A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific T-cell Engager AMG 757 in Subjects With De Novo or Treatment Emergent Neuroendocrine Prostate Cancer
Phase: PHASE1
Conditions: Neuroendocrine Prostate Cancer
Sponsor: Amgen

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 1 of 148 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics and Efficacy of 
Delta-like Protein 3 Half-life Extended Bispecific 
T-cell Engager AMG 757 in Subjects with 
De Novo or Treatment Emergent 
Neuroendocrine Prostate Cancer 
Short Protocol Title: 
A Phase 1b Study of AMG 757 in Subjects with 
Neuroendocrine Prostate Cancer 
Protocol Number: 
20200040 
Investigational Product: 
Tarlatamab (AMG 757) 
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen, Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
+1 (805) 447-1000 
Protocol 
Approver 
Name: 
MD  
Function: 
VP Early Development, TA Head Oncology 
 
Key 
Sponsor 
Contact 
Name: 
 MD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
Email Address: 
 
EU CT Number: 
2024-513316-10 
NCT Number: 
NCT04702737 
Protocol Version Date: 
Document Version 
Date 
Original 
23 June 2020 
Amendment 1 
15 September 2020 
Amendment 2 
09 October 2020 
Amendment 3 
10 December 2020 
Amendment 4 
19 April 2021  
Superseding 
Amendment 4 
25 June 2021 
Amendment 5 
20 December 2021 
Amendment 6 
28 September 2022 
Amendment 7 
21 June 2024 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 2 of 148 
CONFIDENTIAL  
 
 
Data Elements Standards 
Version: 
6.0 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 
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 external review bodies (eg, institutional review board/independent 
ethics committee/regulatory authorities). 
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) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 3 of 148 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics and Efficacy of Delta-like Protein 3 Half-life Extended 
Bispecific T-cell Engager AMG 757 in Subjects with De Novo or Treatment Emergent 
Neuroendocrine Prostate Cancer, dated 21 June 2024, 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) 
 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 4 of 148 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 10 
1.1 
Synopsis ................................................................................................... 10 
Sponsor Name: ..................................................................................................... 15 
1.2 
Study Schema ........................................................................................... 16 
1.3 
Schedule of Activities (SoA) ...................................................................... 17 
2. 
Introduction ........................................................................................................... 26 
2.1 
Study Rationale ......................................................................................... 26 
2.2 
Background ............................................................................................... 26 
2.2.1 
Disease ..................................................................................... 26 
2.2.2 
Amgen Investigational Product Background:  
Tarlatamab ................................................................................ 27 
2.2.2.1 
Pharmacology ......................................................... 27 
2.2.2.2 
Toxicology ............................................................... 28 
2.2.2.3 
Background Clinical Experience With 
Amgen Investigational Product Tarlatamab ............. 29 
2.3 
Benefit/Risk Assessment ........................................................................... 31 
2.3.1 
Additional Potential Safety Concerns for Tarlatamab ................. 33 
2.3.1.1 
Neurological Events ................................................ 33 
2.3.1.2 
Pituitary Dysfunction................................................ 33 
2.3.1.3 
Tumor Lysis Syndrome ........................................... 33 
3. 
Objectives and Endpoints ..................................................................................... 34 
4. 
Study Design ........................................................................................................ 35 
4.1 
Overall Design .......................................................................................... 35 
4.2 
Number of Subjects ................................................................................... 40 
4.2.1 
Replacement of Subjects ........................................................... 40 
4.2.2 
Number of Sites ......................................................................... 40 
4.3 
Justification for Investigational Product Dose ............................................ 41 
4.4 
End of Study ............................................................................................. 41 
4.4.1 
End of Study Definition .............................................................. 41 
4.4.2 
Study Duration for Subjects ....................................................... 41 
4.5 
Patient Input on Study Design ................................................................... 42 
5. 
Study Population .................................................................................................. 42 
5.1 
Inclusion Criteria ....................................................................................... 42 
5.2 
Exclusion Criteria ...................................................................................... 44 
5.3 
Subject Enrollment .................................................................................... 46 
5.4 
Screen Failures ......................................................................................... 47 
6. 
Treatments ........................................................................................................... 47 
6.1 
Treatment(s) Administered ........................................................................ 48 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
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6.1.1 
Investigational Products ............................................................ 48 
6.1.2 
Medical Devices ........................................................................ 50 
6.1.3 
Noninvestigational Product(s)/Auxiliary Medicinal 
Product(s) ................................................................................. 50 
6.1.4 
Other Treatment Procedures ..................................................... 50 
6.1.5 
Product Complaints ................................................................... 50 
6.1.6 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 51 
6.2 
Dose Modification ...................................................................................... 51 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 51 
6.2.1.1 
Dose Level Review Team........................................ 51 
6.2.1.2 
Dose-cohort Study Escalation ................................. 52 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 53 
6.2.2.1 
Amgen Investigational Product:  
Tarlatamab .............................................................. 53 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 55 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 55 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 55 
6.4.1 
Method of Treatment Assignment .............................................. 55 
6.4.2 
Blinding ..................................................................................... 55 
6.5 
Treatment Compliance .............................................................................. 55 
6.6 
Treatment of Overdose ............................................................................. 55 
6.7 
Prior and Concomitant Treatment ............................................................. 56 
6.7.1 
Prior Treatment ......................................................................... 56 
6.7.2 
Concomitant Treatment ............................................................. 57 
6.7.3 
Vaccines .................................................................................... 57 
6.8 
Support Care and Potential Risk Management Guidelines for 
Tarlatamab ................................................................................................ 57 
6.8.1 
Cytokine Release Syndrome (CRS) .......................................... 57 
6.8.2 
Neurologic Events ..................................................................... 63 
6.8.3 
Pituitary Dysfunction .................................................................. 64 
6.8.4 
Covid-19 Management .............................................................. 66 
6.8.5 
Tumor Lysis Syndrome (TLS) .................................................... 69 
6.8.6 
Neutropenia ............................................................................... 69 
7. 
Discontinuation Criteria ......................................................................................... 71 
7.1 
Discontinuation of Study Treatment........................................................... 71 
7.2 
Discontinuation From the Study ................................................................ 72 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 72 
7.2.2 
Reasons for Removal From Study ............................................. 72 
7.3 
Lost to Follow-up ....................................................................................... 72 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 6 of 148 
CONFIDENTIAL  
 
 
8. 
Study Assessments and Procedures .................................................................... 73 
8.1 
General Study Periods .............................................................................. 73 
8.1.1 
Screening and Enrollment ......................................................... 73 
8.1.2 
Treatment Period ....................................................................... 74 
8.1.3 
Safety Follow-up ........................................................................ 75 
8.1.4 
Long-term Follow-up .................................................................. 75 
8.2 
Description of General Study Assessments and Procedures ..................... 76 
8.2.1 
General Assessments ............................................................... 76 
8.2.1.1 
Informed Consent .................................................... 76 
8.2.1.2 
Demographics ......................................................... 76 
8.2.1.3 
Medical History ........................................................ 76 
8.2.1.4 
Physical Examination .............................................. 77 
8.2.1.5 
Physical Measurements .......................................... 77 
8.2.1.6 
Performance Status................................................. 77 
8.2.1.7 
Neurological Examination ........................................ 77 
8.2.1.8 
Writing Test ............................................................. 77 
8.2.1.9 
Mini-Mental Status Examination .............................. 77 
8.2.2 
Efficacy Assessments ................................................................ 78 
8.2.2.1 
Radiologic Imaging Assessment.............................. 78 
8.2.3 
Safety Assessments .................................................................. 79 
8.2.3.1 
Vital Signs ............................................................... 79 
8.2.3.2 
Electrocardiograms (ECGs) ..................................... 79 
8.2.3.3 
Vital Status .............................................................. 79 
8.2.3.4 
Other Safety ............................................................ 80 
8.2.4 
Adverse Events and Serious Adverse Events ............................ 80 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 80 
8.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 82 
8.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 82 
8.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 82 
8.2.4.5 
Safety Monitoring Plan ............................................ 83 
8.2.4.6 
Other Safety Findings/Special Situations ................. 83 
8.2.4.7 
Pregnancy ............................................................... 83 
8.2.5 
Clinical Laboratory Assessments ............................................... 84 
8.2.6 
Pharmacokinetic Assessments .................................................. 84 
8.2.7 
Pharmacogenetic Assessments................................................. 85 
8.2.9 
Biomarkers ................................................................................ 85 
8.2.9.1 
Biomarker Assessment During the Study ................ 86 
8.2.9.2 
Biomarker Discovery ............................................... 86 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 7 of 148 
CONFIDENTIAL  
 
 
9. 
Statistical Considerations ...................................................................................... 87 
9.1 
Statistical Hypotheses ............................................................................... 87 
9.2 
Sample Size Determination ....................................................................... 87 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 88 
9.3.1 
Analysis Sets ............................................................................. 88 
9.3.2 
Covariates ................................................................................. 88 
9.3.3 
Subgroups ................................................................................. 88 
9.3.4 
Handling of Missing and Incomplete Data .................................. 88 
9.4 
Statistical Analyses ................................................................................... 89 
9.4.1 
Planned Analyses ...................................................................... 89 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 89 
9.4.1.2 
Primary Analysis ..................................................... 93 
9.4.1.3 
Final Analysis .......................................................... 93 
9.4.2 
Methods of Analyses ................................................................. 94 
9.4.2.1 
General Considerations ........................................... 94 
9.4.2.2 
Efficacy Analyses .................................................... 94 
9.4.2.3 
Safety Analyses ...................................................... 95 
9.4.2.4 
Other Analyses ........................................................ 96 
9.4.2.5 
Adaptive Design ...................................................... 96 
10. 
References ........................................................................................................... 98 
11. 
Appendices ......................................................................................................... 100 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 101 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 105 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 107 
Monitoring Committee(s) ......................................................................... 107 
Regulatory and Ethical Considerations .................................................... 108 
Informed Consent Process ...................................................................... 109 
Data Protection/Subject Confidentiality ................................................... 110 
Serious Breach ....................................................................................... 111 
Publication Policy .................................................................................... 111 
Results Reporting .................................................................................... 112 
Investigator Signatory Obligations ........................................................... 112 
Data Quality Assurance ........................................................................... 113 
Source Documents .................................................................................. 114 
Study and Site Closure............................................................................ 115 
Compensation ......................................................................................... 115 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 116 
Definition of Adverse Event ..................................................................... 116 
Definition of Serious Adverse Event ........................................................ 117 
Recording Adverse Events and Serious Adverse Events ........................ 119 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 8 of 148 
CONFIDENTIAL  
 
 
Evaluating Adverse Events and Serious Adverse Events ........................ 120 
Reporting of Serious Adverse Event ........................................................ 121 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy Information ............................................................................ 126 
Collection of Pregnancy Information ........................................................ 127 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 129 
11.7 
Appendix 7.  Reporting and Management of potential 
Hepatotoxicity  ........................................................................................ 131 
11.7.1 
Criteria for stopping Amgen Investigational Product 
and noninvestigational product(s)/auxiliary medicinal 
product(s) Due to Potential Hepatotoxicity ............................... 131 
11.7.2 
Reporting Criteria .................................................................... 131 
11.7.3 
Follow up Actions .................................................................... 132 
11.7.3.1 
Investigating Alternative Causes of 
Hepatotoxicity........................................................ 132 
11.7.4 
Rechallenge and Dose Modification in Patients with 
suspected hepatotoxicity in Oncology Trials ............................ 134 
11.7.5 
Permanent Discontinuation of Study Drug(s) ........................... 134 
11.7.6 
Management Flow Chart ......................................................... 134 
11.8 
Appendix 8.  Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1) ...................................................................... 136 
11.9 
Appendix 9.  RECIST 1.1 With Prostate Cancer Working Group 
3 (PCWG3) Modifications  ....................................................................... 142 
11.10 Appendix 10.  Performance Status According to Eastern 
Cooperative Oncology Group (ECOG) Scale .......................................... 145 
11.11 Appendix 11.  New York Heart Association Functional 
Classification ........................................................................................... 146 
11.12 Appendix 12.  Adaptive Design ............................................................... 147 
 
List of Tables 
Table 1-1.  Schedule of Activities:  Single Step Dosing - Cycle 1 Only........................... 17 
Table 1-2.  Schedule of Activities:  Cycle 2 and Beyond ................................................ 19 
Table 1-3.  Schedule of Imaging Assessments (Cycle Independent) ............................. 24 
Table 2-1.  Key Risks for Tarlatamab ............................................................................ 32 
Table 4-1.  Dose Cohort Level (Note:  Dose cohort levels shown here are 
based on updated results from the FIH study in small cell lung 
cancer, and may not represent dose cohort levels in this study) ............. 36 
Table 4-2.  Guideline for Escalation/De-escalation ........................................................ 37 
Table 4-3.  Operating Characteristics for mTPI-2 Model ................................................ 38 
Table 6-1.  Study Treatments ........................................................................................ 49 
Table 6-2.  Grading and Management of Cytokine Release Syndrome.......................... 59 
Table 6-3.  Management of Adverse Events Related to Neurologic Events ................... 63 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 9 of 148 
CONFIDENTIAL  
 
 
Table 6-4.  Tarlatamab Dose Modification Guidelines for Adverse Events ..................... 70 
Table 9-1.  Stopping Boundary for Dose Expansion with Posterior Probability 
of 80% and Grade 4 or Higher Treatment-related Adverse 
Event Limit of 20% .................................................................................. 90 
Table 9-2 Operating Characteristics with Batch Size of 10 Subjects .............................. 90 
Table 9-3.  Guidelines for Futility Analysis ..................................................................... 92 
Table 9-4.  The Criteria for Evaluating the Use of Siltuximab ......................................... 93 
Table 11-1.  Analyte Listing ......................................................................................... 106 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 16 
Figure 6-1.  Monitoring and Management of Pituitary Gland Dysfunction 
(Gonzalez et al, 2016) ............................................................................ 65 
Figure 9-1.  Decision Matrix for Continuous Monitoring of ORR ..................................... 92 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form ................ 123 
Figure 11-2.  Pregnancy Notification Form .................................................................. 128 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 10 of 148 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics 
and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific T-cell Engager AMG 757 
in Subjects with De Novo or Treatment Emergent Neuroendocrine Prostate Cancer 
Short Protocol Title:  A Phase 1b Study of AMG 757 in Subjects with Neuroendocrine 
Prostate Cancer 
Study Phase:  1b 
Indication:  Adult subjects with de novo or treatment-emergent neuroendocrine prostate 
cancer 
Rationale 
Delta-like protein 3 (DLL3), a non-canonical Notch ligand, is a promising therapeutic 
target due to its high expression on the cell surface of small cell lung cancer (SCLC) and 
minimal, mainly cytoplasmic localization in normal tissues.  DLL3 mRNA and protein are 
also highly expressed by other neuroendocrine tumor types, including neuroendocrine 
prostate cancer (NEPC).  RNA sequencing of metastatic tumors showed that 100% (8/8) 
of NEPC tumors expressed DLL3 (MET500 database; Robinson et al, 2017).  A 
separate study identified DLL3 as a gene expressed in 80% (12/15) of NEPC samples 
(Tsai et al, 2017).  A recent study demonstrated that DLL3 protein is expressed in 76.6% 
(36/47) of neuroendocrine prostate tumors, and also in a subset of advanced metastatic 
prostate cancer (Puca et al, 2019). 
Tarlatamab (International Nonproprietary Name [INN]; AMG 757) is a half-life extended 
(HLE) bispecific T-cell engager (BiTE®) antibody construct combining the binding 
specificities for DLL3 and cluster of differentiation 3 (CD3) genetically fused to the 
N-terminus of a single chain immunoglobulin G (IgG) fragment crystallizable (Fc; scFc) 
region.  Currently, a first in human phase 1 study evaluating the safety, tolerability and 
pharmacokinetics of tarlatamab in subjects with SCLC (Study 20160323) is ongoing.  
Tarlatamab demonstrated potent cell killing against DLL3-expressing SCLC and other 
neuroendocrine tumor cell lines in vitro, including the NEPC cell line, NCI-H660.  
Tarlatamab demonstrates anti-tumor activity in small cell lung cancer (SCLC) and 
melanoma xenograft models of neuroendocrine tumors and can enable regression of 
established small cell lung tumors in mouse xenograft models.  Therefore, targeting 
NEPC with tarlatamab may lead to anti-tumor activity. 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 11 of 148 
CONFIDENTIAL  
 
 
Objective(s)/Endpoint(s) 
 
 
Overall Design 
This is an open label phase 1b study evaluating tarlatamab monotherapy. 
Tarlatamab will be administered as a short-term intravenous (IV) infusion every 2 weeks 
(Q2W) (with step dosing) in a 28-day cycle as monotherapy therapy in subjects with 
de novo or treatment-emergent NEPC.  
The study will consist of 2 parts:  dose exploration (Part 1) and dose expansion (Part 2). 
At the time of initiation of the study, the starting dose will be the highest dose deemed 
safe and tolerable in the ongoing phase 1 trial of tarlatamab in subjects with SCLC 
Objectives  
Endpoints  
Primary  
 
Evaluate the safety and tolerability 
of tarlatamab   
 
Treatment-emergent adverse 
events, treatment-related adverse 
events, and changes in vital signs, 
electrocardiogram (ECG), and 
clinical laboratory tests  
 
Determine the maximum tolerated 
dose (MTD) or recommended 
phase 2 dose (RP2D)  
 
Dose limiting toxicities (DLTs)  
Secondary  
 
Evaluate anti-tumor activity of 
tarlatamab as assessed by 
additional measures   
 
Objective response (OR) per 
Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 
 
Duration of response (DOR) per 
RECIST 1.1 
 
Radiographic progression-free 
survival (PFS) per Prostate Cancer 
Working Group 3 (PCWG3) 
 
Overall survival (OS)  
 
Disease Control Rate (DCR) per 
RECIST 1.1 
 
Characterize the pharmacokinetics 
(PK) tarlatamab   
 
PK parameters for tarlatamab 
following intravenous (IV) 
administration including, but not 
limited to, maximum serum 
concentration (Cmax), minimum serum 
concentration (Cmin), area under the 
concentration-time curve (AUC) over 
the dosing interval, 
accumulation ratio, and half-life (t1/2)  

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 12 of 148 
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(Note:  based on emerging safety data from Study 20160323, the starting dose may be 
lower than the highest dose deemed safe and tolerable).  The planned highest dose in 
this study is not anticipated to exceed the maximum tolerated dose (MTD) as 
established in the ongoing Study 20160323. 
Based on emerging data from the tarlatamab monotherapy in this indication and 
emerging data from other trials with tarlatamab, the protocol may be amended to include 
a combination of tarlatamab with anti-PD-1 (L1) agent.  
Number of Subjects 
Approximately 60 subjects will be enrolled in this study.  Up to 20 subjects will be 
enrolled in the dose exploration phase (Part 1) and 40 subjects will be enrolled in the 
dose expansion phase (Part 2).  Based on emerging data in Part 2, the protocol may be 
amended to increase the sample size. 
Summary of Subject Eligibility Criteria 
Adult subjects ( 18 years of age) with metastatic de novo or treatment-emergent NEPC 
defined as one or more of the following will be eligible to enroll:  histological diagnosis of 
small cell NEPC, prostate carcinoma with neuroendocrine differentiation as defined by 
positive immunohistochemical staining for chromogranin and/or synaptophysin in the 
majority of the tumor sample or  2 alterations in Tp53, RB1, and/or PTEN by 
immunohistochemistry (IHC) or genomic analyses of baseline tumor tissue or
 
  Subjects are required to have progressed on at least 1 line of prior 
treatment, including a platinum containing regimen for de novo NEPC (if at the time of 
NEPC diagnosis they had no prior diagnosis or treatment for prostate carcinoma) or an 
androgen signaling inhibitor (eg, abiraterone, enzalutamide, and/or apalutamide) if 
treatment-emergent (had a previous diagnosis of prostate carcinoma prior to NEPC 
diagnosis).  Subjects must have measurable disease per Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1 criteria with Prostate Cancer Working Group 3 (PCWG3) 
guidelines, have an Eastern Cooperative Oncology Group (ECOG) performance status of 
≤ 2, and adequate organ function.  
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.   

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 13 of 148 
CONFIDENTIAL  
 
 
At the time of initiation of the study, the starting dose will be the highest dose deemed 
safe and tolerable in the ongoing phase 1 trial of tarlatamab in subjects with SCLC 
(Note:  based on emerging safety data from Study 20160323, the starting dose may be 
lower than the highest dose deemed safe and tolerable).  Tarlatamab will be 
administered as a short-term IV infusion (approximately 60 minutes followed by a flush) 
on day 1 and day 15 in a 28-day cycle (cycle 2 and beyond).  To reduce the risk of 
cytokine release syndrome (CRS), premedication with dexamethasone 8 mg IV (or 
equivalent dose of other corticosteroids) will be administered within 1 hour prior to all 
cycle 1 doses.  In addition, step-dosing will be implemented (involving a run-in dose on 
cycle 1 day 1 followed by one 
 step doses) during cycle 1, prior to reaching a 
target dose.  Prophylaxis with IV hydration 1 L normal saline over 4 to 5 hours 
immediately following all dose(s) in cycle 1 is required. 
Sites are required to have tocilizumab or siltuximab (if tocilizumab not available) on site 
for potential treatment of CRS.  Siltuximab stopping rules are found in Section 9.4.1.1.1.  
Tarlatamab will be dosed until disease progression (treatment beyond disease 
progression may be allowed per PCWG3 guidelines).  
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage and administration of 
tarlatamab. 
Procedures 
Each subject will follow the same treatment schedule and procedural requirements. 
After written informed consent has been obtained, all screening tests and procedures will 
be performed within 28 days of administration of tarlatamab (day 1), unless otherwise 
noted.  Serial clinical safety and study evaluations as per the schedule of activities will 
be performed including physical examination, vital signs, clinical laboratory tests, 
radiological assessment, tumor biopsy, pharmacokinetics (PK), and biomarker sample 
collections. 
All subjects will be hospitalized for intensive monitoring for 48 hours post tarlatamab 
infusion during all cycle 1 doses.  Hospitalization is not required for cycle 2 unless a 
subject experiences grade 2 or higher CRS or neurological events in cycle 1 (minimum 
of 24 hours hospitalization required post tarlatamab infusion on cycle 2 day 1 if grade 2 
or higher CRS or neurological events are noted in cycle 1).  The subjects may be 
discharged after this period if there are no signs and symptoms of CRS or other acute 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 14 of 148 
CONFIDENTIAL  
 
 
toxicities.  If subjects are not hospitalized during cycle 2, subjects will be observed for 
8 hours post tarlatamab infusion.  
Routine radiological imaging (computed tomography [CT]/magnetic resonance imaging 
[MRI]) and tumor burden assessments will be performed as outlined in the Schedule of 
activities.  Assessment of disease response will be determined based on RECIST 1.1 
per PCWG3 guidelines (Sections 11.8 and 11.9).  To further assess the risk of delayed 
adverse events, the subject must return for safety follow-up (SFU) visit approximately 
60 (5) days after the last dose of tarlatamab.  
Long-term follow-up will be conducted every 3 months up to 3 years 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. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Section 1.3. 
Statistical Considerations 
All subjects who are enrolled and receive at least 1 dose of tarlatamab will be included in 
the analysis, unless otherwise specified.  
The primary analysis will occur when target enrollment is complete and each subject 
either completes at least 6 months on study or withdraws from the study.  The final 
analysis will be performed after the last subject has had an opportunity to complete the 
corresponding end of treatment visit/procedures.  
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.  The 
number and percentage of subjects reporting any treatment-emergent adverse events 
will be tabulated.  Clinical laboratory tests, physical examination findings and vital sign 
data will be listed.  Summaries of laboratory, examination and vital sign data over time 
and/or changes from baseline over time will be provided.  
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.  

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 15 of 148 
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Kaplan-Meier methods will be used to estimate landmarks for time to event endpoints 
with the Greenwood formula (Kalbfleisch and Prentice, 1980) used to estimate the 
standard error used in CI calculation. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
No formal statistical hypotheses will be tested in this phase 1b study. 
Sponsor Name: Amgen, Inc. 
 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
 
Page 16 of 148 
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1.2 
Study Schema 
Figure 1-1.  Study Schema 
Screening (up to 28 days)
Safety Follow-up
Long-term Follow-up
Part 1:  Dose Exploration
(N ≈ 20)
Enrollment
Part 2:  Dose Expansion
(N ≈40)
Safety Follow-up
Long-term Follow-up
Screening (up to 28 days)
Enrollment
Tarlatamaba
End of Treatment
End of Treatment
Tarlatamab IV Q2W w/step dosing
MTD/RP2D
Cohort 1:  100 mg IV Q2W (w/step 
dosing)
N = 3 - 10
 
DLT  dose limiting toxicity; IV  intravenous; MTD  maximum tolerated dose; Q2W  every 2 weeks; RP2D  recommended phase 2 dose 
a At the time of initiation of the study, the starting dose will be the highest dose deemed safe and tolerable in the ongoing phase 1 trial of tarlatamab in subjects with 
small cell lung cancer (Note:  based on emerging safety data from Study 20160323, the starting dose may be lower than the highest dose deemed safe and 
tolerable).  The planned highest dose in this study is not anticipated to exceed the MTD as established in the ongoing Study 20160323.  The dose escalation scheme 
shown here is an example and the actual dose escalation schema will be based on what is established in the ongoing Study 20160323 (please refer to Table 4-1 for 
planned doses per dose cohort level in Study 20160323).  In order to consider a certain Dose Level as the MTD at least 6 DLT evaluable subjects must be enrolled at 
that dose level.  No more than 10 DLT evaluable subjects will be enrolled at any specific dose level in dose exploration phase. 
Study Periods: 
 
Screening:  up to 28 days before enrollment 
 
Treatment:  treatment continues until progression 
 
End of treatment:  should occur as soon as possible (within 14 days) after the last dose of investigational product 
 
Safety follow-up:  approximately 60 (5) days after the end of the last dose of tarlatamab 
 
Long-term follow-up:  every 3 months up to 3 years from the first dose of protocol-required therapy for all subjects who have not withdrawn consent 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
 
Page 17 of 148 
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1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities:  Single Step Dosing - Cycle 1 Only 
STUDY PERIOD/ 
TREATMENT CYCLE 
SCRa 
Cycle 1 only 
WEEKb 
-4 to -1 
1 
2 
3 
4 
DAYb 
-28 to -1 
1 
2 
3 
5 
8 
9 
10 
15 
16 
17 
22 
HOUR (relative to infusion)c 
 
Pre 
EOI 
2 
6 
24 
48 
96 
Pre 
EOI 
2 
6 
24 
48 
Pre 
EOI 
2 
6 
24 
48 
168 
General/Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationd 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Vital signs, pulse oxe 
X 
X 
X 
Xe 
X 
X 
X 
X 
Xe 
X 
X 
X 
Xe 
X 
X 
12-lead ECGf 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
ECHO or MUGA jj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review 
 
 
============================================================================================  
SAE review 
============================================================================================================  
Prior/concomitant medication  
============================================================================================================  
Local Laboratory Assessments 
CBC with differential 
X 
Xg 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Coagulation 
X 
Xg 
 
 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
 
X 
Chemistry panelh 
X 
Xg 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Lipase and Amylase 
X 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety endocrine paneli 
X 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP  
X 
Xg 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Ferritin 
X 
Xg 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
HBsAg, HBsAb, HCV Ab, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central and Biomarker Laboratory Tests 
Cytokines 
 
X 
 
Xj 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Page 1 of 2 
Footnotes following last page of Table 1-2 
 

Product:  Tarlatamab (AMG 757) 
Protocol Number:  20200040 
Date:  21 June 2024 
 
Page 18 of 148 
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Table 1-1.  Schedule of Activities:  Single Step Dosing - Cycle 1 Only 
STUDY PERIOD/ 
TREATMENT CYCLE 
SCRa 
Cycle 1 only 
WEEKb 
-4 to -1 
1 
2 
3 
4 
DAYb 
-28 to -1 
1 
2 
3 
5 
8 
9 
10 
15 
16 
17 
22 
HOUR (relative to infusion)c 
 
Pre 
EOI 
2 
6 
24 
48 
96 
Pre 
EOI 
2 
6 
24 
48 
Pre 
EOI 
2 
6 
24 
48 
168 
Central and Biomarker Laboratory Tests (continued) 
Pharmacogenetics (optional)p 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics Assessments 
Tarlatamab PK Collectionq 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Study Drug Treatment 
Dexamethasone or 
equivalentr 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Tarlatamab IV infusions 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
IV hydration 1 Ls 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Hospital stayt 
 
=======================  
 
=======================  
=======================  
 
Imaging Assessments:  See Table 1-3  Schedule of Imaging Assessments 
Page 2 of 2 
Footnotes following last page of Table 1-2 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040  
Date:  21 June 2024 
Page 19 of 148 
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Table 1-2.  Schedule of Activities:  Cycle 2 and Beyond 
STUDY 
PERIOD/TREATMENT 
CYCLE 
Cycle 2  
Q cycu 
Q2 cycv 
Q3 cycw 
EOT 
SFUx 
LTFUff 
WEEKb 
1 
2 
3 
4 
1 
3 
1 
1 
 
 
 
DAYb 
1 
2 
3 
5 
8 
15 
16 
17 
22 
1 
15 
1 
1 
 
 
 
HOUR (relative to 
infusion)c 
Pr
e 
EOI 
2 
6 
24 
48 
96 
168 
Pre 
EOI 
2 
6 
24 
48 
168 
 
 
 
 
 
 
 
General/Safety Assessments 
Clinical Evaluationd 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Vital signs, pulse oxe 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
12-lead ECGf 
Xy 
Xy 
 
 
 
 
 
 
Xy 
Xy 
 
 
 
 
 
Xy 
Xy 
 
 
 
 
 
AE review 
===============================================================================================================  
SAE 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 
 
 
X 
X 
 
Chemistry panelh 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Lipase and Amylase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Safety endocrine paneli 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
CRP  
X 
 
 
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 
X 
 
HBsAg, HBsAb, HCV 
Ab, HIV  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central and Biomarker Laboratory Tests 
Cytokines 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Xz 
 
 
 
 
 
 
Page 1 of 2 
Footnotes following last page of Table 1-2 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040 
Date:  21 June 2024 
 
Page 20 of 148 
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Table1-2.  Schedule of Activities:  Cycle 2 and Beyond 
STUDY 
PERIOD/TREATMENT 
CYCLE 
Cycle 2  
Q cycu 
Q2 cycv 
Q3 cycw 
EOT 
SFUx 
LTFUff 
WEEKb 
1 
2 
3 
4 
1 
3 
1 
1 
 
 
 
DAYb 
1 
2 
3 
5 
8 
15 
16 
17 
22 
1 
15 
1 
1 
 
 
 
HOUR (relative to infusion)c 
Pre 
EOI 
2 
6 
24 
48 
96 
168 
Pre 
EOI 
2 
6 
24 
48 
168 
 
 
 
 
 
 
 
Central and Biomarker Laboratory Tests (continued) 
Pharmacokinetics Assessments 
Tarlatamab 757 PK 
Collectionq 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Xcc 
Xcc 
 
 
 
X 
 
Study Drug Treatment 
Tarlatamab IV infusions 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
Imaging Assessments:  See Table 1-3  Schedule of Imaging Assessments 
Long-term Follow-up 
Survival Status and/or 
subsequent cancer 
therapydd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 2 of 2 
Footnotes following last page of Table 1-2 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040 
Date:  21 June 2024 
 
Page 21 of 148 
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Abbreviations used:  Ab  antibody; ACTH  adrenocorticotropic hormone; AE  adverse event; BP  blood pressure; C  cycle; CBC = complete blood count; 
CNS  central nervous system; COVID-19 Coronavirus Disease 2019; CRP  C-reactive protein; 
CRS  Cytokine Release Syndrome;
 D  day; ECG  electrocardiogram; ECHO  echocardiogram; 
ECOG  Eastern Cooperative Oncology Group; eCRF  electronic case report form; EOI  end of infusion; EOT  end of treatment;
 FSH  follicle stimulating hormone; FT4  free thyroxine; HBsAg  hepatitis B surface antigen; HBsAb  anti-hepatitis B surface antibody; 
HCV  hepatitis C; HIV  human immunodeficiency virus; HR  heart rate; IHC  immunohistochemistry; IGF-1  insulin-like growth factor 1; IP  investigational 
product; IPIM  Investigational Product Instruction Manual; IV  intravenous;
 LH  luteinizing hormone; LTFU  long-term follow-up; 
MMSE  Mini Mental Status Examination; MRI  magnetic resonance imaging; MUGA  multigated acquisition; NE  neuroendocrine; 
 PCWG3  Prostate Cancer Working Group 3; PD  progressive disease; PK  pharmacokinetic; Pre  pre-infusion;
PTEN = phosphatase and tensin homolog; Q cyc  every cycle; Q2 Cyc = every 2 cycles; Q3 Cyc  every 3 cycles; RB1  retinoblastoma protein; 
RECIST  Response Evaluation Criteria in Solid Tumors; RR  respiratory rate; SAE  serious adverse event; SCR  screening; SFU  safety follow-up; 
SOA  Schedule of Activities; SOI  start of infusion; TLS  tumor lysis syndrome; Tp53  tumor protein p53; TSH  thyroid stimulating hormone 
a 
All screening procedures should be performed within 28 days prior to cycle 1 day 1 dosing.   
b 
Each visit week and day is relative to day 1 of each cycle.  Cycle 1 and cycle 2 visits have a  1-day window from designated time point unless otherwise 
specified.  All subsequent visits beginning in cycle 3 will have a  3-day window. 
c 
 
End of infusion (EOI) assessments or procedures are to be completed immediately after infusion of tarlatamab.  EOI indicates the time when the IP 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 day 1 dosing where laboratory 
assessments should be collected within 4 hours before cycle 1 day 1 dosing of tarlatamab). 
 
All assessments and procedures should be collected at the exact nominal time point as noted in the Schedule of Activities.  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. 
d 
Clinical evaluation including physical exam, ECOG, weight and neurological exams, writing test, and MMSE (neurology specialty consultation service as 
clinically indicated).  Performed at Screening only:  demographics, medical history, and height.  Clinical evaluation should be completed within 6 hours prior to 
the first dose of tarlatamab. On days 3, 10 and 17 of cycle 1 and beginning at cycle 2 and beyond, writing tests and MMSE are not required unless clinically 
indicated. 
e 
Vital signs (BP, HR, RR, temperature) and pulse oximetry will be assessed.  During and after each tarlatamab-infusion for the first cycle and if applicable on 
cycle 2 day 1 (during the hospitalization period [see Footnote r]), vital signs should be assessed accordingly during the following time points:   
 
Every 15 minutes ( 5 minutes) from start of infusion (SOI) and for the first 1-hour after EOI 
 
Every 30 minutes ( 5 minutes) from 2-4 hours EOI (at 2, 2.5, 3, 3.5, and 4 hours after EOI) 
 
Every hour ( 5 minutes) from 5-8 hours EOI (at 5, 6, 7, and 8 hours after EOI) 
 
Every 2 hours ( 5 minutes) from 9-16 hours EOI (at 10, 12, 14, and 16 hours after EOI) 
 
Every 4 hours ( 5 minutes) from 17-24 hours EOI (at 20 and 24 hours after EOI) 
After 24 hours EOI, vital signs, and pulse oximetry should be assessed per institutional standards.  For subjects not hospitalized in cycle 2, vital signs should be 
assessed for up to 8 hours (as above).  For cycle 3 and beyond, sites are to follow institutional guidelines for vital signs collection during and after 
infusion. 
f 
ECGs will be collected as single read and will be considered as safety ECGs. 
g 
Lab should be collected within 4 hours before C1D1 dosing of tarlatamab. 
h 
For cycles 1 and 2 only, please collect LDH and uric acid along with the chemistry panel for TLS monitoring (see Section 11.2). 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040 
Date:  21 June 2024 
 
Page 22 of 148 
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i 
Safety endocrine panels:  Cortisol, TSH, FT4, FSH, LH, testosterone will be evaluated at screening, day 1 of every cycle, EOT, and SFU.  ACTH, prolactin, and 
IGF-1 will be evaluated only at screening and EOT. 
j 
Cytokines (serum) on day 1 hour 2 will be collected for cycle 1 only.  
p 
Pharmacogenetic (optional) sample obtained from cell pellet from a biomarker plasma sample at pre-dose (day 1) during cycle 1 only.  
q 
For visits when subjects are dosed, PK samples should be collected within  30 min of the scheduled time points; pre-dose and EOI PK samples should be 
collected within 30-minutes pre-dose and within 30-minutes post EOI, respectively.  For all other non-dosing visits, please follow the window given for 
procedures stated in Footnote b.  
Note:  It is important to document the exact time of IP administration and PK collection in the eCRF.   
r 
Dexamethasone 8 mg IV (or equivalent dose of other corticosteroids) will be administered within 1 hour prior to all doses (including all step dose[s]) of 
tarlatamab for cycle 1 only. 
s 
Tarlatamab short-term IV infusion over 60 minutes and a flush.  See IPIM for dose administration details.  Prophylaxis with IV hydration 1 L normal saline over 4 
to 5 hours immediately following all dose(s) in cycle 1 is required. 
t 
All subjects will be hospitalized for intensive monitoring for 48 hours post tarlatamab infusion during all cycle 1 doses.  Hospitalization is not required for cycle 2 
unless a subject experiences grade 2 or higher CRS or neurological events in cycle 1 (minimum of 24 hours hospitalization required post tarlatamab infusion 
on C2D1 if grade 2 or higher CRS or neurological events are noted in cycle 1).  The subjects may be discharged after this period if there are no signs and 
symptoms of cytokine release syndrome or other acute toxicities.  If subjects are not hospitalized during cycle 2, subjects will be observed for 8 hours post 
tarlatamab infusion. 
u 
Q Cyc: Collected at specified time point beginning with cycle 3 and at each subsequent cycle unless otherwise specified. 
v 
Q2 Cyc: Collected every 2 cycles starting from cycle 3:  C3D1, C5D1, C7D1, C9D1, C11D1 
w 
Q3 Cyc: Collected every 3 cycles starting from cycle 4:  C4D1, C7D1, C10D1 
x 
SFU visit should be completed 60 (5) days from the last dose of tarlatamab.  For details regarding the tests and procedures to be completed for SFU please 
refer to Section 8.1.3. 
y 
For cycles 2, 3, and 4 only:  please collect ECG at pre- and post-infusion.  No further ECGs are collected after cycle 4.   
z 
Cytokines: after Cycle 2, collect only at Cycles 3 & 4 pre-dose 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040 
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Page 23 of 148 
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cc 
For cycles 3 and 4, collect PK samples at pre- and post-infusion.  For all remaining cycles beginning with cycle 5 through 12, collect at pre-infusion only.  PK 
samples will be collected only until end of cycle 12. 
dd 
LTFU will be conducted every 3 months for 3 years 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 
ee 
For subjects who develop COVID19 during screening period and following screening Echo or MUGA, consider repeating Echo or MUGA following resolution 
ff 
During the LTFU phase SAEs suspected to be related to IP that the investigator becomes aware of will be reported to Amgen immediately and no later than 
the 24 hours following the investigator's awareness of the event.  After the end of study, SAEs suspected to be related to IP will be reported to Amgen.  
Refer to Section 8.2.4.1.3 for additional details.  Concomitant medication will not be collected during LTFU 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040 
Date:  21 June 2024 
 
Page 24 of 148 
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Table 1-3.  Schedule of Imaging Assessments (Cycle Independent) 
 
 SCRa 
Treatment Periodb 
EOT 
SFU 
LTFU Notes 
MRI brain 
X 
 
 
 
 
All subjects must have MRI of the brain performed within 
28 days prior to the first dose of 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 
CT/MRI, bone scanc, 
and tumor burden 
assessmentd 
X 
Every 8 weeks 
X 
X 
Xe 
Radiologic imaging (CT/MRI) is required at the EOT or SFU 
visit if the subject has not had radiologic imaging performed 
within 6 weeks of the visit.  Planar bone scintigraphy should 
be performed using conventional 99mTc-MDP radionuclide, 
or other equivalent 99mTc-labeled radiotracers. 
18F-DCFPyL  2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid 99m; 18F-FDG  fluorodeoxyglucose; 
99mTc-MDP  99mtechnetium methylene diphosphonate; CT  computed tomography; EOT  end 
of treatment;
LTFU  long-term follow-up; MRI  magnetic resonance imaging; PCWG3  Prostate Cancer Working Group 3; 
 SCR  screening; SFU  safety follow-up 
a Results of imaging assessments conducted as standard of care may be use for screening within 30 days of start of study treatment.  
b Timing is based on first dose of Tarlatamab (cycle 1 day 1)  7 days for imaging assessments. 
c Per PCWG3 recommendations, the first post-treatment bone scan (at week 8) will be used as the baseline scan with which all future bone scans are compared. 
d Radiologic imaging and tumor assessments are required at screening and every 8  1 weeks post-therapy initiation until clinically significant disease progression or 
deterioration, withdrawal of consent or start of new anticancer therapy.  Every assessment must include the chest, abdomen, and pelvis, all other known sites of 
disease and MRI of the brain if a subject has signs or symptoms suggestive of CNS metastases.  The MRI/CT can be obtained earlier if clinical deterioration 
necessitates an earlier scan at the discretion of the managing physician.  The same contrast and modality used at screening should be used for all subsequent 
assessments.  99mTc-MDP bone scan is required for each radiologic imaging and tumor assessment.  Tumor burden assessments will be performed based on 
PCWG3 guidelines (Sections 11.8 and 11.9).  To confirm soft tissue disease progression, a second MRI/CT scan must be performed at least 4 weeks after the first 
detection of soft tissue disease progression.  Confirmation of bone disease progression by bone scan should be performed per PCWG3 guidelines.  Responses require 
confirmation by a repeat consecutive assessment at least 4 weeks after the first detection of response as measured by RECIST 1.1. 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040 
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Page 25 of 148 
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e For subjects who discontinued treatment for any reason other than confirmed PD, every effort should be made to perform radiographic imaging (CT/MRI/bone) of the 
chest, abdomen, pelvis, bone, and all other known sites of disease every 3 months until documentation of confirmed PD per PCWG3 guidelines, clinical progression, 
start of new anticancer therapy, or up to 3 years after the first dose of tarlatamab, whichever occurs first. 

Product:  Tarlatamab (AMG 757)  
Protocol Number:  20200040 
Date:  21 June 2024 
Page 26 of 148 
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2. 
Introduction 
2.1 
Study Rationale 
Delta-like protein 3 (DLL3), a non-canonical Notch ligand, is a promising therapeutic 
target due to its high expression on the cell surface of small cell lung cancer (SCLC) and 
minimal, mainly cytoplasmic localization in normal tissues.  DLL3 mRNA and protein are 
also highly expressed by other neuroendocrine tumor types, including neuroendocrine 
prostate cancer (NEPC).  RNA sequencing of metastatic tumors showed that 100% (8/8) 
of NEPC tumors expressed DLL3 (MET500 database; Robinson et al, 2017).  A 
separate study identified DLL3 as a gene expressed in 80% (12/15) of NEPC samples 
(Tsai et al, 2017).  A recent study demonstrated that DLL3 protein is expressed in 76.6% 
(36/47) of neuroendocrine prostate tumors, and also in a subset of advanced metastatic 
prostate cancer (Puca et al, 2019). 
Tarlatamab is a half-life extended (HLE) bispecific T-cell engager (BiTE®) antibody 
construct combining the binding specificities for DLL3 and cluster of differentiation 3 
(CD3) genetically fused to the N-terminus of a single chain immunoglobulin G (IgG) 
fragment crystallizable (Fc; scFc) region.  Currently, a first in human phase 1 study 
evaluating the safety, tolerability and pharmacokinetics of tarlatamab in subjects with 
SCLC (Study 20160323) is ongoing.  Tarlatamab demonstrated potent cell killing against 
DLL3-expressing SCLC and other neuroendocrine tumor cell lines in vitro, including the 
NEPC cell line, NCI-H660.  Tarlatamab demonstrates anti-tumor activity in small cell 
lung cancer (SCLC) and melanoma xenograft models of neuroendocrine tumors and can 
enable regression of established small cell lung tumors in mouse xenograft models.  
Therefore, targeting NEPC with tarlatamab may lead to anti-tumor activity. 
2.2 
Background 
2.2.1 
Disease 
Prostate cancer is the most frequently diagnosed non-cutaneous cancer in men with an 
estimated 191 930 new cases and 33 330 deaths in the United States (US) in 2020 
(American Cancer Society, 2020).  In the European Union (EU), there were an estimated 
365 000 new cases of prostate cancer in 2015, with 72 000 and 77 000 deaths estimated 
in 2012 and 2015, respectively (10% of total cancer deaths) (Crocetti, 2015).  NEPC 
represents an aggressive variant of prostate cancer.  While de novo cases appears to be 
rare, accounting for less than 2% of patients at the time of initial diagnosis (Parimi et al, 
2014), treatment-emergent NEPC, characterized by a histological transformation from 
adenocarcinoma to a high-grade neuroendocrine tumor, is becoming increasingly 

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recognized and may develop in 15% to 20% of patients treated with standard therapies 
for prostate adenocarcinoma, including novel hormonal therapies (Aggarwal et al, 2018).  
The exact mechanisms underlying this histological transformation are unclear, however, 
loss of androgen signaling dependence and the acquisition of alternative lineage 
programs have been associated with the development of NEPC.  Overall, the prognosis 
for NEPC is poor (Wang et al, 2014) and is often treated with platinum-based 
chemotherapy regimens (Aparicio et al, 2013).  There is currently no standard 
therapeutic approach and it remains an unmet need. 
2.2.2 
Amgen Investigational Product Background:  Tarlatamab 
BiTE® (bispecific T-cell engager) molecules have been designed to direct T effector 
memory cells towards target cells.  BiTE® binding to T-cells and target cells triggers 
target cell specific cytotoxicity which closely resembles standard cytotoxic T lymphocyte 
activation.   
Tarlatamab 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 (scFc) region.  Tarlatamab is being developed with the intent to treat patients 
with SCLC.   
Refer to the specific section of the Investigator Brochure (IB) 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 tarlatamab Investigator’s Brochure. 
2.2.2.1 
Pharmacology 
The activity of tarlatamab requires the simultaneous binding to both DLL3 expressed on 
target cells and CD3 expressed on T-cells.  Bispecific binding of BiTE® antibody 
constructs, such as tarlatamab, causes 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). 
Tarlatamab treatment induces T-cell activation and expansion, and redirects cytotoxic 
CD8+ or CD4+ T lymphocytes to kill DLL3+ cells.  The 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 

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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 (Amgen Study Report 122718). 
Tarlatamab is a potent molecule showing mean half-maximal lysis of human SCLC cell 
lines by human effector cells in vitro over a range of 
 pM.  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 (Amgen Study Report 
 
  Tarlatamab also demonstrates cytotoxic activity against other 
DLL3-expressing neuroendocrine cell lines, including the NEPC cell line NCI-H660.  
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 Good Laboratory Practice (GLP) 
compliant 28-day cynomolgus monkey toxicology studies.  In the 28-day study, 
tarlatamab was administered once weekly by intravenous (IV) infusion at 0, 50, 500, and 
4500 µg/kg.  Tarlatamab-related changes were limited to a minor decrease in 
lymphocyte populations (detected after the second dose only) at 4500 µg/kg, a slightly 
increased heart rate (on day 2 but not at day 23) at ≥ 500 µg/kg, and a minimal to mild 
mixed inflammatory cell infiltrate in the pituitary at 50 µg/kg and 500 µg/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 3-month study, AMG 757-related 
clinical pathology changes were limited to a minimal decrease in lymphocytes at 
4500 µg/kg.  In addition, AMG 757-related changes were observed in the pituitary gland 
at  50 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 

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Toxic Dose (HNSTD) was determined to be 4500 µg/kg in both the 28-day and 3-month 
studies based on the absence of any AMG 757-related adverse findings. 
2.2.2.3 
Background Clinical Experience With Amgen Investigational 
Product Tarlatamab 
As of the 15 April 2021 data cutoff, 91 subjects were enrolled in the tarlatamab first-in-
human (FIH) Study 20160323, 88 (96.7%) of whom received at least 1 dose of 
tarlatamab.  Seventy subjects received monotherapy:  1 subject each was assigned 
0.003, 0.01, 0.03, and 0.1 mg of tarlatamab; 12 subjects were assigned 0.3 mg; 
8 subjects were assigned 1 mg; 11 subjects were assigned 1 to 3 mg; 10 subjects were 
assigned 1 to 10 mg; 8 subjects were assigned 1 to 30 mg; 13 subjects were assigned 
1 to 100 mg; and 4 subjects were assigned 1 to 25 to 100 mg of tarlatamab 
monotherapy administered intravenously (IV) every 2 weeks (Q2W).  Overall, 
all subjects (100%) had treatment emergent adverse events (TEAEs); the most 
commonly reported adverse events were cytokine release syndrome (31 subjects 
[44.3%]); pyrexia (22 subjects [31.4%]); fatigue (18 subjects [25.7%]); constipation 
(17 subjects [25.7%]); nausea (16 subjects [24%]); anemia (12 subjects [17.1%]); and 
dysgeusia and dyspnea (11 subjects each [15.7%]).  Serious adverse events were 
reported for 33 subjects (47.1%), treatment related adverse events leading to withdrawal 
from tarlatamab were reported for 3 subjects (3%), and grade ≥ 3 treatment-emergent 
adverse events (TEAEs) were reported for 34 subjects (48.6%).  One subject (1.4%), 
who received 2 doses of tarlatamab at 0.3 mg IV Q2W, had a treatment-emergent fatal 
adverse event of pneumonitis, which was considered to be a dose-limiting toxicity (DLT) 
event. 
Cytokine release syndrome (CRS) is the most frequently reported adverse event 
occurring in 31 subjects (44.3%) with grade 2 CRS occurring in 7 subjects (10%) and 
grade 3 CRS occurring in 1 subject (1.4%).  No grade 4 or higher CRS has been 
reported at the time of the data cutoff date.  CRS presented mainly as fever, tachycardia, 
nausea and fatigue  hypotension and was reversible.  In 8 subjects (11.4%), CRS was 
reported as a serious adverse event, 1 event of which led to treatment discontinuation.  
CRS 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. 
Based on emerging data, neutropenia has been reported in the FIH study.  As of 
28 July 2021, with a total of 113 subjects (112 subjects in Study 20160323 and 1 subject 

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in Study 20200040) exposed, treatment-emergent neutropenia or neutrophil count 
decreased was observed in 11 subjects (9.7%).  Out of the 11 subjects, 3 subjects 
(2.7%) experienced grade 2 adverse events, 3 subjects (2.7%) experienced grade 3 
events, and 5 subjects (4.4%) experienced grade 4 neutropenia events.  There were no 
fatal neutropenia events.  One subject experienced 2 serious adverse events of 
neutropenia (Grade 3 and Grade 4).  Tarlatamab was interrupted in 3 subjects (one 
subject discontinued), and it was withdrawn in 2 subjects.  There were no cases of 
febrile neutropenia. 
As of 15 April 2021, a preliminary efficacy data was available for 69 subjects who 
received monotherapy.  Overall, a confirmed PR was observed starting at a dose level of 
0.3 through 100 mg in a total of 12 subjects for an overall ORR (95% CI) of 17.4% (9.3, 
28.4).  The disease control rate (95% CI) was 46.4% (34.3, 58.8). 
Eight subjects received combination therapy with pembrolizumab in Part C of the 
ongoing FIH Study 20160323 with 5 subjects assigned 0.1 mg and 3 subjects assigned 
0.3 mg of tarlatamab.  Cohort 16 with 0.3 mg of tarlatamab administered over 1-hour 
Q2W 
 
  As of 15 April 
2021, 8 (100%) subjects had TEAEs, 3 (37.5%) subjects had serious TEAEs, 3 (37.5%) 
subjects had grade  3 TEAEs, 0 (0%) subjects had TEAEs that led to treatment 
discontinuation.  The most common adverse events include:  fatigue (5 subjects 
[62.5%]), nausea (4 subjects [50.0%]), decreased appetite (3 subjects [37.5%]), vomiting 
(3 subjects [37.5%]), constipation (2 subjects [25.0%]), contusion (2 subjects [25.0%]), 
dyspnea (2 subjects [25.0%]), headache (2 subjects [25.0%]), insomnia (2 subjects 
[25.0%]), myalgia (2 subjects [25.0%]), and pyrexia (2 subjects [25.0%]).  Cytokine 
release syndrome was reported in 1 (13%) subject (grade 2 CRS event which occurred 
on cycle 1 day 1 following administration of tarlatamab as monotherapy). 
Ten subjects received a CRS mitigation strategy in Part D of the ongoing FIH Study 
20160323 consisting of 1 to 100 mg tarlatamab plus dexamethasone.  Eight subjects 
(80.0%) reported a TEAE.  Grade 3 adverse events were reported for 5 subjects 
(50.0%).  Adverse events by preferred term reported for  20.0% of subjects were CRS 
(6 subjects [60.0%]), pyrexia (3 subjects [30.0%]), dysgeusia (3 subjects [30.0%]), and 
fatigue, constipation, hyponatremia, chills, and decreased neutrophil count (each 
2 subjects [20.0%]).  Reported CRS of grade  2 was reported in 2 subjects (20.0%).  
Serious CRS was reported in 2 subjects (20.0%). 

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Refer to the Tarlatamab Investigator’s Brochure for further description of key safety 
risks. 
As of 26 February 2021, preliminary PK data for tarlatamab were available for 
68 subjects (61 subjects from monotherapy cohorts and 7 subjects from the 
pembrolizumab combination cohorts).  
Within the evaluated target dose range of 0.003 to 100 mg Q2W (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. 
2.3 
Benefit/Risk Assessment 
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.  RNA sequencing of metastatic tumors showed that 100% (8/8) of NEPC tumors 
expressed DLL3 (MET500; Robinson et al, 2017).  A separate study identified DLL3 as a 
gene expressed in 80% (12/15) of NEPC samples (Tsai et al, 2017).  A recent study 
found enhanced expression of DLL3 in advanced metastatic prostate cancer, particularly 
in neuroendocrine prostate cancer (NEPC) (Puca et al, 2019).  Tarlatamab 
demonstrated potent cell killing against neuroendocrine tumor cells in vitro and can 
enable regression of established small cell lung tumors in mouse xenograft models.  
Therefore, targeting NEPC with tarlatamab may lead to anti-tumor activity.  NEPC is 
considered a clinically aggressive variant of advanced prostate cancer with poor 
responses to standard treatments and limited therapeutic options. 
The key safety information for tarlatamab including risk, summarized in Table 2-1 below, 
are based on experience with tarlatamab in the phase 1, FIH Study 20160323 for the 
indication SCLC, on the biological mechanism of action, based on experience with other 
BiTE® molecules, and on the potential for on-target, off-tumor effect.  The additional 
potential safety concerns of neurological events, pituitary dysfunction, tumor lysis 
syndrome (TLS), and renal toxicity is summarized in the sections below.  Neutropenia 
has also been observed in the FIH study and is considered an identified risk. 

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Table 2-1.  Key Risks for Tarlatamab  
Safety Risk  
Description  
Cytokine Release  
Syndrome (CRS) 
 
CRS is a recognized adverse drug reaction of tarlatamab 
administration due to safety data from tarlatamab phase 1 first in 
human 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 acute lymphoblastic leukemia (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 
• 
Skin – rash  
• 
Gastrointestinal – nausea, vomiting, diarrhea  
• 
Respiratory –dyspnea, tachypnea, hypoxemia  
• 
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.  . 
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 6-4. 
ALL  acute lymphoblastic leukemia; BiTE  bispecific T-cell engager; CD19  cluster of differentiation 19; 
CRS  cytokine release syndrome; SCLC  small cell lung cancer. 
Refer to the tarlatamab Investigator’s Brochure for further description of key safety risks. 
A clinical safety monitoring and mitigation strategy with emphasis on cytokine release 
syndrome, neurological toxicities, and pituitary dysfunction will be implemented in this 
study which will include but not be limited to prevention, ongoing monitoring, early 
recognition, and prompt management.  Refer to Section 6.8 for detailed management 
recommendations. 

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Given the evidence provided above, and with the mitigations and safety monitoring built 
into the protocol, the potential benefits to the patient are believed to outweigh the risks. 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure for further data on tarlatamab. 
2.3.1 
Additional Potential Safety Concerns for Tarlatamab 
2.3.1.1 
Neurological Events 
There exists the risk of neurological adverse events with administration of AMG 757.  
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.  
Neurological events have been observed with AMG 757 administration in the AMG 757 
phase 1 FIH Study 20160323 for the indication SCLC.  No neurologic events were 
observed in the AMG 757 28-day and 3-month GLP toxicology studies in cynomolgus 
monkeys. 
2.3.1.2 
Pituitary Dysfunction 
There exists the risk of pituitary dysfunction with administration of AMG 757.  The target 
DLL3 protein is expressed in the pituitary and there were observations of an 
AMG 757-related mixed inflammatory cell infiltrate in the pituitary in the 28-day and 
3-month GLP cynomolgus monkey toxicology studies. 
2.3.1.3 
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, 

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treatment-sensitive solid tumors must be recognized.  Therefore, there is a risk of TLS in 
humans with administration of tarlatamab. 
3. 
Objectives and Endpoints 
 
 
 
 
Exploratory 
Objectives  
Endpoints  
Primary  
 
Evaluate the safety and tolerability 
of tarlatamab   
 
Treatment-emergent adverse 
events, treatment-related adverse 
events, and changes in vital signs, 
electrocardiogram (ECG), and 
clinical laboratory tests  
 
Determine the maximum tolerated 
dose (MTD) or recommended phase 
2 dose (RP2D)  
 
Dose limiting toxicities (DLTs)  
Secondary  
 
Evaluate anti-tumor activity of 
tarlatamab as assessed by 
additional measures   
 
Objective response (OR) per 
Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 
 
Duration of response (DOR) per 
RECIST 1.1 
 
Radiographic progression-free 
survival (PFS) per Prostate Cancer 
Working Group 3 (PCWG3) 
 
Overall survival (OS)  
 
Disease Control Rate (DCR) per 
RECIST 1.1 
 
Characterize the pharmacokinetics 
(PK) tarlatamab   
 
PK parameters for tarlatamab 
following intravenous (IV) 
administration including, but not 
limited to, maximum serum 
concentration (Cmax), minimum serum 
concentration (Cmin), area under the 
concentration-time curve (AUC) over 
the dosing interval, 
accumulation ratio, and half-life (t1/2)  

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4. 
Study Design 
4.1 
Overall Design 
This is an open label phase 1b study evaluating tarlatamab monotherapy. 
Tarlatamab will be administered as a short-term IV infusion Q2W (with step dosing) in a 
28-day cycle as monotherapy therapy in subjects with de novo or treatment-emergent 
NEPC.  
The study will consist of 2 parts:  dose exploration (Part 1) and dose expansion (Part 2). 
Dose Exploration (Part 1) 
The dose exploration part of the study will enroll up to 20 subjects with 
relapsed/refractory (RR) NEPC.  At the time of initiation of the study, the starting dose 
will be the highest dose deemed safe and tolerable in the ongoing phase 1 trial of 
tarlatamab in subjects with small cell lung cancer (Note:  based on emerging safety data 

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from Study 20160323, the starting dose may be lower than the highest dose deemed 
safe and tolerable).  The planned highest dose in this study is not anticipated to exceed 
the maximum tolerated dose (MTD) as established in the ongoing Study 20160323.  
Based on results from study 20160323 in small cell lung cancer, the doses that may be 
explored in this study are presented in Table 4-1. 
Due to its known mechanism of action, subjects are at an increased risk for first dose 
effects (eg, CRS with associated manifestations and any other potentially evolving and 
unknown first dose effects) following the initial infusion of tarlatamab.  To mitigate these 
risks, a step dosing approach will be implemented.  One of the following step dosing 
approaches will be utilized as the initial dosing schedule based on emerging data and 
the dosing schedule associated with the highest dose deemed safe and tolerable from 
the ongoing first-in-human (FIH) study (Note:  based on emerging safety data from 
Study 20160323, the starting dose may be lower than the highest dose deemed safe 
and tolerable). 
 
Single-step dosing involving a run-in dose on day 1, followed by a step dose on 
day 8 (equal to the target dose) and the target dose on day 15 then Q2W. 
Based on emerging safety, pharmacokinetic and pharmacodynamic data from this study 
as well as the ongoing FIH study (20160323) and the recommendations of the DLRT, 
multiple or parallel dosing cohorts may also be opened simultaneously to assess any of 
the step-dosing strategies as described above. 

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Dose exploration will begin with treating 3 to 4 subjects at the Dose Level 1 (dose level 1 
is the highest dose deemed safe and tolerable in ongoing phase 1 trial of tarlatamab in 
subjects with small cell lung cancer [Note:  based on emerging safety data from 
Study 20160323, the starting dose may be lower than the highest dose deemed safe 
and tolerable]).  The study DLT period is 28 days.  Once all subjects enrolled at a certain 
dose level are DLT evaluable, a DLRT will convene.  For any dose level, and depending 
on observed safety data, the following recommendation may occur:  1) dose 
de-escalation to the next lowest dose level, 2) additional enrollment to the current dose 
level, 3) dose escalation to the next highest dose level.  Dose escalation/de-escalation 
recommendations will be guided by a modified toxicity probability interval design 
(mTPI-2) model (Guo et al, 2017) with a target toxicity probability of 0.3 (Table 4-2) and 
equivalence toxicity interval of (25%, 35%). The operating characteristics in Table 4-3 
provide the probability of selecting each dose level and the expected number of treated 
patients at each dose level for given hypothetical true DLT rates. 
Table 4-2.  Guideline for Escalation/De-escalation 
Number of Evaluable 
Subjects 
Number of DLTs 
Decision 
3-4 
0 
Ec 
1 
S 
2 
Db 
≥ 3 
DU 
5 
0-1 
Ec 
2-3 
Db 
≥ 4 
DU 
6 
0-1 
Ec 
2 
S 
3 
Db 
≥ 4 
DU 
7-8 
0-1 
Ec 
2 
S 
3-4 
Db 
≥ 5 
DU 
9 
≤ 2 
Ec 
3 
S 
4 
Db 

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Number of Evaluable 
Subjects 
Number of DLTs 
Decision 
≥ 5 
DU 
10a 
≤ 2 
Ec 
3 
S 
4-5 
Db 
≥ 6 
DU 
DLT  dose-limiting toxicity; D  de-escalate to the next lower dose level (can be re-escalated back based 
on future data); DU  the current dose is unacceptably toxic and can’t be re-escalated; E  escalate to the 
next higher dose; S  stay at the current dose. 
a As appropriate to better understand safety profile for a dose level, the number of evaluable subjects may 
be expanded up to 10. 
b De-escalate guideline applies only when enrollment is allowed to a lower dose level.  
c If a higher dose level is not allowed, then the current dose level can be expanded. 
Table 4-3.  Operating Characteristics for mTPI-2 Model 
 
Dose 1 
Dose 2 
Early Stopping Probability 
Scenario 1 
 
 
 
DLT probability 
30% 
44% 
 
Selection probability 
67% 
20% 
13% 
Expected # Patients 
9 
4 
 
Scenario 2 
 
 
 
DLT probability 
13% 
30% 
 
Selection probability 
27% 
72% 
1% 
Expected # Patients 
7 
9 
 
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.  The maximum 
tolerated dose (MTD) will be estimated using isotonic regression (Ji et al, 2010) and the 
MTD will be the dose level with the estimated DLT rate closest to 0.30.  In order to 
consider a certain dose Level as the MTD at least 6 DLT evaluable subjects must be 
enrolled at that dose level.  No more than 10 DLT evaluable subjects will be enrolled at 
any specific dose level in dose exploration phase. 
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 
6 evaluable subjects overall). 
 
Either Dose Level 1, 2 or 3 is determined to be safe and tolerable (minimum of 
6 evaluable subjects) and the next higher dose level is determined to be unsafe 
and intolerable.  

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 
All planned dose levels (including any intermediate doses or alternate dosing 
schedules) are determined to be unsafe and intolerable 
 
DLRT may decide to explore higher dose levels if it is deemed safe and the MTD 
is not reached at the highest dose planned. 
 
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. 
The planned highest dose in this study is not anticipated to exceed the MTD as 
established in the ongoing Study 20160323. 
At the time of enrollment, the dose-escalation phase (Part 1) will be eliminated if the 
recommended phase 2 dose (RP2D) has been selected in the ongoing phase 1 trial of 
tarlatamab in small cell lung cancer.  Tarlatamab will then be dosed based upon the 
RP2D selected in the phase 1 trial in small cell lung cancer.  Note:  if Part 1 is initially 
eliminated based upon the RP2D selection in the phase 1 trial in small cell lung cancer, 
dose escalation may be opened in the future to explore additional dose(s) and dosing 
schedule(s) as described above. 
Dose Exploration (Part 1) 
Due to its known mechanism of action, subjects are at an increased risk for first dose 
effects (eg, cytokine release syndrome) following the initial infusion of tarlatamab.  To 
mitigate these risks, a step dosing approach will be implemented (involving a run-in dose 
on cycle 1 day 1 followed by one 
 step doses) per the recommendations of the 
DLRT and based on emerging data from the ongoing phase 1 trial in small cell lung 
cancer. 
Dose Expansion (Part 2) 
Once the recommended phase 2 dose (RP2D) has been determined, enrollment will 
commence in the dose expansion phase to confirm the safety and tolerability of the 
selected dose and to further evaluate anti-tumor activity.  
One or more dosing schedules as described in Part 1 may be pursued in parallel during 
the expansion phase. 
Interim futility analyses (non-binding) will be performed in a continuous manner using 
Bayesian predictive probability (Lee & Liu, 2008).  Interim futility analyses will begin after 
approximately 20 subjects have been treated and have met the data cutoff criteria 
defined as a minimum potential follow-up of 9 weeks.  Following this initial interim futility 
analysis subsequent interim futility analyses will be performed after every 10 subjects 

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have reached the data cutoff criteria, until all subjects are enrolled and evaluated.  
Further enrollment may be terminated if futility criteria are met in the interim futility 
analysis. 
The interim safety analyses will begin after n=10 dose expansion subjects have had the 
opportunity to be on treatment for at least 28 days.  Following this initial interim safety 
analysis, subsequent interim safety analyses will be done together with interim futility 
analyses i.e. after every 10 dose expansion subjects have a minimum potential follow-up 
of 9 weeks.  Based on the interim safety results and reviewing an update estimate of the 
MTD or RP2D using all available data including data from dose exploration and 
expansion subjects, the DLRT may modify the dose level of treated subjects.  A final 
estimate of the MTD or RP2D will use all data from dose exploration and dose 
expansion. 
Based on emerging data from the tarlatamab monotherapy in this indication and 
emerging data from other trials with tarlatamab, the protocol may be amended to include 
a combination of tarlatamab with anti-PD-1 (L1) agent.  
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.2 
Number of Subjects 
Approximately 60 subjects will be enrolled in the study, with up to 20 subjects to be 
enrolled in the dose exploration phase (Part 1) and 40 subjects to be enrolled in the 
dose expansion phase (Part 2).  Based on emerging data in Part 2, the protocol may be 
amended to increase the sample size. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
If a subject stops or delays treatment 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.  
4.2.2 
Number of Sites 
Approximately 25 investigative sites in the US, Europe, and Australia will be included in 
the study.  Sites that do not enroll subjects within 4 months of site initiation may be 
closed. 

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4.3 
Justification for Investigational Product Dose 
The selection of the tarlatamab dose and dosing schedule for this study, which includes 
the number of dose steps (run-in and step doses) will be based on the dose levels that 
have been deemed safe and tolerable by the DLRT in the ongoing first-in human 
(Study 20160323).  It is anticipated that the selected regimen will demonstrate a 
comparable safety and tolerability profile to that determined in subjects in SCLC.  In 
addition, the selected regimen is expected to show clinical activity in subjects with NEPC 
based on the preliminary evidence of efficacy in subjects with SCLC. 
Based on Study 20160323, it is expected that the selected regimen will include step 
dosing (run-in dose on cycle 1 day 1 followed by 1
 escalating doses to reach a 
target dose) during cycle 1, followed by the target dose every 2 weeks thereafter.  The 
step-dosing approach has been implemented to mitigate the risk of cytokine release 
syndrome.  The potential doses of tarlatamab to be used for run-in, step or target doses 
include 
 mg (or intermediate dose levels), which are under evaluation 
in Study 20160323.  
4.4 
End of Study 
4.4.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up, 
), as applicable. 
Amgen will not continue provision of investigational product for subjects after 
their study participation ends unless it is a legal requirement. 
4.4.2 
Study Duration for Subjects 
The study duration for subjects will be approximately up to 3 years.  The study duration 
will consist of up to 28 days for screening, a variable period on treatment (depending on 

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the subject’s response), and a safety follow-up (SFU) period of up to approximately 
60 days (5 days) after the last dose of tarlatamab.  For all subjects who have not 
withdrawn consent, long-term follow-up assessment will also be conducted every 
3 months up to 3 years from the first dose of tarlatamab by clinic visit, telephone or chart 
review to assess for survival and/or the commencement of subsequent cancer therapy.  
4.5 
Patient Input on Study Design 
Patient input was not obtained on study design. 
5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Men aged ≥ 18 years at time of signing the informed consent. 
103 
Metastatic de novo or treatment-emergent neuroendocrine prostate cancer 
(NEPC) defined as one or more of the following: 
 
Histological diagnosis of small cell NEPC 
 
Histologic evidence of prostate cancer with neuroendocrine differentiation as 
defined by positive immunohistochemical staining for chromogranin and/or 
synaptophysin in the majority of the tumor sample   
 
≥ 2 alterations in Tp53, RB1, and/or PTEN by immunohistochemistry (IHC) or 
genomic analyses of baseline tumor tissue (by local assessment) or 
(by local assessment).  Tp53 by IHC is 
considered abnormal if ≥ 10% tumor nuclei showed positive staining.  RB1 
and PTEN by IHC is considered abnormal if ≤ 10% tumor cells showed 
positive staining.  On genomic analyses, nonsynonymous missense or 
stop-gain mutations, frameshift or non-frameshift indels (insertions and 
deletions), and/or copy number losses in ≥ 2 of Tp53, RB1, and PTEN is 
considered abnormal. 

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104 
At least 1 line of prior systemic treatment, including a platinum containing 
regimen for de novo neuroendocrine prostate cancer (if at the time of NEPC 
diagnosis they had no prior diagnosis or treatment for prostate carcinoma) or an 
androgen signaling inhibitor (eg, abiraterone, enzalutamide, darolutamide and/or 
apalutamide) if treatment-emergent (had a previous diagnosis of prostate 
carcinoma prior to NEPC diagnosis). 
Exception:  Subjects may also be included if the aforementioned therapeutic 
options were medically not appropriate for them. 
105 
For subjects with treatment-emergent NEPC or de novo NEPC with histologic 
evidence of prostate cancer with neuroendocrine differentiation as defined by 
positive immunohistochemical staining for chromogranin and/or synaptophysin in 
the majority of the tumor sample (unless refractory to prior androgen deprivation 
treatment), a total serum testosterone of ≤ 50 ng/dl or 1.7 nmol/L  
106 
Subjects with treatment-emergent NEPC or de novo NEPC with histologic 
evidence of prostate cancer with neuroendocrine differentiation as defined by 
positive immunohistochemical staining for chromogranin and/or synaptophysin in 
the majority of the tumor sample (unless refractory to prior androgen deprivation 
treatment), without a history of bilateral orchiectomy, are required to remain on 
luteinizing hormone-releasing hormone (LHRH) analogue therapy during the 
course of protocol therapy 
107 
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 per Prostate Cancer Working Group 3 (PCWG3) modifications (Sections 11.8 
and 11.9) 
108 
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 
109 
Life expectancy of > 3 months, in the opinion of the investigator 
110 
Subjects with treated brain metastases are eligible provided they meet the 
following criteria: 
 
Definitive treatment was completed at least 2 weeks prior to the first planned 
dose of study treatment (stereotactic radiosurgery at least 7 days prior to first 
planned dose of study treatment) 
 
At least 7 days prior to treatment:  any central nervous system (CNS) disease 
is clinically stable, subject is off steroids for CNS disease (unless steroids are 
indicated for a reason unrelated to CNS disease), and subject is off or on 
stable doses of anti-epileptic drugs. 
111 
Adequate organ function, defined as follows: 
Adequate hematological laboratory assessments, as follows: 
 
Absolute neutrophil count (ANC) 1 x 109/L 
 
Platelet count 75 x 109/L 
 
Hemoglobin  9 g/dL 
Adequate renal laboratory assessments, as follows: 

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 
Estimated glomerular filtration rate based on Modification of Diet in Renal 
Disease (MDRD) calculation 30 mL/min/1.73 m2 
Adequate hepatic laboratory assessments, as follows: 
 
Aspartate aminotransferase (AST) < 3 x upper limit of normal (ULN) (if liver 
metastases are present,  5 x ULN) 
 
Alanine aminotransferase (ALT) < 3 x ULN (if liver metastases are present, 
5 x ULN) 
 
Total bilirubin (BIL) < 1.5 x ULN (< 2.0 x ULN for subjects with liver 
metastases) 
Adequate coagulation laboratory assessments, as follows: 
 
Prothrombin time/international normalized ratio (PT/INR) and partial 
thromboplastin time (PTT) or activated partial thromboplastin time (APTT) 
≤ 1.5 x institutional ULN.  Subjects on chronic anticoagulation therapy who do 
not meet the criteria above may be eligible to enroll after discussion with the 
medical monitor. 
Cardiac function: 
 
Cardiac ejection fraction ≥ 50% 
 
No clinically significant electrocardiogram (ECG) findings 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
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 non-muscle invasive urothelial carcinoma  
202 
History or presence of hematological malignancies unless curatively treated with 
no evidence of disease 2 years 
203 
Untreated (includes new lesions or progression in previously treated lesions) or 
symptomatic brain metastases and leptomeningeal disease  
204 
History or presence of relevant CNS pathology such as uncontrolled epilepsy or 
seizure disorder, aphasia, paresis, dementia, severe brain injuries, Parkinson’s 
disease, cerebellar disease, organic brain disorder, or psychosis 
205 
Myocardial infarction within 12 months of study day 1, symptomatic congestive 
heart failure (New York Heart Association > class II), unstable angina, or clinically 
significant uncontrolled cardiac arrhythmia  
206 
History of arterial thrombosis (eg, stroke or transient ischemic attack) within 
12 months of first dose of tarlatamab 

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207 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
(prednisone dose > 10 mg per day or equivalent dose) or any other form of 
immunosuppressive therapy within 7 days prior study day 1 
208 
Active autoimmune disease requiring systemic treatment within the past 2 years 
of study day 1 (ie, with the use of disease modifying agents, non-physiologic 
doses of corticosteroids or immunosuppressive drugs); including current 
autoimmune sequelae or previous Grade > 2 autoimmune sequelae from 
checkpoint inhibitors or other immunomodulatory treatments that require 
systemic therapy 
 
Exception:  Participants with autoimmune endocrine disorders on hormonal 
supplementation may be enrolled even if > Grade 2 when it first occurred, if 
approved by the Medical Monitor. 
209 
Presence of fungal, bacterial, viral, or other infection requiring oral or IV 
antimicrobials for management within 7 days of first dose tarlatamab. 
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. 
210 
Exclusion of hepatitis infection based on the following results and/or criteria: 
 
Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic 
Hepatitis B or recent acute hepatitis B). 
 
Negative HepBsAg 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:  Hepatitis C virus RNA by PCR is 
necessary.  Detectable Hepatitis C virus RNA suggests chronic hepatitis C. 
211 
Known positive test for human immunodeficiency virus (HIV) 
212 
Anti-tumor therapy within 28 days of study day 1; concurrent use of hormone 
deprivation therapy for hormone-refractory prostate is permitted; subjects on a 
stable bisphosphonate or denosumab for ≥ 30 days prior to study day 1 are 
eligible 
 
Exceptions: 
 
Subjects who received conventional chemotherapy are eligible if at least 
14 days have elapsed and if all treatment-related toxicities have resolved 
to Grade ≤ 1 
 
Prior palliative radiotherapy must have been completed at least 7 days 
before the first dose of tarlatamab  
 
Subjects who received androgen signaling inhibitor (eg, abiraterone, 
enzalutamide, and/or apalutamide) are eligible if at least 14 days have 
elapsed and if all treatment-related toxicity has been resolved to 
Grade ≤ 1 
213 
Major surgical procedures ≤ 28 days or non–study-related minor procedures 
≤ 7 days prior to study day 1.  In all cases, the subjects must be sufficiently 
recovered and stable before treatment administration 

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214 
Currently receiving treatment in another investigational device or drug study, or 
less than 28 days from study day 1 since ending treatment on another 
investigational device or drug study(ies).  Other investigational procedures while 
participating in this study are excluded with the exception of 
215 
Unresolved toxicities 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 that are stable and well-controlled and there is agreement 
to allow by the investigator and sponsor 
216 
Subject unable to receive both iodinated contrast for CT scans and gadolinium 
contrast for magnetic resonance imaging (MRI) scans 
217 
Subject has known sensitivity and immediate hypersensitivity to any components 
of tarlatamab 
218 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s awareness 
219 
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 
220 
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 60 days after the last dose of tarlatamab.  
Refer to Section 11.5 for additional contraceptive information. 
221 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for 60 days after the last dose of tarlatamab. 
222 
Male subjects unwilling to abstain from donating sperm during treatment and for 
60 days after the last dose of tarlatamab. 
223 
Subjects on prior DLL3-targeted therapy may be eligible if discussed with Amgen 
medical monitor prior to enrollment 
224 
History of hypophysitis or pituitary dysfunction 
225 
Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
226 
Live and live-attenuated vaccines within 4 weeks prior to study drug 
administration. 
227 
History or evidence of SARS-COV2 infection unless agreed upon with Medical 
Monitor and with no acute symptoms of COVID19 disease within 14 days prior to 
first dose of IP (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 external review bodies approval of the protocol, 

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informed consent form (ICF), and all other subject information and/or recruitment 
material, if applicable (see Section 11.3). 
The subject or legally authorized representative must personally sign and date the 
external review bodies (eg, the institutional review board [IRB]/independent ethics 
committee[IEC]/regulatory authorities) and Amgen approved informed consent before 
commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject or legally authorized representative signs the informed consent) 
receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
manually.  This number will be used to identify the subject throughout the clinical study 
and must be used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened one time at the investigator’s decision.  Refer to Section 8.1.1. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), noninvestigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and noninvestigational product(s) 
are referred to as investigational medicinal product and noninvestigational 
product(s)/auxiliary, respectively. 

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The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 6-1 below. 
6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
 

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Table 6-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
Tarlatamab 
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 IV bag with normal saline (
 sodium chloride) and an IV solution 
stabilizer.  The drug product is formulated with L-glutamic acid, sucrose, polysorbate 80, pH
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage Frequency 
At the time of initiation of the study, the starting dose will be the highest dose deemed safe and 
tolerable in the ongoing phase 1 trial of tarlatamab in subjects with small cell lung cancer (Note:  
based on emerging safety data from Study 20160323, the starting dose may be lower than the 
highest dose deemed safe and tolerable). 
Route of Administration 
Tarlatamab will be administered as a short-term IV infusion for 60 minutes followed by a flush once 
every 2 weeks (with step-dosing).   
Accountability 
The date, time, package lot number, dose, and the start and stop time of infusion are to be recorded 
on the individual subject’s Investigational Product Administration CRF.   
Dosing Instructions 
Tarlatamab will be administered at the study center by a qualified staff member.  A physician must 
be available at the time of administration of investigational products.  Please refer to IPIM for more 
details on dosage, administration, and schedule of tarlatamab. 
CRF  case report form; IPIM  Investigational Product Instruction Manual; IV  intravenous. 
a Tarlatamab will be manufactured and packaged by Amgen Inc. and distributed using Amgen clinical study drug distribution procedures. 

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6.1.2 
Medical Devices 
Investigational medical devices will not be used in this study. 
Other noninvestigational medical devices may be used in the conduct of this study as 
part of standard care. 
Noninvestigational 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.   
6.1.3 
Noninvestigational Product(s)/Auxiliary Medicinal Product(s) 
All noninvestigational product(s)/auxiliary medicinal product(s) including, 
dexamethasone and normal saline, 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 noninvestigational product(s)/auxiliary 
medicinal product(s).  Due to the mechanism of action of tarlatamab, CRS and 
neurological events are important potential risks.  Corticosteroid has been used for 
prophylaxis and treatment of CRS and neurological events secondary to blinatumomab 
and other BiTE® molecules. 
Prophylaxis with IV hydration 1 L normal saline over 4 to 5 hours immediately following 
all dose(s) in cycle 1 is required. 
Dexamethasone 8 mg IV (or equivalent dose of other corticosteroids) will be 
administered within 1 hour prior to each dose of tarlatamab in cycle 1. 
Dexamethasone dose and schedule may be changed based on emerging safety data. 
6.1.4 
Other Treatment Procedures 
Sites are required to have tocilizumab or siltuximab (if tocilizumab not available) on site 
for potential treatment of CRS.  
6.1.5 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers delivery systems, labeling, and inserts. 

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This includes any investigational product (tarlatamab) provisioned and/or 
repackaged/modified by Amgen. 
Any product complaint(s) associated with an investigational product supplied by Amgen 
are to be reported. 
6.1.6 
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 
o Exception:  Radiation therapy for symptom control (eg, bone metastasis) 
or brain metastases 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 7 days before the subsequent dose of 
tarlatamab  
 
Chronic systemic corticosteroid therapy (prednisone dose > 10 mg per day or 
equivalent) or any other 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 (PI) 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, 
Bacillus Calmette–Guérin (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 30 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.  
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
6.2.1.1 
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 

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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 MTD or RP2D.  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.   
6.2.1.2 
Dose-cohort Study Escalation 
Details on dose-cohort study escalation and stopping rules will refer to Section 4.1.  
6.2.1.2.1 
Dose Limiting Toxicity 
Dose-limiting toxicity (DLT) is defined as any qualifying toxicity that is at least possibly 
related to tarlatamab with an onset within the first 28 days following first dose with either 
of the following criteria: 
 
Grade 3 adverse event lasting more than 3 days (with the exception of fatigue 
and 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 6.8.6]); 
 
≥ Grade 4 adverse event regardless of duration (with the exception of 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 6.8.6]). 
Laboratory parameters of Grade 4, not considered clinically relevant and improved to 
Grade  2 within 72 hours, will not be considered DLT’s. 
Asymptomatic grade 4 electrolyte abnormalities that last  72 hours, are not clinically 
complicated, and resolve spontaneously or respond to conventional medical 
interventions will not be considered DLTs. 
The following adverse events will NOT be adjudicated as DLT regardless of the grade or 
duration: 
 
Lymphopenia 
 
Fever 
 
Tumor lysis syndrome (TLS) including associated manifestations attributable to 
TLS (eg, electrolyte abnormalities, renal dysfunction, hyperuricemia) 

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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 CRF. 
6.2.2.1.1 
Dosage Adjustment 
Subjects should continue on the same target dose of tarlatamab (not including the initial 
run-in dose and step dose(s)) throughout the study.  The two exceptions are subjects 
who meet criteria for intra-subject dose escalation (see Section 6.2.2.1.4 for more 
details) and subjects who experienced a DLT or other intolerable tarlatamab-related 
adverse events but showing evidence of clinical benefit.  These subjects will have an 
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, after discussion with the Amgen 
Medical Monitor.  The study drug can be resumed once the adverse events recover to 
Grade 0-1 and the reintroduction of tarlatamab is deemed safe by the investigator, 
Medical Monitor, and GSO.  The subjects must be informed of the risk of continuing on 
therapy.  Each subject is only 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. 
6.2.2.1.2 
Dose Delays 
During the first 28 days 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 28-day 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.  The investigator should inform the Amgen Clinical team as soon as 
the unexpected dosing interruption occurs.  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 4 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 (IP).  If the dosing delay occurred under other conditions, the 

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case will be reviewed by the Sponsor to determine whether and when the subject will be 
allowed to resume tarlatamab. 
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 6.2.3) 
Tarlatamab dosing can be resumed if the toxicities resolve to grade ≤ 1 or return to 
subjects’ baseline values within 4 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: 
 
Any grade ≥ 4 adverse events except those not considered DLT as described in 
Section 6.2.1.2.2 
 
Grade 3 adverse event(s) that do not recover to Grade 0-1 within 4 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 4 weeks) 
 
Criteria for permanent withholding of tarlatamab due to potential hepatotoxicity 
(Section 6.2.3) 
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 withholding and 
restarting criteria to pause enrollment. 
At any point during the study, enrollment will be paused at the occurrence of 2 or more 
Grade 4 or one or more Grade 5 IP related adverse events.  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 
the 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 one or more Grade 5 IP 

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related adverse events; additionally, if a pause and a DLRT has already occurred and 
the appropriate safety/toxicity management for Grade 4 adverse events have already 
been implemented a subsequent enrollment pause may not occur). 
6.2.2.1.4 
Intra-subject Dose Escalation 
In Part 1, certain subjects who enroll in the study and receive the full planned dose for at 
least 2 cycles will be allowed to receive a higher dose of tarlatamab once such dose is 
deemed safe by DLRT.  Both the medical monitor and PI must deem it safe before a 
subject is considered for intra-subject dose escalation.  The subject must be informed of 
the potential risks and benefits.  Intra-subject dose escalation should only occur if the 
subject experienced ≤ Grade 1 toxicity during the previous course.  If any cases of 
Grade ≥ 3 toxicity occur at the current or any previous lower dose levels, no intra-patient 
dose escalation should be allowed at that dose level.  See Section 8.1.2 for more details 
on the changes regarding the schedule of activities for subjects who undergo 
intra-subject dose escalation. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be assigned to treatment with tarlatamab. 
6.4.2 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
6.5 
Treatment Compliance 
Compliance with treatment and the corresponding assessments should be followed 
according to the Schedule of Activities (Section 1.3) and the Treatment Procedures 
(Section 8.2).  Refer to the IPIM for additional information. 
6.6 
Treatment of Overdose 
The effects of overdose of this product are not known.  The administered 
investigational product dose may be up to 10% lower or higher than specified in 

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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 as per Section 11.4. 
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” (See 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 prostate cancer, collect 
therapy name, indication, dose, unit, frequency, route, start and stop dates. 
For all prior therapies taken for prostate cancer (eg, chemotherapy or hormonal 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 
 
type of progression (biochemical [ie, a rising 
 
radiographic, and/or symptomatic) 
 
response (resistant versus sensitive):  categorized on the basis of the 
post-therapy
or radiographic change pattern for agents that reduce tumor 
burden 
NOTE:  A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. 

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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 6.1.6. 
Concomitant therapies are to be collected from signing of the informed consent through 
the end of SFU period.  For concomitant therapies being taken for the disease under 
study (eg, steroids, chemotherapy), collect therapy name, dose, unit, frequency, start 
date and stop date.  For all other concomitant therapies, including vaccines collect 
therapy name, indication, dose, unit, frequency, route, start date and stop date, and 
record in the electronic case report form (eCRF). 
6.7.3 
Vaccines 
Every effort should be made to fully vaccinate patients prior to 14 days from first dose of 
IP.  The use of vaccines except live and live-attenuated vaccines will be allowed during 
therapy per regional and institutional standard of care.  However, SARS-COV2 
vaccinations should be avoided during screening (within a minimum of 14 days from first 
dose of IP) and should be also avoided in the first treatment cycle for better assessment 
of safety parameters.  Throughout the trial, SARS-COV2 vaccination should be avoided 
within 3 days after the administration of IP.  In the event where a patient requires 
steroids for treatment of AEs, vaccination should be avoided while on steroids.  Live and 
live attenuated vaccines can be used at least 60 days after the last dose of 
tarlatamab. 
6.8 
Support Care and Potential Risk Management Guidelines for 
Tarlatamab 
6.8.1 
Cytokine Release Syndrome (CRS) 
CRS is clinically defined and may have various manifestations.  There are no 
established diagnostic criteria.  Signs and symptoms of CRS may include 
(Lee et al, 2014):   
 
Constitutional:  fever  rigors, fatigue, malaise, myalgias, anorexia, arthralgias, 
nausea, vomiting, headache 

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 
Neurologic:  headache, mental status changes, confusion, delirium, word finding 
difficulty or frank aphasia, hallucinations, tremor, dysmetria, altered gait, seizures 
 
Respiratory:  dyspnea, tachypnea, hypoxemia 
 
Cardiovascular:  tachycardia, hypotension, widened pulse pressure, increased 
cardiac output (early), potentially diminished cardiac output (late) 
 
Gastrointestinal:  nausea, vomiting, diarrhea 
 
Renal:  azotemia 
 
Hepatic:  transaminitis, hyperbilirubinemia 
 
Hematology/Coagulation:  hypofibrinogenemia  bleeding, elevated D-dimer 
 
Skin:  rash 
CRS 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.  CRS may be life-threatening or fatal.  Infusion reactions may be 
clinically indistinguishable from manifestations of CRS.  Subjects will be hospitalized for 
intensive monitoring for 48 hours post tarlatamab infusion during all cycle 1 doses (refer 
to Section 8.1.2 for hospitalization guidance).  Throughout the infusion with tarlatamab 
and at least 4 hours after the end of infusion, 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 6-2 (Lee et al, 2014).  For subjects with suspected CRS, samples may 
be collected for analysis after discussion with the Medical Monitor. 

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Table 6-2.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of Severity a 
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 
(eg >120 bpm) may also 
indicate the need for 
intervention for 
hypotension. 
Monitor for CRS symptoms 
including vital signs and pulse 
oximetry at least Q2 hours for 
12 hours or until resolution to 
CRS grade ≤ 1, whichever is 
earlier. 
For subjects with extensive 
co-morbidities or poor 
performance status 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 
Amgen Medical Monitor).  
 
Permanently discontinue 
tarlatamab if there is no 
improvement to CRS 
≤ grade 1 within 7 days. 
Page 1 of 2 
Footnotes defined on last page of table 

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Table 6-2.  Grading and Management of Cytokine Release Syndrome (CRS) 
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 8 mg 
(24 mg/day).  The dose 
should then be reduced 
step-wise. 
 
Investigators should consider 
use of tocilizumabc,d 8 mg/kg 
over 1 hour (not to exceed 
800 mg).  Repeat 
tocilizumabc,d every 8 hours 
as needed if not responsive 
to IV fluids or increasing 
supplemental oxygen.  
Maximum of 3 doses in a 
24-hour period.  Maximum 
total of 4 doses. 
 
If tocilizumab is not available, 
siltuximab (an anti-IL-6 
monoclonal antibody) may be 
used.  The recommended 
dose of siltuximab is 
11 mg/kg administered over 
1 hour as an intravenous 
infusion, consistent with the 
prescribing information for the 
treatment of multicentric 
Castleman’s disease (Sylvant 
Prescribing Information), and 
the CARTOX Working Group 
Guidelines for CRS 
management (Neelapu et al, 
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 who 
develops anaphylaxis to 
siltuximab, or gastrointestinal 
perforation after siltuximab. 
 
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 
tarlatamab or reduce to the 
next lower dose if CRS grade 
3 occurs at the initial run in 
dose (ie, at MTD1) 
(applicable only after MTD1 
has been defined).   
 

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CRS 
Grade 
Description of Severity a 
Minimum Expected 
Intervention 
Instructions for Dose 
Modifications of 
Tarlatamab  
4 
Life-threatening symptoms 
 
Requirement for 
ventilator support OR 
Grade 4 organ toxicity 
(excluding transaminitis) per 
CTCAE criteria 
Admit to intensive care unit 
for close clinical and vital sign 
monitoring per institutional 
guidelines. 
Administer dexamethasone 
(or equivalent) IV at a dose 
maximum of 3 doses of 8 mg 
(24 mg/day).  Further steroid 
use should be discussed with 
the Amgen medical monitor. 
Investigators should consider 
use of tocilizumabc,d 8 mg/kg 
IV over 1 hour (not to exceed 
800 mg).  Repeat 
tocilizumabc,d every 8 hours 
as needed if not responsive 
to IV fluids or increasing 
supplemental oxygen.  
Maximum of 3 doses in a 
24-hour period.  Maximum 
total of 4 doses. 
 
If tocilizumab is not available, 
siltuximab (an anti-IL-6 
monoclonal antibody) may be 
used.  The recommended 
dose of siltuximab is 
11 mg/kg administered over 
1 hour as an intravenous 
infusion, consistent with the 
prescribing information for the 
treatment of multicentric 
Castleman’s disease (Sylvant 
Prescribing Information), and 
the CARTOX Working Group 
Guidelines for CRS 
management (Neelapu et al, 
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 who 
develops anaphylaxis to 
siltuximab, or gastrointestinal 
perforation after siltuximab. 
 
Investigators may also 
consider additional therapy, 
based on clinical judgment. 
If CRS occurs during 
tarlatamab treatment, 
immediately stop the infusion.  
Permanently discontinue 
tarlatamab therapy.   
Page 2 of 2 
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 
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 the Management of 
Adverse Events table.  The recommended dose of siltuximab is 11 mg/kg administered over 1 hour as an 
intravenous infusion, consistent with the prescribing information for the treatment of multicentric 

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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. 
d A subgroup analysis for subjects treated with siltuximab will be evaluated, including CRS outcomes, safety, 
and PK data. 

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Re-start of treatment after CRS: 
After a grade 2 or 3 CRS event, the next infusion may be administered if all of 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 6-3 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 6-3.  Management of Adverse Events Related to Neurologic Events 
Toxicity 
Grade* 
Instructions for Treatment Interruption and Restart 
Neurologic 
Events 
3** 
 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 one 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 
* Per CTCAE Guidelines Version 4.0 
** For adverse events Grade ≤ 2, please follow institutional guidelines for management. 

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6.8.3 
Pituitary Dysfunction 
Based on the expression of DLL3 in the pituitary and observations in the cynomolgus 
monkey toxicology studies, there is a key risk of pituitary dysfunction in humans with 
administration of tarlatamab.   
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 Figure 6-1.  Cortisol, thyroid stimulating hormone 
(TSH), free thyroxine (FT4), follicle stimulating hormone/luteinizing hormone (FSH/LH), 
and testosterone will be evaluated at baseline and monitored throughout the study.  
Adrenocorticotropic hormone (ACTH), prolactin, and insulin-like growth factor 1 (IGF-1) 
will also be evaluated only at baseline and at the end of therapy.  If any indications of 
pituitary gland dysfunction arise, a complete set of pituitary hormone panel will be 
evaluated, an endocrinologist will be consulted, and an MRI of the brain/pituitary will be 
conducted.  After a confirmed diagnosis, tarlatamab will be withheld and corticosteroids 
and hormone replacement administered if clinically indicated.  Please see Figure 6-1 for 
guidelines for restarting tarlatamab.  This management recommendation may be revised 
based on emerging clinical data.  
 

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Figure 6-1.  Monitoring and Management of Pituitary Gland Dysfunction (Gonzalez et al, 2016) 
Monitor for  signs and symptoms of 
pituitary gland dysfunction, TSH, FSH, LH, 
cortisol, FT4, testosterone throughout 
study (ACTH, prolactin, IGF-1 only at 
baseline and EOT)
Abnormal Hormone Monitoring Result
OR
Clinical suspicion of pituitary gland 
dysfunction
(Headache, fatigue, asthenia, impaired 
vision, vomiting, hypotension, 
amenorrhea, impotence)
Diagnostic Tests
•Brain MRI (if clinically indicated)
•ACTH, TSH , FSH, LH, IGF-1, plasma 
cortisol, FT4, prolactin, testosterone
•Blood pressure, glycemia, plasma and 
urine osmolarity, electrolytes
Urgent endocrinology consultation
Confirmed diagnosis
Hold scheduled dose of AMG 757 
Treatment
•Methylprednisolone 1-2 mg/kg daily or 
equivalent 
•Hormone replacement and 
corticosteroid tapering under strict 
endocrinological surveillance
Once residual related toxicity ≤ grade 2, 
clinically stable and <10 mg prednisone or 
equivalent, Restart AMG 757 
Continued endocrinological surveillance 

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6.8.4 
Covid-19 Management 
Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
SARS CoV2 infection and COVID19 disease 
asymptomatic 
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 
& 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 & EKG, ECHO 
and cardiology assessment prior to re-start of IP.  
OR 
If subject continues to test positive for SARS-COV-2 
more than 10 days after initial positive test, or if subject 
initially tests positive in the setting of prior COVID 
vaccination, resume IP only after discussion with patient 
and reassessment of individual risk/benefit & perform Ct 
of chest imaging & EKG (required) prior to re-start of IP. 
Consider ECHO and cardiology assessment  
 
Consider hospitalization for re-start of IP based on 
length of treatment interruption, risk of CRS at 
restart, and amount of time since patient was last 
treated 
 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
Immediately stop the 
infusion (if 
applicable) and 
permanently 
discontinue IP 
therapy IF: 
Subject required 
treatment interruption 
greater than 28 days 
and upon discussion 
with Amgen Medical 
Monitor the decision 
is made to 
permanently 
discontinue treatment 
OR 
Initial benefit/risk 
assessment for 
individual patient is 
not maintained any 
longer 

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Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
SARS CoV2 infection and COVID19 disease 
 
Premedication and assessments:  follow guidance in 
SOC tables 
symptomatic 
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 
& 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 & EKG, 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 IP only after discussion with patient 
and reassessment of individual risk/benefit & 
perform Ct of chest imaging & EKG (required) 
prior to re-start of IP.  Consider ECHO and 
cardiology assessment 
 
Consider hospitalization for re-start of IP based on 
length of treatment interruption, risk of CRS at 
restart, and amount of time since patient was last 
treated 
 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
Immediately stop the 
infusion (if 
applicable) and 
permanently 
discontinue IP 
therapy IF 
Subject required 
treatment interruption 
greater than 28 days 
due to severe or 
life-threatening 
COVID-19 
OR 
Initial benefit/risk 
assessment for 
individual patient is 
not maintained any 
longer 

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Grade 
Interruption/ 
Delay 
Specific 
Management 
Re-start guidance 
Permanent 
Discontinuation 
SARS CoV2 infection and COVID19 disease 
 
Premedication and assessments:  follow guidance in 
SOA tables 

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6.8.5 
Tumor Lysis Syndrome (TLS) 
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.  TLS 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 
large tumor burdens 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).  Prophylaxis with IV hydration 1 L normal saline over 4 to 5 hours immediately 
following all dose(s) in cycle 1 is required.  Careful monitoring of fluid status and 
additional IV hydration as clinically appropriate is recommended.  Allopurinol or 
rasburicase can be considered for both prophylaxis and/or treatment of hyperuricemia. 
6.8.6 
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 the Table 6-4.

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Table 6-4.  Tarlatamab Dose Modification Guidelines for Adverse Events 
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 1 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 lasts 
 7 days 
G-CSF = granulocyte colony-stimulating factor 
 

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7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or 
noninvestigational product(s)/auxiliary medicinal product(s), 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 noninvestigational product(s)/auxiliary medicinal product(s), 
protocol procedures, or the study as a whole at any time prior to study completion for the 
reasons listed in Sections 7.1, 7.2.1, and 7.2.2. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or noninvestigational product(s)/auxiliary medicinal 
product(s) 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 noninvestigational 
product(s)/auxiliary medicinal product(s) 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 noninvestigational product(s)/auxiliary 
medicinal product(s) or procedures should not be automatically removed from the 
study.  Whenever safe and feasible, it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or noninvestigational product(s)/auxiliary medicinal product(s) by a separate 
protocol or as provided for by the local country’s regulatory mechanism, based on 
parameters consistent with Section 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
decision by sponsor 
 
lost to follow-up 

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 
death 
 
adverse event (if applicable, refer to Table 6-3) 
 
subject request 
 
ineligibility determined 
 
protocol deviation 
 
non-compliance 
 
no longer clinically benefitting (may include clinical deterioration [disease or therapy 
related] or need for a change in systemic therapy; Scher et al, 2016) 
 
requirement for alternative therapy 
7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further investigational product(s), and/or noninvestigational product(s)/auxiliary 
medicinal product(s) or procedures, and the subject does not wish to or is unable to 
continue further study participation.  Subject data up to withdrawal of consent will be 
included in the analysis of the study, and where permitted, publicly available data can be 
included after withdrawal of consent.  The investigator is to discuss with the subject 
appropriate procedures for withdrawal from the study, and must document the subject’s 
decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Not applicable for this study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  

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The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 1.3).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening and Enrollment  
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject or 
legally authorized representative has signed the ICF, the site will register the subject and 
screen the subject in order to assess eligibility for participation.  The screening window is 
up to 28 days. 
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. 

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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 28-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 28 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 day 1 when the first IV infusion of investigational product is 
administered to a subject.  The study procedures to be completed during the treatment 
period are designated in the Schedule of Activities (Section 1.3).  
The results of the cycle 1 day 1 laboratory tests must be available before starting 
treatment with tarlatamab.  Laboratory assessments that were done within 24 hours prior 
to infusion do not need to be repeated, except for cycle 1 day 1 dosing where laboratory 
assessments should be collected within 4 hours before cycle 1 day 1 dosing of 
tarlatamab.  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.  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 EOT visit will occur at the end of the last treatment cycle.  For subjects who 
prematurely discontinue IP treatment, the EOT visit should occur as soon as possible 
after the last dose of investigational product was administered.   
Hospitalization Guidance 
All subjects will be hospitalized for intensive monitoring for 48 hours post tarlatamab 
infusion during all cycle 1 doses.  Hospitalization is not required for cycle 2 unless a 
subject experiences grade 2 or higher CRS or neurological events in cycle 1 (minimum 
of 24 hours hospitalization required post tarlatamab infusion on C2D1 if grade 2 or 
higher CRS or neurological events are noted in cycle 1).  The subjects may be 

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discharged after this period if there are no signs and symptoms of cytokine release 
syndrome or other acute toxicities. 
Study sites must have immediate access to a medical intensive care unit staffed by 
critical care providers. 
If subjects are not hospitalized during cycle 2, subjects will be observed for 8 hours post 
tarlatamab infusion. 
8.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason to further 
assess the risk of delayed adverse events, an SFU visit will be performed approximately 
60 (5) days after the end of the last dose of tarlatamab. 
The study procedures to be completed during the SFU period are designated in the 
Schedule of Activities (Table 1-2). 
The following procedures will be completed for patients who have not started 
subsequent anti-cancer therapy.  Additional tests can be conducted at the discretion of 
the investigator. 
 
Clinical evaluation 
 
Physical examination as per standard of care (including medical/surgical history).  
Physical examination findings should be recorded on the appropriate eCRF.   
 
ECOG performance status 
 
Weight 
 
Vital signs (ie, blood pressure, heart rate, respiratory rate, and temperature) 
 
Pulse oximetry 
 
Serious adverse event reporting 
 
Adverse event reporting 
 
Documentation of concomitant and rescue medications 
This information may be collected by clinic visit, telephone or chart review. 
8.1.4 
Long-term Follow-up 
Long-term follow up will be conducted every 3 months up to 3 years 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 
(CT/MRI/bone) of the chest, abdomen, pelvis, bone, and all other known sites of disease 
every 3 months until documentation of confirmed disease progression per PCWG3 
guidelines (Sections 11.8 and 11.9), clinical progression, start of new anticancer therapy, 
or up to 3 years after the first dose of tarlatamab, whichever occurs first. 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
external review body approved informed consent before any study-specific procedures 
are performed. 
8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarkers variability 
and PK of the investigational product(s). 
8.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started prior to enrollment through the time of consent.  Medical history will include 
information on the subject’s concurrent medical conditions.  Record all findings on the 
medical history eCRF. 
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 Common 
Toxicology Criteria for Adverse Events (CTCAE) version 4.0 (Section 11.4) unless 
specified otherwise. 
All prior cancer treatment therapies will be collected. 

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8.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes. 
8.2.1.6 
Performance Status  
ECOG performance status (Section 11.10) assessments will occur at time points 
specified in the Schedule of Activities (Section 1.3).  
8.2.1.7 
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. 
8.2.1.8 
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. 
8.2.1.9 
Mini-Mental Status Examination  
The Mini Mental Status Examination (MMSE) Version 2 will be performed as part of the 
Clinical Evaluation as outlined in the Schedule of Activities (Section 1.3).  The MMSE is 
a 30-point healthcare professional administered questionnaire to assess potential 

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subjects for cognitive impairment.  The assessment covers eight 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. 
8.2.2 
Efficacy Assessments 
8.2.2.1 
Radiologic Imaging Assessment 
Radiographic assessments will be obtained as scheduled in Section 1.3 irrespective of 
cycle duration including dose delays and treatment discontinuation. 
For subjects developing COVID19 during screening period following screening imaging, 
consider repeating CT of chest imaging following resolution. 
Standard radiological assessments should take place until clinically significant disease 
progression or deterioration, withdrawal of consent, or start of new anticancer therapy.  
Every assessment must include the chest, abdomen, and pelvis, all other known sites of 
disease and magnetic resonance imaging (MRI) of the brain if a subject has signs or 
symptoms suggestive of CNS metastases.  The MRI/CT can be obtained earlier if 
clinical deterioration necessitates an earlier scan at the discretion of the managing 
physician.  The same contrast and modality used at screening should be used for all 
subsequent assessments.  99mTc-MDP (99mtechnetium methylene diphosphonate) bone 
scan is required for each radiologic imaging and tumor assessment.  
Tumor burden assessments will be performed per PCWG3 guidelines (Sections 11.8 
and 11.9).  To confirm soft tissue disease progression, a second MRI/CT scan must be 
performed at least 4 weeks after the first detection of soft tissue disease progression.  
Responses (partial response [PR] and complete response [CR]) require confirmation by 
a repeat consecutive assessment at least 4 weeks after the first detection of response 
as measured by RECIST 1.1.  Planar bone scintigraphy must be performed using 

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conventional 99mtechnetium methylene diphosphonate radionuclide (99mTc-MDP) or other 
equivalent 99mTc-labeled radiotracers.  Confirmation of bone disease progression by 
bone scan should be performed per PCWG3 guidelines.  Disease progression based on 
both MRI/CT and bone scans will be used in radiographic progression endpoints (eg, 
radiographic PFS) evaluation.  Soft-tissue progression based on MRI/CT scan will be 
used in response endpoints (eg, objective response and DOR) evaluation.  Treatment 
beyond confirmed tumor progression may be allowed as per PCWG3 guidelines 
(Section 11.8; Scher et al, 2016).  Refer to the imaging manual for details on imaging 
assessments. 
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Section 1.3). 
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
8.2.3.2 
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 
PI or designated site physician 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. 
8.2.3.3 
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 

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and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
8.2.3.4 
Other Safety 
8.2.3.4.1 
Echocardiogram (ECHO)/Multigated Acquisition (MUGA) Scan 
Echocardiogram (ECHO) or multigated acquisition (MUGA) will be performed to assess 
cardiac ejection fraction and will occur at time points specified in the Schedule of 
Activities (Section 1.3).  ECHO/MUGA should include an evaluation from left ventricular 
ejection fraction (LVEF).  Additional ECHO/MUGA assessments may be performed as 
clinically indicated. 
For subjects developing COVID19 during screening period following screening ECHO 
assessments, consider repeating ECHO following resolution. 
8.2.3.4.2 
Hypersensitivity 
Hypersensitivity reactions have been reported in patients treated with tarlatamab 
including rare severe events. Clinical signs and symptoms of hypersensitivity may 
include but are not limited to rash and bronchospasm. Monitor patients for signs 
and symptoms of hypersensitivity during treatment with tarlatamab and manage 
as clinically indicated.  Withhold or consider permanent discontinuation of 
tarlatamab based on severity. 
8.2.4 
Adverse Events and Serious Adverse Events  
The method of recording, evaluating, and assessing causality of adverse events 
and serious adverse events and the procedures for completing and transmitting 
serious adverse event reports are provided in Section 11.4. 
8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the safety follow-up visit or 60 days after the last day of the dosing 
interval of investigational product(s) or noninvestigational product(s)/auxiliary 
medicinal product(s), whichever is later, are reported using the Events CRF. 

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8.2.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the safety follow-up visit or 60 days after the last day of the dosing 
interval of investigational product(s) or noninvestigational product(s)/auxiliary 
medicinal product(s), whichever is later 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. 
Since the criteria of the CTCAE grading scale differs from the regulatory criteria 
for serious adverse events, if adverse events correspond to grade 4 CTCAE 
toxicity grading scale criteria (eg, laboratory abnormality reported as grade 4 
without manifestation of life-threatening status), it will be left to the investigator’s 
judgment to also report these abnormalities as serious adverse events.  For any 
adverse event that applies to this situation, comprehensive documentation of the 
event’s severity must be recorded in the subject medical records. 
8.2.4.1.3 
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 after the 
protocol-required reporting period (as defined in Section 8.2.4.1.2) is completed, 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 Events CRF. 
After end of Study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  However, if 
the investigator becomes aware of serious adverse events suspected to be related to 
investigational product, then these serious adverse events will be reported to Amgen 
immediately and no later than 24 hours following the investigator's awareness of the 
event. 
Serious adverse events reported after the end of the 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 

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reporting requirements for a reportable event, then additional information may need to 
be collected from the subject's records after the subjects ends the study. 
8.2.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
8.2.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen immediately and no later than 24 hours following knowledge of the new 
information.  If specifically requested, the investigator may need to provide additional 
follow-up information, such as discharge summaries, medical records, or extracts from 
the medical records.  Information provided about the serious adverse event must be 
consistent with that recorded on the Events CRF. 
8.2.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from investigational product(s), and/or 
noninvestigational product(s)/auxiliary medicinal product(s) because of a serious 
adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor holding the relevant Investigational New Drug/Clinical Trial Application for 
either tarlatamab or 
 has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of tarlatamab or 
 under clinical investigation.  The sponsor will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, external review body, and investigators. 
Individual safety reports for suspected unexpected serious adverse reactions will be 
reported by the sponsor according to local regulatory requirements (eg, electronic 

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submission to the Eudravigilance database in the EU as per EU Clinical Trial 
Regulation 536/2014) as well as 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 IB and will notify the external review 
body, if appropriate according to local requirements. 
Amgen will prepare a single Development Safety Update Report (also referred to 
as Annual Safety Report in the European Union) for the Amgen Investigational 
Product.  To ensure that consolidated safety information for the study is provided, 
this single Development Safety Update Report will also include appropriate 
information on any other investigational products used in the clinical study, if 
applicable. 
8.2.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.2.4.6 
Other Safety Findings/Special Situations 
All medication errors, misuse or abuse of the investigational product when 
associated with a serious adverse event must be reported to Amgen or designee 
immediately and no later than 24 hours of the investigator’s awareness by 
collecting and recording the Other Safety Findings (OSF)/Special Situations (SS) 
event on the Clinical Trial electronic Serious Adverse Event (eSAE) Contingency 
Report Form and submitting the form to Amgen Global Patient Safety or designee. 
Further details and definitions regarding OSF/SS - medication errors, misuse, or 
abuse, can be found in Section 11.4. 
8.2.4.7 
Pregnancy 
Details of all pregnancies in female partners of male subjects will be collected after the 
start of study treatment and until 60 days after last dose of investigational product 
and/or noninvestigational product(s)/auxiliary medicinal product(s). 
If a pregnancy is reported, the investigator is to inform Amgen immediately and no 
later than 24 hours of learning of the pregnancy 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 are provided in Section 11.5. 
8.2.5 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (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 Events CRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events.  However, laboratory value 
changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Section 1.3). 
8.2.6 
Pharmacokinetic Assessments 
All subjects enrolled will have PK samples assessed. 
Blood samples will be obtained for determination of serum concentrations of tarlatamab 
at the time points specified in the Schedule of Activities (Section 1.3).  Blood must not be 
drawn from a port catheter during IP infusion and must wait 5 minutes after end of 
infusion prior to PK sample collection.  If a permanent central line with more than one 
lumen is used, blood draws can be done via the lumen that is not used for drug 
administration.  However, the preference is for PK samples to be drawn peripherally.  
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 
in the eCRF. 
Concentrations of tarlatamab will be measured from collected PK samples on an 
ongoing cohort-by-cohort basis.  Cumulative data from any preliminary PK analyses will 
be made available at the time of dose level review meetings (DLRMs). 

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Sample collection, processing, storage, and shipping instructions are provided in a 
separate laboratory manual. 
8.2.7 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  
 
 
 
 
 
 
The final disposition of samples will be described in Section 11.6.  
8.2.9 
Biomarkers  
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 

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8.2.9.1 
Biomarker Assessment During the Study 
8.2.9.2 
Biomarker Discovery 

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8.2.9.2.1 
Biomarker Development/Future Research 
Biomarker Development refers to using samples collected for Biomarker Discovery for 
future research after the study ends.  In oncology, there is particular interest in the 
molecular changes underlying the oncogenic processes that may identify cancer 
subtypes, stage of disease, assess the amount of tumor growth, or predict disease 
progression, metastasis, and responses to investigational product(s) or 
noninvestigational product(s)/auxiliary medicinal product(s). 
If consent is provided by subjects, biomarker discovery samples collected at the time 
points specified in the Schedule of Activities will be retained for future biomarker 
development as described in Appendix 6 (Section 11.6).  No additional samples will be 
collected for biomarker development/future research.  
Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to tarlatamab. 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
No statistical hypotheses will be tested. 
9.2 
Sample Size Determination 
The sample size in the dose exploration phase is based on practical consideration and is 
consistent with conventional oncology studies with the objective to estimate the MTD.  
With 3 subjects in a dose level, there is a 27% to 70% probability of observing at least 
1 DLT if the true DLT rate is 10% to 33% and with 4 subjects in a dose level, there is 
34% to 80% probability.  With 6 subjects in a dose level, there is a 47% to 91% 
probability of observing at least 1 DLT if the true DLT rate is 10% to 33% and with 
10 subjects in a dose level, there is a 65% to 98% probability. 
In the dose expansion phase, a subject number of 40 will provide an 87% probability of 
observing at least 1 adverse event with 5% incidence rate.  With the 40 subjects and 
20% overall response rate, the expected 95% CI would be 9% to 36%. 

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9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
The Safety Analysis Set will consist of all subjects who receive at least 1 dose of 
tarlatamab.  The analysis of all safety and efficacy endpoints, unless noted otherwise, 
will be conducted on the Safety Analysis Set.  
For Part 1 of the study, the analysis of DLT will be conducted on the DLT Analysis Set, 
defined as all subjects that are enrolled and receive at least 1 dose of tarlatamab 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 IP 
treatment as planned in cycle 1 and has been followed for safety events a minimum of 
28 days from start of treatment  
The Interim Efficacy Analysis Set will contain all subjects in the Safety Analysis Set who 
have had the opportunity to be followed for at least 9 weeks starting from day 1.  
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.  Interim 
efficacy analysis will be performed on this Interim Efficacy Analysis Set. 
The PK Analysis Set will contain all subjects who have received at least 1 dose of 
tarlatamab 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. 
9.3.2 
Covariates 
The relationship between covariates and efficacy endpoints may be explored if 
appropriate. 
9.3.3 
Subgroups 
Subgroups will be prespecified in the statistical analysis plan. 
9.3.4 
Handling of Missing and Incomplete Data 
Descriptive statistics will be used to identify the extent of missing data.  Missing or 
incomplete dates that are critical to efficacy and safety analysis (eg, date of death, 
adverse event start date) will be imputed.  Detailed imputation rules will be documented 
in statistical analysis plan. 

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9.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  During dose exploration and formally 
during DLRMs, Amgen, in consultation with the site investigators, will review all available 
cumulative data by dose level prior to making dose escalation or dose de-escalation 
recommendations.  Adverse events and DLTs observed in all subjects will be evaluated 
continually and fully integrated into all DLRMs and considered in all enrollment and 
dosing decisions. 
During dose expansion, Amgen will conduct evaluations of the grade 4 or higher 
treatment-related adverse event rate to assess if the threshold for possible early trial 
termination has been reached.  If this threshold is met, enrollment to dose expansion will 
be halted pending review of safety data by the DLRT.  After receiving the DLRT 
recommendation, Amgen will choose to take one of the following actions.  
1) Terminate the trial 
2) Resume Dose Exploration with a schedule as outlined in the protocol and 
recommended by the DLRT. 
3) Amend the protocol to potentially improve the benefit/risk for subjects (eg, increase 
safety monitoring, modify dose/schedule, mandate premedication).  
4) Continue dose expansion without any changes. 
The stopping rules use a Bayesian approach proposed by Thall and colleagues 
(Thall et al, 1995) to terminate the study if the posterior probability that the grade 4 or 
higher treatment-related adverse event rate of greater than 20% is > 80%.  The stopping 
boundaries assume a prior distribution of Beta (0.40, 1.60) are presented in Table 9-1 
and the operating characteristics with pre-specified batch size of 10 new subjects per 
batch are presented in Table 9-2.  The operating characteristics in Table 9-2 provide the 
probability of stopping the trial early for given hypothetical true rate of grade 4 or higher 
treatment-related adverse events, whereas the stopping criteria in Table 9-1 are based 

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on situations where the empirical evidence would result in a posterior probability of 
≥ 80% that the true grade 4 or higher treatment-related adverse event rate is ≥ 20%. 
Table 9-1.  Stopping Boundary for Dose Expansion with Posterior Probability of 
80% and Grade 4 or Higher Treatment-related Adverse Event Limit of 20% 
Number of 
Subjects 
Stop Subjects if Observing This Many Grade 4 or Higher 
Treatment-related Adverse Events 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Dose Expansion Complete 
Table 9-2 Operating Characteristics with Batch Size of 10 Subjects 
True Grade 4 or Higher 
Treatment-related 
Adverse Event Rate 
Probability of Early 
Stopping of Dose 
Expansion 
Average Dose 
Expansion Sample Size 
0.10 
2.0% 
39.5 
0.15 
9.7% 
37.6 
0.20 
25.8% 
33.9 
0.25 
47.7% 
28.8 
0.30 
69.2% 
23.4 
Interim futility analyses (non-binding) will be performed in a continuous manner using 
Bayesian predictive probability (Lee & Liu, 2008).  Interim futility analyses in Part 2 will 
begin after approximately 20 subjects have been treated and has a minimum potential 
follow-up of 9 weeks.  Interim futility analyses will be based on the ORR analysis set.  
Following this initial interim futility analysis, subsequent interim futility analyses will be 
performed after every 10 subjects in Part 2 have reached the data cutoff criteria, until all 
subjects are enrolled and evaluated.  For interim futility analyses a response is defined 
as either a confirmed or unconfirmed CR or PR per RECIST 1.1.  For the final analysis, 
a response is defined as a confirmed CR or PR per RECIST 1.1.  
The Target Value (TV) is set to demonstrate a 18% increase in ORR (ie, TV  30%) over 
the benchmark 12% ORR.  For Part 2, at final analysis: 

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 
NoGo criteria will be met if the probability that the true ORR exceeds the 
pre-specified TV of 30% is less than 5% (ie, NoGo:  P[ORR > TV] < 5%). 
Given the existing observed data during the continuous monitoring stage, the Bayesian 
predictive probability is obtained by calculating the probability of reaching a NoGo 
decision should the treatment group be enrolled and evaluated to the maximum planned 
final sample size of 40 in Part 2.  Further enrollment may be terminated if futility criteria 
are met.  Notice the NoGo criteria is for interim futility analysis purpose only. 
 
Futility is met if it is predicted that there is a high probability of reaching a NoGo 
decision upon full enrollment of 40 subjects in Part 2 given the existing observed 
data (ie, predictive probability of a NoGo decision > 95%). 
The decision matrix for continuous monitoring of ORR is provided in Figure 9-1 
assuming a prior distribution of Beta (1, 1).  For example, given TV of 30%, 3 or fewer 
observed responders after 30 subjects have reached the data cutoff criteria would trigger 
stopping enrollment claiming futility due to a high probability of reaching a NoGo 
decision upon full enrollment to 40 subjects given the existing observed data. 

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Figure 9-1.  Decision Matrix for Continuous Monitoring of ORR 
 
 
Operating characteristics of this continuous monitoring method are presented in 
Table 9-3 and are based on 100 000 simulations using the prespecified TV value, and 
NoGo and Futility definitions.  
A false NoGo is defined as observing either futility criteria during the continuous 
monitoring stage or NoGo criteria at final analysis when the true ORR is greater than or 
equal to the TV (ie, False NoGo:  P[Futility or NoGo Decision | True ORR ≥ TV]).  
Table 9-3.  Guidelines for Futility Analysis 
True ORR 
(BM ORR  12%) 
Probability of 
Futility 
Expected N 
% Decision Prior 
to Final 
10% 
96% 
29 
67% 
15% 
76% 
35 
35% 
20% 
44% 
38 
14% 
25% 
19% 
39 
5% 
30% 
6% 
40 
1% 
35% 
1% 
40 
0% 
40% 
0% 
40 
0% 
BM ORR = benchmark objective response rate; TV = target value. 
Criteria:  Target Value (TV) =30%; NoGo:  Pr(ORR >  TV) < 5%; Futility:  PP(NoGo)>95% 
Frequency:  10 subjects; BM ORR:  Benchmark Objective Response Rate 
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 9-4.  If these criteria are met, an ad 
hoc 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 

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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 9-4.  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 
5 
≥ 3 
≥ 2 
10 
≥ 4 
≥ 2 
15 
≥ 5 
≥ 3 
20 
≥ 6 
≥ 3 
25 
≥ 7 
≥ 4 
30 
≥ 9 
≥ 4 
35 
≥ 10 
≥ 5 
40 
≥ 11 
≥ 5 
DLRM  Dose Level Review Meeting; CRS   cytokine release syndrome 
9.4.1.2 
Primary Analysis 
The primary analysis for this subprotocol 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 end of treatment (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, PK, 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 overall survival [OS]) with 
the Greenwood formula (Kalbfleisch and Prentice, 1980) used to estimate the standard 
error used in CI calculation. 
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Listings of secondary efficacy endpoints will be produced for all 
subjects.  
The proportion of subjects with an objective response (OR) (per 
RECIST 1.1 guidelines [Sections 11.8 and 11.9]) and 95% CI will be 
tabulated by planned dose level.  Disease control rate and 95% CI will 
be tabulated by planned dose level.  
For all subjects treated at the MTD and/or RP2D, Kaplan-Meier 
methods will be used to estimate the time to event curve, median time 
to event and percentiles with 95% CI for 1) duration of response 
(DOR), 2) progression-free survival (PFS), 3) OS.  For all subjects 
treated at the MTD and/or RP2D, Kaplan-Meier methods will be used 
to estimate landmarks for time to event events (eg, PFS and OS at 6 
and 12 months) with 95% CI. 
Exploratory 
Will be described in the statistical analysis plan finalized before 
database lock 
 

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9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Unless otherwise specified, statistical analyses on safety endpoints 
will be done using subjects from the safety analysis set, which 
includes subjects that are enrolled and received tarlatamab.  The 
analysis of DLTs will be conducted on the DLT Analysis Set.  Subject 
incidence of DLT will be tabulated by planned dose level.  The 
statistical analysis methods for other safety endpoints are in 
Section 9.4.2.3. 
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or noninvestigational 
product(s)/auxiliary medicinal product(s), 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 are performed as part of standard of 
care for routine safety monitoring, rather than for the purposes of assessment of 
potential QTc effect.  No statistical analyses of ECG measurements are planned. 

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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 
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. 
9.4.2.4 
Other Analyses 
For tarlatamab, PK parameters will be determined from the time concentration profile 
using standard non-compartmental approaches and considering the profile over the 
complete sampling interval.  Based on the review of the data, exploratory analyses to 
describe the relationship between tarlatamab exposure and either PD effect and/or 
clinical outcome may also be performed.  These exploratory analyses may not be part of 
the clinical study report. 
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 a mTPI-2 algorithm (Guo et al, 2017)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%, 35%).   

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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. 
 
3 or more DLTs in ≤ 4 subjects  
 
4 or more DLTs in ≤ 6 subjects  
 
5 or more DLTs in ≤ 9 subjects 
 
6 or more DLTs in 10 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 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%. 

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10. 
References 
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American Cancer Society.  Cancer Facts & Figures.  Atlanta, Ga:  American Cancer 
Society; 2020. 
AMG 757 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Aparicio AM, Harzstark AL, Corn PG, et al.  Platinum-based chemotherapy for variant 
castrate-resistant prostate cancer.  Clin Cancer Res.  2013;19:3621-3630. 
Brookmeyer R, Crowley J.  A confidence interval for the median survival time.  
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Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
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Crocetti E.  Epidemiology of prostate cancer in Europe.  2015.  
http://publications.jrc.ec.europa.eu/repository/handle/JRC101382.  Accessed 
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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. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
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. 
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 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials. 5(2):93-106. 2008 
Neelapu SS, Tummala S, Kebriaei P, et al.  Chimeric antigen receptor T-cell 
therapy — assessment and management of toxicities.  Nat Rev Clin Oncol.  
2018;15:47-62. 
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. 

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Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649–655. 
Parimi V, Goyal R, Poropatich K, et al.  Neuroendocrine differentiation of prostate 
cancer:  a review.  Am J Clin Exp Urol.  2014;2:273-285. 
Puca L, Gavyert K, Sailer V, et al.  Delta-like protein 3 expression and therapeutic 
targeting in neuroendocrine prostate cancer.  Sci Transl Med.  2019;11. pii:  eaav0891. 
Robinson DR, Wu Y-M, Lonigro RJ, et al. Integrative Clinical Genomics of Metastatic 
Cancer. Nature. 2017;548: 297–303. 
Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for 
castration-resistant prostate cancer:  Updated recommendations from the prostate 
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https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125496s000lbl.pdf 
Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for single-arm 
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11. 
Appendices 
 

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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody(ies) 
ADA-IC 
ADA-related immune complexes 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BCG 
Bacillus Calmette–Guérin 
BIL 
bilirubin 
BiTE® 
bispecific T-cell engager 
BM ORR 
benchmark objective response rate 
BUN 
blood urea nitrogen 
Cmax 
maximum serum concentration 
Cmin 
minimum serum concentration 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
U.S. Code of Federal Regulations 
CI 
confidence intervals 
CNS 
central nervous system 
COVID-19 
Coronavirus Disease 2019 
CR 
complete response 
CRF 
case report form 
CRO 
contact research organization 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common terminology Criteria for Adverse Events 
DILI 
drug induced liver injury 
DLL3 
delta-like protein 3 
DLRMs 
dose level review meetings 
DLRT 
Dose Level Review Team 

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Abbreviation or Term 
Definition/Explanation 
DLT 
dose limiting toxicity(ies) 
DOR 
duration of response 
EU 
European Union 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
EI 
equivalence toxicity interval 
EpCAM 
epithelial cell adhesion molecule 
eSAE 
electronic serious adverse event 
Fc 
fragment crystallizable 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GSO 
Global Safety Officer 
HepBsAg 
Hepatitis B Surface Antigen 
HI 
overdosing intervals 
HIV 
human immunodeficiency virus 
HLE 
half-life extended 
HNSTD 
highest non-severely toxic dose 
HRT 
hormonal replacement therapy 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFN- 
interferon gamma 
Ig 
Immunoglobulin 
IGF 
insulin-like growth factor 
IHC 
Immunohistochemistry 

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Abbreviation or Term 
Definition/Explanation 
IL-2 
Interleukin-2 
IL-6 
Interleukin-6 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IV 
intravenous(ly) 
LH 
luteinizing hormone 
LHRH 
luteinizing hormone-releasing hormone 
LI 
under-dosing intervals 
LVEF 
left ventricular ejection fraction 
mCRPC 
metastatic castration-resistant prostate cancer 
MDRD 
modification of diet in renal disease 
MMSE 
Mini Mental Status Examination 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTPI-2 
modified toxicity probability interval design 
MUGA 
multigated acquisition 
NEPC 
neuroendocrine prostate cancer 
NLCB 
no longer clinically benefiting 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
OSF 
Other safety findings 
PAVA 
pool adjacent violators algorithm 
PCR 
polymerase chain reaction 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive disease 
PD-1 
programmed cell death protein 1 
PFS 
progression-free survival 

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Abbreviation or Term 
Definition/Explanation 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PR 
partial response 
PTEN 
phosphatase and tensin homolog 
PTT 
partial thromboplastin time 
PT 
prothrombin time 
Q2W 
every 2 weeks 
QTcF 
QT interval by Fredericia 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase 2 dose 
RR 
relapsed/refractory 
SAP 
statistical analysis plan 
scFC 
single chain fragment crystallizable 
SCLC 
small cell lung cancer 
SFU 
safety follow-up 
SoA 
Schedule of Assessments  
SOI 
start of infusion 
SS 
Special situations 
t1/2 
half-life 
TBL 
total bilirubin 
99mTc-MDP 
99mtechnetium methylene diphosphonate radionuclide 
TLS 
tumor lysis syndrome 
TNF 
tumor necrosis factor 
TSH 
thyroid stimulating hormone 
TV 
target value 
ULN 
upper limit of normal 
UPM 
unit probability mass 
US 
United States 
 

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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 
 
Magnesium 
 
Phosphorus 
 
Glucose 
 
BUN (Blood Urea 
Nitrogen) or 
Serum Urea 
 
Creatinine 
 
Total bilirubin 
 
Direct bilirubin 
 
 
AST (SGOT) 
 
ALT (SGPT) 
 
Creatine kinase 
 
Uric Acid (only 
during the first  
2 cycles) 
 
CBC with differential 
 
RBC 
 
Hemoglobin 
 
MCV 
 
Platelets 
 
WBC 
 
Differentials 
5-part differential: 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils* 
 
Basophils* 
 
Total Neutrophils* 
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) 
 
TSH 
 
FT4 
 
FSH 
 
LH 
 
Testosterone  
Only collected at 
screening and EOT  
 
ACTH (AM 
sample) 
 
IGF-1  
 
Prolactin 
Biomarker analyses  
 
Cytokines 
Other Labs: 
 
Tarlatamab PK 
 
Pharmacogenetic 
(optional) 
Other safety labs 
 
 
CRP 
 
Ferritin 
 
HIV antibody 
testing 
 
 
Amylase 
 
Lipase 
 
Hepatitis Serology 
Testing 
 
Hep B surface 
antigen 
 
Hep C antibody 
 
Hep B total core 
antibody 
 
* Local lab may report Granulocytes instead of Neutrophils, Eosinophils, and Basophils individually. 
ACTH  adrenocorticotropic hormone; ALT  alanine aminotransferase; APTT  activated partial 
thromboplastin time; AST  aspartate aminotransferase; BUN = blood urea nitrogen; 
 EOT  end of treatment; FT4  free thyroxine; Hep  hepatitis; HIV = human 
immunodeficiency virus; ICF-1  insulin-like growth factor receptor 1; INR  international normalized ratio; 
 LH  luteinizing hormone; MCV = mean corpuscular volume; 
PT  prothrombin time; PTT  partial 
thromboplastin time; RBC  red blood cell count; SGOT  serum glutamic-oxaloacetic transaminase; 
SGPT  serum glutamic-pyruvic transaminase; TSH  thyroid stimulating hormone; WBC  white blood cell 
count 

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11.3 
Appendix 3.  Study Governance Considerations 
Monitoring Committee(s) 
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, exploring 
intermediate doses, cohort continuation, or cohort expansion; making recommendations 
about non-dose escalation cohorts (eg, expanded, highest dose and/or final cohort); and 
evaluating safety data for purposes of applying Dose Cohort Stopping Rules.  The Dose 
Level Review Team (DLRT) will make recommendations on implementing step dosing 
and may modify the premedication regimen based on emerging safety data, including 
the recommendation to implement additional corticosteroids (dexamethasone 8 mg 
orally 6 to 16 hours prior to the run-in dose and step dose[s] in cycle 1) based on 
emerging results from Part D in the ongoing first-in-study (FIH) study (20160323).  The 
DLRT members are the Medical Monitor, Global Safety Officer (GSO), and enrolling Site 
Investigators.  The DLRT will include actively screening and enrolling Site Investigators.  
The required Medical Monitor, GSO, and Site Investigators are the only voting DLRT 
members.  The following non-voting Amgen representatives also will 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 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 attend.  A quorum is defined as 
at least 50% of the participating investigators or their qualified designee.  The DLRM will 
be rescheduled if these requirements are not met. 
All available study data, including demographics, investigational product (IP) 
administration, medical history, concomitant medications, adverse events, ECGs, vital 
signs, laboratory data, and PK/pharmacodynamic information will be reviewed.  In 
addition to dose limiting toxicities (DLTs), all ≥ grade 3 toxicities not meeting DLT criteria 

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will be reviewed and may be considered in DLRT recommendations.  Data will not need 
to be source data verified and queries will not need to be resolved prior to the DLRM.   
In the expansion phase, all available study data will be reviewed (with recruitment 
ongoing) by the DLRT after 10 and 20 subjects have at least completed their 
first treatment cycle plus two weeks or dropped out of treatment /study, whichever 
occurs earlier.  Enrollment in dose expansion may continue while the DLRM preparation 
and meeting are in progress.  Ad hoc meetings may be convened any time in case of 
important safety events. 
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 (IB), and other relevant documents (eg, subject recruitment advertisements) 
must be submitted to an external review body (eg, IRB/IEC/regulatory authorities) by 
the investigator and reviewed and approved by the external review body.  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 external review body for all subsequent protocol 
amendments and changes to the informed consent document.  The investigator must 
send a copy of the approval letter from the external review body and amended protocol 
Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the external review body 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the external review body 
 
Obtaining annual external review body approval/renewal throughout the duration of 
the study.  Copies of the investigator’s reports and the external review body 
continuance of approval must be sent to Amgen 

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 
Notifying the external review body 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 external review 
body, and all other applicable local regulations 
Informed Consent Process 
An initial sample ICF 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 ICF 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 external review body or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
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. 

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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 ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  Subject withdrawal of consent or discontinuation from study treatment 
and/or procedures must also be documented in the subject’s medical records; refer to 
Section 7. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(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 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF 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 ICF if the rescreening occurs 
within 28 days from the previous ICF signature date. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional future research.  The investigator or authorized designee will 
explain to each subject the objectives of the future research.  Subjects will be told that 
they are free to refuse to participate and may withdraw their specimens at any time and 
for any reason during the storage period.  A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for future 
research.  Subjects who decline to participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  

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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 ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the external review body 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. 
Serious Breach 
Suspected Serious Breaches must be reported to the study team or the Clinical 
Out-of-Hours Support Program:  https://wwwext.amgen.com/science/clinical-
trials/clinical-out-of-hours-support-program immediately and no later than 
1 calendar day from the time of awareness. 
A Serious Breach is a breach of any of the following: 
 
Good Clinical Practice  
 
the clinical trial protocol 
 
an applicable regulation 
That is likely to impact to a significant degree either of the following: 
 
the safety, physical, or mental integrity and the rights of the subject  
 
the reliability and robustness of the data and the scientific value of the trial 
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.  

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The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
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. 
Results Reporting 
Results will be reported to clinical study registries in accordance with applicable 
regulatory requirements.  The final summary results will be reported after the 
global end of study (as defined in Section 4.4) to ensure data from all sites 
globally are included in the reported results.  
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 

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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, external review body 
review, and regulatory agency inspections and provide direct access to source data 
documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 

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Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, investigational product(s), and/or noninvestigational 
product(s)/auxiliary medicinal product(s) 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 must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the 
interactive response technology (IRT) system (if used, such as subject ID and 
randomization number) and CRF entries if the CRF is the site of the original recording 
(ie, there is no other written or electronic record of data, such as paper questionnaires 
for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 

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inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, ICFs, 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 external 
review body 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 external review body in writing of the study’s completion or early termination 
and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 

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11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events will be defined in the statistical 
analysis plan (SAP). 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram (ECG), radiological scans, vital 
signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected intentional overdose of 
either study treatment or a concomitant medication. 
 
Intentional overdose will be reported as an adverse event/serious adverse event 
when it is taken with possible suicidal/self-harming intent.  Such intentional 
overdoses are to be reported regardless of sequelae on the Events CRF. 
 
Accidental/unintentional overdose will be captured as a Medical Error. 
 
For situations when an adverse event or serious adverse event is due to 
neuroendocrine prostate cancer report all known signs and symptoms.  Death due 
to disease progression in the absence of signs and symptoms should be reported 
as the primary tumor type (eg, metastatic pancreatic cancer).  Note:  The term 
“disease progression” should not be used to describe the adverse event. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.  
 

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

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Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the other outcomes listed in the above definition.  These events are typically to 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
Other Safety Findings/Special Situations: Medication Errors, Misuse or Abuse 
All medication errors, misuse or abuse of the investigational product when 
associated with a serious adverse event, the Other Safety Findings 
(OSF)/Special Situations (SS) must be reported to Amgen or designee 
immediately and no later than 24 hours of the investigator’s awareness by 
submitting paper-based Clinical Trail electronic Serious Adverse Event (eSAE) 
Contingency Report Form. 
Definitions 
Medication Error: A medication error is an unintended 
failure in the drug treatment process that leads to, or 
has the potential to lead to harm to the participant (eg, 
mistake in the process of prescribing, storing, 
dispensing, preparing, or administering medicinal 
products in clinical practice). 
Misuse: A misuse refers to situations where the 
medicinal product, combination product, or medical 
device is intentionally and inappropriately used not in 
accordance or outside what is foreseen in the protocol.   

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Abuse: An abuse corresponds to the persistent or 
sporadic, intentional excessive use of a medicinal 
product, combination product, or medical device, which 
is accompanied by harmful physical or psychological 
effects.    
 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (CRF). 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to the first dose of investigational product; 
o Assessment of Seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product and/or, 
noninvestigational product(s)/auxiliary medicinal product(s); 
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 a single event for each level of severity on the Event electronic 
case report form (eCRF). 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor/responsible contact research organization (CRO) in 
lieu of completion of the Events CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 

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 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Common Terminology Criteria for Adverse Events, version 4.0 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 and noninvestigational product(s)/auxiliary medicinal product(s), and 
each occurrence of each adverse event. 
 
The investigator is obligated to assess the relationship between 
investigational product(s), and noninvestigational product(s)/auxiliary 
medicinal product(s), study-required activity and/or procedure(s) 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 (IB) 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‑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. 

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 
The investigator may change their 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 investigational product(s), and/or 
noninvestigational product(s)/auxiliary medicinal product(s) because of a 
serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Events 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
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 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 Contingency Report Form) 
(see Figure 11-1) immediately and no later than 24 hours of the investigator’s 
awareness of the event. 
 
The primary mechanism for the site to report the Other Safety 
Finding/Special Situation associated with a serious adverse event to Amgen 
is by submitting the Clinical Trial eSAE Contingency Report Form 
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 has been taken off-line, then the site can report this information on a paper 
Serious Adverse Event Report Form. 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen immediately and no 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 Form 
 
 

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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
Information 
Study-specific contraception requirements for males are outlined in Section 5.2. 
Male subjects must receive pregnancy prevention counseling and be advised of the risk 
to the fetus if they father a child during treatment and for 60 days after the last dose of 
investigational product(s), and/or noninvestigational product(s)/auxiliary 
medicinal product(s). 
Contraception Methods for Male Subjects 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with investigational product(s) and/or 
noninvestigational product(s)/auxiliary medicinal product(s); 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 60 days after the last dose of 
investigational product(s) and/or noninvestigational product(s)/auxiliary 
medicinal product(s) 
The female partner should consider using an acceptable method of effective 
contraception such as:  hormonal, intrauterine device (IUD), intrauterine 
hormonal-releasing system (IUS), female barrier method (diaphragm, cap, sponge [a 
female condom is not an option because there is a risk of tearing when both partners 
use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Definition of Females of Childbearing Potential (for female partners of male 
subjects) 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
premenopausal female with 1 of the following: 
 
documented hysterectomy; 
 
documented bilateral salpingectomy; or 
 
documented bilateral oophorectomy. 

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 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
premenarchal female 
 
postmenopausal female: 
 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Unacceptable Methods of Birth Control for Male Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
60 days after discontinuing investigational product(s), and/or noninvestigational 
product(s)/auxiliary medicinal product(s), 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). 
 
The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  

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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. 
Figure 11-2.  Pregnancy Notification Form 
 
 

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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood, tumor, biomarker, or pharmacokinetics (PK) samples collected according to 
the Schedule of Activities (Section 1.3) can be analyzed for any of the tests outlined in 
the protocol and for any tests necessary to minimize risks to study subjects.  This 
includes testing to ensure analytical methods produce reliable and valid data throughout 
the course of the study.  This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
tarlatamab, the dose response and/or prediction of response to tarlatamab, 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. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 

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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
 

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11.7 
Appendix 7.  Reporting and Management of potential Hepatotoxicity  
Subjects with abnormal hepatic laboratory values such as alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBL) 
and/or international normalized ratio (INR) and/or signs and symptoms of 
hepatotoxicity (as described below) may meet the criteria for interruption or 
permanent discontinuation of Amgen investigational product or noninvestigational 
product(s)/auxiliary medicinal product(s).  This instruction is based on the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Reporting and management of hepatotoxicity in subject participating in clinical 
trials is described below and management is summarized in the flow chart in 
subsection 11.7.6. 
11.7.1 
Criteria for stopping Amgen Investigational Product and 
noninvestigational product(s)/auxiliary medicinal product(s) Due to 
Potential Hepatotoxicity 
Stopping rules apply to each of the following criteria in subjects for whom another 
cause for the changes in liver biomarkers (total bilirubin [TBL], international normalized 
ration [INR], and transaminases) has not been identified.  
 
ALT or AST > 8xULN 
 
ALT or AST > 5xULN for more than 2 weeks 
 
ALT or AST > 3xULN and (TBL >2xULN or INR >1.5) 
 
ALT or AST > 3xULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
Of note in subjects with elevated values at baseline (before exposure to the 
investigational medicinal product), fold increases above the baseline values will 
guide the interruption and close observation. 
11.7.2 
Reporting Criteria 
Cases with events of elevation of AST, ALT, TBL, INR, mentioned above, require the 
following: 
 
The event is to be reported to Amgen as a serious adverse event immediately and 
no later than 24 hours after discovery or notification of the event (ie, before 
additional etiologic investigations have been concluded) 
 
The appropriate Case Report Form (CRF) (eg, Events electronic Case Report 
Form [eCRF]) that captures information necessary to facilitate the evaluation of 
treatment-emergent liver abnormalities is to be completed and sent to Amgen  

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Other events of potential hepatotoxicity are to be reported as serious adverse events if 
they meet the criteria for a serious adverse event defined in Section 11.4. 
11.7.3 
Follow up Actions 
All subjects in whom investigational product(s) or noninvestigational 
product(s)/auxiliary medicinal product(s) is/are interrupted (either permanently or 
conditionally) due to potential hepatotoxicity should be undergo a period of “close 
observation” until elevated laboratory values return to normal or to the subject’s 
baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, BIL (total and direct), and INR within 24 hours.  
 
In cases in which laboratory values are still elevated perform repeat 
measurement of liver lab tests every 2 to 3 days until laboratory abnormalities 
improve. 
Testing frequency of the above laboratory tests may decrease if the laboratory 
abnormalities stabilize, or the investigational product(s) or noninvestigational 
product(s)/auxiliary medicinal product(s) has/have been discontinued AND the 
subject is asymptomatic. 
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of study drug (s). 
The hepatotoxicity events and additional information such as medical history, 
concomitant medications and laboratory results must be captured in the 
corresponding CRFs. 
Initiate investigation of alternative causes for hepatotoxicity (Section 11.7.3.1). 
If laboratory values improve, consider rechallenging with the study drug(s) only if 
the benefit: risk ratio is supportive (and as described in Section 11.7.4).  
Otherwise, discontinue study drug(s) permanently. 
11.7.3.1 
Investigating Alternative Causes of Hepatotoxicity 
The following assessment are to be considered depending on the clinical situation: 
 
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. 
 
A more detailed history of:  

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 
prior and/or concurrent diseases or illness 
 
exposure to environmental and/or industrial chemical agents 
 
symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever. 
 
prior and/or concurrent use of alcohol, recreational drugs, and special diets. 
 
concomitant use of medications (including non-prescription medicines and herbal 
and dietary supplements), plants, and mushrooms 
 
Viral serologies. 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase (LDH), and peripheral 
blood smear. 
 
Appropriate liver imaging if clinically indicated. 
 
Appropriate blood sampling for pharmacokinetic (PK) analysis if this has not already 
been collected. 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist). 
11.7.3.1.1 
Important Alternative Causes  
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 
 
NASH (nonalcoholic fatty liver disease AKA MASH) including steatohepatitis 
 
non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
Special consideration is warranted when using products known to cause transient 
elevation of liver enzymes, such as T cell engager molecules (TCE).  For example, 
in the instances of cytokine release syndrome (CRS) following exposure to BiTE 
molecules, transient elevations of isolated liver parameters were frequently noted.  
Careful monitoring of laboratory parameters and the clinical status of patients is 
required, and continuation of the medication maybe considered and will be at the 
discretion of the investigators.  

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11.7.4 
Rechallenge and Dose Modification in Patients with suspected 
hepatotoxicity in Oncology Trials  
 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen.  If rechallenge is considered 
appropriate, the subject must be fully informed about the risk and should give 
written consent.  Any rechallenge must be accompanied by close monitoring, 
with at least weekly liver biochemistry until response to the rechallenge is fully 
characterized. 
 
If signs or symptoms recur with rechallenge, then Amgen investigational product and 
noninvestigational product(s)/auxiliary medicinal product(s), as appropriate is to be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation are never to be rechallenged. 
 
For oncology drugs that demonstrate potential benefit but also potential 
hepatotoxicity, consideration of rechallenge or dose modification (with a 
reduced dose) should be based on benefit: risk and clinical and biochemical 
characteristics of the original liver injury.  
 
Rechallenge is not recommended when there is no evidence of benefit for the 
individual subject, or where alternative treatment options are available.  
 
Rechallenge is generally not recommended for cases of suspected or 
confirmed severe hepatocellular injury (clinical evidence of liver dysfunction 
with jaundice or INR elevation), in the presence of underlying cirrhosis, or 
where there are features of immunologic hepatotoxicity. 
 
Before undertaking a rechallenge, there should be sufficient resolution of liver 
biochemistry abnormalities; although these depend on the patient population, 
reasonable options include ALT reducing to < 3x ULN for those with normal 
baseline ALT or returning to < 4x ULN and < 6x ULN for those with elevated 
baseline ALT of 1.5 to 3x ULN and 3 to 5x ULN, respectively. 
11.7.5 
Permanent Discontinuation of Study Drug(s) 
In the absence of acceptable enzyme level decrease or lack of a plausible 
alternative explanation for the elevated lab pattern, consider permanent 
discontinuation of study drug treatment. 
11.7.6 
Management Flow Chart 
The following flow chart can be used to manage potential hepatotoxicity cases. 

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11.8 
Appendix 8.  Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1) 
Definitions 
 
Measurable Lesions 
 
Measurable Tumor Lesions – Non-nodal lesions with clear borders that can be 
accurately measured in at least 1 dimension with longest diameter ≥ 10 mm in 
computed tomography/magnetic resonance imaging (CT/MRI) scan with slice 
thickness no greater than 5 mm.  When slice thickness is greater than 5 mm, the 
minimum size of measurable lesion should be twice the slice thickness. 
 
Nodal Lesions - Lymph nodes are to be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by 
CT/MRI (scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
▪ 
Nodal size is normally reported as two dimensions in the axial plane.  The 
smaller of these measures is the short axis (perpendicular to the longest 
axis). 
 
Irradiated Lesions - Tumor lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, are not measurable unless there 
has been demonstrated progression in the lesion prior to enrollment. 
 
Non-measurable Lesions 
 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm but to < 15 mm short axis with CT scan slice thickness 
no greater than 5 mm) are considered non-measurable and characterized as 
non-target lesions. 
 
Other examples of non-measurable lesions include: 
▪ 
Lesions with prior local treatment:  tumor lesions situated in a previously 
irradiated area, or an area subject to other loco-regional therapy, should not 
be considered measurable unless there has been demonstrated progression 
in the lesion. 
▪ 
Biopsied lesions 
▪ 
Categorially, clusters of small lesions, bone lesions, inflammatory breast 
disease, and leptomeningeal disease are non-measurable. 

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Methods of Measurement 
 
Measurement of Lesions - The longest diameter of selected lesions should be 
measured in the plane in which the images were acquired (axial plane).  All 
measurements should be taken and recorded in metric notation.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment 
and not more than 4 weeks before study day 1. 
 
Methods of Assessment - The same method of assessment and the same technique 
should be used to characterize each identified and reported lesion throughout the 
trial. 
 
CT/MRI – Contrast-enhanced CT or MRI should be used to assess all lesions.  
Optimal visualization and measurement of metastasis in solid tumors requires 
consistent administration (dose and rate) of intravenous (IV) contrast as well as 
timing of scanning.  CT and MRI should be performed with ≤ 5 mm thick contiguous 
slices. 
Baseline documentation of “Target” and “Non-target” lesions 
 
Target Lesions - All measurable lesions up to a maximum of two (2) lesions per 
organ and five (5) lesions in total, representative of all involved organs should be 
identified as target lesions and recorded and measured at baseline. 
 
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and suitability for accurate repeated measurements. 
 
Pathologic lymph nodes (with short axis ≥ 15 mm) may be identified as target 
lesions.  All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
of diameters.  The baseline sum of diameters will be used as reference by 
which to characterize objective tumor response. 
 
Non-target Lesions - All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be recorded 
at baseline.  Measurements of these lesions are not required, and these lesions 
should be followed as “present”, “absent”, or “unequivocal progression” throughout 
the study.  In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case report form (CRF) (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”).  

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

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Time Point response:  Subjects With Target ( Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
CR = complete response; NE  Not evaluable; PD  progressive disease; PR  partial response; SD  
stable disease. 
Time Point Response:  Subjects With Non-Target Disease Only 
 
CR  complete response; NE  Not evaluable; PD  progressive disease; SD  stable disease. 
 

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

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

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11.9 
Appendix 9.  RECIST 1.1 With Prostate Cancer Working Group 3 
(PCWG3) Modifications  
Imaging provides critical information on disease distribution, prognosis, extent, biology, 
and host reaction to the tumor.  Detailed imaging instructions are provided in the imaging 
manual.  The following Prostate Cancer Working Group 3 (PCWG3) recommendations 
are provided as a reference (Scher et al, 2016): 
Baseline by Site of Disease 
PCWG3 retains the PCWG2 recommendations with modifications that include 
developing, recording, and validating measures of disease burden.  Imaging of the 
chest, abdomen, and pelvis using a contrast-enhanced computed tomography (CT) scan 
with  5-mm axial slices is advised for all subjects.  For those intolerant of contrast, a 
cross-sectional magnetic resonance imaging (MRI) scan of the abdomen and pelvis, with 
a noncontrast CT scan of the chest, may be considered.  In phase I and II trials, 
recognizing that individual lesions may be biologically distinct, PCWG3 recommends 
reporting whether progression on entry was in the growth of pre-existing lesions, the 
development of new lesions, or both.  PCWG3 advises following Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 for extraskeletal disease but recommends that up 
to 5 lesions per site of metastatic spread (eg, lung, liver, lymph nodes as separate sites) 
be recorded to address disease heterogeneity and to track patterns of metastatic 
progression.  Bone lesions should be recorded separately. 
Prostate or prostate bed 
Specific imaging of the prostate or prostate bed is not required for every subject.  If there 
is a question of locally persistent or recurrent disease, a directed MRI of the prostate or 
prostate bed and/or biopsy of the site is recommended. 
Nodes or viscera 
PCWG3 advises that nodal disease be measured in the short axis and recorded by 
location:  pelvic disease should be classified as locoregional, and extrapelvic disease 
(retroperitoneal, mediastinal, thoracic, or other) as metastatic.  Nodes  1.5 cm in the 
short axis are considered pathologic and measurable.  As per RECIST 1.1, lymph nodes 
that are  1.0 cm but less than 1.5 cm in the short axis may be pathologic and can be 
considered nonmeasurable/nontarget lesions.  Visceral disease in metastatic subjects 
should be designated separately as lung, liver, adrenal, or central nervous system (CNS) 
and is considered measurable if an individual lesion is  1 cm in its longest dimension.  

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Given that lung metastases are relatively frequent in metastatic castration-resistant 
prostate cancer (mCRPC) trials (7% prevalence), chest CT imaging is recommended. 
Bone 
The use of 99mTc-methylene diphosphonate (99mTc-MDP) radionuclide bone scintigraphy 
as the standard for bone imaging is retained in PCWG3, with the presence or absence of 
metastasis recorded first.  A quantitative measure of disease burden, such as lesional 
number, the bone scan index, or lesion area is also suggested, recognizing that these 
measures require further analytical and prospective clinical validation.  Changes in 
lesions considered metastatic on bone scintigraphy should be followed and assessed 
serially using a bone scan assessment form.  Areas/lesions on bone scintigraphy that 
are suggestive can be assessed further with CT or MRI and followed separately, but 
such supplemental imaging should not be used to establish indicator lesions for the 
purposes of a trial. 
Neurologic 
PCWG3 upholds the PCWG2 recommendation to perform an MRI or CT of the brain for 
subjects with small-cell/neuroendocrine tumors and to maintain a low threshold for 
performing an MRI of the base of the skull or spine to diagnose and/or detect impending 
neurologic compromise.  Routine imaging of the brain for adenocarcinoma is not 
recommended. 
Type of progression at entry into a trial 
PCWG3 advises recording whether progression was manifested by prostate-specific 
antigen (PSA) alone, bone  nodes by location, nodes by location only, or viscera 
( other sites), and the proportion of subjects who progress in each of these categories, 
because this is prognostic.  PCWG3 also advises reporting whether progression by 
imaging at study entry involved the growth or enlargement of pre-existing lesions, the 
development of new lesions, or both. 
NLCB:  Progression Versus The Decision To Discontinue Therapy 
PCWG2 encouraged the continuation of treatment if a rising PSA or worsening of an 
isolated disease site that was not clinically significant was the sole indicator of disease 
progression and the subject was otherwise tolerating therapy.  Now, recognizing the 
biologic heterogeneity of individual metastatic lesions, PCWG3 draws the distinction 
between documenting progression for consistency of reporting (eg, recording the date of 

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documented progression in a site of disease such as a lymph node that is unlikely to 
adversely affect prognosis) versus the decision to stop therapy. 
To address this, PCWG3 introduces the no longer clinically benefiting (NLCB) reporting 
metric defined as the date and the specific reason(s) a therapy was ultimately 
discontinued.  This end point permits individualized provider-patient decisions to 
continue or discontinue a treatment based on the primary therapeutic objective for which 
it is being administered and assessed, be it quality of life, PROs, or survival.  As an 
example, in cases in which multiple sites of disease continue to respond but 1 to 2 sites 
grow, focal therapy such as radiation or surgery could be administered to the resistant 
site(s) and systemic therapy continued.  Similarly, therapy may be continued if 
progression by PSA or imaging is slow and the disease-related symptoms that were 
present at baseline remain controlled.  Important here is to record in detail the specific 
reasons why a therapy was ultimately discontinued, which may include clinical 
deterioration (clarifying whether it is disease or therapy related) or need for a change in 
systemic therapy.  PCWG3 cannot define the risks/benefits at the individual level for 
continuation of therapy beyond progression, but sets the goal of prospectively defining 
the circumstances in which scenarios are identified where continuing a therapy is 
justified.  Clinical trials evaluating whether therapy a should be stopped and a new one 
started, continued alone, or continued with a new one added, are ongoing. 
Source:  Scher et al, 2016.

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11.10 
Appendix 10.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair 
5 
Dead 
ECOG  Eastern Cooperative Oncology Group. 
Source:  Oken et al, 1982

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11.11 
Appendix 11.  New York Heart Association Functional Classification 
1. Class I  
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation or dyspnea. 
2. Class II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea.  
3. Class III 
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation or dyspnea. 
4. Class IV 
Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
 
 

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11.12 
Appendix 12.  Adaptive Design 
The guidelines described in Section 4.1 for dose escalation or de-escalation to the next 
dose level are determined by a mTPI-2 algorithm (Guo et al, 2017).  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%, 35%).   
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. 
 
3 or more DLTs in  4 subjects  
 
4 or more DLTs in  6 subjects  
 
5 or more DLTs in  9 subjects 
 
6 or more DLTs in 10 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 decision according to the mTPI decision table.  With this 

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constraint, the MTD will be determined as the dose level with the DLT estimate closest 
to the target toxicity level of 30. 

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Page 1 of 42 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 7 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific 
T-cell Engager AMG 757 in Subjects with De Novo or Treatment Emergent 
Neuroendocrine Prostate Cancer 
 
Amgen Protocol Number Tarlatamab (AMG 757) 20200040 
EU CT Number 2024-513316-10 
NCT Number NCT04702737 
Amendment Date: 
21 June 2024 
 
Rationale: 
This protocol has primarily been amended to include the following changes: 
 
Update details about Protocol Approver and Key Sponsor Contact 
 
Remove EudraCT Number from the title page of the protocol. 
 
Align the protocol with the latest clinical protocol template. 
 
Remove 2 and 3 step dosing of cycle 1 scheduling tables (i.e. Table 1-1), 
Schedule of Activities tables (i.e. Table 1-3, Table 1-4), overall design Section 
4.1 and step dosing Section 6.2.1.2.1. 
 
Update footnote e and ff for SoA table. 
 
Update Safety Follow-Up visit from 42 (5) days to 60 (5) days. 
 
Remove Section 2.3.1.4 and Section 6.8.1 sucrose medicated renal impairment. 
 
Update provision of investigational product in Section 4.4.1 
 
Update male subjects use of contraception, use of condom and donating sperm 
timing from 132 days after the last dose of tarlatamab to 60 day after the last 
dose of tarlatamab. 
 
Update the title and content of Noninvestigational Products/Auxiliary Medicinal 
Products Section to be in accordance with European Union Clinical Trials 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  21 June 2024 
Page 2 of 42 
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Regulation (EU CTR) and modify the wording “protocol-required therapy” to 
“noninvestigational product(s)/auxiliary medicinal product(s)” 
 
Remove Section 6.1.3, Other Protocol Required Therapies as this section is not 
applicable in this study. 
 
Remove live and live-attenuated vaccines during study drug therapy from 
exclusion criteria. 
 
Update serious and fatal serious adverse events collection, recording, and 
reporting period to sponsor to be immediately and no later than 24 hours rather 
than within 24 hours. 
 
Add Section 8.2.3.4.2, Hypersensitivity as other safety measure. 
 
Add Serious Breach in Appendix 3, SAE related information, Results Reporting in 
the protocol to align with the latest clinical protocol template. 
 
Other Safety Findings/Special Situations language has been added to Section 
8.2.4.6 and Section 11.4 (Appendix 4). 
 
Update electronic Serious Adverse Event Contingency Form in Appendix 4.  
Safety Events:  Definitions and Procedures for Recording, Evaluating, Follow-Up 
and Reporting, Figure 11-1.  Sample Electronic Serious Adverse Event 
Contingency Form. 
 
Update Section 11.7, Appendix 7. Reporting and Management of potential 
Hepatotoxicity. 
 
Update Section 11.8, Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v1.1) Evaluation of Non-target Lesions table. 
 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  29 September 2022 
Page 1 of 84 
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FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 6 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics 
and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific T-cell Engager 
Tarlatamab in Subjects with De Novo or Treatment Emergent Neuroendocrine Prostate 
Cancer (DeLLpro-300) 
 
Amgen Protocol Number (AMG 757) 20200040  
EudraCT Number 2020-003508-15 
NCT Number:  NCT04702737 
Amendment Date: 
29 September 2022 
 
Rationale: 
The protocol is being amended to address further biomarker exploration with the addition of a 
prospectively selected delta-like protein 3 (DLL3) + neuroendocrine prostate cancer (NEPC) 
cohort (n ~ 40 subjects).  Applicable sections of the protocol are being modified to address this 
addition to the study and the subsequent analyses associated with the new cohort.  Changes 
including, but not limited to, the following are being incorporated into the protocol: 
 
Added language to incorporate prospective DLL3 selection in the eligibility criteria, 
biomarker assessment and all other related sections 
 
Added language to align aspects of data collection and monitoring across the tarlatamab 
program 
 
Key safety information updated to include immune effector cell associated neurotoxicity 
syndrome and reference to the investigator brochure for complete information 
 
Removal of schedule of activities (SOA) tables for 2-step and 3-step-dosing and the 
inclusion of a SOA table for extended intravenous (eIV) dosing 
 
Editorial changes (including typographical, grammatical, and formatting) have been 
made throughout the document 
 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  20 December 2021 
Page 1 of 59 
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Amendment 5 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics 
and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific T-cell Engager AMG 757 
in Subjects with De Novo or Treatment Emergent Neuroendocrine Prostate Cancer 
 
Amgen Protocol Number AMG 757 20200040 
EudraCT number:  2020-003508-15 
NCT Number:  NCT04702737 
 
Amendment Date: 
20 December 2021 
 
Rationale: 
This protocol is being amended to address site shortages of tocilizumab.  Applicable sections of 
the protocol are being modified to clarify the use of siltuximab in place of tocilizumab for the 
treatment of potential cytokine release syndrome (CRS) during a treatment-related adverse 
event.  Tarlatamab clinical experience and safety guidance is being updated.  Language is 
being included throughout to update/clarify the protocol.  Changes including, but not limited to, 
the following are being 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, safety stopping rules, and guidance throughout the protocol are being included. 
 
Table 6-4, “Tarlatamab Dose Modification Guidelines for Adverse Events” is being added. 
 
Updated language on recording and reporting of serious adverse events. 
 
Administrative, typographical, and editorial changes have been made throughout the 
protocol. 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  19 April 2021 
Page 1 of 30 
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Amendment 4 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics 
and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific T-cell Engager AMG 757 
in Subjects with De Novo or Treatment Emergent Neuroendocrine Prostate Cancer 
 
Amgen Protocol Number (AMG 757) 20200040 
 
Amendment Date: 
19 April 2021 
 
Rationale: 
The protocol is being updated: 
 
Due to updates in the mean half-life estimate for AMG 757
 the time to the safety follow up visit from the last 
dose of AMG 757 and the guidance on contraception for males and female partners have 
been updated.  
 
Updated the Secondary Endpoints to include Disease Control Rate 
 
To align with the ongoing first in human (FIH) study (study 20160323), additional exclusion 
criteria have been added, including "Has evidence of interstitial lung disease or active, non-
infectious pneumonitis" and “Live vaccine therapy within 4 weeks prior to study drug 
administration". 
 
To allow for subjects with recurrent Grade 3 abnormalities that are not considered clinically 
significant or that can be managed with supportive care, the protocol has been updated to 
allow subjects with recurrent Grade 3 laboratory parameters not considered clinically 
relevant or recurrent non-febrile Grade 3 neutropenia which resolves with supportive care 
to grade  1 or to baseline values within 3 weeks to remain on study. Additionally the 
protocol has been updated to allow for the use of growth factors, such as erythropoiesis-
stimulating proteins as well as granulocyte colony stimulating factor (G-CSF), throughout 
the study as needed. 
 
Removed 1 Exclusion criterion meant for female subjects of childbearing potential, since 
this study will allow only male subjects. 
 
Updated section 2.2.2.3 (Background Clinical Experience with Amgen Investigational 
Product AMG 757), based on emerging clinical data from the ongoing FIH study 
(20160323). 
 
To allow for the subject’s legally authorized representative to sign the consent on their 
behalf. 
 
The number of investigative sites was increased from approximately 20 to approximately 
25. 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  19 April 2021 
Page 2 of 30 
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 
Clarified that ECG measurements from this clinical study are performed as part of standard 
of care for routine safety monitoring, rather than for statistical analysis. 
 
Updated the Dose Cohort Levels that may be explored in Table 4-1 based on results from 
study 20160323 in small cell lung cancer 
 
Updated the toxicity interval in the mTPI-2 design. Updated Escalation/De-escalation 
guidelines (Table 4-2) and the decision rule when a dose level will be considered unsafe 
based on the mTPI2 design. 
 
Added a table of operating characteristics for the mTPI2 design (Table 4-3), so that it is 
clear how this design performs under given hypothetical true DLT rates. 
 
Added Management and restrictions for Covid-19 and vaccines 
 
To make editorial and formatting changes as applicable. 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  10 December 2020 
Page 1 of 17 
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Amendment 3 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific 
T-cell Engager AMG 757 in Subjects with De Novo or Treatment Emergent 
Neuroendocrine Prostate Cancer 
 
Amgen Protocol Number (AMG 757) 20200040 
 
Amendment Date: 
10 December 2020 
 
Rationale: 
The protocol is being updated: 
 
To add IV hydration at week 3 day 15 in Tables 1-2 and 1-3. 
 
To update Table 1-6 to include new footnotes and a central and biomarker laboratory 
test. 
 
To correct the abbreviations in the exploratory endpoints. 
 
To add safety language related to Coronavirus Disease 2019 (COVID-19) in the 
risk-benefit section. 
 
To clarify on the laboratory assessment collection timepoint. 
 
To remove the list of procedures performed at safety follow-up period section. 
 
To clarify that Mini-Mental Status Examination (MMSE) Version 2 will be performed 
as a part of the clinical evaluation. 
 
To remove the language stating that radiological imaging assessment will be 
performed every 12 weeks for response assessment only in the dose exploration 
phase. 
 
To clarify the sponsor responsibility for reporting of serious adverse events. 
 
To remove the language about requirement of local laboratory results only in the 
absence of central laboratory results in Appendix 11.2. 
 
To further clarify on the Dose Level Review Team (DLRT) recommendations on 
premedication based on emerging results from an ongoing first-in-human (FIH) study 
(20160323) in Appendix 11.3. 
 
To make editorial and formatting changes as applicable. 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  09 October 2020 
Page 1 of 6 
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Amendment 2 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific 
T-cell Engager AMG 757 in Subjects with De Novo or Treatment Emergent 
Neuroendocrine Prostate Cancer 
 
Amgen Protocol Number (AMG 757) 20200040 
 
Amendment Date: 
09 October 2020 
 
Rationale: 
This protocol is being updated: 
 
To add prophylaxis with intravenous (IV) hydration immediately after doses in cycle 1 
 
To restrict the 
 collection timepoints at day 1 
of cycles 1 and 4, and at end of treatment (EOT). 
 
To make editorial and formatting changes as applicable. 

Product:  AMG 757 
Protocol Number:  20200040 
Date:  15 September 2020  
Page 1 of 5 
Confidential 
 
Amendment 1 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific 
T-cell Engager AMG 757 in Subjects with De Novo or Treatment Emergent 
Neuroendocrine Prostate Cancer 
 
Amgen Protocol Number (AMG 757) 20200040 
 
Amendment Date: 
15 September 2020 
 
Rationale: 
This protocol is being updated based on Food and Drug Administration (FDA) requested 
changes. 

Approval Signatures
Document Name:
Protocol Amendment tarlatamab 20200040 7
Document Description:
AMG 757 Study 20200040 Global Protocol Amendment 7
Document Number:
CLIN-000086419
Approval Date:
21 Jun 2024
Type of Study Protocol:
Amendment
Protocol Amendment No.: 7
Document Approvals
Reason for Signing: Management
Name:
Date of Signature: 21-Jun-2024 15:25:15 GMT+0000
Reason for Signing: Management
Name:
Date of Signature: 21-Jun-2024 22:32:12 GMT+0000