, End of Radiographic Follow-Up and End of Safety Follow-up 
 
Events 
 
End of Investigational Product Administration (AMG 757), End of 
Investigational Product Administration (AMG 404) 
 
Survival Status  
Long Term Follow-Up 
Long term follow-up will be conducted every 3 months (±2 weeks) up to 1 year from the 
first dose of tarlatamab 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 only.  


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For subjects who discontinued treatment for any reason other than confirmed 
progressive disease, every effort should be made to perform radiographic imaging 
(computed tomography [CT]/MRI) of the chest, abdomen, pelvis, and all other known 
sites of disease every 3 months until documentation of confirmed disease progression 
per modified RECIST 1.1, clinical progression, start of new anticancer therapy, or up to 
12 months after the first dose of tarlatamab, whichever occurs first. 
Modified Toxicity Probability Interval (mTPI) 
The modified toxicity probability interval for target dose-limiting toxicity (DLT) probability 
of 30% is defined as equivalence toxicity of interval as (25%, 33%) and probability of 
overdosing of 95% with Beta (1,1) as the prior distribution. 
Objective response (OR) 
Objective Response is defined as a best overall response of either Complete Response 
(CR) or Partial Response (PR) per RECIST 1.1. Radiographic response 
(Complete Response, Partial Response) requires confirmation by a repeat, consecutive 
scan at least 4 weeks after the first documentation of response. 
Objective Response Rate (ORR) 
ORR is defined as the incidence of a BOR of a confirmed CR or PR while on study as 
defined by modified RECIST 1.1. All subjects that do not meet the criteria for objective 
response by the analysis cut-off date will be considered as non-responders. 
Objective Response Rate (ORR) based on Unconfirmed Response 
ORR based on unconfirmed response is defined as the incidence of a BOR of CR or 
PR which do not require confirmation while on study as defined by modified RECIST 
1.1. Only unconfirmed response awaiting confirmatory scan is considered in the ORR 
based on unconfirmed response. 
Overall Survival (OS) 
OS (in Months) is defined as the interval from the earlier date of first dose of tarlatamab 
or AMG 404 to the event of death due to any cause. Subjects still alive will be censored 
at the date last known to be alive. If the date last known to be alive is after the date that 
triggers the analysis (ie, the data cutoff date), the subject will be censored at the 
analysis trigger date. 


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Percent change from Baseline 
Percent change from baseline is the arithmetic difference between post-baseline and 
baseline divided by baseline values times 100.  
Progression-free survival (PFS) per Modified RECIST 1.1  
PFS (in Months) per RECIST 1.1 is defined as the interval from the earlier date of  first 
dose of Tarlatamab or AMG 404 to the earlier of PD per RECIST 1.1 or death due to 
any cause. 
The censoring rules for the progression-free survival analysis are detailed in Appendix 
C.  
 
Relative Dose Intensity 
Relative dose intensity is calculated as actual cumulative dose / planned 
cumulative dose.  
 
Actual cumulative dose [mg] is defined as the total dose given during the study 
treatment exposure up to the study visit. For subjects who did not take any drug 
the actual cumulative dose is 0 mg.  
 
Planned cumulative dose [mg] is defined as the per-protocol planned dose 
accumulated over the actual duration on study treatment, whether the actual 
visit is missing or not. 
Safety Follow-Up (SFU) 
The first SFU visit is defined as the subject visit up to 
 after last dose of 
tarlatamab or AMG 404, whichever occurs later, or prior to initiation of other anti-cancer 
therapy, whichever occurs first. The second SFU visit is defined as the subject visit up 
to 
 after the end of the last dose of AMG 404 or prior to initiation of other 
anti-cancer therapy, whichever occurs first.  
Study Day 1 
It is defined as the first day that tarlatamab or AMG 404 is administered to the subject. 
Time to Response (TTR)  


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TTR is defined as the time from the date of first dose of tarlatamab to the date of 
the first documented CR or PR that is subsequently confirmed per Modified 
RECIST1.1. TTR will be calculated only for confirmed responders.  
Treatment-Emergent Adverse Event (TEAE) 
Events categorized as Adverse Events (AEs) starting on or after first dose of tarlatamab 
or AMG 404 as determined by "Did event start before first dose of investigational 
product" equal to "No" or missing on the Events eCRF and up to and including 
 days 
after the last dose of tarlatamab or AMG 404 or the End of Study date, whichever is 
earlier.  
The severity of each adverse event will be graded using the CTCAE version 4.0. 
Adverse events will be coded using MedDRA 26.0 or later.  
Treatment-Emergent Adverse Event (TEAE) For Extended Period 
An adverse event that occurs after the 
 day since the last dose of tarlatamab 
or AMG 404 and up to 
 days after last dose of tarlatamab or AMG 404 or the 
End of Study date, whichever occurs later. The severity of each adverse event will 
be graded using the CTCAE version 4.0. Adverse events will be coded using MedDRA 
26.0 or later.  
Treatment-Related AE 
A treatment-related AE is any treatment-emergent AE with the relationship flag on the 
Events eCRF indicating there is a reasonable possibility that the event may have been 
caused by tarlatamab or AMG 404. Event with missing relationship with protocol-
defined treatment regimen in each cohort will be assumed to be treatment-related. 
6. 
Analysis Sets 
The following sub-sections describe the analysis sets to be used. 
6.1 
Full Analysis Set 
  Not applicable for this study. 
6.2 
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who received at least 1 dose of any 
Investigational Products (tarlatamab/AMG 404). The analysis of all safety endpoints, 
unless noted otherwise, will be conducted on the Safety Analysis Set. 


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6.3 
DLT Analysis Set 
For the dose exploration part of the study, the analysis of DLT will be conducted on the 
DLT Analysis Set, defined as all subjects that are enrolled and received at least 1 dose 
of tarlatamab or AMG 404 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 and receives tarlatamab or AMG 404 treatment as planned in cycle 1 
and has been followed for safety events a minimum of 
 from date of first dose 
administration of tarlatamab or AMG 404. 
6.4 
Pharmacokinetic 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. These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing. 
6.5 
Interim Efficacy Analysis Set 
The Interim Efficacy Analysis Set is a subset of the safety analysis set. The Interim 
efficacy analysis set includes subjects whose data cut-off date is at least 9 weeks after 
the first dose date of tarlatamab or AMG 404. Subjects who stopped disease 
assessments prior to 9 weeks will be included in this analysis set if the data cutoff is at 
least 9 weeks after their first dose date.  
7. 
Planned Analyses  
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  
During dose exploration (Part 1) and formally during dose level review meetings 
(DLRMs), Amgen, in consultation with the site investigators, will review all available 
cumulative data by cohort prior to making dose escalation or dose de-escalation 
recommendation. Adverse events and DLTs observed in all subjects will be evaluated 
continually and fully integrated into all DLRMs and considered in all enrolment and 
dosing decisions.  
During dose expansion (Part 2), Amgen will conduct evaluations of the ongoing grade 4 
or higher treatment-related TEAEs to assess if the threshold for possible early trial 
termination has been reached. The safety interim will occur for every 
 subjects 


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enrolled who have had opportunity to have at least 
 of follow up since the first 
dose of tarlatamab. If this threshold is met, enrollment to dose expansion will be halted 
pending review of safety data by the DLRT. After receiving the DLRT recommendation, 
Amgen will choose to take one of the following actions. 
1) Terminate the trial 
2) Amend the protocol to potentially improve the benefit/risk for subjects (eg, 
increase safety monitoring, modify dose/schedule, mandate premedication)  
3) Continue dose expansion without any changes.  
The stopping rules use a Bayesian approach proposed by Thall (Thall et al, 1995) to 
terminate the study if the posterior probability that the grade 4 or higher treatment 
related TEAE rate is greater than 20% is > 80%. The stopping boundaries assume a 
prior distribution of Beta (0.40, 1.60) are presented in Table 4 and the operating 
characteristics with pre-specified batch size of 
 new subjects per batch are presented 
in Table 5. 
Table 4. 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 Subjects if Observing This Many 
Grade 4 or Higher Treatment-related 
Adverse Events  
≥ 4 
≥ 6 
≥ 9 
Dose Expansion Complete 
Table 5. Operating Characteristics with Batch Size of 
 Subjects 
True Grade 4 or Higher 
Treatment-related 
Adverse Event Rate  
Probability of Early 
Stopping of Dose 
Expansion  
Average Dose Expansion 
Sample Size 
0.10 
2.0% 
39.5 
0.15 
9.7% 
37.6 
0.20 
25.8% 
33.9 
0.25 
47.7% 
28.8 
0.30 
69.2% 
23.4 
7.1.1 
Criteria for Evaluating Treatment With Siltuximab 
Amgen will conduct evaluations of the treatment and outcome of the CRS events 
treated with siltuximab on an ongoing basis to assess if the threshold for evaluating 


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siltuximab treatment has been reached as outlined in the Table 6. If these criteria are 
met, an adhoc DLRM will be triggered to review safety data and available 
pharmacokinetic, pharmacodynamics, and efficacy data. If recommended by DLRT, the 
use of siltuximab will resume. The criteria to trigger an adhoc DLRM to review 
siltuximab treatment use a Bayesian approach proposed by Thall et al, 1995; an adhoc 
DLRM will be triggered if the posterior probability that the CRS progression to Grade 3 
rate of greater than 20 is > 80 or the posterior probability that the CRS progression 
to Grade 4 rate of greater than 7.5 is >80; or observation of any grade 5 CRS after 
the event has been treated with siltuximab. The boundaries presented below assume a 
prior distribution of Beta (0.4, 1.6) for progression to grade 3 CRS and a prior 
distribution of Beta (0.15, 1.85) for progression to grade 4 CRS. The evaluations could 
occur more frequently if necessary to address emerging safety concerns. If the 
triggered ad hoc DLRM coincide with regular DLRM, they may be combined. 
Table 6 . The Criteria for Evaluating the Use of Siltuximab 
Number of 
subjects treated 
with siltuximab 
Trigger DLRM if severity of any CRS event treated with siltuximab 
progresses to Grade 5 
Or this number of subjects with 
severity of CRS progressed to 
Grade 3 after being treated with 
siltuximab 
Or this number of subjects with 
severity of CRS progressed to 
Grade 4 after being treated with 
siltuximab 
≥ 3 
≥ 2 
≥ 4 
≥ 2 
≥ 5 
≥ 3 
≥ 6 
≥ 3 
≥ 7 
≥ 4 
≥ 9 
≥ 4 
≥ 10 
≥ 5 
≥ 11 
≥ 5 
CRS   cytokine release syndrome; DLRM  Dose Level Review Meeting 
 
 
7.2 
Primary Analysis 
The primary analysis for this study will occur when target enrollment is complete and 
each subject either completes at least 6 months on study or withdraws from the study.  


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7.3 
Final Analysis 
The final analysis will be performed after the last subject has had an opportunity to 
complete the corresponding EOT visit/procedures.  
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. The database will be subject to edit checks outlined in the Clinical Data 
Management Plan (DMP). See details of this section in the DMP. 
8.3 
Handling of Missing and Incomplete Data 
The following imputation for missing or incomplete data will be performed if required: 
Incomplete adverse event, concomitant medication, death and time to event 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) concentration data will be evaluated for outliers by visual 
inspection, and decision to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. Descriptive statistics will be used to 
identify potential outliers in key variables. Suspected outliers will be included in all 
analyses unless there is sufficient scientific justification to exclude them.  
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric 
methods of analyses will be utilized.  


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8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, 
pharmacokinetic, efficacy 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 and Pearson, 1934). Kaplan-Meier methods will 
be used to estimate the median and percentiles for time to event endpoints with CI 
calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) 
method. Kaplan-Meier methods will be used to estimate landmarks for time to event 
endpoints (eg, 1-year OS) with the Greenwood formula (Kalbfleisch and Prentice, 1980) 
used to estimate the standard error used in CI calculation. 
9.2 
Subject Accountability 
The number and percentage of subjects who were enrolled, received investigational 
product, discontinued from investigational product (including reasons for discontinuing, 
completed study), discontinued the study (including reason for discontinuing) will be 
summarized by dose/cohort, combining data from each part and overall. Key study 
dates for the first subject enrolled, last subject enrolled, and last subject’s end of study 
will be presented.  
A subject listing and summary noting inclusion in each analysis subset will be provided 
for all subjects enrolled. A subject listing noting duration of tarlatamab and AMG 404 


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administrations, reason for discontinuation of treatment, and reason for discontinuing 
the study will be provided.  
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. The final IPD list is used to produce the Summary of IPDs table and 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 
The following descriptive summaries of demographic and baseline characteristics will 
be produced by dose/cohort, combining data from each part (i.e., Part 1 – Dose 
exploration phase and Part 2 – Dose expansion phase) and overall.  
The Demographic characteristics will include – age at enrollment in years (summary 
statistics), age groups (<65, ≥65), sex (Male, Female), race (White, Asian, Black or 
African American, vs other categories depending on frequency observed) and ethnicity 
(Hispanic, Not Hispanic). If multiple races have been reported for a subject, the subject 
will be categorized as multiple.  
The baseline characteristics will include – Height, Weight, Body Mass Index, sum 
of diameters of target lesions at baseline, presence of metastatic disease, 
Eastern Cooperative Oncology Group (ECOG) performance status (0, 1), Time 
from initial diagnosis to enrollment, Disease stage at initial diagnosis (Limited, 
Extensive), Prior lines of therapy (1, 2, 3, >3), Prior anti-cancer therapy (Yes, No), 
Prior radiotherapy for current malignancy (Yes, No), prior PD-1 or PD-L1, 
platinum sensitivity to first line platinum based treatment, Prior surgery for 
current malignancy (Yes, No), neurological exams, writing test and mini-mental 
status exams, Brain metastases at initial diagnosis (No brain mets present, Brain 
mets present – treated, Brain mets present - not treated), Liver metastases at 
initial diagnosis (No liver mets present, Liver mets present), Smoking history 
(Never, Current, Former), ECHO or MUGA scan, if available.  


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A listing of the demographic and baseline characteristics will be provided if 
required. In additional listings of medical and surgical history, prior anti-cancer 
therapy and prior radiation therapy usage will be provided, if required. 
9.5 
Efficacy Analyses 
Table 7. Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and 
Analysis method 
Interim 
Analysis Set 
Primary 
Analysis and 
Final Analysis 
Set 
ORR 
The percentage of subjects with 
an objective response (per 
modified RECIST criteria v1.1) 
will be summarized by planned 
dose level along with exact 2-
sided 95% confidence interval 
using Clopper–Pearson method. 
Subjects without a post-baseline 
tumor assessment will be 
considered non-responders. 
Interim Efficacy 
Analysis Set 
Safety Analysis 
Set 
DCR 
The percentage of subjects with 
disease control (per modified 
RECIST criteria v1.1) will be 
summarized along with 95% 
exact 2-sided confidence interval 
using Clopper –Pearson method.  
Subjects without a post-baseline 
tumor assessment will be 
considered non-responders.  
Interim Efficacy 
Analysis Set 
Safety Analysis 
Set 
DOR 
The K-M quartiles along with 2-
sided 95% CIs and rates for 
selected duration of response 
(eg, >3, >6, >9, >12 months) will 
be estimated by planned dose 
level using Kaplan-Meier method  
Interim Efficacy 
Analysis Set 
Safety Analysis 
Set 


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Endpoint 
Primary Summary and 
Analysis method 
Interim 
Analysis Set 
Primary 
Analysis and 
Final Analysis 
Set 
TTR 
Time to response (TTR) will be 
summarized with the non-
missing sample size (n), mean, 
standard deviation, median, 
Q1, Q3, minimum, and 
maximum for subjects who 
achieve best overall response 
of CR, or PR. 
N/A 
Safety 
Analysis Set 
PFS 
KM curve for PFS, K-M quartiles 
along with 2-sided 95% CIs and 
rate for selected time points (eg, 
6-months PFS, 1 year [12 
months] PFS) will be estimated 
by planned dose level using 
Kaplan-Meier method. 
Interim Efficacy 
Analysis Set 
Safety Analysis 
Set 
OS 
KM curve for OS, K-M quartiles 
along with 2-sided 95% CIs and 
rate for selected time points (eg, 
6-months PFS, 1 year [12 
months] PFS) will be estimated 
by planned dose level using 
Kaplan-Meier method. 
Interim Efficacy 
Analysis Set 
Safety Analysis 
Set 
The efficacy endpoints include ORR, DCR, DOR, TTR, PFS, and OS. For primary and 
final analyses, the analysis of efficacy endpoints will be done on the Safety Analysis 
Set. For interim analysis, the analysis of efficacy endpoints will be done on the Interim 
Efficacy Analysis Set. Overall response assessments occurring after the start of the first 
subsequent anticancer therapy will not be included in the efficacy analyses. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
Not applicable for this study. 


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9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The objective response rate and disease control rate (per modified RECIST criteria 
v1.1) will be summarized by cohort along with 95% exact 2-sided confidence interval 
using Clopper-Pearson method (Clopper and Pearson, 1934). The subjects without a 
post-baseline tumor assessment will be considered non-responders. 
The duration of response (DOR) will be summarized only for those subjects who 
achieve a best overall response (either PR or CR). The distribution of DOR including 
median and quartiles will be presented by cohort using Kaplan-Meier (KM) method 
along with 2-sided 95% CI using Brookmeyer and Crowley (Brookmeyer and Crowley, 
1982) method. The KM rates of selected durations (eg, >3, >6, >9, >12 months) will 
also be reported. KM curve can be produced for DOR, provided at least 
of subjects 
achieve either CR or PR.  
The distribution of PFS including median and quartiles will be presented by cohort using  
Kaplan-Meier method along with 2-sided 95% CI using Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) method. The standard error used in CI calculation will 
be estimated using the Greenwood formula (Kalbfleisch and Prentice, 1980). The KM 
rates of selected time points (eg, 6-month PFS, 1-year PFS) will also be reported.  
The overall survival (OS) will be analyzed using the same approach as described for 
the PFS endpoints.  
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
Not applicable. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Dose Limiting Toxicities 
The subject incidence of DLT will be tabulated by planned dose level. The analysis of 
DLTs will be conducted on DLT analysis set. The subject incidence of DLTs will be 
used to estimate final DLT rates for each dose level using isotonic regression (Ji et al, 
2010). Refer the Section 3.3 of adaptive design for more details. 


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9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 26.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. AEs of interest (EOI) categories will be based on search strategies 
defined by Medical Coding. 
The subject incidence of treatment-emergent adverse events, treatment-related 
adverse events, serious adverse events, adverse events leading to discontinuation of 
investigational product, adverse events leading to interruption and/or reduction of 
investigational product, grade 3 and above, grade 4 and above and fatal adverse 
events, serious treatment-related adverse events, grade 3 or above treatment-related 
adverse events, grade 4 or above treatment-related adverse events, fatal treatment-
related adverse events, treatment-related adverse events leading to interruption and/or 
reduction of investigational product, and treatment-related adverse events leading to 
discontinuation of investigational product or other protocol-required therapies will be 
tabulated for each cohort by system organ class and preferred term in descending order 
of frequency of highest dose group. The tables will also be presented by worse grade, 
wherever appropriate or applicable.  
The summary of the subject incidence of treatment-emergent adverse events, 
treatment-related adverse events, serious adverse events and fatal adverse events for 
the extended period will be provided. 
The severity of each adverse event will be graded using CTCAE version 4.0 criteria and 
CRS events will be graded using Lee et al, 2014 criteria.   
Adverse Events of Interest (EOI): 
EOIs identified for tarlatamab: 
Cytokine Release Syndrome (Broad), Cytokine Release Syndrome (Narrow), 
Neutropenia (Broad), Neutropenia (Narrow), Immune effector Cell Associated 
Neurotoxicity Syndrome (ICANS) and associated neurological events (Broad), 
Neurological Events [Nervous system disorders (SOC) + Psychiatric disorders (SOC)]. 
For the list of EOIs mentioned above, the subject incidence of treatment-emergent 
adverse events of interest (standardized MedDRA queries and/or Amgen Medical 


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Queries), grade ≥ 2, grade ≥ 3, grade ≥ 4, serious, fatal, and events leading to 
interruption, reduction or discontinuation of IP will be summarized.  
The subject incidence of above treatment-emergent EOIs, serious treatment-emergent 
EOI, grade 3 or higher treatment-emergent EOI, fatal treatment-emergent EOI, 
treatment-emergent EOI leading to discontinuation of investigational product and 
treatment-emergent EOI leading to interruption of investigational product will be 
tabulated by preferred term. CRS will be graded according to Lee et al, 2014. 
The summaries of time to onset of EOI from first dose of IP (days), which comes earlier, 
time to onset of EOI after each dose from last prior dose of IP (days), which comes 
later(days), time to onset of CRS from first dose of tarlatamab (hours), time to onset of 
CRS from each last prior tarlatamab dose (hours), and duration of treatment-emergent 
EOI will be provided. Additionally, summaries of time to onset and duration of EOI will 
be provided for grade 2 or higher and grade 3 or higher EOIs respectively. 
9.6.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at selected 
time points by cohort. Shifts in grades of safety laboratory values between the baseline 
and the worst on-study value will be tabulated by cohort. 
Summaries of the absolute value and/or changes from baseline at each scheduled 
assessment will be provided for selected laboratory parameters of interest. 
Shift tables indicating the change between the baseline and the maximum post dose 
CTCAE grades for an increased value, and the maximum post dose grade for a 
decreased value will be provided for selected laboratory parameters of interest. 
Unscheduled assessments will be included in the shift tables.  
Potential Hy’s law cases will be listed and may also be summarized by cohort. Hy’s law 
cases will have the following three components: 1) ALT or AST > 3 X ULN, 2) ALP < 2 
X ULN and 3) TB >2 X ULN, on any day. A listing of AST, ALT and Total Bilirubin 
values at each time point will be produced for the subjects suspected of Hy’s law case. 


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9.6.4 
Vital Signs 
The analyses of vital signs will include summary statistics at selected time points by 
treatment group. Shifts in vital sign values between the baseline and the worst on-study 
value will be tabulated by treatment group. 
The vital sign includes systolic/diastolic blood pressure, heart rate, respiratory rate, 
temperature and pulse oximetry and will be summarized using descriptive statistics. 
The summary statistics will be presented for baseline and scheduled post-baseline 
visits. In addition, summaries for changes from baseline over time may be summarized, 
provided the scope and size of changes is feasible.  
Shifts in scores for ECOG performance status scores between the baseline and each 
scheduled / assessed time point will be tabulated. ECOG performance status scores 
will be summarized for each cohort at the relevant time points. 
9.6.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at baseline by 
treatment group. Depending on the size and scope of the changes, the summaries of 
changes from baseline over time may be provided. These summaries will also include 
the unscheduled visits.  
9.6.6 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for 
available ECG parameters. 
 
9.6.8 
Exposure to Investigational Product 
Subject exposure to investigational product and combination therapy will be 
summarized using descriptive statistics. The number of doses per subject, cumulative 
dose (mg), relative dose intensity (%), treatment duration (weeks) will be summarized. 
The number and percent of subjects with dose modifications (eg, dose reductions, dose 
interruptions) and reason for modification will also be summarized. Subject-level data 


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may be provided instead of the summary if the subject incidence is low or single dose is 
given. 
9.6.9 
Exposure to Non-investigational Product  
Not applicable for this study. 
9.6.10 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe the exposure to other protocol 
specified therapy (i.e., corticosteroids such as dexamethasone and tocilizumab).  
Descriptive statistics of the number of doses per subject, cumulative dose (mg), relative 
dose intensity (%), treatment duration (weeks).  
9.6.11 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest may be summarized 
by preferred term for each cohort as coded by the World Health Organization, 2018. A 
subject listing of all prior and concomitant medications may be provided. 
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints 
Pharmacokinetic parameters will be determined from the time concentration profile 
using standard non-compartmental approaches and considering the profile over the 
complete sampling interval. 
 
 
 
. 
9.7.2 
Analyses of Clinical Outcome Assessments 
Not applicable for this study. 
9.7.3 
Analyses of Health Economic Endpoints 
Not applicable for this study. 
9.7.4 
Analyses of Biomarker Endpoints 


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10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
Literature Citations / References 
Brookmeyer R, Crowley J.  A confidence interval for the median survival time.  
Biometrics.  1982;38:29-41. 
Clopper CJ and Pearson ES.  The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial.  Biometrika.  1934;26:404-413. 
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design 
addressing Ockham’s razor:  mTPI-2.  Contemp Clin Trials. 2017;58:23-33. 
Ji Y, Liu P, Li Y, Bekele BN.  A modified toxicity probability interval method for 
dosefinding trials.  Clin Trials. 2010;7:653-663. 
Kalbfleisch JD, Prentice RL.  The statistical analysis of failure time data. John Wiley & 
Sons, Inc., New York, 1980. xi + 321 pp 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Statistics in Medicine. 1995;14:357-379. 
12. 
Prioritization of Analyses 
The definitive list of TFLs to be produced for this study will be documented in the 
Program Index. 
13. 
Data Not Covered by This Plan 
Exploratory data not included in this plan and may be analyzed at later date or by 
different Amgen Department.  


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14. 
Appendices 
Appendix A.  Date Imputation Rules  
Imputation rules for partial or Missing Dates for Adverse Events and concomitant 
Medication are detailed below. Date of on-study anti-cancer therapy will be imputed 
using the same rule when only the day is missing (no imputation when month or 
year is missing). 
Imputation Rules for Partial or Missing Start Dates 
 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 
2 
1 
n/a 
1 
1 
 1st dose 
yyyymm 
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. 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 
1. 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. 


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If the imputed stop date is after the death date, impute as death date. 
2. Imputation rules for partial or missing death dates: 
 
If death year and month are available but day is missing: 
 
If mmyyyy for last contact date  mmyyyy for death date, set death date to 
the day after the last contact date. 
 
If mmyyyy for last contact date  mmyyyy for death date, set death date to 
the first day of the death month. 
 
If mmyyyy for last contact date  mmyyyy for death date, data error and do 
not impute. 
 
If both month and day are missing for death date or a death date is totally missing, 
do not impute. 
Note that the last contact date refers to the last contact (i.e. a visit or an assessment) 
with patient instead of family members. Last contact date would be derived from the 
latest patient visit/assessment date. 


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Appendix B. BOR Calculation Algorithm 
Confirmed BOR by Investigator 
At each time point, BOR will be derived based upon the evaluated time points up to and 
including the current assessment. The following rules will apply to BOR: 
 
CR is better than PR is better than SD is better than PD is better than NE 
 
For a BOR of SD, a duration of ≥ 
days since the cycle 1 
 is required 
 
For a BOR of CR, PR or PD, confirmation is required in a consecutive 
assessment ≥ 28 days after the initially observed assessment of CR, PR or PD 
except the following cases  
o An unlimited number of intermittent assessments of NE or CR <28 
days can occur between the initial response and the confirmation of 
CR. For example, BL, CR, NE, NE, NE, CR – the CR at post-baseline 
1 is confirmed at post-baseline 5. SD is not allowed between CR and 
subsequent confirmation CR. 
o An unlimited number of intermittent assessments of NE, SD, PR or 
CR <28 days can occur between the initial response and the 
confirmation of PR. For example, BL, PR, SD, SD, SD, PR – the PR 
at post-baseline 1 is confirmed by post-baseline 5. 
o An unlimited number of intermittent assessments of NE can occur 
between the initial PD and the confirmation. (No reference though) 
o 
PD doesn’t need confirmation if PD is the last evaluable assessment 
PD and determines BOR or PD time of PFS.  
Table 8 provides the BOR determination per modified RECIST 1.1 for trials where 
confirmation for response and progressive disease are required. A BOR determined by 
Table 8 is considered a Confirmed_BOR. Table 9 outlines the steps to derive 
Confirmed_BOR (step 1) given investigator’s time point assessments. 
Interim BOR by Investigator 
At interim futility analyses, due to lack of sufficient follow-up time for confirmation san, 
study team may choose to report both confirmed responders and unconfirmed 
responders (subjects had an initial PR or CR and still has potential for future 
confirmative scans). Interim BOR is defined to include unconfirmed responders in 
addition to those who achieve Confirmed BOR. Table 9 step 2 is the step to derive 
these unconfirmed responders.  
Confirmed and Interim BOR by Central Review 


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Confirmed and Interim BOR by Central Review will be derived from Time point 
response by Central.  The steps are same as derivation for Confirmed and Interim BOR 
by Investigator (Table 8 and Table 9) 


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Table 8.  BOR per Modified RECIST 1.1 
Criterion Timepoint 
T1 
Response 
T1 ≥ (X-
1)*7 days 
after 
C1
? 
Timepoint 
T2 
Response 
T2 ≥ (X-
1)*7 days 
after 
C1
? 
T2 ≥ 28days 
after T1? 
BOR_temp 
C1 
CR 
Yes 
CR 
- 
Yes 
CR 
C2 
 
CR 
- 
No 
SD 
C3 
PR, SD 
- 
- 
Query data* 
C4 
PD 
- 
- 
SD 
C5 
NE, No further evaluations 
SD 
C6 
No 
 
CR 
- 
Yes 
CR 
C7 
CR 
Yes 
No 
SD 
C8 
CR 
No 
No 
NE 
C9 
PR, SD 
- 
- 
Query data* 
C10 
PD 
- 
- 
NE** 
C11 
NE, No further evaluations 
NE 
C12 
PR 
 
Yes 
CR, PR 
- 
Yes 
PR 
C13 
CR, PR 
- 
No 
SD 
C14 
SD 
- 
- 
SD 
C15 
PD 
- 
- 
SD 
C16 
NE, No further evaluations 
SD 
C17 
No 
CR, PR 
- 
Yes 
PR 
C18 
CR, PR 
Yes 
No 
SD 
C19 
CR, PR 
No 
No 
NE 
C20 
SD 
Yes 
- 
SD 
C21 
SD 
No 
 
NE 
C22 
PD 
- 
- 
NE** 
C23 
NE, No further evaluations 
NE 
C24 
SD 
Yes 
CR, PR, SD, PD, NE, no more evaluation 
SD 
C25 
No 
 
CR, PR, SD 
Yes 
- 
SD 
C26 
CR, PR, SD 
No 
- 
NE 
C27 
PD 
- 
- 
NE** 
C28 
NE, No further evaluations 
NE 
C29 
PD 
 - 
CR, PR, SD        Yes                         
SD 
C30 
 
 
CR, PR, SD        No                         
NE 
C31 
 
 
PD                                             Yes 
PD 
C32 
 
 
PD                                             No 
NE** 
C33 
 
 
NE, No further evaluations 
NE** 
C34 
NE 
- 
NE, No further evaluations 
NE 
C35 
 
- 
CR, PR, SD 
Yes 
- 
SD 
C36 
 
- 
CR, PR, SD 
No 
- 
NE 
C37 
 
- 
PD 
- 
- 
NE** 


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CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
not evaluable. 
X is the scan schedule of every X weeks per protocol. X  8 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
** For rows C10, C22, C27, C32, C37, if timepoint T2 response of PD is the last evaluable assessment, 
then BOR_temp is PD, otherwise the BOR_temp is NE. For row C33, if timepoint T1 response of PD is the 
last evaluable assessment, then BOR_temp is PD, otherwise the BOR_temp is NE. 
Table 9.  BOR Derivation Step 
 
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 8 to derive Confirmed 
BOR. 
ii) At Visit 2 onward: 
(a) If current visit is CR, PR or PD: Find last scan that is 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 
PD 
PD 
PD 
(b) If none of above fits, find last scan reference Table 8 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 DCO 
For subjects who discontinue 
tumor assessment (i.e. had 
confirmed PD, next therapy, or end 
of study): 
 
For subjects with potential for more assessment 
(i.e. no confirmed PD, next therapy, or end of 
study), unconfirmed PR/CR can be considered 
responders.   


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Assign Interim BOR = Confirmed 
BOR 
 
If any scan is CR and haven’t get the 
opportunity to receive next scan, then Interim 
BOR = CR. 
 
If any scan is PR and haven’t get the 
opportunity to receive next scan, then Interim 
BOR = PR.  
 
Else, Interim BOR = Confirmed BOR at the 
latest scan. 
 
 
 
 


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Appendix C. PFS Calculation and Censoring Rule 
Table 10 defines PFS censoring rule per modified RECIST 1.1 PD from radiographic 
scans. 
Table 10.  PFS Censoring Rule 
Situation up to DCO/EOS 
Date of Event or Censor 
Outcome 
No evaluable post-baseline tumor 
assessments, no death recorded 
Date of Randomization date 
(or first dose date of IP in non-
randomized trials) 
Censor  
PD  
Date of first detection of PD  
Event  
No PD, but death recorded 
Date of death 
Event  
Start of new anti-cancer therapy prior 
to any PD or death  
Date of last evaluable tumor 
assessment before or on start 
of new anti-cancer therapy 
Censor 
No PD, no death recorded, no start 
of new anti-cancer therapy 
Date of last evaluable tumor 
assessment  
Censor 
Death or PD immediately after 2 or 
more missed tumor assessment (18 
weeks) 
Date of last evaluable tumor 
assessment prior to missing 
assessment(s) a 
Censor 
DCO = Data Cutoff; EOS = End of Study; PD = Progressive disease 
a This supersedes the previous rules that result in PFS event at date of PD or death. 
Note: PD’s does not require confirmation if based on RECIST 1.1.