Clinical trial NCT04740034
Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: Prostate specific membrane antigen PSMA Prostate cancer Metastatic Castrate-resistant
Sponsor: Amgen
Start date: 2021-04-29; Completion date: 2024-06-24
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a phase 1, open-label study evaluating the safety, clinical pharmacology and clinical activity of AMG 340, a PSMA x CD3 T-cell engaging bispecific antibody, in subjects with metastatic castrate-resistant prostate cancer (mCRPC) who have received 2 or more prior lines of therapy. The study consists of 2 parts, a monotherapy dose escalation (Arm A) and a monotherapy dose expansion (Arm B). Once the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is identified in Arm A, Arm B will be initiated to further characterize the safety, tolerability and pharmacokinetic (PK) profile of the MTD/RP2D dose of AMG 340 monotherapy in subjects with mCRPC.

Detailed description:

Arms: arm 1: Sequential dose escalation cohorts are planned until maximum tolerated dose (MTD) is reached or recommended phase 2 dose (RP2D) is identified. arm 2: An expansion cohort in subjects with mCRPC will be enrolled after RP2D is established.
Interventions: intervention 1: AMG 340
Intervention descriptions: intervention 1: AMG 340 is a bispecific antibody targeting prostate-specific membrane antigen (PSMA) on tumor cells and CD3 on T-cells

Protocol documents:
Prot_000.pdf: 
Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
Page 1 of 160 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Multicenter, Phase 1, Open-label, 
Dose-escalation and Expansion Study of 
AMG 340, a Bispecific Antibody Targeting PSMA 
in Subjects with Metastatic Castrate-resistant 
Prostate Carcinoma (mCRPC) 
Short Protocol Title: 
Open-label, Dose-escalation, and Expansion 
Study of AMG 340 in Subjects with Metastatic 
Castrate-resistant Prostate Carcinoma 
Protocol Number: 
20210249 (formerly TNB585.001) 
Investigational Product: 
AMG 340 (formerly TNB-585) 
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen, Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
+1 (805) 447-1000 
Protocol 
Approver 
Name: 
 MD 
Function: 
Vice President of Early Development 
 
Key 
Sponsor 
Contact 
Name: 
MD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
Email Address: 
 
EudraCT Number: 
Not applicable 
NCT Number: 
NCT04740034 
Protocol Version Date: 
Document Version 
Date 
Original 
11 December 2020 
Amendment 1 
21 December 2021 
Amendment 2 
18 March 2022 
Amendment 3 
04 May 2022 
Amendment 4 
26 September 2022 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
Page 2 of 160 
CONFIDENTIAL  
 
 
Amendment 5 
07 December 2022 
Data Elements Standards 
Version: 
8.0 
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 (International Council for Harmonisation 
[ICH] E6). 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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CONFIDENTIAL  
 
 
Confidentiality Notice 
 
 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Amgen’s 
general number in the US, 1-805-447-1000. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
Page 4 of 160 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Multicenter, Phase 1, Open-label, 
Dose-escalation and Expansion Study of AMG 340, a Bispecific Antibody Targeting 
PSMA in Subjects with Metastatic Castrate-resistant Prostate Carcinoma (mCRPC), 
dated 07 December 2022, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 5 
1. 
Protocol Summary ................................................................................................ 10 
1.1 
Synopsis ................................................................................................... 10 
1.2 
Study Schema ........................................................................................... 14 
1.3 
Schedule of Activities (SoA) ...................................................................... 16 
2. 
Introduction ........................................................................................................... 24 
2.1 
Study Rationale ......................................................................................... 24 
2.2 
Background ............................................................................................... 24 
2.2.1 
Disease ..................................................................................... 24 
2.2.2 
Available Therapies for Castrate-resistant Prostate 
Cancer ...................................................................................... 25 
2.2.3 
Scientific Rationale/Role of PSMA in the Disease ..................... 26 
2.2.4 
Amgen Investigational Product Background:  
AMG 340 ................................................................................... 27 
2.2.4.1 
Nonclinical Data ...................................................... 27 
2.2.4.2 
Potential Risks/Toxicities from AMG 340 ................. 31 
2.2.4.3 
Clinical Data ............................................................ 34 
2.2.5 
Non-Amgen Investigational Product Background:  
Imaging Products ...................................................................... 35 
2.3 
Benefit/Risk Assessment ........................................................................... 35 
2.3.1 
Key Risks .................................................................................. 36 
3. 
Objective(s) and Endpoint(s) ................................................................................ 38 
4. 
Study Design ........................................................................................................ 39 
4.1 
Overall Design .......................................................................................... 39 
4.1.1 
Part A:  Monotherapy Dose Escalation ...................................... 40 
4.1.2 
Part B:  Monotherapy Dose Expansion ...................................... 43 
4.2 
Patient Input into the Study Design ........................................................... 43 
4.3 
Justification for Dose ................................................................................. 43 
4.3.1 
Justification for Investigational Product Dose............................. 43 
4.4 
End of Study ............................................................................................. 44 
5. 
Study Population .................................................................................................. 44 
5.1 
Inclusion Criteria ....................................................................................... 45 
5.2 
Exclusion Criteria ...................................................................................... 45 
5.3 
Subject Enrollment .................................................................................... 48 
5.4 
Screen Failures ......................................................................................... 48 
6. 
Study Intervention ................................................................................................. 48 
6.1 
Study Interventions Administered .............................................................. 49 
6.1.1 
Investigational Products ............................................................ 49 
6.1.2 
Non-Amgen Investigational Imaging Products ........................... 51 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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6.1.3 
Non-investigational Products ..................................................... 51 
6.1.4 
Medical Devices ........................................................................ 51 
6.1.5 
Other Protocol-required Therapies ............................................ 51 
6.1.6 
Product Complaints ................................................................... 52 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 52 
6.2 
Dose Modification ...................................................................................... 53 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 53 
6.2.1.1 
Dose Escalation and Selection of the 
MTD/RP2D Dose .................................................... 53 
6.2.1.2 
Dose Priming........................................................... 54 
6.2.1.3 
Dose Cohort Stopping Rules ................................... 55 
6.2.1.4 
Toxicity Management .............................................. 55 
6.2.1.5 
Echocardiogram/Multigated Acquisition 
Scan ........................................................................ 58 
6.2.1.6 
Specific Guidance for Cytokine Release 
Syndrome ................................................................ 58 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 62 
6.2.2.1 
Amgen Investigational Product:  AMG 340 .............. 62 
6.2.2.2 
Management of COVID-19 Infection ........................ 63 
6.2.2.3 
Management of Monkeypox Infection ...................... 63 
6.2.2.4 
Infusion Interruptions/Delays/Withholding 
and Re-start in Case of 
Technical/Logistical Issues ...................................... 84 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 85 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 85 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 85 
6.4.1 
Method of Treatment Assignment .............................................. 85 
6.4.2 
Blinding ..................................................................................... 85 
6.5 
Treatment Compliance .............................................................................. 85 
6.6 
Treatment of Overdose ............................................................................. 85 
6.7 
Prior and Concomitant Treatment ............................................................. 86 
6.7.1 
Prior Treatment ......................................................................... 86 
6.7.2 
Concomitant Treatment ............................................................. 86 
6.7.2.1 
Vaccines ................................................................. 87 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 87 
7.1 
Discontinuation of Study Treatment........................................................... 88 
7.2 
Subject Discontinuation/Withdrawal From the Study ................................. 88 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 89 
7.2.2 
Reasons for Removal From Study ............................................. 89 


Product:  AMG 340 (formerly TNB-585) 
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Date:  07 December 2022 
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7.3 
Lost to Follow-up ....................................................................................... 90 
8. 
Study Assessments and Procedures .................................................................... 90 
8.1 
General Study Periods .............................................................................. 90 
8.1.1 
Screening, Enrollment, and/or Randomization ........................... 90 
8.1.2 
Treatment Period ....................................................................... 91 
8.1.3 
Safety Follow-up ........................................................................ 91 
8.1.4 
Long-term/Survival Follow-up .................................................... 91 
8.1.5 
End of Study .............................................................................. 92 
8.2 
General Assessments ............................................................................... 92 
8.2.1 
Informed Consent ...................................................................... 92 
8.2.2 
Demographics ........................................................................... 92 
8.2.3 
Medical History .......................................................................... 92 
8.2.4 
Physical Examination ................................................................ 92 
8.2.4.1 
Neurological Examination ........................................ 92 
8.2.5 
Physical Measurements ............................................................ 93 
8.2.6 
Performance Status ................................................................... 93 
8.3 
Efficacy Assessments ............................................................................... 93 
8.3.1 
Radiographic Assessments ....................................................... 93 
8.4 
Safety Assessments .................................................................................. 95 
8.4.1 
Vital Signs ................................................................................. 95 
8.4.2 
Electrocardiograms (ECGs) ....................................................... 95 
8.4.3 
Clinical Laboratory Assessments ............................................... 95 
8.4.4 
Survival Status .......................................................................... 96 
8.4.5 
Other Safety .............................................................................. 96 
8.4.6 
Adverse Events and Serious Adverse Events ............................ 96 
8.4.6.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 96 
8.4.6.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 98 
8.4.6.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 98 
8.4.6.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 98 
8.4.6.5 
Safety Monitoring Plan ............................................ 99 
8.4.6.6 
Pregnancy and Lactation ......................................... 99 
8.5 
Pharmacokinetic Assessments ................................................................ 100 
8.7 
Antibody Testing Procedures .................................................................. 100 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
Page 8 of 160 
CONFIDENTIAL  
 
 
9. 
Statistical Considerations .................................................................................... 103 
9.1 
Statistical Hypotheses ............................................................................. 103 
9.2 
Sample Size Determination ..................................................................... 103 
9.3 
Populations for Analysis .......................................................................... 103 
9.3.1 
Covariates ............................................................................... 104 
9.3.2 
Subgroups ............................................................................... 104 
9.4 
Statistical Analyses ................................................................................. 104 
9.4.1 
Planned Analyses .................................................................... 104 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................. 104 
9.4.1.2 
Primary Analysis ................................................... 105 
9.4.1.3 
Final Analysis ........................................................ 105 
9.4.2 
Methods of Analyses ............................................................... 105 
9.4.2.1 
General Considerations ......................................... 105 
9.4.2.2 
Efficacy Analyses .................................................. 106 
9.4.2.3 
Safety Analyses .................................................... 106 
9.4.2.4 
Other Analyses ...................................................... 107 
10. 
References ......................................................................................................... 109 
11. 
Appendices ......................................................................................................... 114 
11.1 
Appendix 1.  List of Abbreviations ........................................................... 115 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 118 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 121 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 132 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 142 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 146 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 148 
11.8 
Appendix 8.  Eastern Cooperative Oncology Group (ECOG) 
Performance Score ................................................................................. 152 
11.9 
Appendix 9.  Activity Measurements ........................................................ 153 
11.10 Appendix 10.  Specific Guidance for Cytokine Release 
Syndrome................................................................................................ 155 
11.11 Appendix 11.  Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading............................................................................. 156 
11.12 Appendix 12.  RECIST 1.1 With Prostate Cancer Working 
Group 3 (PCWG3) Modifications ............................................................. 158 
 
List of Tables 
Table 1-1.  Schedule of Activities ................................................................................... 16 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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Table 1-3.  Schedule of Disease Response Assessments ............................................. 23 
Table 2-1.  Summary of Lowest In Vitro EC50 Values and In Vivo Activity .................... 30 
Table 2-2.  Key Safety Risk for AMG 340 ...................................................................... 37 
Table 4-1.  Dose Escalation and De-escalation Boundaries .......................................... 42 
Table 6-1.  Investigational Products ............................................................................... 50 
Table 6-2.  CRS Grading (ASTCT; Lee et al, 2019) ....................................................... 58 
Table 6-3.  American Society for Transplantation and Cellular Therapy 
Immune Effector Cell-associated Neurotoxicity Syndrome 
Consensus Grading for Adults (Lee et al, 2019) ..................................... 59 
Table 6-4.  Encephalopathy Assessment Tools for Grading of Immune 
Effector Cell-associated Neurotoxicity Syndrome (Lee et al, 
2019) ...................................................................................................... 61 
Table 6-5.  Suggested Guidelines for Management of Neurological Toxicity ................. 61 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events ........................ 64 
Table 9-1.  The Criteria for Evaluating the Use of Siltuximab ....................................... 105 
Table 11-1.  Analyte Listing ......................................................................................... 119 
Table 11-2.  DILI Potential Analyte Listing ................................................................... 120 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 149 
Table 11-4.  Response Categories Based on Assessment of Target Lesions .............. 153 
Table 11-5.  Time Point Response:  Subjects with Target ( Non-target) 
Disease ................................................................................................ 154 
Table 11-6.  Time Point Response:  Subjects with Non-target Disease Only ............... 154 
Table 11-7.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome ................. 156 
Table 11-8.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 156 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 14 
Figure 1-2.  Part A:  Monotherapy Dose Escalation ....................................................... 15 
Figure 11-1.  Sample Serious Adverse Event Report Form (paper-based 
form) ..................................................................................................... 137 
Figure 11-2.  Pregnancy Notification Form .................................................................. 145 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion 
Study of AMG 340, a Bispecific Antibody Targeting PSMA in Subjects with Metastatic 
Castrate-resistant Prostate Carcinoma (mCRPC) 
Short Protocol Title:  Open-label, Dose-escalation, and Expansion Study of AMG 340 
in Subjects with Metastatic Castrate-resistant Prostate Carcinoma 
Study Phase:  1 
Indication:  Metastatic Castrate-resistant Prostate Carcinoma (mCRPC) 
Study Rationale 
To evaluate the safety, pharmacokinetic/pharmacodynamic (PK/PD) properties, and 
clinical activity of the T-cell-engaging bispecific antibodies (T-BsAb) AMG 340 in 
subjects with metastatic castrate-resistant prostate carcinoma (mCRPC), this study will 
enroll subjects with progressive mCRPC that have been exposed to 2 or more lines of 
therapy.  In order to be eligible for this study subjects should have previously been 
exposed to, intolerant of, ineligible for, or declined therapy with both a novel 
anti-androgen (eg, abiraterone, enzalutamide) and a taxane (eg, docetaxel).  
Single-subject cohorts will initially receive AMG 340 once every 3 weeks (Q3W) 
beginning at a dose of 
 mg (based on minimum anticipated biological effect level 
[MABEL]); once toxicity or activity emerges, subjects will be enrolled based on Bayesian 
optimal interval (BOIN) design.  The objective of this study is to evaluate the safety of 
AMG 340 as monotherapy, find the maximum tolerated dose (MTD)/recommended 
phase 2 dose (RP2D) of AMG 340, and to establish the PK and PD characteristics of 
AMG 340.  A Q3W dosing frequency was selected for initial dosing in Part A to allow 
adequate time for detection of toxicity between doses, and to limit drug accumulation. 
Therapeutic options for advanced mCRPC are limited.  Despite the success of 
chemotherapy, second generation non-steroidal anti-androgens, and androgen receptor 
blockers, patients that progress after treatment with these therapies have few 
therapeutic options.  Therefore, patients that have progressive mCRPC and that have 
been exposed to 2 or more lines of therapy are proposed as eligible subjects for this 
study.  Subjects should have previously been exposed to, intolerant of, ineligible for, or 
declined therapy with both a novel anti-androgen (eg, abiraterone, enzalutamide) and a 
taxane (eg, docetaxel). 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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Objective(s) and Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability 
of AMG 340 when administered as 
monotherapy. 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs and clinical 
laboratory tests 
 
Determine the maximum tolerated 
dose (MTD) or recommended 
phase 2 dose (RP2D) for 
AMG 340 when administered as 
monotherapy. 
 
Dose-limiting toxicities (DLTs) 
 
Evaluate the pharmacokinetics 
(PK) of AMG 340 when 
administered as monotherapy. 
 
PK parameters of AMG 340 
including, but not limited to: 
 Cmax 
 Time to Cmax (Tmax) 
 Area under the 
concentration-time curve within 
a dosing interval (AUC0-t) 
Secondary 
 
Evaluate the clinical activity of 
AMG 340 when administered as 
monotherapy. 
 
Objective response (OR) per 
RECIST 1.1 
 
Overall survival (OS) 
 
Progression-free survival (PFS) 
(radiographic and PSA) 
 
6-month landmark radiographic 
PFS 
 
PSA response (30%, 50%, 70% 
and 90%) 
 
Time to progression (radiographic 
and PSA) 
 
Duration of response (DOR) per 
RECIST 1.1 
 
PSA DOR based on PSA50 
 
Time to symptomatic skeletal 
events (SSE) 
 
 
Overall Design 
This is a phase 1 open-label, dose-escalation and expansion study evaluating the safety, 
PK, PD, and clinical activity of AMG 340 in subjects with progressive mCRPC who have 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
Page 12 of 160 
CONFIDENTIAL  
 
 
received at least 2 or more prior lines of systemic therapy (‘Line/regimen of therapy’ is 
defined as a course of therapy [at least 1 cycle uninterrupted by progressive disease, 
cycle disruption due to toxicity or intolerance is acceptable]).  To be eligible for 
enrollment in this study, subjects should have previously been exposed to, intolerant of, 
ineligible for, or declined therapy with both a novel anti-androgen (eg, abiraterone, 
enzalutamide) and a taxane (eg, docetaxel). 
The study will consist of 2 parts:  a monotherapy dose escalation (Part A; Section 4.1.1) 
and a monotherapy dose expansion (Part B, Sections 4.1.2).   
Number of Subjects 
The total number of subjects enrolled in both parts of the study is anticipated to be 
approximately 100 subjects (up to 60 subjects in Part A [monotherapy dose escalation] 
and up to 40 subjects in Part B [monotherapy dose expansion]) at sites in the US with a 
potential expansion to sites in Europe and the Asia-Pacific (APAC) region. 
Summary of Subject Eligibility Criteria 
Adult male subjects with progressive mCRPC who have received 2 or more prior lines of 
systemic therapy approved for the treatment of mCRPC will be enrolled.  Subjects 
should have previously been exposed to, intolerant of, ineligible for, or declined therapy 
with both a novel anti-androgen (eg, abiraterone, enzalutamide) and a taxane (eg, 
docetaxel). 
For a full list of eligibility criteria, please refer to Section 5.1 and Section 5.2. 
Treatments 
AMG 340 will initially be administered as an IV infusion Q3W, where 1 cycle of treatment 
will be 21 days.  The starting dose of AMG 340 will be 
 mg administered as an IV 
infusion (Q3W) in Part A and escalate to a projected maximum of 
 mg in subsequent 
cohorts.  In Part B, all subjects will receive AMG 340 at the MTD and/or RP2D.  The 
dose(s) selected for evaluation in Part B may be a dose at or below the MTD defined in 
Part A or the RP2D.  Dosing frequency for Part B will be chosen by the sponsor based 
on safety, tolerability, PK/PD, and clinical activity data collected from Part A, in 
consultation with the study investigators. 
Statistical Considerations 
Descriptive statistics will be provided for selected demographics, safety data by dose, 
dose schedule, and time as appropriate.  Descriptive statistics on continuous data will 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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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 proportion of subjects with an OR per RECIST 1.1 along with the corresponding 
exact 95% CI will be calculated using the Clopper-Pearson method (Clopper and 
Pearson, 1934); similarly, the proportion of subjects, 95% CI will be tabulated for PSA 
response.  Kaplan-Meier quartiles, rates and curves will be used to summarize OS, 
rPFS, 6-month landmark rPFS, PSA PFS, time to progression (radiographic and PSA), 
time to symptomatic skeletal events (SSE), and DOR.   
Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the Safety Analysis Set, which includes subjects that are enrolled and 
received AMG 340.  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 described in Sections 9.4.2.3.2 through 
9.4.2.3.6. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
In Part A, a safe and tolerable dose of AMG 340 will have evidence of anti-tumor activity 
in subjects with mCRPC as measured by objective response rate (ORR).  In Part B, 
AMG 340 will improve ORR in subjects with mCRPC to 20% compared with the 
reference ORR of 5%. 
Sponsor Name:  Amgen, Inc. 
 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
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1.2 
Study Schema 
Figure 1-1.  Study Schema 
Part A:
Monotherapy 
Dose Escalation
Approximately 60 subjects
Cohorts 1 to N
Adult subjects with progressive mCRPC that have 
received 2 or more prior lines of systemic therapy 
approved for the treatment of mCRPC will undergo 
dose escalation with AMG 340 to identify the
MTD (RP2D).
Part B:
Monotherapy 
Dose Expansion
Approximately 40 subjects
AMG 340 dosing at the MTD (RP2D) in adult 
subjects with progressive mCRPC that have 
received 2 or more prior lines of systemic therapy 
approved for the treatment of mCRPC.
Part B will be initiated once the MTD (or RP2D) has 
been selected on data from Part A.
MTD/RP2D Dose Expansion
 
mCRPC = metastatic castrate-resistant prostate carcinoma; MTD = maximum tolerated dose; RP2D = recommended phase 2 dose


Product:  AMG 340 (formerly TNB-585) 
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Figure 1-2.  Part A:  Monotherapy Dose Escalation 
 
Note:  The approximate number of subjects is based on lack of DATs in any cohort.  The actual numbers of subjects will depend on safety and other findings. 
BOIN = Bayesian Optimal Interval; DAT = drug-associated toxicity; DLT = dose limiting toxicity; MTD = maximum tolerated dose; RP2D = recommended phase 2 dose. 
 


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1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities 
Study Activity 
Screening 
C1 Treatment Period 
DLT Window (Days 1-21) 
Treatment Period (3-week cycles) 
UNS 
Visita 
EOTb 
SFUn 
Survival 
FU/LTFUo 
C2 
C3 
C4 & 
C5 
C6 
C7 
W1 
W2d 
W3 W1 W3 W1 W2 W3 W1 
W1 
W3 W1 
Within 
30d after 
last dose 
90d after 
last 
dose 
Every 
6 months 
Study Day 
Day -28 to 
Day -1 
D1 
D2 
D3 
D5 D6 D7 D8 D9 D10 D15 D1 D15 D1 D8 D15 
D1 
D1 D2 D15 
D1 
Window 
 
 
±1h ±1h ±1d ±1h ±1h ±1d ±1h ±1h ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d 
 
 
7d 
±7d 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incl/Excl Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient Stayc 
 
X 
X 
X 
X c X c X c X c X c X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical & Cancer 
History, Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Symptom-directed 
Physical Exam 
 
X 
X 
X 
X 
Xi 
Xi 
X 
Xk Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
Vital Signsd 
X 
X 
X 
X 
X 
Xi 
Xi 
X 
Xk Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
Performance 
Status 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
 
Clinical Chemistry 
and Hematology e 
X 
X 
X 
X 
X 
Xi 
Xi 
X 
Xk Xk 
X 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
 
Coagulation Panele 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Screen  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 340 
administrationf 
 
X 
 
 
X 
 
 
Xj 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
Anti-AMG 340 
antibodye 
Refer to
 
 
 
 


Product:  AMG 340 (formerly TNB-585) 
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Study Activity 
Screening 
C1 Treatment Period 
DLT Window (Days 1-21) 
Treatment Period (3-week cycles) 
UNS 
Visita 
EOTb 
SFUn 
Survival 
FU/LTFUo 
C2 
C3 
C4 & 
C5 
C6 
C7 
W1 
W2d 
W3 W1 W3 W1 W2 W3 W1 
W1 
W3 W1 
Within 
30d after 
last dose 
90d after 
last 
dose 
Every 
6 months 
Study Day 
Day -28 to 
Day -1 
D1 
D2 
D3 
D5 D6 D7 D8 D9 D10 D15 D1 D15 D1 D8 D15 
D1 
D1 D2 D15 
D1 
Window 
 
 
±1h ±1h ±1d ±1h ±1h ±1d ±1h ±1h ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d ±1d 
 
 
7d 
±7d 
Disease  
Assessmentse, h 
 
Refer to Table 1-3 
 
 
Adverse event 
collectionl 
X 
Recorded from the time of consent through SFUn 
X 
 
Serious adverse 
event collectionm 
Continuously throughout the study 
Concomitant 
medications/ 
therapyp 
 
Recorded within 2 weeks from the first dose of study drug through SFUn 
 
Survival  
 
 
X 
ADA = antidrug antibody; D = day; D/C = discharge; DLT = dose-limiting toxicity; ECG  electrocardiogram; ECHO  echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EOT = end-of-treatment; FU  follow-up; LTFU  long-term follow-up; PK = pharmacokinetic(s); SFU = safety follow-up; T1/2 = terminal half-life; 
UNS = unscheduled; W = week. 
Note:  Every effort should be made to keep the Schedule of Events on time for each subject. 
a ;B;@0521B921C6@6A:.F<00B?.A.;FA6:21B?6;4A52@AB1F(AB1F.0A6C6A62@@5<D;D699/2=2?3<?:21.AA526;C2@A64.A<?Q@discretion. 
b The EOT visit should occur within 30 days after the last dose of AMG 340.  If an alternate therapy will be initiated during this period, the EOT visit should be 
conducted prior to the first dose of alternate therapy.   
c Subjects will be admitted for 48 hours after the infusion on C1D1 and, if implemented, after a second priming dose on C1D5.  If priming doses are 
implemented, subjects will also be admitted for 48 hours on C1D8 (note that a second priming dose may be implemented based on emerging data). 
d Vital sign measurements include measurements of diastolic and systolic blood pressure, heart rate, respiratory rate, and temperature.  On day 1 dosing, vital signs 
should be measured prior to study drug administration (up to 10 minutes before), 30 ± 10 minutes after initiation of study drug administration, at completion of study 
drug administration (±10 minutes), and 1 hour ± 10 minutes after completion of study drug administration; on C1D1 and on C1D5 and C1D8, if priming doses have 
been implemented, vital signs should also be measured 3, 6, and 9 hours ± 10 minutes after completion of study drug administration.  Vital signs should be taken 
after 5 minutes of sitting or lying down. 
f AMG 340 will be administered intravenously by continuous infusion pump over 120 minutes (± 10 minutes) unless otherwise noted in Section 6.1 of the protocol. 
g 
h Samples will be collected for disease response as indicated in Table 1-3.  Subjects off-treatment for reasons other than disease progression or withdrawal of consent 
should continue with disease response assessments as described in Table 1-3, until documented disease progression, initiation of subsequent anticancer therapy, or 
withdrawal (see Table 1-3). 
i C1D6 and C1D7 assessments will only be performed if a priming dose has been implemented on C1D5. 
j A dose will only be administered on C1D8 if a priming dose has been implemented. 
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k C1D9 and C1D10 assessments will only be performed if a priming dose has been implemented on C1D8. 
l All adverse events observed by the investigator or reported by the subject that occur from the time of consent through the safety follow-up visit 
90 (+ 7) days after the last dose of study drug should be reported.  For subjects that start a new line of therapy before the 90 (+ 7) day follow-up visit, all 
adverse events should be collected and reported through 30 days post last dose of investigational product/protocol-required therapies or until the subject 
begins a new line of therapy, whichever occurs later (please refer to Section 8.1.3). 
m All serious adverse events observed by the investigator or reported by the subject that occur from the time of consent through the safety follow-up visit 
90 (+ 7) days after the last dose of study drug should be reported.  For subjects that start a new line of therapy before the 90 (+ 7) day follow-up visit, all 
serious adverse events should be collected and reported through 30 days post last dose of investigational product/protocol-required therapies or until 
the subject begins a new line of therapy, whichever occurs later (please refer to Section 8.1.3).  During the survival (long-term) follow-up phase, serious adverse 
events (regardless of causality) that the investigator becomes aware of will be reported to Amgen.  After end of study, serious adverse events suspected to be 
related to investigational product should be reported to Amgen.  Please refer to Section 8.4.6.1.3. 
n The SFU visit should occur approximately 90 (+ 7) days after the end of the last dose of AMG 340.  If a new line of therapy is initiated during this period, the SFU visit 
should be conducted through 30 days post last dose of AMG 340 or until the subjects begins a new line of therapy, whichever occurs later.   
o Subjects will be followed for survival and/or the commencement of subsequent cancer therapy via clinic visits, telephone, or chart review call every 6◦months from the 
last SFU visit for up to a maximum of 3 years. 
p Concomitant medications/therapy should be recorded within 2 weeks from the first dose of investigational product through the SFU or 30 days after last day of the 
dosing interval of investigational product/protocol-required therapies, whichever is later.   
 


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Footnotes described on last page of table 
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Footnotes described on last page of table 
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CCI


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Protocol Number:  20210249 (formerly TNB585.001) 
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Table 1-3.  Schedule of Disease Response Assessments  
 
SCR 
Treatment Perioda,g 
EOT 
SFU 
Survival 
FU/LTFU 
Notes 
MRI brain 
X 
 
 
 
 
All subjects must have MRI of the brain performed within 28 days prior to 
the first dose of AMG 340.   
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/MRIb, bone scanc,f, 
and tumor burden 
assessment 
X 
Week 1-24 
Day 1 of every 3rd cycle  
(at C3D1 then every 9 weeks  
after C3D1) 
 
Week 25+ 
Day 1 of every 4th cycle 
 (= every 12 weeks)  
Xᵈ 
Xᵈ 
Xe 
CR/PR require confirmation after at least 4 weeks. 
Bone PD requires confirmation after at least 6 weeks. 
For subjects who discontinue for any reason other than radiographic 
disease progression, follow-up scans should occur every 3 months until 
documentation of disease progression per PCWG3. 
18F-FDG PET/CTf 
X 
Every 12 weeks 
Xd 
Xd 
 
Dose-expansion phase 
PSA 
X 
Day 1 of every cycle 
X 
X 
 
Disease assessments will be performed centrally. 
 
18F-FDG  18F-fluorodeoxyglucose;
 99mTc-MDP  99mtechnetium methylene diphosphonate; 
C3D1  cycle 3 day 1; CR  complete response; CT  computed tomography; EOT  end of treatment; FDG  fluorodeoxyglucose; FU  follow-up; LTFU  long-term 
follow-up; MRI  magnetic resonance imaging; PCWG3  Prostate Cancer Clinical Trials Working Group 3; PD  progressive disease; PET  positron emission 
tomography; PR  partial response; PSA  Prostate Specific Antigen; PSMA  prostate specific membrane antigen; RECIST  Response Evaluation Criteria in Solid 
Tumors; SCR  screening; SFU  safety follow-up 
a  7 days.  Timing is based on first dose of AMG 340 (cycle 1 day 1). 
ᵇ Responses (PR and CR) require confirmation by a repeat consecutive CT/MRI assessment no sooner than 4 weeks after the first detection of radiographical 
response. 
c Per PCWG3 recommendations, the first post-treatment bone scan (at C3D1) will be used as the baseline scan with which all future bone scans are compared.  To 
confirm disease progression by bone scan, a second bone scan must be performed at least 6 weeks after the 2nd of the 2 lesions is noted (“2+2” rule set).   
ᵈ Radiologic imaging (CT/MRI) and bone scan scintigraphy are required at the EOT or SFU visit if the subject has not had these imaging assessments performed 
within 6 weeks of the visit.  For PET/CT imaging 
and 18F-FDG), every effort should be made to acquire PET/CT scans at the EOT or SFU visit, or 
prior to initiation of other therapy if the subject has not had PET/CT imaging performed within 8 weeks of the visit. 
e For subjects who discontinued treatment for any reason other than radiographic disease progression, every effort should be made to perform radiographic imaging 
(CT/MRI/bone scan) of the chest, abdomen, pelvis, and all other known sites of disease every 3 months until documentation of radiographic disease progression per 
PCWG3, clinical progression, biochemical progression, start of new anticancer therapy, or up to 3 years after the first dose of study treatment. 
f Blood samples or tumor biopsy must not be collected until at least 24 hours after a PET/CT scan, or at least 60 hours (or 2.5 days) following a bone scintigraphy 
scan. 
g Subjects off-treatment for reasons other than disease progression or withdrawal of consent should continue with disease response assessments every 12 weeks ( 7 
days) until documented disease progression, initiation of subsequent anticancer therapy, or withdrawal.


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2. 
Introduction 
2.1 
Study Rationale 
To evaluate the safety, pharmacokinetic/pharmacodynamic (PK/PD) properties, and 
clinical activity of the T-cell-engaging bispecific antibodies (T-BsAb) AMG 340 in 
subjects with metastatic castrate-resistant prostate carcinoma (mCRPC), this study will 
enroll subjects with progressive mCRPC that have been exposed to 2 or more lines of 
therapy.  In order to be eligible for this study subjects should have previously been 
exposed to, intolerant of, ineligible for, or declined therapy with both a novel 
anti-androgen (eg, abiraterone, enzalutamide) and a taxane (eg, docetaxel).  
Single-subject cohorts will initially receive AMG 340 once every 3 weeks (Q3W) 
beginning at a dose of 
 mg (based on minimum anticipated biological effect level 
[MABEL]); once toxicity or activity emerges, subjects will be enrolled based on Bayesian 
optimal interval (BOIN) design.  The objective of this study is to evaluate the safety of 
AMG 340 as monotherapy, find the maximum tolerated dose (MTD)/recommended 
phase 2 dose (RP2D) of AMG 340, and to establish the PK and PD characteristics of 
AMG 340.  A Q3W dosing frequency was selected for initial dosing in Part A to allow 
adequate time for detection of toxicity between doses, and to limit drug accumulation. 
Therapeutic options for advanced mCRPC are limited.  Despite the success of 
chemotherapy, second generation non-steroidal anti-androgens, and androgen receptor 
blockers, patients that progress after treatment with these therapies have few 
therapeutic options.  Therefore, patients that have progressive mCRPC and that have 
been exposed to 2 or more lines of therapy are proposed as eligible subjects for this 
study.  Subjects should have previously been exposed to, intolerant of, ineligible for, or 
declined therapy with both a novel anti-androgen (eg, abiraterone, enzalutamide) and a 
taxane (eg, docetaxel). 
2.2 
Background 
2.2.1 
Disease 
Prostate cancer (CaP) is the most common cancer and the second leading cause of 
cancer death in men worldwide, with 1.6 million cases and > 350 000 deaths annually 
(Fitzmaurice et al, 2017).  In the US, an estimated 191 930 new cases and 33 330 deaths 
from CaP occurred in 2019 (American Cancer Society 2020).  At presentation, 76% of 
cases are localized, 13% show spread to regional lymph nodes, and 6% are metastatic 
to distant sites (National Cancer Institute [NCI] Surveillance, Epidemiology and End 
Results [SEER] 2020).  Many men with local or locoregional disease eventually progress 


Product:  AMG 340 (formerly TNB-585) 
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to metastatic disease.  The initial management of CaP is dependent on the degree of 
spread as well as other factors such as the Gleason grade of the tumor, patient age, 
comorbidities, and prostate specific antigen (PSA) levels.  Based on these factors men 
are risk-stratified using various classification systems (D’Amico et al, 1998; Cooperberg 
et al, 2011; Mottet et al, 2017; Sanda et al, 2018; Gnanapragasam et al, 2016; Lukka et 
al, 2001; Memorial Sloan Kettering Cancer Center 2020; National Comprehensive 
Cancer Network [NCCN] 2022).  The NCCN system stratifies men with localized disease 
from very low risk, where active surveillance is recommended, to very high risk where 
radiation and/or surgery are preferred.  Once CaP has spread beyond the local environs 
of the prostate, systemic therapy is indicated. 
First line therapy in disseminated CaP is androgen deprivation therapy (ADT) with or 
without radiation; however, patients invariably progress to mCRPC, defined as 
progression while receiving ADT and with castrate levels of testosterone (< 50 ng/dL).  
Therapeutic options for mCRPC are limited (Fizazi et al, 2012; Ryan et al, 2015; Scher 
et al, 2012; Kantoff et al, 2010; De Bono et al, 2010; Berthold et al, 2008).  Thus novel, 
paradigm-shifting therapies in mCRPC represent an urgent unmet medical need. 
2.2.2 
Available Therapies for Castrate-resistant Prostate Cancer 
Both first- and second-line therapy in mCRPC usually add either a second-generation 
non-steroidal anti-androgen (eg, enzalutamide), an androgen biosynthesis inhibitor (eg, 
the CYP17A1 inhibitor abiraterone), or taxane chemotherapy (eg, docetaxel or 
cabazitaxel) to ongoing ADT (NCCN, 2022).  Other employed agents include 
Radium-223, the dendritic cell vaccine Sipuleucel-T, mitoxantrone, the anti-PD-1 
antibody pembrolizumab, and Poly ADP Ribose-Polymerase inhibitors (PARPi).  The 
latter two agents are deployed in the setting of mismatch repair or BRCA/ATM 
deficiencies in a patient’s tumor, respectively.  After first-line therapy, overall survival 
benefits are typically 5 months or less for currently approved therapies. 
Therapy in the third line and beyond is often experimental and undertaken in the context 
of a clinical trial.  Tumor vaccines and various tyrosine kinase inhibitors (eg, the AKT 
inhibitor ipatasertib or the c-Kit inhibitor masitinib), as well as novel androgen receptor 
(AR) blockers and PARPis are in development for the treatment of progressive mCRPC.  
A very promising area of development is targeted agents, most prominently those 
against prostate specific membrane antigen (PSMA).  PSMA-targeted agents include 
antibody-drug-conjugates (ADCs), T-BsAbs, chimeric antigen receptor T-cells (CAR-Ts), 
and radioligand therapies (RLTs).  To date, ADCs, T-BsAbs, and CAR-T therapies have 


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been hampered by limited activity and substantial toxicity (Bendell et al, 2020).  RLTs, 
notably the Lutetium-177-PSMA-617 conjugate that combines a small molecule that 
specifically binds PSMA with radioactive Lutetium, have shown promise.  In March 2022, 
Lutetium-177-PSMA-617 was approved by US Food and Drug Administration (FDA) for 
the treatment of adult patients with PSMA-positive mCRPC who have been treated with 
AR pathway inhibition and taxane-based chemotherapy.  Lu177-PSMA-617 has shown ≥ 
50% PSA decrease in approximately 40% to 60% of treated patients in multiple studies 
(van Kalmthout et al, 2019; McBean et al, 2019; Heck et al, 2019; Emmett et al, 2019; 
Hofman et al, 2018).  In two small studies it was also shown that re-challenge with 
Lu177-PSMA-617 resulted in 37.5 to 40% of subjects achieving a PSA decrease of ≥ 
50% (Yordanova et al, 2019; Gafita et al, 2019).  While these results validate PSMA as 
an excellent target in mCRPC, repeated use of RLTs is inherently limited by maximal 
total radiation burden. 
2.2.3 
Scientific Rationale/Role of PSMA in the Disease 
PSMA is an 84 kD class II membrane glycoprotein encoded by the folate hydrolase 
(FOLH1) gene.  It is a zinc metalloenzyme that catalyzes the hydrolysis of 
N-acetylaspartylglutamate to glutamate and N-acetylaspartate (O’Keefe et al, 1998; 
Barinka et al, 2004; Rojas et al, 2002; Mesters et al, 2006), and is predominantly 
expressed on prostatic epithelium.  Marked overexpression is observed in prostatic 
adenocarcinoma (CaP) and expression increases together with grade and stage (Silver 
et al, 1997; Olafsen et al, 2007; FDA, 2012).  Overexpression also correlates with more 
rapid progression and risk of relapse (Perner et al, 2007; Ross et al, 2003).  The high 
expression of PSMA in CaP coupled with largely prostate-restricted expression in normal 
tissue makes this antigen ideally suited to targeted CaP therapy. 
Nevertheless, very weak and predominantly cytoplasmic expression of PSMA has also 
been described in epithelial cells of the breast, small intestine, parotid salivary gland 
(which also shows luminal/apical PSMA expression), and fallopian tube (Trover et al, 
1995, Wright et al, 1995; Silver et al, 1997; Kawakami and Nakayama, 1997; Cunha et 
al, 2006; Kinoshita et al, 2006; Mhawech Fauceglia et al, 2007).  According to ICH 
S6(R1) and others, monoclonal antibody binding to membranes is considered significant, 
however cytoplasmic sites are generally considered of little to no toxicologic significance 
(Hall et al, 2010; Leach et al, 2010).  This conclusion is consistent with the toxicity 
profiles of existing PSMA-targeted therapeutics.  The small molecule RLT 
Lu177-PSMA-617 has been shown to induce grade 1–2 xerostomia (dry mouth) in up to 


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87% of subjects (Hofman et al, 2018), but other on-target, off-tumor toxicities have not 
been observed.  Large molecule therapies, such as those incorporating antibodies, do 
not show xerostomia (Tagawa et al, 2019), presumably because they are too big to 
cross into the luminal space where membranous parotid glandular epithelium PSMA is 
localized.  While Lu177 PSMA 617 is also associated with significant bone marrow 
toxicity, this is attributed to the radioactive warhead and is not considered 
PSMA-specific.  Overall clinical studies of PSMA-targeted therapeutics confirm PSMA as 
a highly CaP-specific target, especially for antibody-based therapies. 
2.2.4 
Amgen Investigational Product Background:  AMG 340 
AMG 340 binds to CD3 on human T-cells and cell-surface PSMA on CaP cells.  In 
mixtures of human T-cells and PSMA-positive tumor cells, this simultaneous binding to 
CD3 and PSMA resulted in T-cell activation and potent and efficient killing of tumor cells 
in vitro.  Furthermore, AMG 340 killed PSMA-expressing tumor cells in vivo in the 
presence of human T-cells, as evidenced by dose dependent tumor eradication in 
mouse xenograft models.  T-cell activation by AMG 340 is likely to result in markedly 
attenuated cytokine production compared to PSMA-targeted bispecific anti-CD3 
antibodies currently in clinical development.  This suggests that AMG 340 may show 
reduced immune-mediated toxicity (such as cytokine release syndrome [CRS] and/or 
neurotoxicity [NT]) in human patients as compared to other T-cell redirecting therapies, 
thereby addressing one of the major limitations of T-cell redirecting therapy. 
Despite recent advancements, and the availability of multiple therapies for the treatment 
of mCRPC, relapse is inevitable.  Furthermore, T-cell redirecting bispecific antibodies 
currently in development are hampered by safety challenges related to CRS (Bendell et 
al, 2020; Marshall and Antonarakis, 2020).  CAR-Ts have been associated with severe 
CRS and have seen limited adoption because of the need to administer them at certified 
centers, as well as challenges related to cost and manufacturing.  AMG 340, with its 
unique mechanism, could provide an efficacious and potentially safer approach to 
selectively destroy PSMA-positive mCRPC cells, and represents a novel 
immunotherapeutic for the treatment of mCRPC. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AMG 340 
is provided in the Investigator’s Brochure (IB). 
2.2.4.1 
Nonclinical Data 
AMG 340 is a fully human bispecific monoclonal IgG4 antibody being developed for the 
treatment of mCRPC.  It consists of 2 heavy and 1 light chain(s) paired using 


Product:  AMG 340 (formerly TNB-585) 
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knob-in-hole technology.  Heavy chain 1 and the kappa light chain form the paratope 
that binds to human CD3.  Heavy chain 2 is comprised of a single VH domain that 
targets PSMA.  The nonclinical data supporting initiation of this FIH study of AMG 340 
are summarized herein; for further details see the IB. 
2.2.4.1.1 
In Vitro Pharmacodynamics 
AMG 340 mediated tumor killing and cytokine production by human T-cells in the 
presence of PSMA-positive and PSMA-negative cells was tested in vitro.  T-cells were 
co-cultured with multiple tumor cell lines including PC3 (± PSMA), LNCaP, 22Rv1, and 
MDA-Pca-2B and increasing concentrations of AMG 340, positive control (PC), or 
negative control (NC) antibody in vitro.  Tumor cell death and cytokine release (including 
IFNγ, IL-2, IL-6, IL-10, and TNFα) were assessed.  The data demonstrated that 
AMG 340-mediated tumor killing and cytokine production were dose- and antigen- 
dependent and demonstrated that AMG 340 mediated killing of PSMA-expressing tumor 
cells with reduced cytokine production compared to a positive control antibody that 
contains a high affinity anti-CD3 domain. 
The ability of AMG 340 to mediate PSMA-dependent activation of CD4 and CD8 T-cells 
was assessed in vitro.  T-cells were co-cultured with either PSMA-expressing (LNCaP) 
or PSMA-negative (DU145) tumor cells and increasing concentrations of AMG 340, PC, 
or NC antibody.  AMG 340 induced activation of both CD4 and CD8 T-cells comparable 
to the PC antibody, but with lower potency (higher EC50 value). 
Activation of the Treg subset within activated CD4 and CD8 T-cell subsets was 
assessed.  AMG 340 induced maximal activation of both CD4 and CD8 T-cells 
comparable to the PC.  Relative to the PC antibody, however, AMG 340 induced 
significantly less Treg activation across 3 healthy donors.  The ability of AMG 340 to 
induce equivalent T-cell activation compared to the PC antibody but with reduced Treg 
activation could bolster effector T-cell function and increase immune destruction of tumor 
targets. 
In addition to T-cell activation, the ability of AMG 340 to mediate PSMA-dependent 
proliferation of CD4 and CD8 T-cells was assessed in vitro.  T-cells were co-cultured 
with either PSMA-expressing (22Rv1) or PSMA-negative (DU145) tumor cells and 
increasing concentrations of AMG 340, PC, or NC antibody.  AMG 340 induced 
dose-and PSMA-dependent CD4 and CD8 T-cell proliferation comparable to the PC 
antibody but with lower potency (higher EC50 value). 


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Overall, the data demonstrated that AMG 340 mediated efficient T-cell activation and 
proliferation in an antigen- and dose-dependent manner. 
2.2.4.1.2 
Ex Vivo Pharmacodynamics 
The ability of AMG 340 to mediate tumor cell lysis of primary PSMA-positive tumor cells 
and the associated cytokine release was assessed.  Dissociated tumor cells from de-
identified prostate cancer patients were incubated with or without PBMC in the presence 
of AMG 340, PC or NC and assessed for tumor cell death.  Supernatants were collected 
and assessed for secreted cytokines.  AMG 340 mediated dose-dependent killing of 
PSMA-positive tumor cells in the presence or absence of externally added PBMC was 
comparable to the PC but with greatly reduced cytokine levels. 
CCI


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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2.2.4.1.4 
Determination of MABEL 
To determine the MABEL for AMG 340, data were compiled from multiple in vitro and in 
vivo studies (Table 2-1).  The most relevant and sensitive measure of pharmacologic 
activity was IL-6 release by human T-cells in the presence of AMG 340 and the 
PSMA-expressing prostate tumor cell line MDA-Pca-2B.  The EC50 for this assay was 
5.6 nM (0.622 µg/mL) and this EC50 was therefore determined to be the MABEL for 
AMG 340. 
Table 2-1.  Summary of Lowest In Vitro EC50 Values and In Vivo Activity 
In Vitro 
Readout 
EC50 (nM) 
Tumor Cell Killing 
6.5 
IFNγ Release 
19.6 
IL-2 Release 
7.8 
IL-6 Release 
5.6 
IL-10 Release 
22.9 
TNFα Release 
10.8 
T-Cell Proliferation 
20.4 
T-Cell Activation 
11.2 
In Vivo 
Readout 
Ctrough of MED (nM) 
Tumor Volume 
32.1 
EC50  half maximal effective concentration; IL  interleukin; TNFα  tumor necrosis factor alpha; 
IFNγ  interferon gamma; MED  minimum efficacious dose; Ctrough  trough concentration at steady state 
The table above lists the lowest EC50 values from multiple in vitro studies as well as the Ctrough (measured 
before the second dose) of the in vivo minimum effective dose (16.7 µg/mouse). 
2.2.4.1.5 
Pharmacokinetics 
2.2.4.1.6 
Toxicology 
No cross-reactivity to CD3 or PSMA from rodent species or non-human primates is 
observed.  Therefore, standard nonclinical toxicology studies to evaluate AMG 340 are 
not feasible.  Evaluation of the nonclinical safety profile of AMG 340 to support clinical 
studies in humans included in vitro (T-cell cytotoxicity, T-cell proliferation/activation, and 
cytokine release assays) and ex-vivo assays (T-cell cytotoxicity and cytokine release) as 
described in Sections 2.2.4.1.1 through 2.2.4.1.3.  Other nonclinical safety studies 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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conducted with AMG 340 in support of the IND included a single-dose non-GLP 
cynomolgus monkey PK and tolerability study of AMG 340 and a GLP tissue 
cross-reactivity study in a panel of normal human tissues. 
The potential for off-target or unanticipated toxicity with AMG 340 were evaluated in a 
non GLP single-dose cynomolgus monkey PK and tolerability study.  AMG 340 was 
administered as a single intravenous (IV) dose to male cynomolgus monkeys at nominal 
doses of 0, 0.1, 1 and 10 mg/kg.  Based on the human equivalent dose, the active 
treatment doses were up to 151-times higher than the anticipated clinical starting dose of 
 mg.  There were no test article-related changes noted in clinical observations 
(including appetite assessment), body weight, clinical pathology parameters (including 
IgG), immunophenotyping or cytokines.  The PK results confirmed exposure to AMG 340 
and are described in Section 2.2.4.1.5.  In conclusion, AMG 340 showed no evidence of 
toxicity following a single IV bolus dose of up to 10.39 mg/kg. 
The potential off-target cross-reactivity of AMG 340 was assessed using cryosections 
from a full panel of normal human tissues from at least 3 different donors.  Specific 
AMG 340 staining in the human tissue panel included cytoplasmic staining of epithelial 
cells in several tissues:  breast, small intestine, parotid salivary gland, fallopian tube, and 
prostate gland.  Cytoplasmic binding of anti-PSMA antibodies via immunohistochemistry 
has previously been described in all of these tissues (Trover et al, 1995; Wright et al, 
1995; Silver et al, 1997; Cunha et al, 2006; Kinoshita et al, 2006; Mhawech Fauceglia et 
al, 2007).  Monoclonal antibody binding to cytoplasmic sites are generally considered to 
be of little to no toxicologic significance (ICH S6 [R1]).  In conclusion, the observed 
binding to the cytoplasm of epithelial cells from various tissues is of little to no toxicologic 
significance and there was no unanticipated AMG 340 staining in human tissues. 
2.2.4.2 
Potential Risks/Toxicities from AMG 340 
As previously described, AMG 340 does not recognize CD3 or PSMA in animal species 
commonly used in toxicology studies, including rodent, dog, and monkey.  Because 
AMG 340 has no relevant animal species cross-reactivity and only binds to human 
targets, standard nonclinical toxicology animal studies to evaluate AMG 340 were not 
feasible. 
The potential toxicities of AMG 340 were carefully considered and are summarized 
below.  Results from the toxicology studies described in Section 2.2.4.1.6, as well as 
existing clinical and nonclinical safety profiles for similar therapies with the same targets 
(eg, anti-CD3 mAbs such as OKT3, and anti-CD3/PSMA bispecific antibodies), suggest 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
Page 32 of 160 
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these potential toxicities will be addressed by the use of a MABEL approach to 
determine the first-in-human (FIH) starting dose (Saber 2017).  In addition, monitoring 
and risk mitigation of known toxicities associated with previous bispecific CD3/PSMA 
therapies will be conducted. 
2.2.4.2.1 
Cross-linking CD3 with PSMA on Tumors and Potential T-cell 
Mediated Toxicities 
Pasotuxizumab is a PSMA-targeting bispecific T-cell engager or BiTE therapy being 
developed for metastatic castrate-resistant prostate cancer (mCRPC).  In a phase 1 
study in patients with mCRPC refractory to standard therapy (N = 16), pasotuxizumab 
was reported to have an acceptable safety profile with decreased lymphocytes and 
infections as the most common adverse events grade ≥ 3 (Hummel 2019). 
Results from a phase 1 trial of HPN424 (a tri-specific anti-PSMA T-cell activating 
therapeutic candidate) being developed for mCRPC, reported that in 7 patients one 
grade 3 CRS event was noted which resolved within 8 hours.  Three patients reported 
grade 2 rigors or fevers that were clinically manageable (Bendell et al, 2020).  Overall, 
HPN424 was considered well-tolerated with all 7 patients continuing on study and no 
dose-limiting toxicities (DLTs) observed. 
To reduce the risk of central nervous system (CNS) adverse events and CRS, 
AMG 340 is engineered to have reduced in vitro cytokine release (Section 2.2.4).  
Additionally, AMG 340 carries mutations in the Fc region that prevent Fc mediated 
effector function.  Importantly, the potential for antibody dependent cellular cytotoxicity 
mediated killing of T-cells has been eliminated thus preserving T-cell function and 
reducing toxicity towards T-cells.  The affinity of AMG 340 for PSMA is also at least 25-
fold stronger than for CD3, based on cell surface binding.  The potential risks of off-
tumor T-cell-mediated CNS toxicity and CRS are anticipated to be reduced. 
Additionally, the Schedule of Activities (Section 1.3) is designed to monitor and risk 
mitigate other known toxicities associated with previous bispecific CD3/PSMA therapies 
that include infections, tumor lysis syndrome, neutropenia, elevated liver enzymes, and 
leukoencephalopathy. 
2.2.4.2.2 
Targeting CD3 
Muromonab (OKT3), an anti-CD3 murine IgG2a monoclonal antibody (mAb) previously 
approved for the prevention of acute organ transplant rejection, is known to result in 
CRS due to the activation of T-cells following administration.  While it was marketed, 
OKT3 had a black box warning for CRS.  Upon administration, OKT3 initially activates 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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T-cells but then blocks CD3/T-cell function, which within minutes results in a rapid 
reduction of circulating T-cells (CD2, CD3, CD4, CD8).  Additional adverse effects of 
muromonab include neuropsychiatric events, neoplasias, infections, intravascular 
thrombosis, and hematopoietic changes.  Toxicities related to T-cell depletion or T-cell 
inhibition by OKT3, are anticipated to be reduced for AMG 340 based on its mechanism 
of action, preferential activity towards PSMA expressing tumor cells, and lack of Fc 
effector activity (silenced IgG4). 
2.2.4.2.3 
Targeting PSMA 
Investigational immunotherapy products targeting PSMA include mAbs, radiotherapies, 
CAR-Ts, and ADCs.  For anti-PSMA-targeted radiotherapies, hematotoxicity 
predominantly due to the radioactive warhead is the main reported adverse event in the 
clinic (Rahbar 2018).  Similarly, the observed adverse events in patients treated with 
CAR-Ts and ADCs appear to be related to the mechanism of action of the therapy and 
not a direct effect of targeting PSMA (eg, CRS in the case of CAR-T).  Two products 
(described above), pasotuxizumab and HPN424, are most similar to AMG 340 and to 
date have shown acceptable safety profiles.  The reported adverse events for these 
products (CRS, rigors, fevers, infections, decreased lymphocytes) will be monitored in 
the proposed clinical trial. 
2.2.4.2.4 
Unanticipated Toxicity 
The potential for unanticipated toxicity (eg, off target or potential impurities or 
contaminants) with AMG 340 was characterized in the non-GLP single-dose IV 
PK/tolerability study in cynomolgus monkeys (RPT.NC.0045).  AMG 340 was 
well-tolerated in this study and no unanticipated toxicity was observed. 
In addition, the potential for off-target or on-target, off-tumor binding was addressed in 
the GLP tissue cross-reactivity study (RPT.NC.0047) using a broad panel of tissues from 
multiple human donors.  Cytoplasmic binding in epithelial cells from various tissues was 
observed but is of little to no toxicologic significance. 
2.2.4.2.5 
Overall Nonclinical Safety Assessment 
In summary, AMG 340 binds to CD3 and PSMA, which are targets with safety profiles 
that are well-characterized in the literature.  In vitro pharmacology studies in human cells 
have well characterized AMG 340 (Section 2.2.4.1.1), and results demonstrate that 
AMG 340 has anti-tumor killing activity with reduced T-cell cytokine release.  Therefore, 
although a nonclinical model for toxicity testing could not be developed, the potential 
clinical toxicities associated with AMG 340 cross-linking CD3 on T-cells with PSMA on 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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tumor cells can be reasonably predicted and mitigated in the proposed clinical trial 
based on the existing literature, the non-GLP PK/tolerability study in cynomolgus 
monkeys, the GLP tissue cross reactivity study, and the pharmacology studies in human 
cells that characterize the in vitro activity of AMG 340. 
2.2.4.3 
Clinical Data 
The safety, tolerability, PK, and clinical activity of AMG 340 are currently being evaluated 
in this ongoing phase 1, open-label, dose-escalation and expansion study of AMG 340 in 
subjects with mCRPC.  As of the safety data cutoff date of 08 March 2022, a total of 
24 subjects were enrolled in the study; 1 subject did not receive investigational product.  
In cohort 5, a single grade 3 CRS event was observed that triggered the implementation 
of a priming dose per protocol Section 6.2.1.2. 
All 23 subjects who received at least 1 dose of investigational product had a treatment 
emergent adverse event (defined as events that occurred or worsened on or after the 
first dose of AMG 340 until 90 days after discontinuation of AMG 340 or until the subject 
started another anticancer therapy, whichever occurred earlier).  The most frequently 
reported adverse events ( 20% of subjects) were nausea (13 subjects, 56.5%), 
vomiting (12 subjects, 52.2%), CRS (9 subjects, 39.1%), diarrhea (8 subjects, 34.8%), 
hypocalcemia (8 subjects, 34.8%), hypomagnesemia (7 subjects, 30.4%), dysgeusia 
(6 subjects, 26.1%), and hypophosphatemia (5 subjects, 21.7%).  Eight subjects (34.8%) 
had at least 1 grade ≥ 3 adverse events.  Grade 3 adverse events include anemia 
(3 subjects, 13.0%), aspartate aminotransferase increased (2 subjects, 8.7%), and 
thrombocytopenia, alanine aminotransferase increased, neutrophil count decreased, 
cytokine release syndrome, brain abscess, failure to thrive, confusional state, 
hydronephrosis, and hypoxia (each 1 subject, 4.3%).  One subject (4.3%) had a grade 4 
adverse events of neutropenia and thrombocytopenia, and 1 subject (4.3%) had a fatal 
adverse event of hemorrhage (cerebral hemorrhage following a fall). 
One subject (4.3%) had an adverse event leading to discontinuation of AMG 340 
(grade 2 cerebrovascular accident).  Eight subjects (34.8%) had serious adverse events, 
including cytokine release syndrome (2 subjects, 8.7%), aspartate aminotransferase 
increased (2 subjects, 8.7%), and alanine aminotransferase increased, 
thrombocytopenia, brain abscess, failure to thrive, cerebrovascular accident, hematuria, 
and hemorrhage (cerebral hemorrhage following a fall) (each 1 subject, 4.3%).  One 
subject had DLT events of neutropenia and thrombocytopenia. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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As of 15 February 2022, preliminary PK data for AMG 340 were available for 20 subjects 
with progressive mCRPC in Study 20210249.  Briefly, within the evaluated target dose 
range (
to 
 mg Q3W), the serum AMG 340 exposures increased in an 
approximately dose-proportional manner with mean estimated terminal half-life (t1/2,z) 
ranging from 4.16 to 8.57 days after a single dose. 
Refer to the IB for additional information on AMG 340. 
2.2.5 
Non-Amgen Investigational Product Background:  Imaging Products 
In some countries/regions,
and 18F-Fluorodeoxyglucose (18F-FDG) are investigational products 
administered as part of positron emission tomography (PET)/computed tomography (CT) 
imaging assessments in this study.  PET/CT imaging will be performed only at a select 
subset of participating study centers. 
68Gallium and 18F-FDG are used for in vitro radiolabeling of specific carrier molecules 
which have been specifically developed and are used for diagnostic imaging with PET.  
and 18F-FDG PET/CT are investigational imaging modalities used with 
increased frequency in several clinical indications including staging of 
intermediate-to-high -risk prostate cancer patients or restaging in patients with 
biochemical recurrence, showing superiority to choline PET/CT due to their higher 
accuracy (Kurash et al, 2020).  A study by Fendler et al (2019) established high 
detection rates, positive predictive value, inter-reader reproducibility, and safety of 
PET for localization of biochemically recurrent prostate cancer in a 
prospective multicenter trial meeting the primary endpoint:
PET 
demonstrated 84% to 92% positive predictive value at 75% overall detection rate. 
Additional information will be included in the imaging manual. 
2.3 
Benefit/Risk Assessment 
AMG 340 is a T-cell redirecting immunotherapy that exhibits robust preclinical efficacy in 
models of advanced mCRPC.  The pharmacology, toxicology, and PK profiles of 
AMG 340 have been adequately characterized to support initiation of phase 1 FIH 
clinical trials in subjects with mCRPC at a starting dose of 
 mg Q3W.  Taken together, 
these data and high unmet medical need in the proposed patient population reflect an 
acceptable rationale and risk for treating adult subjects with advanced mCRPC with 
AMG 340 in the context of a clinical trial.  Refer to the IB for details. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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As a FIH phase 1 study, Study 20210249 (formerly TNB585.001) has inherent risks.  
Patient monitoring, both clinical and via laboratory studies, necessitates more visits to 
the hospital and more blood draws compared to treatment with approved therapies.  As 
there is limited information about the safety profile of AMG 340, unanticipated toxicities 
may occur.  T-cell engaging therapies can cause immune mediated side effects that may 
require hospitalization, and rarely, fatal outcomes have been reported.  In some 
circumstances these risks may even be amplified.  Specifically, the risks associated with 
increased monitoring have been heightened by the COVID-19 pandemic that began in 
2019. 
Both the AMG 340 molecule and Study 20210249 are designed to minimize risk to 
subjects.  Only subjects that are not candidates for treatment regimens known to provide 
clinical benefit in mCRPC are eligible to enroll.  These subjects have exhausted all 
proven therapies to treat their cancer, and therefore the risk of not receiving an 
experimental therapy for which they are eligible is high.  As described in Section 2.2.4, 
AMG 340 incorporates a unique anti-CD3 moiety selected for reduced cytokine 
secretion.  The molecule is therefore expected to show reduced CRS, the main toxicity 
observed with T-cell activating-therapies.  Without compromising the need for 
heightened subject monitoring in a clinical trial, the 20210249 Schedule of Activities was 
designed to minimize subject visits and inpatient stay. 
Taken together, the preclinical data and study design reflect an acceptable rationale and 
favorable risk-benefit ratio for treating adult subjects with advanced mCRPC with 
AMG 340 within the context of a clinical trial.  Refer to the IB for detailed data supporting 
AMG 340 development for the treatment of RR mCRPC.   
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the IB for further data on AMG 340. 
2.3.1 
Key Risks 
Based on the biological mechanism, non-clinical studies and clinical experience with 
AMG 340, CRS is designated as an adverse drug reaction (ADR).  The key safety risks 
for AMG 340 are summarized in Table 2-2. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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Table 2-2.  Key Safety Risk for AMG 340 
Safety Risk 
Description 
Identified Risk 
 
Cytokine release 
syndrome (CRS) 
Signs and symptoms may include (but not limited to) the 
following: 
 constitutional – fever, rigors, fatigue, malaise 
 neurologic – confusion, headache, mental status changes, 
dysphasia, tremors, dysmetria, gait abnormalities, seizure 
(refer to immune-effector cell associated neurologic 
syndrome [ICANS] guidance in Section 6.2.1.6.1.1) 
 respiratory – dyspnea, tachypnea, hypoxemia 
 cardiovascular – tachycardia, hypotension 
 gastrointestinal – nausea, vomiting, diarrhea  
 hepatic – transaminitis, hyperbilirubinemia 
 hematology – thrombocytopenia, bleeding, 
hypofibrinogenemia, elevated D-dimer 
 skin – rash 
Potential Safety Concerns 
Tumor lysis syndrome 
Signs and symptoms may include hyperkalemia, 
hyperphosphatemia, hyperuricemia, hyperuricosuria, and 
hypocalcemia, potentially causing lethal cardiac arrhythmias, 
seizures, and/or renal failure. 
Gastrointestinal toxicities 
Signs and symptoms may include nausea, vomiting, diarrhea, 
abdominal pain, gastrointestinal inflammation and ulceration; 
mostly associated with CRS. 
Neurological toxicities 
Signs and symptoms include confusional state, headache, 
dizziness, encephalopathy, tremor, aphasia, and syncope; mostly 
associated with CRS. 
Clinical signs and symptoms of CRS will be continually monitored throughout the 
duration of the study and at the time points indicated in Schedule of Activities 
(Section 1.3).  Refer to Table 6-6, and Sections 6.1.5, 6.2.1.6.1.1, and 11.10 for specific 
recommendations regarding the mitigation and management of the risk. 
Coronavirus disease 2019 (COVID-19) infection may theoretically increase the signs and 
symptoms of CRS.  Refer to Section 5.2 and section below for additional guidance 
related to COVID-19. 
The key safety risks are described further in the AMG 340 IB. 
COVID-19 Assessment 
Amgen closely monitors the COVID-19 pandemic around the world.  As part of this 
effort, Amgen performs a rigorous assessment, considering the study design, patient 
safety, public health risk, benefit-risk assessment, as well as the burden on country 
healthcare systems.  Decisions are made on a study-by-study and country-by-country 
basis to minimize risk to patients and avoid undue burden on healthcare facilities.   


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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Patients who display symptoms consistent with COVID-19 infections or who have tested 
positive for COVID-19 should contact the investigator to ensure appropriate care as well 
as documentation and management of study activities. 
Amgen considers that it is important to continue the proposed development of AMG 340 
in this study in order to advance potential therapy options for patients as rapidly as 
possible, while balancing this with appropriate measures to monitor and mitigate the 
potential impact of COVID-19. 
Subjects enrolled in this study are permitted to receive vaccinations for COVID-19.   
3. 
Objective(s) and Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability 
of AMG 340 when administered as 
monotherapy. 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs and clinical 
laboratory tests 
 
Determine the maximum tolerated 
dose (MTD) or recommended 
phase 2 dose (RP2D) for 
AMG 340 when administered as 
monotherapy. 
 
Dose-limiting toxicities (DLTs) 
 
Evaluate the pharmacokinetics 
(PK) of AMG 340 when 
administered as monotherapy. 
 
PK parameters of AMG 340 
including, but not limited to: 
 Cmax 
 Time to Cmax (Tmax) 
 Area under the 
concentration-time curve within 
a dosing interval (AUC0-t) 
Secondary 
 
Evaluate the clinical activity of 
AMG 340 when administered as 
monotherapy. 
 
Objective response (OR) per 
RECIST 1.1 
 
Overall survival (OS) 
 
Progression-free survival (PFS) 
(radiographic and PSA) 
 
6-month landmark radiographic 
PFS 
 
PSA response (30%, 50%, 70% 
and 90%) 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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 
Time to progression (radiographic 
and PSA) 
 
Duration of response (DOR) per 
RECIST 1.1 
 
PSA DOR based on PSA50 
 
Time to symptomatic skeletal 
events (SSE) 
 
 
Exploratory 
 
Evaluate immunogenicity of 
AMG 340 
 
Incidence of anti-AMG 340 
antibody formation 
 
 
4. 
Study Design 
4.1 
Overall Design 
This is a phase 1 open-label, dose-escalation and expansion study evaluating the safety, 
PK, PD, and clinical activity of AMG 340 in subjects with progressive mCRPC who have 
received at least 2 or more prior lines of systemic therapy (‘Line/regimen of therapy’ is 
defined as a course of therapy [at least 1 cycle uninterrupted by progressive disease, 
cycle disruption due to toxicity or intolerance is acceptable]).  To be eligible for 
enrollment in this study, subjects should have previously been exposed to, intolerant of, 
ineligible for, or declined therapy with both a novel anti-androgen (eg, abiraterone, 
enzalutamide) and a taxane (eg, docetaxel).  Approximately 100 subjects will be enrolled 
at sites in the US. 
The study will consist of 2 Parts:  a monotherapy dose escalation (Part A; Section 4.1.1) 
and a monotherapy dose expansion (Part B, Sections 4.1.2).  The overall study design is 
described by a study schema in Section 1.2.  The endpoints are defined in Section 3. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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Participants in this clinical investigation shall be referred to as “subjects”.  For the 
sample size justification, see Section 9.2. 
Study visits and evaluations will be performed at screening and at day 1 of each cycle.  
Based on a 3-week cycle, additional study visits and evaluations will be performed on 
days 2, 3, 8, and 15 during cycle 1, on day 15 only in cycles 2 and 3, and on days 2 and 
15 in cycle 6.  If a priming dose or multiple priming doses are implemented, additional 
visits and evaluations will occur during cycle 1. 
Evaluations will include physical examination, hematology, and chemistry tests prior to 
all study drug dosing, at the End of Treatment (EOT) visit (within 30 days after the last 
dose of study drug), and safety follow-up (SFU) visit.  PSA will be assessed at screening 
and on day 1 of every cycle.  Computed tomography (CT), bone scintigraphy, FDG-PET 
and PSMA-PET (in subjects that sign optional consent, in Part B) will be assessed at 
screening and then on day 1 of every third cycle.  Once reliable PK data are available for 
AMG 340, and if T1/2 exceeds 18 days, the 90-day post-last treatment visit may be 
performed at a time more remote from the last dose in order to capture PK data at T ≥ 
5 x T1/2.  Adverse events, serious adverse events, concomitant medications, laboratory 
data, and vital signs will be assessed throughout the study. 
Blood and tissue samples for evaluation of the PK and ADA (see Section 8.5 and 
Section 8.7, respectively) and PD (see Section 8.8) of AMG 340 will be collected at 
designated time points throughout the study. 
4.1.1 
Part A:  Monotherapy Dose Escalation 
Part A was initiated and employs a dose escalation design to evaluate the safety, 
tolerability, PK and PD profiles of single-agent AMG 340 administered Q3W.  Up to 
60 subjects with progressive mCRPC who have received at least 2 prior lines of therapy 
will be enrolled in Part A.  Subjects should have previously been exposed to, intolerant 
of, ineligible for, or declined therapy with both a novel anti-androgen (eg, abiraterone, 
enzalutamide) and a taxane (eg, docetaxel).  In Part A, cohorts have initially enrolled 
single subjects (Yuan et al, 2016).  Proposed dose levels for AMG 340 are outlined in 
 but the number of dose levels tested will depend on safety, PK/PD, and 
activity data. 
Upon the first occurrence of a grade ≥ 2 adverse event that is not unequivocally due to 
the subject’s underlying malignancy or other extraneous cause, the corresponding 
cohort, and all subsequent cohorts in Part A, will be enrolled according to a BOIN design 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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with the target toxicity rate of 30%.  Cohorts will enroll a minimum of 3 subjects; up to 
6 subjects may be enrolled concurrently (if transition from single subject cohorts to BOIN 
is triggered by a DLT, 6 subjects will be enrolled in that cohort).  A maximum of 
60 subjects will be enrolled in Part A.  No more than 2 subjects should be dosed on the 
same day when enrolling new cohorts.  Following the first assessment of BOIN dose 
escalation/de-escalation at a given dose level, additional subjects may be enrolled 
according to the BOIN criteria (Yuan et al, 2016). 
If a response (partial response [PR] or complete response [CR]) is observed in a single 
subject cohort, cohorts enrolling thereafter will follow a BOIN design as above.  The 
BOIN dose escalation and de-escalation boundaries (λe of 0.236 and a λd of 0.358) are 
shown in Table 4-1. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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Table 4-1.  Dose Escalation and De-escalation Boundaries 
 
Number of subjects treated at current dose cohort 
Actions 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Escalate if # of DLTs ≤ 
0 
0 
0 
0 
1 
1 
1 
1 
2 
2 
De-escalate if # of DLTs ≥ 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
DLT  dose limiting toxicity 
Source:  Yuan et al, 2016 
Dose escalation has been started as planned with a Q3W dosing schedule, which may 
be altered after cumulative review of safety and PK data and a protocol amendment.  
Administration of the first dose of AMG 340 to the first subject in each cohort must await 
completion of the first cycle (3 weeks) of the prior dose level, and a review of the safety 
data by the Dose Level Review Team (DLRT) (formerly referred to as the Safety 
Monitoring Group [SMG] – see Section 11.3).  Input from biostatistical, PK and other 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001)  
Date:  07 December 2022 
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experts will be sought as necessary.  Cohorts Na (where N represents a Cohort 
number), b, c, etc, may be conducted in parallel.  Not all dose level cohorts may be 
enrolled based on emerging safety data. 
Based on the DLRT’s ongoing review of emerging safety, PK/PD and clinical activity 
data, cohorts receiving intermediate doses between those proposed above may be 
implemented.  Furthermore, it may become necessary to switch to an alternative dosing 
regimen.  If the dosing schedule is switched, no dose modification should result in a 
predicted steady state Cmax or AUC greater than that identified for the immediately prior 
lower dose level. 
4.1.2 
Part B:  Monotherapy Dose Expansion 
Part B will evaluate the MTD (or RP2D) of AMG 340 monotherapy in up to 40 subjects 
with biopsy-proven progressive mCRPC.  To be eligible for this study, subjects should 
have previously been exposed to, intolerant of, ineligible for, or declined therapy with 
both a novel anti-androgen (eg, abiraterone, enzalutamide) and a taxane (eg, 
docetaxel).  Part B will be initiated once the MTD (or RP2D) has been selected based on 
data from the Part A.  The MTD (or RP2D) and dosing frequency for Part B will be 
chosen by the DLRT based on safety, tolerability, PK/PD, and clinical activity data 
collected during the dose escalation portion of the study. 
4.2 
Patient Input into the Study Design 
Patient input was not obtained pertaining to study design. 
4.3 
Justification for Dose 
4.3.1 
Justification for Investigational Product Dose 


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4.4 
End of Study 
An individual subject is considered to have completed the study if they have completed 
the last visit shown in the Schedule of Activities (Section 1.3).  The total study duration 
for an individual subject will vary as subjects may continue to receive AMG 340 as long 
as they do not meet any criteria for subject discontinuation (see Section 7.1). 
The end of study date is defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), including any additional parts in the study (eg, long-term follow-up, antibody 
testing), as applicable. 
5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 


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5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject must be ≥ 18 years of age at the time of signing informed consent. 
102 
Subject has a history of pathologically confirmed prostatic adenocarcinoma. 
103 
Subject has history of metastatic disease. 
104 
Subject is chemically or surgically castrate (testosterone ≤ 0.5 ng/mL or 
1.7 nmol/L).  Subjects must continue on an LHRH/GnRH agonist or antagonist 
while on study unless they are surgically castrate. 
105 
Subject has received at least 2 lines of systemic therapy approved for mCRPC, 
with disease progression on the most recent systemic therapy as defined in 
PCWG3.  Subjects should have previously been exposed to, intolerant of, 
ineligible for, or declined therapy with both a novel anti-androgen (eg, 
abiraterone, enzalutamide) and a taxane (eg, docetaxel). 
106 
Subject has an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of ≤ 2 (see Section 11.8). 
107 
Subject has provided informed consent/assent prior to initiation of any study 
specific activities/procedures. 
108 
Subject must have adequate bone marrow function, defined as:  absolute 
neutrophil count (ANC) ≥ 1500/mm3; platelets ≥ 100 000/mm3 (without platelet 
transfusion within 7 days from screening assessment); hemoglobin ≥ 9.0 g/dL 
(without blood transfusion within 7 days from screening assessment). 
109 
Subject must have an eGFR ≥ 50 mL/min as estimated by the MDRD formula.  
Note:  Per FDA draft guidance, ‘renal impairment is not likely to alter PK enough 
to justify dosage adjustment’ for protein therapeutics > 69 kDa, specifically 
including antibodies, such as AMG 340 (FDA 2020). 
110 
Subject must have total bilirubin ≤ 1.5 × upper limit of normal (ULN; except if the 
subject has a known diagnosis of Gilbert’s syndrome, in which case bilirubin 
must be < 3 × ULN).  Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) must be ≤ 3 × ULN (except if the subject has a known 
diagnosis of Gilbert’s syndrome or liver metastases, in which case AST/ALT must 
be < 5 × ULN). 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
201 
Subject has been diagnosed with or treated for another malignancy within the 
past 2 years whose natural history or treatment may interfere with the safety or 
efficacy assessment of the investigational regimen.  Subjects with a prior or 
concurrent malignancy whose natural history or treatment does not have the 
potential to interfere with the safety or efficacy assessment of the investigational 
regimen are eligible for this trial. 
Exception(s) to the above include:   
 
malignancy treated with curative intent and with no known active disease 
present for ≥ 2 years before enrollment and judged to be at low risk for 
reoccurrence by the treating physician  


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 
adequately treated non-melanoma skin cancer or lentigo malignancy without 
evidence of disease  
 
adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ  
202 
Pathological finding consistent with pure small cell, neuroendocrine carcinoma of 
the prostate or any other histology different from adenocarcinoma. 
203 
Subject has a history of CNS involvement by their mCRPC.  Metastases 
stemming from bone are allowed. 
204 
Subject has clinically significant CNS pathology.  Examples include spinal cord 
compression, epilepsy, stroke, severe brain injury, dementia, neurodegenerative 
disorder, or severe mental illness.  If the subject has a history of clinically 
significant spinal cord/nerve compression the subject must be neurologically 
stable for ≥ 21 days without steroid treatment prior to dosing with AMG 340 to be 
eligible. 
205 
Currently receiving treatment in another investigational device or drug study, 
within 5 x T1/2 (of that agent) or less than 28 days since ending treatment on 
another investigational device or drug study(ies), whichever is shorter.  Other 
investigational products/procedures while participating in this study are not 
permitted. 
206 
Subject requires chronic immunosuppressive therapy (including steroids > 10 mg 
prednisone/day or equivalent).  At the discretion of the Medical Monitor and the 
sponsor, subjects may be eligible if immunosuppressive therapy is discontinued 
14 days or 5 half-lives prior to the first dose of study treatment (whichever is 
shorter). 
207 
Subject has any medical or psychiatric condition which, in the opinion of the 
investigator or Medical Monitor, places the subject at an unacceptably high risk 
for toxicities, could interfere with successful or safe delivery of therapy, or could 
interfere with evaluation of the investigational product or interpretation of subject 
safety or study results.  Examples include history of significant mucosal/internal 
bleeding within 3 months prior to the first dose of study treatment, major 
psychiatric illness, drug abuse (including active alcoholism), active graft versus 
host disease, or known allergy or hypersensitivity to components of the study 
drug formulation. 
208 
Subject has received any therapy to treat cancer (including, chemotherapy, 
biologics, or cellular therapies) other than therapy to maintain chemical castration 
or undergone a major surgical procedure within 28 days, or within 5 half-lives of 
an anticancer drug, prior to the first dose of study treatment, whichever is shorter.  
Subject who has received radiation therapy within 4 weeks of first dose (or local 
or focal radiotherapy within 2 weeks of first dose with the exception of 
radiotherapy for palliative care, such as bone pain; this is only permitted after 
discussion with Amgen Medical Monitor) of study treatment (cycle 1 day 1). 
209 
Subject has known active infection requiring parenteral antibiotic treatment.  
Upon completion of parenteral antibiotics and resolution of symptoms, the 
subject may be considered eligible for the study from an infection standpoint. 
NOTE:  Simple urinary tract infections and uncomplicated bacterial pharyngitis 
are permitted if responding to active treatment and after consultation with 


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Medical Monitor.  Screening for chronic infectious conditions is not required 
unless otherwise noted as exclusion criteria. 
220 
Subject with symptoms and/or clinical signs and/or radiographic signs that 
indicate an acute and/or uncontrolled active systemic infection within 
10 days prior to the first dose of investigational product administration. 
210 
Major cardiac abnormalities, such as but not limited to the following:  uncontrolled 
angina or unstable life-threatening arrhythmias, history of myocardial infarction 
and/or symptomatic congestive heart failure (New York Heart Association  class 
II) within 12 months of first dose of AMG 340, severe cardiac insufficiency, or 
QTc prolongation > 470 msec (Fridericia). 
211 
Subject has unresolved adverse events ≥ grade 2 (National Cancer Institute 
[NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) from prior 
anticancer therapy except for: 
 
Alopecia. 
 
Vitiligo. 
 
Subjects with irreversible toxicity not reasonably expected to be exacerbated 
by any of the investigational products (eg, hearing loss) may be included after 
consultation with the Medical Monitor. 
212 
Positive/non-negative test for Human Immunodeficiency Virus (HIV) 
213 
Hepatitis infection based on the following results and/or criteria: 
 
Positive for hepatitis B surface antigen (HbsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B). 
 
Negative HbsAg and positive for hepatitis B core antibody:  
hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary.  
Detectable hepatitis B virus DNA suggests occult hepatitis B. 
 
Positive Hepatitis C virus antibody (HCVAb):  hepatitis C virus RNA by PCR 
is necessary.  Detectable hepatitis C virus RNA suggests chronic hepatitis C. 
215 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use 
contraception during treatment and for an additional 6 months after the last dose 
of investigational product.  Refer to Section 11.5 for additional contraceptive 
information. 
216 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional 6 months after the last dose 
of investigational product. 
217 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 6 months after the last dose of investigational product. 
218 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
219 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge. 


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5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
Each subject who enters into the screening period for the study (as the point when the 
subject signs the ICF) receives a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned manually.  This number will be used to identify the subject throughout the 
clinical study and must be used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria, and the subject receives the first dose of study drug.  The 
investigator is to document this decision and date, in the subject’s medical record and 
in/on the Subject Enrollment case report form (CRF). 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened.  Refer to Section 8.1.1. 
6. 
Study Intervention 
Study intervention is defined as any investigational product(s), non-investigational 
product(s), placebo, combination product(s), or medical device(s) intended to be 
administered to a study subject according to the study protocol. 


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Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
A summary of the dosing and administration of each treatment is shown in Table 6-1 
below. 
6.1 
Study Interventions Administered 
6.1.1 
Investigational Products 


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Table 6-1.  Investigational Products 
Study Treatment Name 
Amgen Investigational Product:a 
AMG 340 
Dosage Formulation 
The AMG 340 drug product (active) will be provided as a solution in vials, formulated at 5 mg/mL with 20 mL of 
extractable volume of drug product per vial. 
Unit Dose Strength(s)/ 
5 mg/mL 
Dosage Level(s) 
See 
 for proposed doses 
Route of Administration 
IV QW3 
Accountability 
The total volume of preparation, amount of investigational product used in preparation, total volume (mL) 
administered, start date/time, stop date/time, and lot number are to be recorded on each subject’s CRF(s). 
Dosing Instructions 
AMG 340 will initially be administered as an IV infusion Q3W, where 1 cycle of treatment will be 21 days.  The 
starting dose of AMG 340 will be 
 mg administered as an IV infusion (Q3W) in Part A and escalate to a projected 
maximum of 
 mg in subsequent cohorts 
  In Part B, all subjects will receive AMG 340 at the MTD 
and/or RP2D.  The dose(s) selected for evaluation in Part B may be a dose at or below the MTD defined in Part A or 
the RP2D (see Section 6.2.1.1).  Dosing frequency for Part B will be chosen by the sponsor based on safety, 
tolerability, PK/PD, and clinical activity data collected from Part A, in consultation with the study investigators. 
The first AMG 340 infusion will be given over 2 hours (± 10 minutes).  If no infusion reactions occur during the first 
dose of AMG 340, the duration of infusion for subsequent doses of AMG 340 may be shortened to 1 hour thereafter.  
Subjects will be admitted for 48 hours after the first infusion on cycle 1 day 1 and, if implemented, after a second 
priming dose on cycle 1 day 5.  If priming doses are implemented, subjects will also be admitted for 48 hours on 
cycle 1 day 8 (note that a second priming dose may be implemented based on emerging data).  Subjects will be 
closely monitored for 2 hours after each infusion in all other cycles. 
Dosage Preparation 
Study drug will be prepared in a single dilution step, with dose dependent volumes of AMG 340 transferred from 
drug product vial directly into a suitable IV bag.  The diluent is saline with IVSS added prior to the addition of active 
AMG 340 drug product.   
For all cohorts, total storage time (including infusion time) of the IV bag containing the
 
 to minimize 
degradation of the drug product and the risk of microbiological contamination.  The storage time may be updated as 
additional sterility/stability data become available. 
The total volume administered at each dose will be 250 to 500 mL.  Infusion rates will be controlled with infusion 
pumps and their respective DEHP-free infusion sets containing inline filters. 
AMG 340 drug product vials are stored at 5 ± 3ºC.  The IVSS vial is stored at ambient temperature. 
 
BID = twice daily; CRF  case report form; DEHP  Di(2-ethylhexyl) phthalate; IM = intramuscular; IV = intravenous; IVSS  Universal IV solution Stabilizer; 
MTD   maximum tolerated dose; NA = nonapplicable, PD  pharmacodynamic; PK  pharmacokinetic; SC = subcutaneous; RP2D  recommended phase 2 dose; 
QD = once daily; Q3W = every 3 weeks  
a AMG 340 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures.


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6.1.2 
Non-Amgen Investigational Imaging Products 
18F-FDG (in some countries/regions when used for prostate cancer) and
(in countries where it is approved as a diagnostic agent) are non-Amgen investigational 
products administered as part of PET/CT imaging assessments in this study. 
6.1.3 
Non-investigational Products 
Not applicable for this study. 
6.1.4 
Medical Devices 
There are no investigational medical devices in this study.  Other non-investigational 
medical devices may be used in the conduct of this study as part of standard care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
6.1.5 
Other Protocol-required Therapies 
All other protocol-required therapies including, dexamethasone, diphenhydramine, 
acetaminophen, ranitidine, tocilizumab (or siltuximab if tocilizumab is not available), that 
are commercially available are not provided or reimbursed by Amgen (except if required 
by local regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
Subjects will be premedicated twice with dexamethasone.  Subjects will be 
premedicated with dexamethasone (10 mg PO or IV) or equivalent 12 to 16 hours prior 
to AMG 340 administration, and then again with dexamethasone 10 mg IV or equivalent 
within 1 hour or AMG 340 administration.  If a subject does not experience an 
infusion-related reaction (IRR) or an immune-mediated toxicity (IMT; eg, CRS or NT) in a 
given cycle, the dexamethasone premedication dose may be reduced to 5 mg IV.  If a 
subject does not experience an IRR or IMT in a cycle where they received 5 mg 
dexamethasone IV as premedication, dexamethasone may subsequently be omitted 
from the premedication regimen.  If a subject experiences an IRR or IMT at any time, or 
if the subject undergoes an intra-subject dose escalation, they should be premedicated 
with 10 mg dexamethasone with the next dose of AMG 340 and tapered as described 
above. 
Subjects will also routinely be premedicated with diphenhydramine (25 to 50 mg IV) or 
equivalent (eg, cetirizine 10 mg orally [PO] x 1), acetaminophen 650 to 1000 mg PO, 


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and ranitidine 150 mg PO/IV or equivalent, 15 to 60 minutes prior to AMG 340 infusion to 
reduce the risk and severity of hypersensitivity reactions commonly observed with mAb 
therapy.  Subjects may also be premedicated with tocilizumab (8 mg/kg IV) at the 
discretion of the investigator and after approval by the Medical Monitors. 
Sites are required to have tocilizumab or siltuximab (if tocilizumab is not available) on 
site for potential treatment of CRS.  For administration of dexamethasone or tocilizumab 
after occurrence of CRS, follow guidance in Table 6-6.  Tocilizumab should be 
administered according to local prescribing information.  If tocilizumab is not available, 
siltuximab (an anti-IL-6 monoclonal antibody) may be used in the management of 
cytokine release syndrome, following the criteria outlined in Table 6-6.  The 
recommended dose of siltuximab is 11 mg/kg administered over 1 hour as an 
intravenous infusion, consistent with the prescribing information for the treatment of 
multicentric Castleman’s disease (Sylvant Prescribing Information), and the CARTOX 
Working Group Guidelines for CRS management (Neelapu, 2018).  Siltuximab may be 
repeated if needed, in the event that CRS recurs after a subsequent infusion of 
AMG 340.  Siltuximab may not be repeated in an individual subject that develops 
anaphylaxis to siltuximab, or gastrointestinal perforation after siltuximab. 
6.1.6 
Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers, delivery systems, labeling, and inserts. 
This includes any investigational/non-investigational product(s) or combination 
product(s) provisioned and/or repackaged/modified by Amgen: 
 
AMG 340 
Any product complaint(s) associated with an investigational product(s), 
non-investigational products(s), or combination product(s) supplied by Amgen are to be 
reported. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments and/or procedures are excluded during the treatment period of 
the study: 


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 
any anticancer agents other than AMG 340, such as: 
 
chemotherapy, biologics, cellular, or hormonal therapies (other than therapy to 
maintain chemical castration)  
 
anticancer medicinal/herbal remedies  
 
radiation therapy (within 4 weeks of first dose, or local, or focal radiotherapy 
within 2 weeks of first dose with the exception of radiotherapy for palliative care, 
such as bone pain; this is only permitted after discussion with Amgen Medical 
Monitor)  
 
immunosuppressive therapy (except if discontinued 14 days or 5 half-lives, 
whichever is shorter, prior to the first dose of study treatment at the discretion of 
Medical Monitor and Sponsor) 
 
any other investigational agent with the exception of
and 18F-FDG (refer 
to Section 6.7.2.1 for exclusionary vaccine considerations) 
 
plasmapheresis should not be performed while a subject is participating in 
Study 20210249 
 
intravenous immune globulin should not be given to a subject within 48 hours (before 
or after) of AMG 340 administration 
 
live and live-attenuated vaccines are prohibited within 28 days prior to the first dose 
of investigational product and during treatment with investigational product 
 
live viral non-replicating vaccine (eg, Jynneos) for Monkeypox infection 
is allowed during the study in accordance with local standard of care 
and institutional guidelines 
 
any major surgical procedures (upon consultation with Medical Monitor)  
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
6.2.1.1 
Dose Escalation and Selection of the MTD/RP2D Dose 
DLT criteria (see Section 6.2.1.4.1) will be used to make decisions regarding dose 
escalation.  Dose escalation decisions will be based on clinically significant toxicity, DLT 
events and clinical pharmacology findings, and will be made by the DLRT.  A simple 
majority of the DLRT is required to proceed with dose escalation; for quorum 
requirements, see Section 11.3. 
Dose escalation will be based on the BOIN escalation/de-escalation criteria described 
above (and as illustrated in Yuan et al, 2016; Figure 1-2), with a target toxicity rate of 
30% (λe of 0.236 and a λd of 0.358).  The MTD will be identified via isotonic regression of 
pooled escalation cohort data (Table 4-1), according to the BOIN method (Yuan et al, 
2016).  An expansion dose (eg, RP2D) may be selected by the DLRT prior to the 
identification of the MTD based on an assessment of available safety, PK/PD, and 
activity data; in this case the DLRT will also decide whether dose escalation in Part A 
should continue in parallel.  Additional priming doses and intermediate dose levels may 


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be investigated based on emerging safety, PK, PD, and efficacy data to identify the 
minimum safe and biologically effective dose (MSBED) 
 
When the DLRT completes their safety review of cycle 1 for a Cohort N (where N 
represents a Cohort number), and if that dose is deemed safe (eg, the DLRT endorses 
further dose escalation or the dose for Cohort N is determined to be the RP2D), any 
subjects that remain on study at a lower dose of AMG 340 may subsequently be treated 
at the dose assigned to Cohort N (eg, when the DLRT review for Cohort 5 is complete 
and the decision to escalate to Cohort 6 has been made, any subjects still on study from 
Cohorts 1 to 4 may have their dose increased to the dose corresponding to Cohort 5).  
Subject eligibility for such an escalation must be approved by the Medical Monitor(s) and 
treating investigator and will be determined on a case-by-case basis.  At a minimum, to 
be eligible subjects must have previously received at least 2 cycles of AMG 340 at their 
current dose without any drug related toxicities that led to a dose reduction. 
6.2.1.2 
Dose Priming 
Based on the nonclinical pharmacology of AMG 340, a lower rate of CRS is anticipated 
than with other T-cell-engaging bispecifics; however, based on the mechanism of action 
of AMG 340, the most likely DLT to occur is still CRS ≥ grade 3.  Cytokine release 
syndrome will be managed per Principal Investigator discretion and institutional 
guidelines (a guide for management of CRS is provided in Table 6-6 if institutional 
guidelines have not been established).  Definitions for adverse events, serious adverse 
events, and DLTs are provided in Section 8.4.6.1.1, 8.4.6.1.2, and  6.2.1.4.1, 
respectively. 
If a grade ≥ 3 CRS event occurs in Cohort N (where N represents a Cohort number) 
during the DLT period, or at the discretion of the DLRT, a dose equal to or less than the 
dose for Cohort N will be designated as the ‘Priming Dose’ and dose administration in 
subsequent cohorts (Cohorts N+1 and on) may be modified as follows: 
 
On Cycle 1 Day 1, subjects will receive the Priming Dose. 
 
On Cycle 1 Day 8, subjects will receive the full dose corresponding to the cohort in 
which they have been enrolled. 
Note:  a second priming dose may be introduced based on emerging data. 
If a subject experiences CRS grade ≥ 2, or any other grade ≥ 2 toxicity after receiving a 
priming dose that is not unequivocally due to the subject’s underlying malignancy or 
other extraneous cause, administration of the full dose on cycle 1 day 8 must await 
approval by the Amgen Medical Monitor(s).  At a minimum, CRS must have resolved to 


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grade ≤ 1 before the next is administered.  The dose and timing of the full dose for such 
a subject may be modified at the discretion of the Amgen Medical Monitor and the 
Investigator; if the subject has their full dose reduced in cycle 1, the subject will be 
considered DLT-unevaluable and should be replaced.  In subsequent cycles, subjects 
will receive the full dose on day 1. 
Following implementation of a priming dose, if administration of the full dose is delayed 
in cycle 1, the DLT period for that subject should be extended to the same degree (eg, if 
the full dose is delayed by 4 days, the DLT period will also be extended 4 days).  For 
clarity, treatment-emergent adverse events meeting criteria for a DLT will be treated as a 
DLT whether they occur after administration of the priming or the full dose. 
6.2.1.3 
Dose Cohort Stopping Rules 
6.2.1.3.1 
Safety 
In Part A, the occurrence of DLTs will drive identification of the MTD and/or RP2D in line 
with standard practices in an FIH phase 1 study, as outlined in Figure 1-2.  If in 
aggregate > 33% of subjects in Part A experience an unacceptable toxicity, including 
those that occur outside the DLT window, accrual will be suspended.  Enrollment may be 
re-initiated following a review of all available data by the DLRT and consultation with 
FDA. 
In Part B, accrual to a part will be suspended if > 33% of subjects (ie, > 10 of the 
planned 40 subjects in Part B) to be enrolled in that part experience unacceptable 
toxicity.  The final decision on suspension of enrollment will be made by the DLRT 
following review of all available data when the stopping rule threshold is exceeded. 
6.2.1.4 
Toxicity Management 
For the purpose of medical management, all adverse events and laboratory 
abnormalities that occur during the study must be evaluated by the investigator.  The 
table of clinical toxicity grades from the NCI-CTCAE, Version 5.0 (available on CTEP 
home page:  http://ctep.info.nih.gov) is to be used in the grading of adverse events and 
laboratory abnormalities that are reported as adverse events, each of which will be 
followed to satisfactory clinical resolution, except for CRS and NT which will be graded 
according to Lee et al (2019).  AMG 340 has not been tested clinically in humans, so the 
adverse event profile in humans is not known. 
Adverse events should be classified as pre-existing or as treatment-emergent adverse 
events: 


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 
A treatment-emergent adverse event is defined as an adverse event not present 
prior to initiation of AMG 340 treatment, or an adverse event present prior to 
AMG 340 initiation that worsens in intensity and/or frequency after initiation of 
AMG 340 treatment. 
 
A pre-existing adverse event is an adverse event that does not meet these criteria.  
Subjects with pre-existing adverse events should be assessed for any underlying 
illness or other causes and treated as appropriate. 
Subjects with treatment-emergent adverse events should also be assessed for 
intercurrent illness or other causes and treated as appropriate.  If a treatment-emergent 
adverse event is unequivocally due to a subject’s underlying malignancy or other 
extraneous cause, dosing with AMG 340 may be modified at the discretion of the 
Principal Investigator, following discussion with the Medical Monitors.  If a 
treatment-emergent adverse event is not unequivocally due to the subject’s underlying 
malignancy or other extraneous cause, regardless of whether there is a ‘reasonable 
possibility’ that the treatment-emergent adverse event is AMG 340-related, the dose of 
AMG 340 should be modified as follows: 
 
For subjects who have completed cycle 1 and have at least clinically or 
radiographically stable disease (SD, MR, PR or CR) but have experienced a 
reversible treatment-emergent adverse event, the dose of study drug can be delayed 
for up to 14 days after the scheduled dosing date.  A subject for whom dosing is 
delayed > 14 days should be discontinued from the study. 
 
During any cycle, if a subject develops an ANC < 500/μL, platelets < 10,000/μL, or a 
hemoglobin < 6.5 g/dL, blood samples must be collected every 3 days and study 
treatment withheld.  Treatment may resume when ANC returns to ≥ 1,000/μL, 
platelet counts return to ≥ 50,000/μL or baseline platelet count levels (in subjects 
with baseline platelets < 50,000/μL), or hemoglobin returns to ≥ 8.0 g/dL. 
 
AMG 340 should be discontinued in any subject who experiences CRS, TLS, or a 
non-hematologic treatment-emergent adverse event that meets DLT equivalent 
criteria until resolution of the toxicity to ≤ grade 1 or baseline; thereafter study drug 
may be resumed with one dose level reduction with Medical Monitor approval. 
Up to 2 dose reductions are allowed to manage toxicity; thereafter toxicity will be 
deemed ‘unacceptable’ and the subject will be discontinued from therapy.  Assessment 
schedules and cycles are fixed and should continue regardless of whether a dose is 
held. 
While investigator discretion should be used for subject management with regards to 
toxicities, guidelines for management of CRS and NT are provided in Table 6-6 and 
Table 6-5. 


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6.2.1.4.1 
Dose Limiting Toxicity Definition for Dose Escalation 
The DLT observation period for dose escalation purposes is 21 days and covers the first 
complete treatment cycle of AMG 340 (1 dose of AMG 340; or up to 3 doses if priming 
has been implemented).  Regular teleconferences will be conducted among the DLRT to 
examine/confirm potential DLTs, assess adverse events, and evaluate laboratory 
abnormalities.  Events occurring outside the DLT window may be evaluated during these 
calls when making dose escalation decisions.  A DLT is defined as a treatment emergent 
adverse event that is not unequivocally due to the subject’s underlying malignancy or 
other extraneous cause and meets the criteria below. 
The NCI-CTCAE version 5.0 will be used.  DLT definitions are provided below. 
6.2.1.4.1.1 
Non-hematologic Dose-limiting Toxicity 
 
Non-hematological adverse events grade ≥ 3 with the following exceptions: 
 
Grade 3 or 4 isolated electrolyte abnormalities (ie, those occurring without clinical 
consequence) that resolve, with or without intervention, to grade ≤ 1 within 
72 hours. 
 
Grade 3 hyperglycemia responsive to optimal medical management within 
72 hours. 
 
Grade 3 nausea/vomiting/diarrhea responsive to optimal medical management 
within 72 hours. 
 
Alopecia or vitiligo of any grade. 
 
Grade 3 fatigue lasting < 10 days. 
 
Grade 3 fever (defined as a temperature ≥ 40°C with a duration of ≤ 24 hours 
occurring outside the context of CRS 
 
Laboratory parameters of grade 3, not considered clinically relevant, and 
improved to grade (less than or equal to) 2 within 72 hours, will not be 
considered DLTs.  Laboratory parameters with long half-lives, (ie, ALT, GGT, 
ALP, and lipase), will likewise not be considered DLTs if they are not considered 
clinically relevant, and improve to grade  2 within 7 days. 
 
Adverse events that require a delay in initiation of the next scheduled cycle by 
> 14 days. 
6.2.1.4.1.2 
Hematologic Dose-limiting Toxicity 
 
Grade 3 CRS that does not resolve to ≤ grade 1 within 72 hours or grade 4 CRS. 
 
Grade 3 TLS that does not resolve to ≤ grade 1 within 72 hours or grade 4 TLS. 
 
Grade 4 neutropenia for > 5 days or febrile neutropenia. 
 
Grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia. 
 
Grade 4 anemia. 
 
Grade 5 adverse events. 
 
Lymphopenia will not be considered a DLT. 


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 
Adverse events that require a delay in initiation of the next scheduled cycle by 
> 14 days. 
6.2.1.5 
Echocardiogram/Multigated Acquisition 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.  
Additional ECHO/MUGA assessments may be performed as clinically indicated. 
6.2.1.6 
Specific Guidance for Cytokine Release Syndrome 
Refer to Appendix 10 (Section 11.10) for CRS definitions.   
The symptoms associated with the CRS event do not meet the definition of an adverse 
event as defined in Section 11.4.  Therefore, the CRS associated event (ie, CRS, 
cytokine storm) should be documented on the Event CRF as the diagnosis.  However, 
since it is important to document all symptoms related to a CRS event, a CRS 
Symptoms eCRF will also be available to record the symptoms associated with each 
CRS event.  If the severity of a CRS event changes from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the Event CRF 
and fill out an associated CRS Symptoms eCRF.  If the symptoms worsen enough to 
impact the overall CRS grade, it is important to remember to record a new CRS event on 
the Event eCRF with the appropriate grade.  Temperature may normalize within a few 
hours of treatment, whereas the other components of CRS take longer to resolve.  Once 
treatments are used to manage the fever, the subject is considered to still have CRS, 
even in the absence of fever, until all signs and symptoms leading to the diagnosis of 
CRS have resolved.  Likewise, CRS can be downgraded in an afebrile subject treated 
with anti-cytokine therapy as their hemodynamic status and/or hypoxia improves.  
Typically, a subject with severe CRS whose fever, oxygen, and pressor requirements 
have resolved may be assumed to have resolved CRS unless there are alternative 
causes for the fever, hypoxia, and/or hypotension. 
Table 6-2.  CRS Grading (ASTCT; Lee et al, 2019) 
CRS 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature 
 38°C 
Temperature 
 38°C 
Temperature  38°C 
Temperature  38°C 


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With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a single 
vasopressor (not 
including vasopressin) 
Requiring multiple 
vasopressors (not 
including vasopressin) 
 
 
And/orb 
Hypoxia 
None 
Requiring 
low-flow oxygen 
( 6 L/minute) 
nasal cannula or 
blow-by 
Requiring high-flow nasal 
cannula ( 6 L/min), 
facemask, 
non-rebreather mask, or 
Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bilevel positive airway 
pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence 
CRS grading. 
a Fever is defined as temperature  38°C not attributable to any other cause.  In subjects who have CRS 
then receive antipyretic or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required 
to grade subsequent CRS severity.  In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event:  hypotension or hypoxia not attributable to any other 
cause.  For example, a subject with temperature of 39.5°C, hypotension requiring 1 vasopressor, and 
hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. 
6.2.1.6.1.1 
Neurological Dose-limiting Toxicity 
The etiology of NT is unclear but has been postulated to stem from endothelial 
activation/microangiopathy, possibly downstream of IL-1 secretion by 
monocytes/macrophages (Gust et al, 2017; Giavidris et al, 2018; Norelli et al, 2018).  
Onset usually occurs with or after CRS (mostly CRS grade ≥ 3).  Isolated NT has been 
described after administration of anti-PSMA T-BsAbs (Velasquez et al, 2017).  Early 
symptoms of NT include tremor, dysgraphia, expressive aphasia, impaired attention, and 
lethargy; delirium, headache, agitation, cerebral edema, ataxia, confusion, seizure, and 
coma may subsequently develop. 
If NT symptoms are suspected, grading should be performed to guide appropriate 
management; a consensus grading scheme published by Lee and colleagues is 
reproduced here and may be used to grade NT (Table 6-3; Lee et al, 2019). 
Table 6-3.  American Society for Transplantation and Cellular Therapy Immune 
Effector Cell-associated Neurotoxicity Syndrome Consensus Grading for Adults 
(Lee et al, 2019) 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7–9 
3–6 
0–2 
0 (subject is unarousable 
and unable to perform 
ICE) 


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Depressed 
level of 
consciousnessb 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to 
tactile stimulus 
Subject is unarousable 
or requires vigorous or 
repetitive tactile stimuli to 
arouse.  Stupor or coma. 
Seizure 
NA 
NA 
Any clinical seizure 
focal or generalized 
that resolves rapidly 
or nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening 
prolonged seizure (> 5 
min); or repetitive clinical 
or electrical seizures 
without return to baseline 
in between 
Motor findingsc 
NA 
NA 
NA 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
ICP/cerebral 
edema 
NA 
NA 
Focal/local edema 
on neuroimagingd 
Diffuse cerebral edema 
on neuroimaging; 
decerebrate or 
decorticate posturing; or 
cranial nerve 6th palsy; or 
papilledema; or 
Cushing’s triad 
EEG = electroencephalogram; ICANS = immune effector cell-associated neurotoxicity syndrome; 
ICE = immune effector cell-associated encephalopathy; ICP = intracranial pressure; NA = not applicable. 
Note:   ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, 
motor findings, raised ICP/cerebral edema) not attributable to any other cause; for example, a subject with 
an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS. 
a A subject with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a 
subject with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
c Tremors and myoclonus associated with immune effector cell therapies may be graded according to 
CTCAE v5.0, but they do not influence ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is 
excluded from ICANS grading.  It may be graded according to CTCAE v5.0. 
Source:  Lee et al, 2019 
Neurological adverse events in subjects receiving AMG 340 mandate frequent 
CAR-T-cell therapy associated toxicity (CARTOX-10) or immune effector cell 
encephalopathy (ICE) examinations (Table 6-4) and neurological exams.  Early 
neurology consultation, use of anti-epileptics, and intensive care unit/airway support as 
needed are encouraged.  Table 6-5 provides a guideline for treatment that may be used 
for subject management, however, it is recommended that investigators adhere to 
institutional guidelines for NT management, if they exist. 


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Table 6-4.  Encephalopathy Assessment Tools for Grading of Immune Effector 
Cell-associated Neurotoxicity Syndrome (Lee et al, 2019) 
CARTOX-10 
ICE 
 Orientation:  orientation to year, month, 
city, hospital, president/prime minister of 
country of residence:  5 points 
 Orientation:  orientation to year, month, city, 
hospital:  4 points  
 Naming:  ability to name 3 objects (eg, point 
to clock, pen, button):  3 points 
 Naming:  ability to name 3 objects (eg, 
point to clock, pen, button):  3 points 
 Following commands:  ability to follow simply 
commands (eg, “Show me 2 fingers” or 
“Close your eyes and stick out your tongue”):  
1 point 
 Writing:  ability to write a standard 
sentence (eg, Our national bird is the 
bald eagle”):  1 point 
 Writing:  ability to write a standard sentence 
(eg, Our national bird is the bald eagle”):  
1 point 
 Attention:  ability to count backwards 
from 100 by 10:  1 point 
 Attention:  ability to count backwards from 
100 by 10:  1 point 
CARTOX-10 = chimeric antigen receptor toxicity; ICE = immune effector cell encephalopathy. 
Note:  CARTOX-10 (left column) has been updated to the ICE tool (right column).  ICE adds a command 
following assessment in place of 1 of the CARTOX-10 orientation questions.  The scoring system remains 
the same. 
Note:  Scoring:  10, no impairment; 7-9, grade 1 ICANS; 3-6, grade 2 ICANS; 0-2, grade 3 ICANS; 0 due to 
subject unarousable and unable to perform ICE assessment, grade 4 ICANS. 
Source:  Lee et al, 2019 
Table 6-5.  Suggested Guidelines for Management of Neurological Toxicity 
Adverse Event 
Category 
Guidelines 
Neurologic adverse 
event after dosing 
with AMG 340 
 Consult neurologist 
 Continue neurologic monitoring 
 Prophylactic anti-epileptic (ie, levetiracetam) 
 Consider MRI/CT, EEG, and/or LP 
 Contact Medical Monitor 
If adverse event is 
grade ≥ 2, add 
 Consider Corticosteroids (eg, dexamethasone 10 to 20 mg IV every 
12 to 24 hours, higher doses or with more frequency, if clinically 
indicated) 
 Withhold AMG 340 until resolution to grade ≤ 1. 
If adverse event is 
grade ≥ 3, add 
 High-dose corticosteroids (methylprednisolone 2 mg/kg loading 
dose followed by 2 mg/kg/day divided 4 times per day).  
Higher /more frequent doses if indicated.  Taper when grade 1 or 
better) 
 Anti-epileptics for seizures/seizure-like activity 
 ICU monitoring  
 Airway protection 
 Consider continuous EEG monitoring 
If adverse event is 
grade 4, add 
 If cerebral edema/other grade 4 toxicity is rapid onset or the 
subjects is unresponsive to above:  methylprednisolone IV 
1 g/day x 3 days, followed if clinically indicated by taper. 
 Consider hyperventilation / hyperosmolar therapy for cerebral 
edema. 
CT = computed tomography; EEG = electroencephalogram; ICU = intensive care unit; IV = intravenous; 
LP = lumbar puncture; MRI = magnetic resonance imaging 


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6.2.1.6.1.2 
Miscellaneous Dose-limiting Toxicity 
Any toxicity thought to be related to the study drug that, at the discretion of the 
investigator, is thought to warrant withholding the drug.  Other adverse events may be 
considered a DLT as determined by the Medical Monitor, in conjunction with the 
investigator. 
All decisions regarding continued dosing for individual subjects will be medically 
managed by the investigator, in conjunction with the Medical Monitor(s), as appropriate.  
These decisions will be driven by the DLT criteria as described above. 
Any subject who does not complete the full 21-day DLT observation period for any 
reason other than DLT will be considered non-DLT-evaluable for dose escalation and/or 
MTD assessment and will be replaced at the same dose level.  Additional subjects may 
be enrolled at a given dose level in the absence of DLT to explore factors influencing 
adverse events or to accumulate additional safety data. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  AMG 340 
The reason for dose change of AMG 340 is to be recorded on each subject’s CRF(s). 
Subjects experiencing CRS must continue to be hospitalized as described in Table 6-6 
and as deemed appropriate by the investigator.  Subjects should be monitored for CRS 
symptoms, including vital signs and pulse oximetry at least every 2 hours for 12 hours, 
or until CRS grade ≤ 1, whichever is earlier. 
Re-starting treatment after an interruption/delay due to an adverse event or if the 
interruption/ delay was > 72 hours, regardless of the reason, should be performed under 
medical supervision.  Dexamethasone premedication is mandatory prior to re start, and 
prior to re-escalation to the target dose in case of dose reduction.  The following 
assessments should be performed as per the Schedule of Activities for cycle 1, 
depending on duration of hospitalization: 
 
vital signs, pulse oximetry 
 
physical examination 
 
neurological examination (only in case the treatment interruption was due to a 
neurologic event) 
 
weight 
 
ECOG 
 
safety labs (hematology, chemistry, coagulation, urinalysis) 


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The subject should be hospitalized for up to 48 hours after re-start of the infusion 
depending on the specific adverse event that has led to the interruption/delay (causality 
and severity, see Table 6-6 for adverse event management and restart guidance) or 
tolerability prior to delay for logistical reason and as per agreement with the Amgen 
Medical Monitor.  Re-introduction of the step dosing may be required for long 
delays and should be considered on a case-by-case basis with the Amgen Medical 
Monitor. 
6.2.2.2 
Management of COVID-19 Infection 
Subjects with evidence of COVID-19 infection should be closely monitored while 
being treated with AMG 340.  Follow the guidelines in Table 6-6 for AMG 340 
treatment interruption, resumption, and discontinuation due to COVID-19 
infection.  Subjects with active COVID-19 infection should not be dosed with 
AMG 340 until infection has resolved and if being treated with an anti-infective 
therapy, the course of such therapy should have been completed.  Management of 
COVID-19 infection should be tailored to the appropriate prophylaxis and/or 
treatment according to the local standard of care and institutional guidelines. 
6.2.2.3 
Management of Monkeypox Infection 
Subjects with evidence of Monkeypox infection should be closely monitored while 
being treated with AMG 340.  Follow the guidelines in Table 6-6 for AMG 340 
treatment interruption, resumption, and discontinuation due to Monkeypox 
infection.  Management of Monkeypox infection should be tailored to the 
appropriate prophylaxis and/or treatment for the Monkeypox infection according 
to the local standard of care and institutional guidelines. 
  


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Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Description of Severity 
Interruption/Delay 
Specific Management 
Re-start Guidance 
Permanent 
Discontinuation 
Infusion-related Reaction 
1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
N/A 
Consider medication to 
control infusion reaction 
as deemed appropriate 
by the investigator 
according to local 
standard of care and 
institutional guidelines. 
Increase monitoring of 
vital signs as medically 
indicated until the subject 
is deemed medically 
stable. 
N/A 
N/A 
2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
 24 hours 
Short-term infusion:  
Immediate 
interruption/delay 
until event has 
improved to 
grade  1 
 
 
Re-start possible, if successfully managed and 
improvement to  grade 1 in  14 days. 
 
Delay of the next infusion: 
 
 7 days:  administer the delayed infusion 
(as long as the next scheduled infusion is  
6 days from delayed infusion) and follow 
the schedule of assessments for the cycle 
day on which the infusion was originally 
planned.   
 
 7 days:  skip the delayed infusion and 
resume schedule of assessments for the 
next scheduled infusion. 
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated  
If subject missed 
more than 
2 consecutive 
doses of 
AMG 340 
Page 1 of 19 
Abbreviations and footnotes defined on last page of table. 
 


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Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Description of 
Severity 
Interruption/Delay 
Specific Management 
Re-start Guidance 
Permanent 
Discontinuation 
Infusion-related Reaction (continued) 
3 
Prolonged (eg, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for clinical 
sequelae 
Immediate 
interruption/delay until 
event has improved to 
grade 1 
Consider supportive 
therapy including 
steroids as clinically 
indicated. 
Increase monitoring of 
vital signs as medically 
indicated until the subject 
is deemed medically 
stable. 
 
As for grade 2 infusion-related reaction, with the 
exception of mandatory dose modification:  
reduce to next lower dose 
If subject missed 
more than 
2 consecutive 
doses of 
AMG 340 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
N/A 
As for grade 3 
infusion-related reaction 
N/A 
Immediately stop 
the infusion (if 
applicable) and 
permanently 
discontinue 
AMG 340 
(monotherapy or 
in combination 
with 
pembrolizumab) 
therapy 
Page 2 of 19 
Abbreviations and footnotes defined on last page of table. 


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Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Description of Severity 
Interruption/ Delay 
Specific Management 
Re-start guidance 
Permanent Discontinuation 
Neurologic Events 
 2 
For CRS-related 
neurological events, use 
ICANS grading and 
management system 
(Section 6.2.1.6.1.1) 
Interrupt AMG 340 
until the event 
improves to grade  1 
Follow institutional guidelines 
for management 
Resume AMG 340 no less than 72 hours 
after the initial observation of the grade 1 or 
2 adverse event. 
N/A 
3 
Administer corticosteroids per 
local practice 
Resume AMG 340 no less than 7 days after 
the initial observation of the grade 3 
adverse event.  Reduce AMG 340 by 
1 dose level. 
 
Initial grade 3 neurologic 
event does not improve to 
grade  1 within 7 days, 
OR 
 
Grade 3 neurologic event 
reoccurs at the lower dose 
level within 7 days of 
re-initiation 
4 
-- 
-- 
-- 
Permanently discontinue 
AMG 340 
Seizure  
Interrupt AMG 340 
until the event 
improves to grade  1 
Administer corticosteroids 
and anti-seizure medication 
per local practice 
 Refer to grade 3 neurologic events above 
for dose level rules for re-instituting 
infusion. 
 Do not re-initiate AMG 340 until 7 days 
after the last seizure and after therapeutic 
levels of anti-seizure medication are likely 
to have been achieved. 
If a second seizure occurs with 
re-initiation of AMG 340 at any 
dose 
Page 3 of 19 
Abbreviations and footnotes defined on last page of table. 
 


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Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome (see Section 6.2.1.6 for additional guidance and grading scale details) 
1 
Symptoms are not 
life-threatening and 
require 
symptomatic 
treatment only 
 Feverb:   38C 
 Hypotension:  
none 
 Hypoxia:  none 
No action 
required 
Administer: 
 Symptomatic treatment (eg, paracetamol/acetaminophen) for fever 
Monitor: 
 CRS symptoms including temperature, blood pressure, and pulse 
oximetry 
 Fluid status, maintain IVF as needed 
 Consider Chest X-Ray and obtaining appropriate cultures to rule out 
infection 
For subjects with rapid onset ( 4 hours from start of infusion), extensive 
co-morbidities or poor performance status, strong suggestion to manage 
per grade 3 CRS guidance below. 
 
Thrombocytopenia occurring in the setting of CRS can be managed per 
Section 6.2.1.4 and/or per institutional guidelines. 
N/A 
N/A 
Page 4 of 19 
Abbreviations and footnotes defined on last page of table. 
 


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Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Description of 
Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 6.2.1.6 for additional guidance and grading scale details) 
2 
Symptoms require 
and respond to 
moderate 
intervention 
 Feverb:   38C 
WITH 
 Hypotension:  not 
requiring 
vasopressors 
AND/ORc 
 Hypoxia:  
requiring low-flow 
nasal cannulad or 
blow-by 
Delay AMG 340 
until event 
improves to CRS 
grade  1. 
 
 
Administer: 
 Symptomatic treatment (eg, paracetamol/acetaminophen) for fever 
 Supplemental oxygen when oxygen saturation is < 90% on room air 
(low-flow [≤ 6 L/minute] nasal cannula or blow-by) 
 IVF when systolic blood pressure is < 85 mmHg.  Persistent tachycardia 
(eg, > 120 bpm) may also indicate the need for intervention for 
hypotension. 
Monitor: 
 CRS symptoms including temperature, blood pressure, and pulse 
oximetry  
 Fluid status, maintain IVF as needed 
 Cardiac and other organ function 
 Consider Chest X-Ray and obtaining appropriate cultures to rule out 
infection 
For subjects with rapid onset (< 4 hours from start of infusion), extensive 
co-morbidities or poor performance status, strong suggestion to manage 
per grade 3 CRS guidance below. 
 
Thrombocytopenia occurring in the setting of CRS can be managed per 
Section 6.2.1.4 and/or per institutional guidelines. 
 The next infusion may 
be administered if all of 
the following criteria 
are met: 
 If CRS occurred 
during AMG 340 
infusion, infusion 
has been 
interrupted for at 
least 72 hours 
 Resume AMG 340 
at same dose or 
reduce to next 
lower dose if 
clinically indicated. 
 The event has 
resolved to 
grade ≤ 1 prior to 
restarting treatment 
If there is no 
improvement to 
CRS  grade 1 
within 7 days 
Page 5 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 69 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade Description of Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 6.2.1.6 for additional guidance and grading scale details) 
3  
Symptoms require and 
respond to aggressive 
intervention 
 Feverb:   38C 
WITH 
 Hypotension:  requiring a 
single vasopressor 
(excluding vasopressin) 
AND/ORc 
 Hypoxia:  requiring high-flow 
nasal cannulad, facemask, 
nonrebreather mask, or 
Venturi mask 
Delay AMG 340 
until event 
improves to CRS 
grade  1. 
Administer: 
 Symptomatic treatment (eg, paracetamol/acetaminophen) 
for fever 
 Supplemental oxygen (high-flow nasal cannula 
[> 6 L/min], facemask, non-rebreather mask, or Venturi 
mask), as needed 
 A vasopressor  vasopressin, as needed  
 Dexamethasone (or equivalent) IV at a dose maximum of 
(3 doses of 8 mg [24 mg/d]).  The dose should then be 
reduced step-wise. 
AND/OR 
 Consider use of tocilizumab (in countries where available) 
as an additional therapy in this setting at a dose of 
4-8 mg/kg as a single dose.  Tocilizumab can be repeated 
for an additional 3 doses with at least an 8 hour interval 
between doses 
 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 
AMG 340 infusion, 
infusion has been 
interrupted for at least 
72 hours 
 The event has resolved 
to grade ≤ 1 prior to 
re-starting treatment 
If there is no 
improvement to 
CRS ≤ grade 2 
within 5 days 
and CRS 
≤ grade 1 within 
7 days. 
In the case of 
2 separate 
grade 3 CRS 
events. 
Page 6 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 70 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade Description of Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 6.2.1.6 for additional guidance and grading scale details) 
 
 
 
 If tocilizumab is not available, siltuximab (an anti-IL-6 
monoclonal antibody) may be used in the management of 
CRS.  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, 2019), and the 
CARTOX Working Group Guidelines for CRS 
management (Neelapu, 2018).  Siltuximab may be 
repeated if needed, in the event that CRS recurs after a 
subsequent infusion of AMG 340.  Siltuximab may not be 
repeated in an individual subject that develops 
anaphylaxis to siltuximab, or gastrointestinal perforation 
after siltuximab. 
Monitor: 
 CRS symptoms including temperature, blood pressure, 
and pulse oximetry 
 Fluid status, maintain IVF as needed 
 Consider Chest X-Ray and obtaining appropriate cultures 
to rule out infection 
 If refractory hypotension (after 2 fluid boluses), consider 
ECHO 
Admit to intensive care unit for close clinical and vital sign 
monitoring per institutional guidelines. 
 
Thrombocytopenia occurring in the setting of CRS can be 
managed per Section 6.2.1.4 and/or per institutional 
guidelines. 
 
 
Page 7 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 71 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade Description of Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 6.2.1.6 for additional guidance and grading scale details) 
4 
Life-threatening symptoms 
 Feverb:   38C 
WITH 
 Hypotension:  requiring 
multiple vasopressors 
(excluding vasopressin) 
AND/ORc 
 Hypoxia:  requiring positive 
pressure (eg, CPAP, BiPAP, 
intubation, and mechanical 
ventilation) 
N/A 
Administer: 
 Symptomatic treatment (eg, paracetamol/acetaminophen) 
for fever 
 Supplemental oxygen (positive pressure [eg, CPAP, 
BiPAP, intubation and mechanical ventilation]), as needed 
 Multiple vasopressors, as needed 
 Dexamethasone (or equivalent) IV at a dose maximum of 
(3 doses of 8 mg [24 mg/d]).  Further corticosteroid use 
should be discussed with the Amgen medical monitor. 
 Tocilizumab should be administered at a dose of 
4-8 mg/kg as a single dose.  Tocilizumab can be repeated 
for an additional 3 doses with at least an 8 hour interval 
between doses  
N/A 
Immediately stop 
the infusion (if 
applicable) and 
permanently 
discontinue 
AMG 340 
Page 8 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 72 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade Description of Severitya 
Interruption/ 
Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Cytokine Release Syndrome continued (see Section 6.2.1.6 for additional guidance and grading scale details) 
 
 
 
 If tocilizumab is not available, siltuximab (an anti-IL-6 
monoclonal antibody) may be used in the management of 
CRS, following the criteria outlined in the Management of 
Adverse Events table.  The recommended dose of 
siltuximab is 11 mg/kg administered over 1 hour as an 
intravenous infusion, consistent with the prescribing 
information for the treatment of multicentric Castleman’s 
disease (SYLVANT Prescribing Information, 2019), and the 
CARTOX Working Group Guidelines for CRS management 
(Neelapu, 2018).  Siltuximab may be repeated if needed, in 
the event that CRS recurs after a subsequent infusion of 
AMG 340.  Siltuximab may not be repeated in an individual 
subject that develops anaphylaxis to siltuximab, or 
gastrointestinal perforation after siltuximab. 
Monitor: 
 CRS symptoms including temperature, blood pressure, and 
pulse oximetry 
 Fluid status, maintain IVF as needed 
 Consider Chest X-Ray and obtaining appropriate cultures to 
rule out infection 
 If refractory hypotension (after 2 fluid boluses), consider 
ECHO 
Admit to intensive care unit for close clinical and vital sign 
monitoring per institutional guidelines. 
Thrombocytopenia occurring in the setting of CRS can be 
managed per Section 6.2.1.4 and/or per institutional 
guidelines. 
 
 
Page 9 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 73 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Description of 
Severitya 
Interruption/ Delay 
Specific Management 
Restart Guidance 
Permanent 
Discontinuation 
Tumor Lysis Syndrome (TLS) – Grading according to Cairo-Bishop Criteria (see Section 11.11) 
2 
 Clinical TLS 
Immediate interruption/ 
delay until event has 
improved to grade  1 
TLS should be managed according to the local 
standard of care and institutional guidelines. 
 
Restart possible if successfully 
managed and improvement to 
 grade 1 in  14 days 
 
In case of infusion interruption, 
continue treatment with next 
scheduled infusion, do not resume 
prior infusion or administer delayed 
infusion. 
 
Delay of next infusion: 
- 
 72 hours:  follow the Schedule 
of Activities for the cycle day on 
which the infusion was originally 
planned.  The following infusion 
should then be administered 
after 7 ( 1) days 
- 
 72 hours:  skip the infusion and 
resume Schedule of Activities for 
the next scheduled infusion  
 
Hospitalization:  40 to 48 hours 
N/A 
 3 
 Clinical TLS 
N/A 
TLS should be managed according to the local 
standard of care and institutional guidelines 
N/A 
Immediately stop 
the infusion (if 
applicable) and 
permanently 
discontinue 
AMG 340 
therapy 
Page 10 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 74 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Interruption/ Delay 
Specific Management 
Re-start Guidance 
Permanent 
Discontinuation 
Gastrointestinal events related to AMG 340 
2 
Interruption/delay required if 
deemed intolerable by the 
subject or investigator and 
not responding to 
appropriate medical 
management until event has 
improved to grade  1 
Gastrointestinal (GI) 
toxicities should be 
managed according to 
the local standard of care 
and institutional 
guidelines 
 
Re-start possible if successfully managed and 
improvement to  grade 1 in  14 days. 
 
Delay of next infusion: 
 
 7 days:  Administer the delayed infusion (as long 
as the next scheduled infusion is  6 days from 
delayed infusion) and follow the schedule of 
assessments for the cycle day on which the 
infusion was originally planned.   
 
 7 days:  Skip the delayed infusion and resume 
schedule of assessments for the next scheduled 
infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  Resume at the same dose or 
reduce to next lower dose if clinically indicated 
If subject missed more 
than 2 consecutive doses 
of AMG 340 
Page 11 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 75 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Interruption/ Delay 
Specific Management 
Re-start Guidance 
Permanent 
Discontinuation 
Gastrointestinal events related to AMG 340 (continued) 
 3 
Interruption/delay until event 
has improved to grade  1 
Gastrointestinal (GI) 
toxicities should be 
managed according to 
the local standard of care 
and institutional 
guidelines  
 
Re-start possible if successfully managed and 
improvement to  grade 1 in  14 days. 
 
Delay of next infusion: 
 
 7 days:  Administer the delayed infusion (as long 
as the next scheduled infusion is  6 days from 
delayed infusion) and follow the schedule of 
assessments for the cycle day on which the 
infusion was originally planned.   
 
 7 days:  Skip the delayed infusion and resume 
schedule of assessments for the next scheduled 
infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  Resume at the same dose or 
reduce to next lower dose if clinically indicated 
If subject missed more 
than 2 consecutive doses 
of AMG 340 
OR 
In case of reappearance 
of same event at grade 4 
OR 
In case of repeat 
grade  3 event despite 
dose reduction 
Page 12 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 76 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Interruption/Delay 
Specific Management 
Re-start Guidance 
Permanent 
Discontinuation 
Any other AMG 340-related events not meeting DLT criteria 
 3 
Interruption/delay required if 
deemed intolerable and/or 
clinically significant by the 
subject or investigator and 
not responding to appropriate 
medical management until 
event has improved to 
grade  1 
N/A 
 
Re-start possible if successfully managed and 
improvement to  grade 1 in  14 days. 
 
Delay of next infusion: 
 
 7 days:  Administer the delayed infusion (as long 
as the next scheduled infusion is  6 days from 
delayed infusion) and follow the schedule of 
assessments for the cycle day on which the 
infusion was originally planned.   
 
 7 days:  Skip the delayed infusion and resume 
schedule of assessments for the next scheduled 
infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  Resume at the same dose or 
reduce to next lower dose if clinically indicated 
If subject missed more 
than 2 consecutive doses 
of AMG 340 
OR 
In case of reappearance 
of same event at grade 4 
OR 
In case of repeat 
grade  3 event despite 
dose reduction 
Page 13 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 77 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Grade 
Interruption/Delay 
Specific 
Management 
Re-start Guidance 
Permanent 
Discontinuation 
Any Non-AMG 340-related events 
4 
Interruption/ delay required if 
deemed intolerable by the 
subject or investigator and 
not responding to 
appropriate medical 
management until event has 
improved to grade  1 
N/A 
 
Re-start possible if successfully managed and improvement to  
 grade 1 in  28 days. 
 
Delay of next infusion: 
 
 7 days:  Administer the delayed infusion (as long as the next 
scheduled infusion is  6 days from delayed infusion) and follow 
the schedule of assessments for the cycle day on which the 
infusion was originally planned.   
 
 7 days:  Skip the delayed infusion and resume schedule of 
assessments for the next scheduled infusion  
 
Hospitalization:  48 hours 
 
Dose modification:  Resume at the same dose or reduce to next lower 
dose if clinically indicated 
If subject missed more 
than 2 consecutive doses 
of AMG 340 
OR 
In case of reappearance 
of same event at grade 4 
Page 14 of 19 
Abbreviations and footnotes defined on last page of table. 
 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 78 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
Pituitary Gland Dysfunction (González-Rodríguez and Rodríguez-Abreu, 2016; Brahmer et al, 2018) 
 
Monitor for signs and symptoms of pituitary gland dysfunction, TSH, FT4, cortisol, and ACTH throughout study (prolactin, FSH, LH, testosterone/estradiol 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:  Consider brain MRI (if clinically indicated) with or without contrast with pituitary/sellar cuts in subjects with multiple endocrine 
abnormalities and/or with new headache or vision changes.  Evaluate ACTH, AM Cortisol, TSH, FT4, electrolytes and consider evaluating LH, FSH, and 
testosterone levels in males or estrogen in females. 
 
Obtain endocrinology consultation for hypophysitis or if clinically indicated 
 
Once pituitary gland dysfunction is confirmed, hold further treatment with AMG 340 pending completion of evaluation.  Manage pituitary dysfunction according to 
NCCN or ASCO guidelines for Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy (NCCN 
Guidelines, 2022; Brahmer et al, 2018). 
 
Once stabilized on any replacement hormones and taking 10 mg or less of prednisone or equivalent may consider restarting AMG 340.  If subject experienced 
grade 3 or higher pituitary dysfunction, must discuss with medical monitor prior to restarting treatment. 
 
Continue endocrinological surveillance 
Hepatotoxicity 
For Stopping and Rechallenge Rules please refer to Section 11.7. 
Page 15 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 79 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
CTCAE Gradee 
Interruption/ Delayf 
Specific 
Management 
Re-start Guidancef 
Permanent 
Discontinuationf 
Monkeypox Infection 
Grade 1: 
Asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Interruption is not 
required unless the 
subject must be 
isolated for the 
event per local 
standard of care 
and institutional 
guidelines taking 
into consideration 
the benefit/risk of 
withholding 
treatment  
 
Follow local 
guidelines and 
standard of care for 
Monkeypox 
treatment and 
isolation, if 
applicable. 
 
If interruption is required: 
 
Resolution of Monkeypox infection 
 
Resume at the same dose 
None 
Grade 2: 
Moderate 
symptoms:  
minimal, 
non-invasive 
intervention 
indicated; limited 
age-appropriate 
instrumental 
ADLg 
Interruption 
required until the 
event resolves 
 
Follow local 
guidelines and 
standard of care for 
Monkeypox 
treatment and 
isolation, if 
applicable. 
 
 
Resolution of Monkeypox infection 
 
Resume at the same dose 
None 
Page 16 of 19 
Abbreviations and footnotes defined on last page of table. 
 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 80 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
CTCAE Gradee 
Interruption/ Delayf 
Specific 
Management 
Re-start Guidancef 
Permanent 
Discontinuationf 
Monkeypox Infection 
Grade 3: 
Severe or 
medically 
significant but 
not immediately 
life-threatening; 
hospitalization 
or prolongation 
of existing 
hospitalization 
indicated; limited 
selfcare ADLh 
Interruption 
required until the 
event resolves 
 
Follow local 
guidelines and 
standard of care for 
Monkeypox 
treatment and 
isolation, if 
applicable. 
 
 
Resolution of Monkeypox infection 
 
Resume at the same dose or lower dose as clinically 
indicated 
Permanently 
discontinue 
investigational product 
therapy, if a subject 
required treatment 
interruption greater than 
28 days due to grade 3 
infection considering 
the individual 
benefit/risk  
 
Grade 4: 
Life-threatening; 
consequences; 
urgent 
intervention 
indicated 
Interruption 
required until the 
event resolves 
 
Follow local 
guidelines and 
standard of care for 
Monkeypox 
treatment and 
isolation, if 
applicable. 
 
Resolution of Monkeypox infection 
 
Reduce to next lower dose 
 
Permanently 
discontinue 
investigational product 
therapy, if a subject 
required treatment 
interruption greater than 
28 days due to grade 4 
Monkeypox infection 
considering the 
individual benefit/risk 
 
Page 17 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 81 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
CTCAE Gradee 
Interruption/Delay 
Specific 
Management 
Restart Guidancef 
Permanent 
Discontinuationf 
SARS-CoV-2 infection and COVID-19 disease 
Grade 1: 
Asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention 
not indicated 
Interruption 
required until at 
least 5 daysi since 
positive SARS-
COV-2 test or 
since resolution 
of acute 
symptoms. 
Follow local 
guidelines and 
standard of 
care for COVID-
19 treatment 
and isolation 
 
Resolution of the acute symptoms  
 
Subject tests negative for SARS-COV-2,  
o 
If subject continues to test positive for SARS-COV-2 more than 5 
daysi after initial positive test or after resolution of symptoms, 
resume investigational product only after discussion with 
subject and reassessment of individual risk/benefit 
 
Resume at the same dose 
None 
Grade 2: 
Moderate 
symptoms:  
minimal, 
non-invasive 
intervention 
indicated; 
limited age-
appropriate 
instrumental 
ADL 
Interruption 
required until at 
least 5 daysi since 
resolution of 
acute symptoms 
Follow local 
guidelines and 
standard of 
care for 
COVID-19 
treatment and 
isolation 
 
Resolution of the acute symptoms 
 
Subject tests negative for SARS-COV-2,  
o 
If subject continues to test positive for SARS-COV-2 more 
than 5 daysi after resolution of symptoms, resume 
investigational product only after discussion with subject 
and reassessment of individual risk/benefit 
 
Resume at the same dose 
None 
Page 18 of 19 
Abbreviations and footnotes defined on last page of table. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 82 of 160 
CONFIDENTIAL  
 
 
 
Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse Events 
CTCAE Gradee 
Interruption/Delay 
Specific 
Management 
Restart Guidancef 
Permanent 
Discontinuationf 
SARS-CoV-2 infection and COVID-19 disease 
Grade 3: 
Severe or 
medically 
significant but 
not immediately 
life-threatening; 
hospitalization 
or prolongation 
of existing 
hospitalization 
indicated; 
limited self- 
care ADL 
Interruption 
required until at 
least 10 days 
since resolution 
of acute 
symptoms 
Follow local 
guidelines 
and standard 
of care for 
COVID-19 
treatment and 
isolation 
 
 
Resolution of the acute symptoms 
 
Subject tests negative for SARS-COV-2 
o 
If subject continues to test positive for SARS-COV-2 more 
than 10 days after resolution of symptoms, resume 
investigational product only after discussion with subject 
and reassessment of individual risk/benefit 
 
Resume at the same dose or reduce to next lower dose if 
clinically indicated 
Permanently 
discontinue 
investigational product 
therapy if subject 
required treatment 
interruption greater than 
28 days due to grade 3 
COVID-19 infection 
Grade 4: 
Life-
threatening; 
consequences; 
urgent 
intervention 
indicated 
Interruption 
required until at 
least 10 days 
since resolution 
of acute 
symptoms 
Follow local 
guidelines 
and standard 
of care for 
COVID-19 
treatment and 
isolation 
 
 
Resolution of the acute symptoms 
 
Subject tests negative for SARS-COV-2 
o 
If subject continues to test positive for SARS-COV-2 more 
than 10 days after resolution of symptoms, resume 
investigational product only after discussion with subject 
and reassessment of individual risk/benefit 
 
Resume at the same dose or reduce to next lower dose if 
clinically indicated 
Permanently 
discontinue 
investigational product 
therapy if subject 
required treatment 
interruption greater than 
28 days due to grade 4 
COVID-19 infection 
Page 19 of 19 
ACTH = adrenocorticotropic hormone; ASCO = American Society of Clinical Oncology; BiPAP  bilevel positive airway pressure; CRS  cytokine release syndrome; 
COVID-19  coronavirus disease 2019; CPAP  continuous positive airway pressure; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events; DLT = dose-limiting toxicity; ECG  electrocardiogram; ECHO  echocardiogram; EOT = end of treatment; FSH = follicle stimulating hormone; 
FT4 = free t4; ICANS  immune effector cell associated neurologic syndrome; IL6 = interleukin6; IV = intravenous; IVF = intravenous fluid(s); LH = luteinizing 
hormone; MRI = magnetic resonance imaging; N/A  not applicable; NCCN = National Comprehensive Cancer Network; NSAIDs = non-steroidal anti-inflammatory 
drug(s); RTPCR  real-time polymerase chain reaction; SARS-CoV-2  severe acute respiratory syndrome coronavirus 2; SOC  standard of care; 
TLS = tumor lysis syndrome; TSH = thyroid stimulating hormone 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  07 December 2022 
 
Page 83 of 160 
CONFIDENTIAL  
 
 
 
a American Society for Transplantation and Cellular Therapy (ASTCT) grading system for CRS (Lee et al, 2019). 
b Fever is defined as temperature  38°C not attributable to any other cause.  In subjects who have CRS then receive antipyretic or anticytokine therapy such as 
tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity.  In this case, CRS grading is driven by hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event:  Hypotension or hypoxia not attributable to any other cause.  For example, a subject with temperature of 39.5°C, 
hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at  6 L/minute.  Low-flow also includes blow-by oxygen delivery, sometimes used in pediatrics.  High-flow 
nasal cannula is defined as oxygen delivered at  6 L/minute. 
e Document severity of COVID-19 or Monkeypox related adverse events utilizing the “Infection and Infestations – Other, specify” category per CTCAE 
version 5.0 as specified in the clinical protocol. 
f Amgen Medical Monitor to decide based on investigational product safety risk and patient population whether to allow a subject who demonstrates a 
clinical benefit with a documented response of stable disease or better to resume therapy if there are reasons that the above dose withholding and 
restarting rules cannot be implemented.  The investigator should contact and discuss these reasons with Amgen Medical Monitor.  The investigator must 
obtain written agreement from Amgen Medical Monitor before any changes in the dose modification rules can be implemented. 
g Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
h Selfcare ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
i Amgen Medical Monitor to decide if investigational product should be interrupted for 10 days for grade 1 or grade 2 COVID-19 adverse event, based on 
investigational product safety risk and patient population. 


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6.2.2.4 
Infusion Interruptions/Delays/Withholding and Re-start in Case of 
Technical/Logistical Issues 
Events leading to infusion interruption or delay for technical/logistical reasons may 
include:  technical problem with the infusion pump or the investigational product is 
incorrectly prepared or administered. 
Infusion Interruptions due to Technical/Logistical Issues 
The IV infusion administration of AMG 340 should not be interrupted, if possible.  In case 
of infusion interruption, due to any technical or logistic reason, the interruption should be 
as short as possible, and the infusion continued at the earliest time possible. 
In case of infusion interruption of  2 hours, the IV infusion administration can be 
restarted.  In case of infusion interruption of  2 hours, immediately consult with Amgen 
Medical Monitor to determine if:   
 
investigational product stability is sufficient to administer the remaining infusion or  
 
a new infusion can be administered or  
 
the dose should be withheld  
For short-term (120 minutes) infusions, if the remaining infusion can be administered, no 
specific precautions have to be taken.  If a new infusion can be administered, follow the 
procedures in the Schedule of Activities (Section 1.3) or the cycle day on which the 
original (interrupted) infusion was administered.  Premedication as described in 
Section 6.1.5 for treatment cycle 1 should be administered.   
Any interruption of an infusion should be recorded in the eCRF, providing the start and 
stop date/time of the infusion if the interruption is  2 hours. 
Infusion Delay due to Technical/Logistical Issues 
If the infusion delay was  7 days, the dose can be administered without specific 
precautions.  Procedures performed will follow the schedule of assessments for the 
cycle day on which the infusion was originally planned.  The following infusion should 
then be administered after 21 ( 1) days (eg, if the day 8 infusion needs to be delayed 
for logistical issues, and could only be administered on day 10, the next infusion should 
be administered 21 days later [ 1 day]).  The  1-day window is allowed until the 
original dosing schedule is met again. 


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6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009. 
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on drug accountability for the investigational product and 
other protocol-required therapies will be provided to the site. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria and enroll in the study will be assigned to treatment 
with AMG 340. 
6.4.2 
Blinding 
This is an open-label study; procedures to blind treatment assignment are not 
applicable. 
6.5 
Treatment Compliance 
When subjects are dosed at the site, they will receive AMG 340 directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the 
CRF. 
6.6 
Treatment of Overdose 
The administered AMG 340 monotherapy dose may be up to 10% lower or higher than 
specified in the protocol.  A dose of up to 10% higher than the intended dose may not 
require specific intervention. 
In any case of overdose, consultation with the Amgen medical monitor is required for 
prompt reporting of clinically apparent or laboratory adverse events possibly related to 
overdosage.  Consultation with the Amgen medical monitor is also required even if there 
are no adverse events, in order to discuss further management of the subject.  If the 
overdose results in clinically apparent or symptomatic adverse events, the subject 
should be followed carefully until all signs of toxicity are resolved or returned to baseline 
and the adverse event(s) should be recorded/reported per Section 11.4. 
A dose of > 10% higher than the intended AMG 340 dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 11.4. 


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6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements, the name of the medication, dosage information including 
dose, route and frequency, date(s) of administration including start and end dates, and 
reason for use must be recorded from 2 weeks (14 days) prior to dosing. 
Additionally, all prior cancer treatment therapies will be collected.  Other 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, and start and stop dates. 
For all prior therapies taken for prostate cancer (eg, chemotherapy, immunotherapy, 
biological therapy, or targeted therapy), collect (in the order they were administered): 
 
therapy name 
 
indication 
 
dose and schedule of the agent(s) 
 
unit 
 
frequency 
 
start and stop dates 
 
disease state in which it was administered 
 
reason for discontinuation (disease progression, clinical progression, toxicity, 
subject’s decision) 
Additionally, details of the dates, portals, and total administered dose by portal should be 
recorded for all courses of radiation therapy, including those directed at the primary and 
metastatic site(s). 
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.7. 
Concomitant therapies are to be collected from informed consent through the end of 
SFU period. 
For concomitant therapies being taken for the disease under study (eg, steroids, 
chemotherapy on oncology studies), 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. 


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6.7.2.1 
Vaccines 
Every effort should be made to fully vaccinate patients prior to 14 days from first dose 
of investigational product.  However, SARS-COV-2 vaccinations should be avoided 
during screening (within a minimum of 14 days from first dose of investigational 
product) and should be also avoided in the first treatment cycle for better assessment 
of safety parameters.  Throughout the trial, SARS-COV-2 vaccination should be avoided 
within 7 days after the administration of investigational product.  In the event where a 
patient requires steroids or other immunosuppressive therapy for treatment of 
adverse events, vaccination should be avoided while on steroids or other 
immunosuppressive therapy. 
The following vaccines (Live and live-attenuated vaccines) are excluded during 
the following study periods: 
 
Screening and during study treatment:  Live and live-attenuated vaccines are 
prohibited within 28 days prior to the first dose of investigational product and 
for the duration of the study. 
o Live viral non-replicating vaccine (eg, Jynneos) for Monkeypox infection 
is allowed during the study in accordance with local standard of care 
and institutional guidelines, but is restricted within 7 days prior to first 
dose of investigational product and during the DLT assessment period. 
 
End of study treatment:  Live and live-attenuated vaccines can be used at least 
5X half-life of investigational product after the last dose of investigational 
product. 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Section 7.1. 


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7.1 
Discontinuation of Study Treatment 
Subjects (or a legally authorized representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies and/or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see 
Section 1.3) including different options of follow-up (eg, in person, by phone/mail, 
through family/friends, in correspondence/communication with other treating physicians, 
from the review of medical records) and collection of data, including endpoints, adverse 
events, and must document this decision in the subject’s medical records.  Subjects who 
have discontinued investigational product and/or other protocol-required therapies 
and/or procedures should not be automatically removed from the study.  Whenever safe 
and feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
decision by sponsor 
 
lost to follow-up 
 
death 
 
adverse event 
 
noncompliance with protocol 
 
subject request 
 
disease progression (refer to Appendix 12 [Section 11.12])  
 
requirement for alternative therapy 
 
protocol-specified criteria including: 
 
intercurrent illness preventing further drug administration 
 
treatment delay > 14 days, unless the cause is unequivocally due to the subject’s 
underlying disease or other extraneous cause and continuation is approved by 
the Medical Monitor(s) and treating investigator. 
7.2 
Subject Discontinuation/Withdrawal From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 


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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.  Subjects who are 
withdrawn or removed from treatment or the study will not be replaced unless they are 
not evaluable for DLT in cycle 1.   
If a subject discontinues study drug treatment, an EOT visit should be conducted within 
30 days after the last dose of AMG 340, as well as a 90-day follow-up visit if possible, 
provided the subject has not initiated a new line of therapy.  Subjects with grade 3 or 
4 drug associated toxicities through the 90-day follow-up visit will be followed until the 
subject is stable, toxicities resolve to an acceptable level, or until another anticancer 
therapy is initiated, whichever occurs earlier. 
If a subject withdraws or is discontinued from the study, the reason(s) for discontinuation 
from the study will be recorded if known, and an EOT visit (and associated procedures) 
will be performed within 30 days after the last dose of study drug.  Additional blood 
samples for drug measurement may be collected from subjects who are discontinued 
due to adverse events.  Subjects will be asked to return, if possible, for a 90-day 
(7 days) follow-up visit after the last dose of AMG 340.  However, if subjects start a 
new line of therapy before the 90 (7) days follow-up visit, subjects will be asked to 
return for a SFU visit approximately 30 days after the last dose of AMG 340 or until the 
subject begins a new line of therapy, whichever occurs later.  Once reliable half-life data 
are available for AMG 340 and if T1/2 exceeds 18 days, subjects may be asked to return 
at a time more remote from the last dose of AMG 340 for a SFU visit to capture PK and 
ADA data at T  5 x T1/2. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Not applicable for this study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 


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 
decision by sponsor 
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
For subjects who are lost to follow-up, the investigator should search publicly 
available records [where permitted] to ascertain survival status.  This ensures that 
the data set(s) produced as an outcome of the study is/are as comprehensive as 
possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 1.3). 
If an enrolled subject is subsequently determined to be ineligible for the study, this must 
be discussed with the sponsor immediately upon occurrence or awareness to determine 
if the subject is to continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IRT and screen 


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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. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 1 time. 
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 28 days 
after the original signing of the informed consent form, all screening procedures (with the 
exception of tumor biopsy, PSMA PET and FDG PET scans), including informed 
consent, must be repeated. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Section 1.3).  On-study visits may be 
completed within the deviation window presented in the Schedule of Activities 
(Section 1.3).  The date of the first dose of AMG 340 is defined as day 1.  All subsequent 
doses and study visits will be scheduled based on the day 1 date.  Administration of 
AMG 340 is to be administered last during each visit that it is required. 
8.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, a SFU visit will 
be performed approximately 90 (+ 7) days after the end of the last dose of 
investigational product and/or protocol-required therapies.  However, if subjects start a 
new line of therapy before the 90 (+ 7) days follow-up visit, safety follow-up will be 
performed through 30 days post last dose of investigational product or until the subject 
begins a new line of therapy, whichever occurs later.  All procedures to be completed 
during safety follow-up are indicated in the Schedule of Activities (Section 1.3). 
8.1.4 
Long-term/Survival Follow-up 
Subjects will be followed for survival and/or the commencement of subsequent cancer 
therapy via clinic visits, telephone, or chart review call every 6 months from the last SFU 


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visit for up to a maximum of 3 years.  All procedures to be completed during long-
term/survival follow-up are indicated in the Schedule of Activities (Section 1.3). 
8.1.5 
End of Study 
A subject is considered to have completed the study if he has completed the study 
including the last visit/last follow-up as shown in the Schedule of Activities (Section 1.3). 
8.2 
General Assessments  
8.2.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
8.2.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness, 
as allowed by local regulations.  Additionally, demographic data will be used to study the 
impact on biomarkers variability and pharmacokinetics of AMG 340. 
8.2.3 
Medical History 
The investigator or designee will collect a complete medical, surgical, and disease 
history through day 1.  Medical history will include information on the subject's 
concurrent medical conditions.  Record all findings on the medical history CRF.  In 
addition to the medical history above, mCRPC history must date back to the original 
diagnosis.  Known prostate cancer mutations (eg, BRCA1, BRCA2) prior to start of 
treatment should also be recorded.  The current toxicity will be collected for each 
condition that has not resolved. 
8.2.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.4.1 
Neurological Examination 
If clinically indicated, subjects will be specifically queried for neurological symptoms 
observed in the interval since the last extended neurological examination.  Abnormalities 
of the following should be recorded:  level of consciousness, orientation, vision, cranial 
nerves and brain stem functions, pyramidal and extra pyramidal motor system, reflexes, 
muscle tone and trophic findings, coordination, sensory system, neuropsychological 
findings (eg, speech, cognition, and emotion). 


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The individual performing the neurological examination will characterize the findings as 
either normal or abnormal.  Abnormal findings found predose will be reported on the 
medical history page of the CRF.  Abnormal findings found after the subject is dosed will 
be reported on the Event page of the CRF. 
A more detailed neurological assessment may be performed in subjects at selected 
sites. 
8.2.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes.  Body Mass Index should be calculated using the following 
formula:  BMI (kg/m2) = weight (kg)/[height (cm)/100]2 
A limited, symptom-directed physical examination will be performed at other study visits. 
8.2.6 
Performance Status  
The ECOG performance status will be assessed at timepoints indicated in the Schedule 
of Activities in Section 1.3.  The ECOG performance status is documented using the 
scoring method in Section 11.8. 
8.3 
Efficacy Assessments 
8.3.1 
Radiographic Assessments 
Radiographic assessments will be obtained as scheduled in Table 1-3 (Schedule of 
Disease Assessments) relative to cycle 1 day 1 ( 7 days) irrespective of cycle duration 
including dose delays and treatment discontinuation. 
Radiographic scans taken to confirm disease progression following prior anti-cancer 
therapy may be used for baseline tumor assessments, provided they were performed 
within 28 days of enrollment and using the same contrast and modality planned to be 
used for all subsequent assessments. 
Standard radiological assessments per protocol should take place until clinically 
significant disease progression or deterioration, withdrawal of consent, or start of new 
anticancer therapy.  For subjects with PD continuing on treatment beyond progression, 
imaging should be continued as per local standard of care and images submitted to 
central reader.  Every assessment must include computed tomography (CT)/magnetic 
resonance imaging (MRI) of 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 CT/MRI can be obtained earlier if clinical deterioration necessitates an 


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earlier scan at the discretion of the managing physician.  The same scanner, contrast, 
and modality used at screening should be used for all subsequent assessments. 
In the dose expansion phase only
PET/CT will be performed at baseline 
to assess PSMA-positive tumor burden, and every 12 weeks for response assessment.  
To identify PSMA-negative disease burden, 18F-FDG PET/CT will also be performed at 
baseline, and every 12 weeks for response assessment.  All imaging assessments have 
a  7-day window.  The use of
PET/CT and 18F-FDG PET/CT (in some 
countries/regions for prostate cancer) is investigational.   
Tumor burden assessments will be performed based on Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 with PCWG3 modifications (see Appendix 12 
[Section 11.12] for details).  Responses (PR and CR) require confirmation by a repeat 
consecutive CT/MRI assessment no sooner than 4 weeks after the first detection of 
radiographical response.  At the discretion of the investigators, the repeat, consecutive 
confirmation scan may be delayed until the next scheduled scan to avoid unnecessary 
procedures or radiation burden.  Planar bone scintigraphy (for disease status and 
disease progression assessment) must be performed using conventional 99mtechnetium 
methylene diphosphonate (99mTc-MDP) radionuclide, or other equivalent 99mTc-labeled 
radiotracers.  Confirmation of bone disease progression by bone scan should be 
performed as described (“2+2” rule set in PCWG3 guidelines).  Disease progression 
based on both CT/MRI and bone scans will be used in radiographic progression 
endpoints (eg, time to radiographic progression and [radiographic progression-free 
survival] rPFS) evaluation.  Soft-tissue progression based on CT/MRI scans will be used 
in response endpoints (eg, objective response and duration of response [DOR]) 
evaluation.  Treatment beyond tumor progression may be allowed as per PCWG3 
guidelines (Section 11.12) (Scher et al, 2016).  Refer to the imaging manual for details 
on imaging assessments.   
For subjects who agree to the optional biopsy, scans must be performed prior to 
obtaining a biopsy.  Blood samples or tumor biopsy must not be collected until at least 
24 hours after a PET/CT scan, or at least 60 hours (or 2.5 days) following a bone 
scintigraphy scan.   
For subjects developing COVID-19 during screening period and following 
screening imaging assessments, consider repeating chest imaging following 
resolution.  For subjects developing COVID-19 during treatment period, consider 
whether chest imaging should be performed before resuming investigational 


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product treatment to rule out COVID-19 pneumonia especially in subjects with 
pulmonary comorbidities. 
8.4 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Section 1.3). 
8.4.1 
Vital Signs 
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. 
8.4.2 
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 (eg, designated site physician, central reader) 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. 
8.4.3 
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 


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events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-1). 
8.4.4 
Survival Status 
Survival status must be obtained for all subjects within the limits of local law.  This 
includes subjects who may have discontinued study visits with or without withdrawing 
consent and should include interrogation of public databases, if necessary.  If deceased, 
the date and reported cause of death should be obtained. 
8.4.5 
Other Safety 
Left ventricular ejection fraction will be assessed by echocardiography at screening.  For 
subjects developing COVID-19 during screening period and following screening 
ECHO assessments, consider repeating ECHO following resolution.  For subjects 
developing COVID-19 during treatment period, consider whether ECHO should be 
performed before resuming investigational product treatment to rule out COVID-19 
myocarditis especially in subjects with cardiac comorbidities.   
8.4.6 
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. 
8.4.6.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.4.6.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Section 11.4.  CRS, which will be graded using the criteria referenced in the 
publication by Lee et al (2019) (see Section 11.10) and TLS, which will be graded 
according to the Cairo Bishop criteria referenced in the publication by 
Coiffier et al (2008) (see Section 11.11), and ICANS will be using the criteria referenced 
in the publication by Lee et al (2019) (see Section 6.2.1.6.1.1). 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from the time of consent through the 
safety follow-up visit 90 (+ 7) days after the last dose of study drug, are reported using 


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the Events CRF.  For subjects that start a new line of therapy before the 90 (+ 7) day 
follow-up visit, all adverse events should be collected and reported through 30 days post 
last dose of investigational product/protocol-required therapies or until the subject begins 
a new line of therapy, whichever occurs later. 
8.4.6.1.2 
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 from the time of consent through 
the safety follow-up visit 90 (+ 7) days after the last dose of study drug, are reported 
using the Events CRF.  For subjects that start a new line of therapy before the 
90 (+ 7) day follow-up visit, all serious adverse events should be collected and 
reported through 30 days post last dose of investigational 
product/protocol-required therapies or until the subject begins a new line of 
therapy, whichever occurs later. 
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 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. 
8.4.6.1.3 
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 (regardless of causality) after the protocol-required reporting period (as 
defined in Section 8.4.6.1.2) is complete, then these serious adverse events will be 
reported to Amgen.  The investigator will report serious adverse events to Amgen 
immediately and no later than 24 hours following the investigator’s awareness of the 
event on the Events CRF. 


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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 reporting requirements for 
a reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study. 
8.4.6.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to inquire 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 about adverse event occurrence. 
8.4.6.3 
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 awareness of the new 
information.  If specifically requested, the investigator may need to provide additional 
follow-up information, such as discharge summaries, medical records, or extracts from 
the medical records.  Information provided about the serious adverse event must be 
consistent with that recorded on the Events CRF. 
8.4.6.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met. 


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The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.  The 
sponsor holding the relevant Investigational New Drug/Clinical Trial Application for either 
AMG 340 or
or 18F-FDG has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of AMG 340 or 
or 18F-FDG, respectively, under clinical investigation.  The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 
Amgen will prepare a single Development Safety Update Report (DSUR) (also referred 
to as Annual Safety Report [ASR] in the European Union) for the Amgen Investigational 
Product.  In order to ensure that consolidated safety information for the trial is provided, 
this single DSUR will also include appropriate information on any other investigational 
products used in the clinical trial, if applicable. 
8.4.6.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.4.6.6 
Pregnancy and Lactation 
Details of all pregnancies in female partners of male subjects will be collected after the 
start of study treatment and until 6 months after last dose of investigational 
product/protocol-required therapies. 
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, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy are provided in Section 11.5. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.5 
Pharmacokinetic Assessments 
Blood samples will be collected for measurement of serum concentrations of AMG 340 
as specified in the Schedule of Activities (Section 1.3).  Instructions for the collection and 
handling of biological samples will be provided by the sponsor.  The actual date and time 
(24-hour clock time) of each sample will be recorded. 
8.7 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities 
 for the measurement of anti-AMG 340 
binding antibodies.  Samples testing positive for binding antibodies may be further 
characterized.  Additional blood samples may be obtained to evaluate any anti-AMG 340 
antibody mediated impact on safety, PK and/or PD, and efficacy during the study.  At the 
end of treatment time point or potentially earlier, whole blood will be collected to further 
characterize a possible antibody response. 
Subjects who test positive for antibodies at the final scheduled antibody time point and 
have clinical sequelae that are considered potentially related to an anti-AMG 340 
antibody response will also be asked to return for additional follow-up testing.  This 
testing is to occur approximately every 3 months from the final scheduled antibody time 
point and continue until:  (1) antibodies are no longer detectable; or (2) the subject has 
been followed for a period of at least 1 year (± 4 weeks) post administration of AMG 340.  


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More frequent testing or testing for a longer period of time may be requested in the event 
of safety-related concerns. 
Refer to the Schedule of Activities (Section 1.3), as applicable, for specific time points, 
and the laboratory manual for detailed collection and handling instructions. 


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
In Part A, a safe and tolerable dose of AMG 340 will have evidence of anti-tumor activity 
in subjects with mCRPC as measured by ORR.  In Part B, AMG 340 will improve ORR in 
subjects with mCRPC to 20% compared with the reference ORR of 5%. 
9.2 
Sample Size Determination 
In Part A, at least 3 subjects are planned for enrollment into each cohort, with the goal of 
determining the MTD and/or RP2D of AMG 340.  Approximately 60 subjects are 
anticipated in Part A; however, the total number of subjects in Part A will depend upon 
the occurrence of DLT events and how dose escalation progresses.  If the unknown true 
toxicity rate/DLT rate is 33% in a given cohort, at least 2 DLTs are likely to be observed. 
In Part B, up to 40 subjects will be enrolled to further evaluate safety and tolerability, to 
explore activity of AMG 340 and to evaluate the relationship between PD markers and 
PK, safety and clinical response.  A sample size of 40 subjects was selected to achieve 
92% power for testing the hypothesis on ORR at 1-sided alpha of 0.1 using the binomial 
exact test. 
9.3 
Populations for Analysis 
The following populations are defined: 
Population 
Description 
PK  
subjects who have received at least 1 dose of AMG 340 
and have at least 1 PK sample drawn post dose 


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ADA 
subjects who have received at least 1 dose of AMG 340 
and have at least 1 ADA sample drawn post dose 
RECIST 1.1 Evaluable 
subjects who have received at least 1 dose of AMG 340, 
have measurable disease per RECIST 1.1 at baseline and 
have the opportunity to be followed for at least 6 weeks 
from start of AMG 340 treatment. 
PSA Response 
Evaluable 
subjects who have received at least 1 dose of AMG 340, 
have a measurable (ie, > 0) PSA at baseline, and have the 
opportunity to be followed for at least 9 weeks from start of 
AMG 340 treatment. 
DLT-evaluable 
subjects who are evaluable for DLTs.  A subject is 
considered “DLT Evaluable” if the subject has completed 
at least the first full treatment cycle or has experienced a 
DLT during the first treatment cycle 
Safety 
subjects who have received at least 1 dose of AMG 340 
ADA  antidrug antibody; DLT  dose limiting toxicity; PK  pharmacokinetic; PSA  prostate specific 
antigen; RECIST  Response Evaluation Criteria in Solid Tumor 
9.3.1 
Covariates 
Not applicable for this study. 
9.3.2 
Subgroups 
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. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Amgen will conduct evaluations of the treatment and outcome of the CRS events treated 
with siltuximab on an ongoing basis to assess if the threshold for pausing siltuximab 
treatment has been reached as outlined in the table below.  If these stopping rules are 
met, an ad hoc DLRT will be triggered to review safety data and available PK, PD, and 
efficacy data.  If recommended by DLRT, the use of siltuximab will resume.  The 
stopping rules to trigger an ad hoc DLRT to review siltuximab treatment use a Bayesian 
approach proposed by Thall, et al (1995); an ad hoc DLRT will be triggered if the 
posterior probability that the CRS progression to grade 3 rate is greater than 30% is > 
80% or the posterior probability that the CRS progression to grade 4 rate is greater than 
10% is >80%; or observation of any grade 5 CRS after the event has been treated with 


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siltuximab.  The stopping boundaries presented below assume a prior distribution of 
Beta (0.6, 1.4) for progression to grade 3 CRS and a prior distribution of Beta (0.2, 1.8) 
for progression to grade 4 CRS.  The evaluations could occur more frequently if 
necessary to address emerging safety concerns.  If the triggered ad hoc DLRT coincide 
with regular DLRT, they may be combined. 
Table 9-1.  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 the number of subjects with 
severity of CRS progressed to 
Grade 3 after being treated with 
siltuximab is 
Or the number of subjects with 
severity of CRS progressed to 
Grade 4 after being treated with 
siltuximab is 
5 
≥ 3 
≥ 2 
10 
≥ 5 
≥ 3 
15 
≥ 7 
≥ 3 
20 
≥ 8 
≥ 4 
25 
≥ 10 
≥ 5 
30 
≥ 12 
≥ 5 
35 
≥ 13 
≥ 6 
40 
≥ 15 
≥ 6 
CRS = cytokine release syndrome; DLRM = dose level review meeting 
9.4.1.2 
Primary Analysis 
The primary analysis will occur 6 months following the enrollment of the last subject in 
Part B.  The data will be analyzed once they have been entered, cleaned, and locked. 
9.4.1.3 
Final Analysis 
The final analysis will occur after all subjects have ended the study.  The data will be 
analyzed once they have been entered, cleaned, and locked. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety 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. 


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9.4.2.2 
Efficacy Analyses 
 
Endpoint/ 
Estimand 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
The proportion of subjects with an OR per RECISIT 1.1 along with the 
corresponding exact 95% CI will be calculated using the 
Clopper-Pearson method (Clopper and Pearson, 1934); similarly, the 
proportion of subjects, 95% CI will be tabulated for PSA response.  
Kaplan-Meier quartiles, rates and curves will be used to summarize 
OS, rPFS, 6-month landmark rPFS, PSA PFS, time to progression 
(radiographic and PSA), time to symptomatic skeletal events (SSE), 
and DOR. 
Listings may be provided instead of summary tables if the number of subjects for 
analysis is small. 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint/Estimand Statistical Analysis Methods 
Primary 
Unless otherwise specified, statistical analyses on safety 
endpoints will be done using subjects from the Safety Analysis 
Set, which includes subjects that are enrolled and received 
AMG 340.  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 
described in Sections 9.4.2.3.2 through 9.4.2.3.6. 
Descriptive statistics for the continuous variables and the 
frequencies/percentages for the discrete variables will be 
provided. 
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to discontinuation from investigational product or other 
protocol-required therapies will also be provided. 
A subgroup analysis of safety with CRS outcomes and PK will be performed for subjects 
who were administered siltuximab. 


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9.4.2.3.3 
Laboratory Test Results 
Clinical laboratory data will be reviewed for each subject.  Depending on the size and 
scope of changes in laboratory data, the analyses of safety laboratory endpoints may 
include summary statistics over time and/or changes from baseline over time.  Shifts in 
grades of safety laboratory values from baseline for selected laboratory values may also 
be provided. 
9.4.2.3.4 
Vital Signs 
The analyses of vital signs will include summary statistics over time and/or changes from 
baseline over time. 
9.4.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at baseline. 
9.4.2.3.6 
Electrocardiogram 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; summaries and 
statistical analyses of ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other trials. 
9.4.2.3.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 340 antibodies at any 
time will be tabulated overall and by planned dose level. 
9.4.2.3.8 
Exposure to Investigational Product 
Descriptive statistics of cumulative dose, number of cycles, duration of usage, number 
and percentage of subjects with dose modifications and interruptions will be produced to 
describe the exposure to AMG 340. 
9.4.2.3.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category as coded by the World Health Organization Drug dictionary. 
9.4.2.4 
Other Analyses 
9.4.2.4.1 
ECOG Performance Scores 
The ECOG performance scores will be summarized by visit and change from baseline 
by visit. 


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9.4.2.4.2 
Pharmacokinetic Analyses 
Serum concentrations of AMG 340 and PK parameter values will be tabulated for each 
subject, each dose level, and summary statistics will be computed for each sampling 
time and each parameter. 
Pharmacokinetic parameters of AMG 340 from a particular dosing schedule assessed on 
cycle 1 day 1 will be analyzed according to the statistical analysis plan (SAP).  An 
analysis will be performed for dose normalized Cmax and dose-normalized AUC provided 
that they can be adequately determined from the data.   
Additional analyses will be performed if useful and appropriate. 


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Mhawech-Fauceglia P, Zhang S, Terracciano L, et al.  Prostate-specific membrane 
antigen (PSMA) protein expression in normal and neoplastic tissues and its sensitivity 
and specificity in prostate adenocarcinoma:  An immunohistochemical study using 
mutiple tumour tissue microarray technique.  Histopathology.  2007;50(4):472-483. 
Mottet N, Bellmunt J, Bolla M, et al.  EAU-ESTRO-SIOG Guidelines on Prostate Cancer.  
Part 1:  Screening, Diagnosis, and Local Treatment with Curative Intent.  European 
Urology.  2017;71(4):618-629. 


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National Cancer Care Network (NCCN).  Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®):  Prostate Cancer.  Version 4 2022. 
National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) 
Program.  Cancer Stat Facts:  Prostate Cancer.  Accessed 15 September 2020.  
https://seer.cancer.gov/statfacts/html/prost.html 
Neelapu SS, Tummala S, Kebriaei P, et al.  Chimeric antigen receptor T-cell 
therapy-assessment and management of toxicities.  Nat Rev Clin Oncol.  
2018;15(1):47-62. 
Norelli M, Camisa B, Barbiera G, et al.  Monocyte-derived IL-1 and IL-6 are differentially 
required for cytokine-release syndrome and neurotoxicity due to CAR T cells.  Nature 
Medicine.  2018;1. 
O'Keefe DS, Su SL, Bacich DJ, et al.  Mapping, genomic organization and promoter 
analysis of the human prostate-specific membrane antigen gene.  Biochimica et 
Biophysica Acta.  1998;1443(1-2):113-127. 
Olafsen T, Gu Z, Sherman MA, et al.  Targeting, imaging, and therapy using a 
humanized antiprostate stem cell antigen (PSCA) antibody.  Journal of Immunotherapy.  
2007;30(4):396-405. 
Perner S, Hofer MD, Kim R, et al.  Prostate-specific membrane antigen expression as a 
predictor of prostate cancer progression.  Human Pathology.  2007;38(5):696-701. 
Rahbar K, Afshar-Oromieh A, Jadvar H, et al.  PSMA theranostics:  current status and 
future directions.  Molecular Imaging.  2018;17:1536012118776068. 
Ross JS, Sheehan CE, Fisher HA, et al.  Correlation of primary tumor prostate-specific 
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Rojas C, Frazier ST, Flanary J, Slusher BS.  Kinetics and inhibition of glutamate 
carboxypeptidase II using a microplate assay.  Analytical Biochemistry.  
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Ryan CJ, Smith MR, Fizazi K, et al.  Abiraterone acetate plus prednisone versus placebo 
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constructs and first-in-human dose selection.  Regul Toxicol Pharmacol.  
2017;90:144-52. 
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AUA/ASTRO/SUO Guideline.  Part I:  Risk Stratification, Shared Decision Making, and 
Care Options.  Journal of Urology.  2018;199(3):683-690. 
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cancer after chemotherapy.  New England Journal of Medicine.  
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Scher HI, Morris MJ, Stadler WM, et al.  Trial design and objectives for 
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Silver DA, Pellicer I, Fair WR, et al.  Prostate-specific membrane antigen expression in 
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11. 
Appendices 


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11.1 
Appendix 1.  List of Abbreviations 
 
Abbreviation 
Explanation 
ADA 
Antidrug antibody 
ADR 
Adverse drug reaction 
ADT  
Androgen deprivation therapy 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Androgen receptor 
ASR 
Annual Safety Report  
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUCt 
Area under the serum concentration-time curve from time zero to 
time of last measurable concentration 
BOIN 
Bayesian Optimal Interval 
BRCA 
Breast cancer gene  
CaP 
Prostate cancer 
CAR 
Chimeric antigen receptor 
CARTOX 
CAR-T-cell therapy associated toxicity 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum observed serum concentration 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRS 
Cytokine release syndrome 
Css, trough 
Trough concentration at steady state 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
DLRM 
Dose Level Review Meeting 
DLRT 
Dose Level Review Team 
DLT 
Dose limiting toxicity  
DOR 
Duration of objective response 
DSUR 
Development Safety Update Report  
EC50 
Half maximal effective concentration 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EOI 
End of infusion 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
18F-FDG 
18F-Fluorodeoxyglucose 
FIH 
First-in-human  


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Abbreviation 
Explanation 
FISH 
Fluorescence in situ hybridization 
FL 
Follicular lymphoma 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C virus antibody 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
IB 
Investigator’s Brochure 
ICE 
Immune effector cell encephalopathy 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFNγ 
Interferon gamma 
IL 
Interleukin 
IMT 
Immune mediated toxicity 
IRB 
Institutional Review Board 
IRR 
Infusion related reaction 
IV 
Intravenous 
mAb 
Monoclonal antibody 
MABEL 
Minimal anticipated biological effect level 
mCRPC 
Metastatic castrate-resistant prostate carcinoma 
MED 
Minimum efficacious dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Minor response 
MRI 
Magnetic Resonance Imaging 
99mTc MDP 
99mtechnetium methylene diphosphonate 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
NCA 
Noncompartmental analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NLCB 
No longer clinically benefiting 
NT 
Neurotoxicity 
ORR 
Objective response rate 
OS 
Overall survival 
PARPi 
Poly-ADP-ribose-polymerase inhibitors 
PBMC 
Peripheral blood mononuclear cells 
PC 
Positive control 
PCR 
Polymerase Chain Reaction 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Pharmacodynamic(s) or Progressive Disease 


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Abbreviation 
Explanation 
PET 
Positron emission tomography 
PI 
Prescribing information 
PK 
Pharmacokinetic 
PFS 
Progression-free Survival 
PO 
Orally 
PR 
Partial response 
PRO 
Patient Report Outcomes 
PSA 
Prostate-specific antigen 
PSA30 
Rate of prostate-specific antigen decrease ≥ 30% 
PSA50 
Rate of prostate-specific antigen decrease ≥ 50% 
PSMA 
Prostate-specific membrane antigen 
PT 
Prothrombin time 
Q3W 
Once every 3 weeks 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RLT 
Radioligand therapies 
rPFS 
Radiographic progression-free survival 
RP2D 
Recommended phase 2 dose  
RR 
Relapsed or refractory 
RT-PCR 
Reverse transcriptase-polymerase chain reaction 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCT 
Stem cell transplant 
SD 
Stable disease 
SMG 
Safety Monitoring Group 
SSE 
Time to symptomatic skeletal events 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 or T1/2 
Terminal half-life 
T-BsAbs 
T-cell engaging bispecific antibodies 
TLS 
Tumor lysis syndrome 
Tmax 
Time to maximum observed serum concentration 
TNFα 
Tumor necrosis factor alpha 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
United States 
V1 
Central compartment volume 
Vss 
Volume of distribution at steady state 
WHO 
World Health Organization 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the local laboratory with the 
exception of the tests noted below.  Additional analyte test results may be reported by 
the local or central laboratory, in accordance with standard laboratory procedures (eg, 
components of a hematology panel). 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 


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Table 11-1.  Analyte Listing 
Local 
Laboratory:  
Chemistry 
Local 
Laboratory:  
Coagulation 
Local 
Laboratory:  
Urinalysis 
Local Laboratory:  
Hematology 
Other Lab 
Analytes 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
-glutamyl 
transferase 
B2-microglobulin 
CRP 
Ferratin 
d-dimer 
Fibrinogen 
Urine 
telopeptide 
PT/INR 
PTT/aPTT 
 
Urobilinogen 
Blood 
Protein 
Glucose 
Bilirubin 
Microscopic 
examination 
RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
Platelets 
WBC 
NLR 
Differential 
• Bands/stabs 
Neutrophils (only %) 
Eosinophils (if 
detected; absolute and 
%) 
Basophils (if detected; 
absolute and %) 
Lymphocytes (absolute 
and %) 
Monocytes (absolute 
and %)  
Central 
Laboratory:  
Local 
Laboratory: 
Serum or Urine 
Pregnancy 
Testosterone 
Hep B surface 
antigen 
Hep C antibody 
HIV Ab/Aga 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CRP  C-reactive protein; HDL = high density lipoprotein; Hep = hepatitis; 
HIV = human immunodeficiency virus; HLA = human leukocyte antigen; INR = international normalized ratio; 
LDH = lactate dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; NLR = neutrophil 
to lymphocyte ratio;
PT = prothrombin time; PTT = partial thromboplastin 
time; RBC = red blood cell count; RDW = red cell distribution width; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell count 
a HIV assessment is recommended. 
If the subject is being followed for possible drug induced liver injury (DILI), the following 
analytes may be tested at the local laboratory depending on the clinical situation (see 
Appendix 7 [Section 11.7]). 


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Table 11-2.  DILI Potential Analyte Listing 
Chemistry 
Total bilirubin, direct bilirubin, ALP, LDH, AST (SGOT), ALT (SGPT), 
creatine kinase, ferritin, gamma-glutamyl transferase, haptoglobin, CRP, 
fibrinogen, d-dimer 
Hematology 
Hemoglobin, Platelets, RBC Morphology, RBC Count, WBC Count, WBC 
Differential 
Coagulation 
PT, INR, APTT 
Immunology 
5 Prime Nucleotidase, Alpha-1 Antitrypsin, Antinuclear Antibodies, Anti-
Smooth Muscle Antibody, Anti-Soluble Liver Ag/Liver-Pancreas Ag, 
Cytomegalovirus IgG Antibody, Cytomegalovirus IgM Antibody, Endomysial 
IgA Antibody, Epstein-Barr Virus EDA IgG Antibody, Epstein-Barr Virus NA 
IgG Antibody, Epstein-Barr Virus VCA IgG Antibody, Epstein-Barr Virus 
VCA IgM Antibody, Hepatitis A Virus IgG Antibody, Hepatitis A Virus IgM 
Antibody, Hepatitis B Core Antibodies, Hepatitis B Core IgM Antibody, 
Hepatitis B Surface Antigen, Hepatitis B Virus DNA Genotyping, Hepatitis B 
Virus Surface Antibody, Hepatitis C Antibodies, Hepatitis C Virus RNA 
Genotyping, Hepatitis D Virus Antibody, Hepatitis D RNA, Hepatitis E RNA, 
Hepatitis E IgG Antibody, Hepatitis E IgM Antibody, Herpes Simplex Virus 
Type 1_2 IgG AB, Herpes Simplex Virus Type 1_2 IgM AB, Human Herpes 
Virus 6 DNA, Human Herpes Virus 7 DNA, Human Herpes Virus 8 DNA, 
Immunoglobulin G, Liver Kidney AB 1,  
Parvovirus IgM/IgG Antibody, Serum Caeruloplasmin, Tissue 
Transglutaminase IgA Antibody, Toxoplasma IgM/IgG, Varicella Zoster 
Virus Antibody 
Toxicology 
Acetaminophen 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
DILI = drug-induced liver injury; EDA = early antigen; Ig = immunoglobulin; INR = international normalized 
ratio; LDH = lactate dehydrogenase; NA = nuclear antigen; PT = prothrombin time; RBC = red blood cell; 
RNA = ribonucleic acid; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic pyruvic 
transaminase; VCA = viral capsid antigen; WBC = white blood cell 


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11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings (DLRM) 
A DLRM is conducted to review and interpret safety data for the purposes of making 
recommendations about dose-level escalation (either to the next planned dose or to an 
intermediate dose), dose level de-escalation, subject group/cohort continuation, or 
cohort expansion; making recommendations about non-dose escalation subject 
group/cohorts (eg, expanded, highest dose and/or final subject group/cohort); and 
evaluating safety signals for purposes of applying Dose Group/Cohort Stopping Rules.  
The required DLRT members are the medical monitor, global safety officer (GSO), and 


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site investigators.  The DLRT will include all site investigators.  The medical monitor, 
GSO, and site investigators are the only voting DLRT members.   
The medical monitor must be in attendance and cannot be represented by a voting 
designee or delegate.  Voting designees can be identified as appropriate by the GSO or 
site investigator(s).  A site investigator may identify a delegate (eg, sub-Investigator) who 
is listed in the Delegation of Authority.  If a site investigator does this, the site 
investigator must provide written agreement with the designee or delegate’s vote. 
For a DLRM to occur, the medical monitor must attend, and the GSO or delegate must 
attend.  In addition, a quorum of site investigators must be present (may occur at more 
than one meeting).  A quorum is defined as greater than or equal to 50% of the 
participating investigators or their qualified designee.  The DLRM will be rescheduled if 
these requirements are not met. 
All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, electrocardiogram (ECG), 
vital signs, and laboratory results will be reviewed.   
Data will be reviewed blinded (ie, treatment assignment will not be revealed) unless 
unblinding is deemed necessary for the review team to make dosing recommendations.  
If deemed necessary, unblinding will be performed to assist dose change 
recommendations, in accordance with Amgen standard procedures. 
Dose level review meetings voting will occur as follows:  there will be a total of 3 votes, 1 
for the medical monitor, 1 for the GSO or delegate, and 1 for all of the site investigators 
or delegates combined.  Regardless of how many site investigators there are, all of the 
site investigators combined will have a total of 1 vote decided by a majority of the 
investigators (defined as greater than or equal to 50%). 
DLRM recommendations to escalate to the next planned subject group/cohort, or to an 
intermediate subject group/cohort, must be by unanimous vote.  If the voting members of 
the DLRT are not able to reach a unanimous recommendation on whether to escalate to 
the next planned subject group/cohort or to an intermediate subject group/cohort, then 
this should be reflected in the DLRM Memo.  Other recommendations, such as 
expanding a subject group/cohort or lowering a dose will be made by a majority vote. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 


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 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure (IB), 
and other relevant documents (eg, subject recruitment advertisements) must be 
submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by 
the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all protocol amendments and changes 
to the informed consent document that Amgen distributes to the site.  The investigator 
must send a copy of the approval letter from the IRB/IEC and amended protocol 
Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
During the course of the study, if new information becomes available that alters the 
benefit-risk of the study or the study drug, Amgen will follow applicable regulations to 
notify investigators, the IRB/IEC, and regulatory authorities, as appropriate. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 


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informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 
withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 7.1. 


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Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study. 
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
authorized representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 28 days from the previous informed consent form signature 
date. 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 
signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
The subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 


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Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study. 
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the sponsor’s systems.  The 
sponsor uses access-controlled systems to house, review and analyze subject data.  
These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 


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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, or the acquisition, analysis, or interpretation of data for the work; (2) drafting the 
work or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An investigator contributing a high number of eligible subjects 


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Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Quality tolerance limit parameters (QTLs) will be predefined in the QTL definitions table 
to identify possible systematic issues that can impact participant safety and/or reliability 


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of the study results.  These predefined parameters will be monitored during the study.  
Important deviations from the QTL threshold limits for these parameters and remedial 
actions taken will be summarized in the clinical study report. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case Report Forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the IRT 
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment or certain 
demographic information, such as gender, race, and ethnicity). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 


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Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, IB, copies of prestudy 
documentation, and all correspondence to and from the IRB/IEC and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Remote Source Data Review and Verification 
If permitted by national and/or local regulations, remote Source Data Review and 
Verification (rSDR/V) can be implemented.  The clinical monitor should be provided with 
a secure, read-only access to the Electronic Medical Record (EMR) system, including all 
modules relevant for review.  This access should be restricted to the records of only 
those patients who participate in the trial and who did not object to remote access to 
their medical records.  A list of the monitors to whom remote access has been granted 
should be maintained.  In order to prevent unauthorized access, access rights should be 
revoked once rSDR/V tasks have been completed for the trial.  The EMR system should 
have an audit trail and be able to log information on who accessed data and when.  
Remote access to the EMR should only be possible using a two-factor authentication. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP. 
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by a separate protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 


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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, 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 preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as 
an adverse event/serious adverse event unless it is an intentional overdose taken 
with possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
For situations when an adverse event or serious adverse event is due to mCRPC 
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. 
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. 


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 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of preexisting 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 preexisting condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 


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Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Events case report form (CRF). 
 
The investigator must assign the following mandatory adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Did the event start prior to first dose of investigational product 
 
Assessment of seriousness; 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to investigational product(s), other 
protocol-required therapies, and/or study-mandated activity and/or procedures, 
including
and 18F-FDG 
 
Action taken; and 
 
Outcome of event. 
 
If the severity of an adverse event worsens from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the Event 
CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor/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 


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medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Section 11.4.  CRS, which will be graded using the criteria referenced in 
the publication by Lee et al (2014) (see Section 11.10) and TLS, which will be graded 
according to the Cairo Bishop criteria referenced in the publication by 
Coiffier et al (2008) (see Section 11.11), and ICANS will be using the criteria 
referenced in the publication by Lee et al (2019) (see Section 6.2.1.6.1.1). 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product(s) protocol-required therapies, and/or study-mandated activity and/or 
procedure(s), including
18F-FDG, and each occurrence of each 
adverse event/serious 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 


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 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any postmortem 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 Paper CRF 
 
Facsimile transmission of the Serious Adverse Event Report Form (see 
Figure 11-1) is the preferred method to transmit this information. 
 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the Serious Adverse Event Report Form 
sent by overnight mail or courier service. 
 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting time frames. 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen if the investigator becomes 
aware of a serious adverse event.  The investigator should use the paper-based 
Serious Adverse Event Report Form to report the event. 
 


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Figure 11-1.  Sample Serious Adverse Event Report Form (paper-based form) 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for males are outlined in Section 5.2.  
Contraceptive use and methods should be consistent with local regulations for subjects 
participating in clinical studies. 
Male subjects should be advised of the pregnancy prevention requirements and the 
potential risk to the fetus if they father a child during treatment and for 6 months after the 
last dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Females with 
documented permanent infertility due to an alternate medical cause (eg, Mullerian 
agenesis, androgen insensitivity, gonadal dysgenesis), can be considered not of 
childbearing potential. 
Note:  Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of ≥ 55 years with no menses for 12 months without an alternative medical 
cause OR 
 
A woman age < 55 years with no menses for at least 12 months and with a follicle-
stimulating hormone (FSH) level within the definition of “postmenopausal range” for 
the laboratory involved.  In the absence of 12 months of amenorrhea, confirmation 
with more than 1 FSH measurement is required. 


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Contraception Methods for Females 
Highly Effective Contraceptive Methods 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Contraception Methods for Male Subjects 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject)  
 
Use a condom during treatment and for an additional 6 months after the last dose of 
protocol-required therapies 
The female partner should consider using a method of contraception for female subjects 
stated above (a female condom should not be used because there is a risk of tearing 
when both partners use a condom). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Collection of Pregnancy Information 
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 
6 months after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) must be 
submitted to Amgen Global Patient Safety 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). 


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 
Males with pregnant partners or whose partners become pregnant during treatment 
and for an additional 6 months after the last dose of protocol-required therapies must 
practice sexual abstinence or use a condom through 6 months after the last dose of 
protocol-required therapies. 
 
The investigator will attempt to obtain a signed consent for release of pregnancy and 
infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed consent for release of pregnancy and 
infant health information, the investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 
 
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. 


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Figure 11-2.  Pregnancy Notification Form 
 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood (eg, biomarker, pharmacokinetics) sample collected according to the 
Schedule of Activities (Section 1.3) can be analyzed for any of the tests outlined in the 
protocol and for any tests necessary to minimize risks to study subjects.  This includes 
testing to ensure analytical methods produce reliable and valid data throughout the 
course of the study.  This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
metastatic castrate-resistant prostate carcinoma, the dose response and/or prediction of 
response to AMG 340, 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 


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


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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified. 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-1 antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 


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If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix. 
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product and 
other protocol-required therapies, as appropriate is to be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Table 11-3) are never to be rechallenged. 


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Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event immediately and 
no later than 24 hours of discovery or notification of the event (ie, before additional 
etiologic investigations have been concluded) 
 
The appropriate case report form (CRF) (eg, Events CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 11-3 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include: 
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


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


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11.8 
Appendix 8.  Eastern Cooperative Oncology Group (ECOG) 
Performance Score 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 


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11.9 
Appendix 9.  Activity Measurements 
Table 11-4.  Response Categories Based on Assessment of Target Lesions 
 
Complete Response 
Partial Response 
Stable Disease 
Progression of Disease 
Measurable 
lesions 
 Disappearance of all 
target lesions.  Any 
pathological lymph nodes 
(whether target or 
non-target) must have 
reduction in short axis to 
 10 mm. 
  30 decrease in the sum 
of diameters of target 
lesions, taking as reference 
the baseline sum 
diameters. 
 Neither sufficient shrinkage to 
qualify for PR nor sufficient 
increase to qualify for PD, 
taking as reference the 
smallest sum diameters while 
on study. 
  20 increase in the sum of diameters of 
target lesions, taking as reference the 
smallest sum on study (this includes the 
baseline sum if that is the smallest on study). 
 The sum of diameters of target lesions must 
also demonstrate an absolute increase of at 
least 5 mm. 
 The appearance of 1 or more new lesions. 
Non-
measurable 
lesions 
 Disappearance of all 
lesions. 
Not applicable 
Not applicable 
 Unequivocal progression of non-measurable 
lesions. 
 The appearance of 1 or more new lesions. 
Bone lesions 
 Disappearance of all 
lesions. 
Not applicable 
Not applicable 
 At least 2 new lesions on first post-treatment 
scan, with at least 2 additional lesions on the 
next scan (22 rule). 
o 
If at least 2 additional new lesions are 
seen on the next (confirmatory) scan, the 
date of progression is the date of the first 
post-treatment scan, when the first 2 new 
lesions were documented. 
o 
For scans after the first post-treatment 
scan, at least 2 new lesions relative to 
the first post-treatment scan confirmed 
on a subsequent scan. 
PSA 
Not applicable 
Not applicable 
Not applicable 
An isolated PSA increase is not sufficient for PD 
per PCWG3 
PCWG3  Prostate Cancer Working Group 3; PD  progressive disease; PR  partial response; PSA  prostate-specific antigen. 
Source:  Eisenhower et al, 2009; Scher et al, 2016.


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Table 11-5.  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 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluated; PD  progressive disease; PR  partial response; SD  stable disease. 
Source:  Eisenhower et al, 2009. 
Table 11-6.  Time Point Response:  Subjects with Non-target Disease Only 
Non-target Lesions 
New Lesions 
Overall Response  
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/ Non-PDa 
Not evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR  complete response; NE  note evaluated; PD  progressive disease; SD  stable disease. 
a Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised. 
Source:  Eisenhower et al, 2009.


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11.10 
Appendix 10.  Specific Guidance for Cytokine Release Syndrome 
Cytokine release syndrome (CRS) is clinically defined and may have various 
manifestations.  There are no established diagnostic criteria.  Signs and symptoms of 
CRS may include: 
 
constitutional:  fever, rigors, fatigue, malaise 
 
neurologic:  headache, mental status changes, dysphasia, tremors, dysmetria, gait 
abnormalities, seizure 
 
respiratory:  dyspnea, tachypnea, hypoxemia 
 
cardiovascular:  tachycardia, hypotension 
 
gastrointestinal:  nausea, vomiting, transaminitis, hyperbilirubinemia 
 
hematology:  bleeding, hypofibrinogenemia, elevated D-dimer 
 
skin:  rash 
Subjects may be at an increased risk for CRS during the first few days following the 
initial injection or infusion of AMG 340.  CRS may be life threatening or fatal.  Injection or 
infusion reactions may be clinically indistinguishable from manifestations of CRS.  
Throughout the treatment with AMG 340, monitor subjects for clinical signs (eg, fever, 
tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) 
which may be related to CRS. 
Grading and management of CRS should be performed according to the guidelines 
provided in Section 11.10 (based on the adopted grading system referenced in Lee et al, 
2019). 
Please also refer to the general guidance for re-start of injection or infusion after 
interruptions/delay/withholding and dose modifications in Section 6.2.2.4. 
For grade 3 and 4 CRS, please also see Section 6.2.1.4.1 for dose-limiting toxicity (DLT) 
considerations.  Fever reported outside the context of CRS will be graded per CTCAE 
version 5.


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11.11 
Appendix 11.  Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 classifies tumor 
lysis syndrome (TLS) in grade 3 (present), grade 4 (life threatening consequences; 
urgent intervention indicated) and grade 5 (death).  Presence of TLS is not clearly 
defined by CTCAE version 5.0.  Cairo and Bishop developed a system for defining and 
grading TLS based on Hande-Garrow classification of laboratory or clinical TLS (Coiffier 
et al, 2008).  For this trial, the Cairo-Bishop classification will be used to define presence 
of TLS, ie, presence of laboratory TLS and clinical TLS (see Table 11-8) including 
grading. 
Based on the Cairo and Bishop system, laboratory TLS is defined as any 2 or more 
abnormal serum values present within 3 days before or 7 days after initiation of 
treatment in the setting of adequate hydration (with or without alkalinization) and use of a 
hypouricemic agent (Table 11-7). 
Table 11-7.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
Element 
Value 
Change from baseline 
Uric acid 
 476 mol/L or 8 mg/dL 
25 increase 
Potassium 
 6.0 mmol/L or 6 mg/L 
25 increase 
Phosphorus 
 2.1 mmol/L for children or 
 1.45 mmol/L for adults 
25 increase 
Calcium 
 1.75 mmol/L 
25 decrease 
Note:  Two or more laboratory changes within 3 days before or 7 days after cytotoxic therapy will constitute 
laboratory tumor lysis syndrome. 
Clinical TLS requires the presence of laboratory TLS in addition to 1 or more of the 
following significant complications:  renal insufficiency, cardiac arrhythmias/sudden 
death, and seizures.  The grade of clinical TLS is defined by the maximal grade of the 
clinical manifestations as detailed in Table 11-8. 
Table 11-8.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
Grade 
Creatininea, b 
Cardiac arrhythmiaa 
Seizurea 
0 
 1.5 x ULN 
None 
None 
1 
1.5 x ULN 
Intervention not 
indicated 
-- 
2 
 1.5 – 3.0 x ULN 
Non-urgent medical 
intervention indicated 
One brief, generalized seizure; 
seizure(s) well controlled by 
anticonvulsants or infrequent focal 
motor seizures not interfering with ADL 


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Grade 
Creatininea, b 
Cardiac arrhythmiaa 
Seizurea 
3 
 3.0 – 6.0 x ULN 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (eg, 
defibrillator)  
Seizure in which consciousness is 
altered; poorly controlled seizure 
disorder; with breakthrough 
generalized seizures despite medical 
intervention 
4 
 6.0 x ULN 
Life threatening (eg, 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Seizure of any kind which are 
prolonged, repetitive or difficult to 
control (eg, status epilepticus, 
intractable epilepsy) 
5 
Death 
Death 
Death 
Note.  Laboratory TLS and at least 1 clinical complication will constitute clinical TLS. 
ADL  activities of daily living, CHF  congestive heart failure, TLS  tumor lysis syndrome, ULN  upper 
limit of normal 
a Not directly or probably attributable to therapeutic agent. 
b If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:   1 to  12 years of 
age, both male and female, 61.6 mol/L;  12 to  16 years, both male and female, 88 mol/L;  16 years, 
female 105.6 mol/L, male 114.4 mol/L.


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11.12 
Appendix 12.  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 patients.  For those intolerant of iodinated 
contrast, a cross-sectional magnetic imaging resonance (MRI) scan with contrast of the 
abdomen and pelvis, with a non-contrast CT scan of the chest, may be considered.  In 
phase 1 and 2 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 patient.  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 non-measurable/nontarget lesions.  Visceral disease in metastatic patients 
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 and the “22” rule set.  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 
patients 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 patients 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 patient 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 endpoint 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, Patient Reported Outcomes 
(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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FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Amendment 5 
Protocol Title:  A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion Study 
of AMG 340, a Bispecific Antibody Targeting PSMA in Subjects with Metastatic 
Castrate-resistant Prostate Carcinoma (mCRPC)  
Amgen Protocol Number:  20210249 (formerly TNB585.001) 
EudraCT number:  Not applicable 
NCT number:  NCT04740034 
 
Amendment Date: 
07 December 2022  
 
Rationale: 
This protocol is primarily being amended to include a second priming dose at cycle 1 day 5 as 
10-fold increases in the individual steps may not effectively mitigate the incidence and severity 
of the adverse drug reaction of cytokine release syndrome (CRS), an adverse event associated 
with T cell engager therapy.  The new step dosing schedule in cycle 1 will be 
 mg on day 1, 
 mg on day 5, with the target dose of 
 mg to be administered on day 8.  The addition of 
step doses has been successful in mitigating CRS while increasing early exposure and efficacy.  
 
.  Additional language was included to update and/or clarify other items in the protocol.  
Changes including, but not limited to, the following were incorporated into the protocol: 
 
Updated text and 
  Schedule of 
 
 
 
 
Text and Table 6-6.  AMG 340 Dose Modification Guidelines for Adverse events were 
updated to reflect current template language regarding management of both COVID-19 
and Monkeypox Infection. 
 
Exclusion criterion 214 was removed and replaced with a more general statement 
regarding active systemic infection as COVID moves into an endemic phase. 


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FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
 
Statistical analyses language in 9.4.2.4.2 was removed in the protocol for presentation in 
the Statistical Analysis Plan. 
 
Administrative, typographical, and formatting changes were made throughout the 
protocol. 


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Page 1 of 71 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Multicenter, Phase 1, Open-label, Dose escalation and Expansion Study 
of AMG 340, a Bispecific Antibody Targeting PSMA in Subjects with Metastatic Castrate-
resistant Prostate Carcinoma (mCRPC) 
 
Amgen Protocol Number AMG 340 20210249 
NCT Number NCT04740034 
 
Amendment Date: 
26 September 2022 
 
Rationale: 
This protocol has been amended to incorporate the following key revisions.   
 
Updated key safety risks to add thrombocytopenia as a sign of cytokine release 
syndrome (CRS) based on safety evaluation of the study drug (Table 2-2 and Table 6-6). 
 
Reduced total number of subjects enrolled in the study.  Number of subjects anticipated 
to be enrolled in part A (dose escalation) was decreased from 100 to 60 subjects to align 
with the Clinical Development Plan and in part B (dose expansion) was increased from 
30 to up to 40 subjects to address regulatory mandate of dose optimization (Sections 
1.1, 1.2, 4.1, and 9.2). 
 
Updated monotherapy 
 
 
 
, and activity data (Section 4.1.1).  
The following updates are considered minor adjustments supporting the continuous effort to 
align this protocol to other Amgen internal protocols within the prostate portfolio as well as 
ensuring alignment with AMG 160 and AMG 509. 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  26 September 2022 
Page 2 of 71 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Removed electrocardiogram (ECG) from the primary endpoints since statistical analyses 
of ECG measurements are not planned and the schedule of activities only include ECG 
assessment during screening (Sections 1.1 and 3). 
 
Added 6-month landmark radiographic progression-free survival as a secondary 
endpoint to evaluate clinical activity of study drug (Sections 1.1, 3, 9.4.2.2).   
 
Clarified definition of ‘line/regimen of therapy’ as it is a key factor defining the study 
population (Sections 1.1, 4.1).   
 
Provided important clarifications for timing of the safety follow-up (SFU) visit and 
recording of concomitant medication/therapy (Sections 1.3, 6.7.2, 7.1, 8.1.3, Table 1-1). 
 
Updated survival follow-up/long-term follow-up to specify the surveillance methods and 
period which extends for up to a maximum of 3 years from the last SFU visit occurring 
every 6 months (Table 1-1 and Section 8.1.4).  
 
 
) regarding the on-treatment biopsy to guide physicians to discuss the biopsy 
collection process with subjects and conduct it only if feasible and safe.  An additional 
update was to clarify definition of ‘end of infusion’ to ensure consistency across all study 
sites. 
 
Added a 
 only for end 
of treatment visit.  Removed a timepoint for 
 
for the safety follow-up visit 
  
 
Updated procedures and schedule for radiologic assessments (Table 1.3 and 
Section 8.3).   
 
Updated inclusion criteria (Section 5.1) to: 
o Add that subjects must demonstrate adequate platelets and hemoglobin levels 
without platelet and blood transfusion, respectively, within 7 days from screening 
assessment (code 108) 


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  26 September 2022 
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o Increase the minimum value for the estimated glomerular filtration rate (eGFR) to 
≥ 50 mL/min (code 109) 
 
Updated exclusion criteria (Section 5.2) to: 
o Provide a 2-year window from enrollment for diagnosed or treated malignancies 
with potential to interfere with the safety or efficacy assessments of the 
investigational regimen.  Additionally, examples for exceptions to this exclusion 
criterion were listed (code 201) 
o Add pathological findings that must be excluded, such as histology of pure small 
cell, neuroendocrine carcinoma of the prostate and any other histology different 
from adenocarcinoma (code 202)  
o Increase window prior to first dose of study treatment for subjects who have 
undergone major surgical procedures to 28 days.  Provide specific windows from 
first dose of study treatment for subjects that have received radiotherapy and 
include language to define palliative care regarding radiation therapy (code 208 
and Section 6.1.7).   
o Clarify that not all active infections are considered as an exclusion criterion and 
provide specific examples of infections that are permitted if responding to 
treatment (code 209). 
o Update window for major cardiac abnormalities from 12 weeks to within 
12 months of first dose of study treatment and decrease corrected QT 
prolongation to > 470 msec (code 210). 
o Update to align general infection language to the new Bispecific T-cell Engager 
(BiTE®) Covid guide for Phase 1 Protocols of BiTE® Molecules in Early 
Development (code 214). 
 
Updated and clarified information regarding excluded treatments, medical devices, 
and/or procedures during study period (Section 6.1.7).    


Product:  AMG 340 (formerly TNB-585) 
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  26 September 2022 
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 
Clarified dose limiting toxicity (DLT) definition for dose escalation to specify that up to 
3 priming doses of study drug will be equivalent to 1 dose of study drug within the 
duration of the DLT observation period (Section 6.2.1.4.1). 
 
Added a guide for re-start of intravenous (IV) infusion administration in case of infusion 
interruptions or delays due to technical or logistical issues (Section 6.2.2.2). 
 
Included additional guidance regarding management of overdose and for reporting of 
adverse events possibly related to overdose (Section 6.6). 
 
Included guidance for the use of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) vaccines, live vaccines, and live-attenuated vaccines during screening 
and treatment period (Section 6.7.2.1).   
 
Added that as part of the medical history, known prostate cancer (CaP) mutations (eg, 
breast cancer gene 1 [BRCA1] and breast cancer gene 2 [BRCA2]) should also be 
recorded (Section 8.2.3).   
 
Included guidance for conduction of neurological examination as part of the physical 
examination (Section 8.2.4.1).   
 
Included information regarding the process for radiographic assessments to evaluate 
efficacy of AMG 340 treatment (Section 8.3).   
 
Clarified language describing analyses of primary safety endpoints (Section 9.4.2.3.1). 
 
Added an Appendix for RECIST (Response Evaluation Criteria in Solid Tumor) 1.1 with 
Prostate Cancer Working Group 3 (PCWG3) modifications (Appendix 12). 
 
Updated collection and reporting of safety events to align with current procedures 
described in the protocol template (Table 1-1, Table 1-3, Sections 8.4.6.1.1, 8.4.6.1.2, 
8.4.6.1.3, 8.4.6.3, 8.4.6.4, 8.4.6.6, Appendix 11.4, Appendix 11.5).  
 
Administrative, typographical, and formatting changes were made throughout the 
protocol.  


Product:  AMG 340 
Protocol Number:  20210249 
Date:  04 May 2022 
Page 1 of 28 
 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion Study 
of AMG 340, a Bispecific Antibody Targeting PSMA in Subjects with Metastatic 
Castrate-resistant Prostate Carcinoma (mCRPC) 
 
Amgen Protocol Number AMG 340 (formerly TNB-585) 20210249 (formerly TNB585.001) 
NCT Number:  NCT04740034 
Amendment Date: 
04 May 2022 
 
Rationale: 
This protocol is being amended to: 
 
Based on the biological mechanism, non-clinical data and clinical experience, cytokine 
release syndrome (CRS) was designated as an adverse drug reaction.  The protocol is 
being updated with CRS as a key safety risk in Section 2.3.1. 
 
Update with available clinical data for AMG 340 as per Investigator’s Brochure. 
 
Added timepoint to better define the 
 and duration of 
change. 
 
Other minor administrative/editorial corrections to improve readability and clarity of the 
protocol. 


Product:  AMG 340 
Protocol Number:  20210249 
Date:  18 March 2022 
Page 1 of 19 
 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion Study 
of AMG 340, a Bispecific Antibody Targeting PSMA in Subjects with Metastatic 
Castrate-resistant Prostate Carcinoma (mCRPC) 
 
Amgen Protocol Number AMG 340 (formerly TNB-585) 20210249 (formerly TNB585.001) 
NCT Number:  NCT04740034 
Amendment Date: 
18 March 2022 
 
Rationale: 
The main driving force of this amendment was to bring this study into the current Amgen 
protocol template.  The original version (dated 11 December 2020) and Amendment 1 (dated 
21 December 2021) were authored using the TeneoBio protocol template.  All text from these 
versions have been transcribed into the current Amgen protocol template.  Only study-specific 
changes from Amendment 1 to Amendment 2 are described specifically in this document and 
associated tracked changes. 
Other key changes are highlighted below: 
 
The 
 and schedule have been amended to align this study with the 
current Amgen 
 


Product:  AMG 340 
Protocol Number:  20210249 
Date:  21 December 2021 
Page 1 of 1 
 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 1 
Protocol Title:  A Multicenter, Phase 1, Open-label, Dose-escalation and Expansion Study 
of TNB-585, a Bispecific Antibody Targeting PSMA in Subjects with Metastatic 
Castrate-Resistant Prostate Carcinoma 
Amgen Protocol Number AMG 340 Study 20210249 
 
Amendment Date: 
21 December 2021 
 
Rationale: 
This protocol is being amended to optimize safety on the study in accordance with Amgen 
standards and practice.  The following changes are included in this amendment: 
 
Update new contact and reporting information. 
 
Update safety language to align with Amgen standard procedures and practice. 
 
Update CRS mitigation and management measures to reduce CRS incidence and severity.  
 
Update dose escalation plan to investigate priming doses and smaller dose increments 
between dose levels. 
 
Increase sample size in Arm A from 42 subjects to 100 subjects to accommodate 
investigations of intermediate dose levels, and of different priming and target dose 
combinations. 
 
Add language to allow siltuximab use when tocilizumab is not available per FDA guidance 
provided to Amgen. 

SAP_001.pdf: 
Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 1 of 42 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Multicenter, Phase 1, Open-label, Dose-escalation 
and Expansion Study of AMG 340, a Bispecific 
Antibody Targeting PSMA in Subjects with 
Metastatic Castrate-resistant Prostate Carcinoma 
(mCRPC) 
Short Protocol Title: 
Open-label, Dose-escalation, and Expansion Study 
of AMG 340 in Subjects with Metastatic Castrate-
resistant Prostate Carcinoma 
Protocol Number: 
20210249 (formerly TNB585.001) 
NCT Number: 
NCT04740034 
Authors: 
 (Parexel) 
 (Parexel) 
(Amgen) 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
17 February 2023 
Amendment 1 (v2.0) 
31 July 2024 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
17FEB2023 
NA 
Amendment 1 (v2.0) 
31JUL2024 
 
Updates in definition of treatment 
emergent adverse event (Section 
5.1.1). 
 
 
 
Updates in definitions of RECIST 
1.1 evaluable analysis set and 
PSA response evaluable analysis 
Set (Section 6.3). 
 
 
 
Listings for ECOG is removed 
(Section 9.6.4), updates in 
exposure to IP (Section 9.6.8) 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 2 of 42 
CONFIDENTIAL  
 
 
 
 
 
Updates in primary analysis text 
(Section 7.2) 
 
 
 
Updates in changes from protocol 
specified analyses (Section 10) 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 3 of 42 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ............................................................................................................ 3 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.2 
Sample Size .............................................................................................. 11 
4. 
Covariates and Subgroups ................................................................................... 11 
4.1 
Planned Covariates ................................................................................... 11 
4.2 
Subgroups ................................................................................................. 11 
5. 
Definitions ............................................................................................................. 12 
5.1 
Study Endpoints ........................................................................................ 12 
5.1.1 
Primary Endpoints Definitions .................................................... 12 
5.1.2 
Secondary Endpoints Definitions ............................................... 12 
5.2 
Study Time Points ..................................................................................... 15 
5.3 
Demographics and Baseline Related Definitions ....................................... 16 
6. 
Analysis Sets ........................................................................................................ 17 
6.1 
Safety Analysis Set ................................................................................... 17 
6.2 
Pharmacokinetic/
 Analyses Set .................................... 17 
6.3 
Study-specific Analysis Sets...................................................................... 17 
6.3.1 
RECIST 1.1 Evaluable Analysis Set .......................................... 17 
6.3.2 
PSA Response Evaluable Analysis Set ..................................... 17 
6.3.3 
DLT Evaluable Analysis Set ...................................................... 18 
7. 
Planned Analyses ................................................................................................. 18 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 18 
7.2 
Primary Analysis ....................................................................................... 19 
7.3 
Final Analysis ............................................................................................ 19 
8. 
Data Screening and Acceptance ........................................................................... 19 
8.1 
General Principles ..................................................................................... 19 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 19 
8.3 
Handling of Missing and Incomplete Data ................................................. 20 
8.4 
Detection of Bias ....................................................................................... 20 
8.5 
Outliers ..................................................................................................... 20 
8.6 
Distributional Characteristics ..................................................................... 20 
8.7 
Validation of Statistical Analyses ............................................................... 20 
9. 
Statistical Methods of Analysis.............................................................................. 21 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
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CONFIDENTIAL  
 
 
9.1 
General Considerations ............................................................................. 21 
9.2 
Subject Accountability ............................................................................... 21 
9.3 
Important Protocol Deviations ................................................................... 21 
9.4 
Demographic and Baseline Characteristics ............................................... 22 
9.5 
Efficacy Analyses ...................................................................................... 22 
9.5.1 
Analyses of Primary Efficacy Endpoints ..................................... 22 
9.5.2 
Analyses of Secondary Efficacy Endpoints ................................ 22 
9.5.3 
Analyses of Exploratory Efficacy Endpoint ................................. 24 
9.6 
Safety Analyses ........................................................................................ 25 
9.6.1 
Analyses of Primary Safety Endpoints ....................................... 25 
9.6.2 
Adverse Events ......................................................................... 25 
9.6.3 
Laboratory Test Results ............................................................ 26 
9.6.4 
Vital Signs ................................................................................. 26 
9.6.5 
Physical Measurements ............................................................ 26 
9.6.6 
Electrocardiogram ..................................................................... 26 
9.6.7 
Antibody Formation ................................................................... 26 
9.6.8 
Exposure to Investigational Product .......................................... 26 
9.6.9 
Exposure to Other Protocol-required Therapy ........................... 27 
9.6.10 
Exposure to Concomitant Medication ........................................ 27 
9.7 
Other Analyses ......................................................................................... 27 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/
 Endpoints ......................... 27 
10. 
Changes From Protocol-specified Analyses.......................................................... 28 
11. 
Literature Citations / References ........................................................................... 28 
12. 
Prioritization of Analyses....................................................................................... 28 
13. 
Data Not Covered by This Plan............................................................................. 28 
14. 
Appendices ........................................................................................................... 29 
 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 5 of 42 
CONFIDENTIAL  
 
 
List of Tables 
Table 3-1. Dose Escalation and De-escalation Boundaries ............................................. 8 
Table 7-1. The Criteria for Evaluating the Use of Siltuximab .......................................... 17 
Table 9-1.  Secondary Efficacy Endpoints Summary Table ........................................... 21 
Table 9-2.  Exploratory Efficacy Endpoints Summary Table .......................................... 23 
Table 9-3.  Safety Endpoint Summary Table ................................................................. 23 
Table 14-1.  Confirmed BOR per RECIST 1.1 where Confirmation of CR/PR 
is Required ............................................................................................. 30 
 
Table 14-3.  Bone Progression Status as per PCWG3 .................................................. 34 
Table 14-4.  Radiographic Progression by RECIST 1.1 with PCWG3 
Modifications .......................................................................................... 35 
 
List of Figures 
No table of figures entries found. 
 
 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 6 of 42 
CONFIDENTIAL  
 
 
List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
Adverse event 
AUC 
Area under the concentration-time curve 
AUCt 
Area under the serum concentration-time curve from time zero to 
time of last measurable concentration 
BOIN 
Bayesian optimal interval 
CI 
Confidence interval 
Cmax 
Maximum observed serum concentration 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRS 
Cytokine release syndrome 
CT 
Computerized tomography 
CTCAE 
Common terminology criteria for adverse events 
DLRM 
Dose level review meeting 
DLRT 
Dose level review team 
DLT 
Dose limiting toxicity  
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EOI 
End of infusion 
EOT 
End of treatment 
18F-FDG 
18F-Fluorodeoxyglucose 
FIH 
First-in-human  
LPLV 
Last patient last visit 
mCRPC 
Metastatic castrate-resistant prostate carcinoma 
MedDRA 
Medical dictionary for regulatory activities 
MRI 
Magnetic Resonance Imaging 
99mTc MDP 
99mtechnetium methylene diphosphonate 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
PCWG3 
Prostate cancer working group 3 
PET 
Positron emission tomography 
PSA 
Prostate-specific antigen 
PSMA 
Prostate-specific membrane antigen 
Q3W 
Once every 3 weeks 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended phase 2 dose  
SSE 
Symptomatic skeletal event 
t1/2 or T1/2 
Terminal half-life 
TLS 
Tumor lysis syndrome 
Tmax 
Time to maximum observed serum concentration 
 
 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 7 of 42 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 5 for study 20210249 
(formerly TNB585.001), AMG 340 (formerly TNB-585) dated 07 December 2022. The 
scope of this plan includes the final analysis that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the safety and tolerability 
of AMG 340 when administered as 
monotherapy. 
 
Treatment-emergent adverse 
events 
 
Treatment-related adverse events 
 
Changes in vital signs and clinical 
laboratory tests 
 
Determine the maximum tolerated 
dose (MTD) or recommended 
phase 2 dose (RP2D) for 
AMG 340 when administered as 
monotherapy. 
 
Dose-limiting toxicities (DLTs) 
 
Evaluate the pharmacokinetics 
(PK) of AMG 340 when 
administered as monotherapy. 
 
PK parameters of AMG 340 
including, but not limited to: 
 Cmax 
 Time to Cmax (Tmax) 
 Area under the 
concentration-time curve within 
a dosing interval (AUC0-t) 
Secondary 
 
Evaluate the clinical activity of 
AMG 340 when administered as 
monotherapy. 
 
Objective response (OR) per 
RECIST 1.1 
 
Overall survival (OS) 
 
Progression-free survival (PFS) 
(radiographic and PSA) 
 
6-month landmark radiographic 
PFS 
 
PSA response (30%, 50%, 70% 
and 90%) 
 
Time to progression (radiographic 
and PSA) 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 8 of 42 
CONFIDENTIAL  
 
 
 
Duration of response (DOR) per 
RECIST 1.1 
 
PSA DOR based on PSA50 
 
Time to symptomatic skeletal 
events (SSE) 
 
 
Exploratory 
 
Evaluate immunogenicity of 
AMG 340 
 
Incidence of anti-AMG 340 
antibody formation 
 
2.2 
Hypotheses and/or Estimations 
In Part A, a safe and tolerable dose of AMG 340 will have evidence of anti-tumor activity 
in subjects with mCRPC as measured by objective response rate (ORR). In Part B, 
AMG 340 will improve ORR in subjects with mCRPC to 20% compared with the 
reference ORR of 5%. 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1 open-label, dose-escalation and expansion study evaluating the safety, 
PK, PD, and clinical activity of AMG 340 in subjects with progressive mCRPC who have 
received at least 2 or more prior lines of systemic therapy (‘Line/regimen of therapy’ is 
defined as a course of therapy [at least 1 cycle uninterrupted by progressive disease, 
cycle disruption due to toxicity or intolerance is acceptable]). To be eligible for enrollment 
in this study, subjects should have previously been exposed to, intolerant of, ineligible 
for, or declined therapy with both a novel anti-androgen (e.g., abiraterone, enzalutamide) 
and a taxane (e.g., docetaxel). 
The study will consist of 2 parts:  


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 9 of 42 
CONFIDENTIAL  
 
 
 
a monotherapy dose escalation (Part A) and  
 
a monotherapy dose expansion (Part B). 
Part A: Monotherapy Dose Escalation: 
Part A was initiated and employs a dose escalation design to evaluate the safety, 
tolerability, PK and PD profiles of single-agent AMG 340 administered Q3W. Up to 
60 subjects with progressive mCRPC who have received at least 2 prior lines of therapy 
will be enrolled in Part A. Subjects should have previously been exposed to, intolerant 
of, ineligible for, or declined therapy with both a novel anti-androgen (e.g., abiraterone, 
enzalutamide) and a taxane (e.g., docetaxel). In Part A, cohorts have initially enrolled 
single subjects (Yuan et al, 2016). Proposed dose levels for AMG 340 are outlined in 
 but the number of dose levels tested will depend on safety, PK/PD, and 
activity data. 
Upon the first occurrence of a grade ≥ 2 adverse event that is not unequivocally due to 
the subject’s underlying malignancy or other extraneous cause, the corresponding 
cohort, and all subsequent cohorts in Part A, will be enrolled according to a BOIN design 
with the target toxicity rate of 30%. Cohorts will enroll a minimum of 3 subjects; up to 
6 subjects may be enrolled concurrently (if transition from single subject cohorts to BOIN 
is triggered by a DLT, 6 subjects will be enrolled in that cohort). A maximum of 
60 subjects will be enrolled in Part A. No more than 2 subjects should be dosed on the 
same day when enrolling new cohorts. Following the first assessment of BOIN dose 
escalation/de-escalation at a given dose level, additional subjects may be enrolled 
according to the BOIN criteria (Yuan et al, 2016). 
If a response (partial response [PR] or complete response [CR]) is observed in a single 
subject cohort, cohorts enrolling thereafter will follow a BOIN design as above. The 
BOIN dose escalation and de-escalation boundaries (λe of 0.236 and a λd of 0.358) are 
shown in Table 3-1.  
Table 3-1. Dose Escalation and De-escalation Boundaries 
 
Number of subjects treated at current dose cohort 
Actions 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Escalate if # of DLTs ≤ 
0 
0 
0 
0 
1 
1 
1 
1 
2 
2 
De-escalate if # of DLTs ≥ 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
DLT = dose limiting toxicity 
Source:  Yuan et al, 2016 


Product:  AMG 340 (formerly TNB-585)  
Protocol Number:  20210249 (formerly TNB585.001) 
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Page 10 of 42 
CONFIDENTIAL  
 
 
Dose escalation has been started as planned with a Q3W dosing schedule, which may 
be altered after cumulative review of safety and PK data and a protocol amendment.   
Administration of the first dose of AMG 340 to the first subject in each cohort must await 
completion of the first cycle (3 weeks) of the prior dose level, and a review of the safety 
data by the Dose Level Review Team (DLRT) (formerly referred to as the Safety 
Monitoring Group [SMG]). Input from biostatistical, PK and other experts will be sought 
as necessary. Cohorts Na (where N represents a Cohort number), b, c, etc. may be 
conducted in parallel. Not all dose level cohorts may be enrolled based on emerging 
safety data. 
Based on the DLRT’s ongoing review of emerging safety, PK/PD and clinical activity 
data, cohorts receiving intermediate doses between those proposed above may be 
implemented. Furthermore, it may become necessary to switch to an alternative dosing 
regimen. If the dosing schedule is switched, no dose modification should result in a 


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Protocol Number:  20210249 (formerly TNB585.001) 
Date:  31 July 2024 
Page 11 of 42 
CONFIDENTIAL  
 
 
predicted steady state trough Cmax, or AUC greater than that identified for the 
immediately prior lower dose level. 
Part B: Monotherapy Dose Expansion: 
Part B will evaluate the MTD (or RP2D) of AMG 340 monotherapy in up to 40 subjects 
with biopsy-proven progressive mCRPC. To be eligible for this study, subjects should 
have previously been exposed to, intolerant of, ineligible for, or declined therapy with 
both a novel anti-androgen (e.g., abiraterone, enzalutamide) and a taxane (e.g., 
docetaxel). Part B will be initiated once the MTD (or RP2D) has been selected based on 
data from the Part A. The MTD (or RP2D) and dosing frequency for Part B will be 
chosen by the DLRT based on safety, tolerability, PK/PD, and clinical activity data 
collected during the dose escalation portion of the study. 
3.2 
Sample Size 
In Part A, at least 3 subjects are planned for enrollment into each cohort, with the goal of 
determining the MTD and/or RP2D of AMG 340.  Approximately 60 subjects are 
anticipated in Part A; however, the total number of subjects in Part A will depend upon 
the occurrence of DLT events and how dose escalation progresses.  If the unknown true 
toxicity rate/DLT rate is 33% in a given cohort, at least 2 DLTs are likely to be observed. 
In Part B, up to 40 subjects will be enrolled to further evaluate safety and tolerability, to 
explore activity of AMG 340 and to evaluate the relationship between PD markers and 
PK, safety and clinical response.  A sample size of 40 subjects was selected to achieve 
92% power for testing the hypothesis on ORR at 1-sided alpha of 0.1 using the binomial 
exact test. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable for this study. 
4.2 
Subgroups 


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5. 
Definitions 
5.1 
Study Endpoints  
5.1.1 
Primary Endpoints Definitions 
Treatment-Emergent Adverse Event (TEAE): 
Events categorized as Adverse Events (AEs) starting on or after the first dose of AMG 
340 as determined by “Did event start before first dose of AMG 340” equal to “No” or 
missing on the Adverse Events eCRF and up to and including 90 days after the last 
dose of AMG 340 (however, if subject start a new line of therapy before 90 days follow-
up visit, safety follow-up will be performed through 30 days post last dose of AMG 340 or 
until subject begins a new line of therapy, whichever occurs later) excluding events 
reported after End of Study Date. Events that are directly related to metastatic 
castrate-resistant prostate carcinoma cancer or disease progression (including, 
but not limited to, preferred terms “prostate cancer”, “progression of prostate 
cancer”, “prostate cancer metastatic”, “disease progression” etc.) will be 
excluded from TEAE analysis. 
Treatment-Related Adverse Event (TRAE): 
A treatment-related AE is any treatment-emergent AE with the relationship flag on the 
Adverse Events eCRF indicating there is a reasonable possibility that the event may 
have been caused by AMG 340. In the unlikely event that the relationship is missing, the 
treatment-emergent event will be considered treatment-related and documented in a 
footnote of the treatment-related summary.  
Dose-limiting Toxicities (DLTs): 
Investigators determine whether a TEAE qualifies as a DLT per the definition described 
in protocol section 6.2.1.4.1. For an adverse event to qualify as DLT, the start date must 
be within 21 days from the date of first dose of AMG 340.  
5.1.2 
Secondary Endpoints Definitions  
Objective Response per RECIST 1.1 (OR): 
OR is defined as a partial response (PR) or complete response (CR) per RECIST 1.1, 
confirmed by a repeat assessment at least 4 weeks later. Subjects who do not 
experience a confirmed PR/CR or do not have any follow-up tumor assessments will be 
regarded as non-responders. This endpoint applies only to subjects with measurable 
baseline disease per RECIST 1.1.  
Details for derivation of Objective Response per RECIST 1.1 are described in Appendix 
B. 


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Overall Survival: 
Overall survival is defined as the time from the date of Study Day 1 until death due to 
any cause:  
OS time (Days) = date of death - Study Day 1 + 1.  
Any subject not known to have died at the time of analysis will be censored based on the 
last recorded date on which the subject was alive.  
PSA Progression: 
PSA progression is defined as per PCWG3.  
 
After a decline in PSA from baseline to post-treatment, a PSA increase of ≥ 25% and 
≥ 2 ng/mL above the nadir (the lowest value up to the assessed visit date). This PSA 
progression must be confirmed by a second consecutive value ≥ 3 weeks later.  
 
No decline in PSA from baseline, a PSA increase of ≥ 25% and ≥ 2 ng/mL from 
baseline at or beyond 12 weeks after treatment initiation.  
Radiographic Progression: 
A radiographic progression occurs if either of the following occurs: 
 
Progressive disease per RECIST 1.1 occurs.  
 
Bone disease progression as per PCWG3 occurs. Bone disease progression for the 
first post-treatment bone scan (e.g. Week 8) showing two or more additional lesions 
relative to screening/baseline must be confirmed by the next bone scan (e.g. Week 
16) showing two or more additional lesions relative to first post-treatment bone scan 
(e.g. Week 8) at least 6 weeks later. Bone disease progression for scans after the 
first post-treatment scan (e.g. Week 16) showing two or more additional lesions 
relative to the first post-treatment bone scan (e.g. Week 8) can be confirmed by 
second scan showing persistence of the additional lesion relative to the first post-
treatment scan (e.g. Week 8) at least 6 weeks later.  
PSA Progression-free Survival (PSA PFS): 
PSA PFS is defined as the interval from Study Day 1 to the earlier of a PSA progression 
or death from any cause; otherwise, PSA PFS is censored on the date of the last PSA 
measurement. If a subject has no baseline or post-baseline PSA measurement and a 
vital status of alive or unknown, PSA PFS will be censored at Study Day 1.  
More details about censoring rules are included in Appendix D.  


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Radiographic Progression-free Survival (rPFS): 
rPFS is defined as the interval from Study Day 1 to the earlier of a radiographic 
progression or death from any cause; otherwise, rPFS is censored based on the criteria 
in Appendix D. 
PSA Response (PSA 30):  
A PSA response (PSA30) is defined as a ≥ 30% decrease below baseline confirmed by 
a second consecutive value obtained 3 or more weeks later. An increase in PSA in the 
first 12 weeks does not preclude a response thereafter. Only subjects with measurable 
(i.e., > 0) baseline PSA will be evaluated for PSA response.  
PSA Response (PSA 50):  
A PSA response (PSA50) is defined as a ≥ 50% decrease below baseline confirmed by 
a second consecutive value obtained 3 or more weeks later. An increase in PSA in the 
first 12 weeks does not preclude a response thereafter. Only subjects with measurable 
(i.e., > 0) baseline PSA will be evaluated for PSA response. 
PSA Response (PSA 70):  
A PSA response (PSA70) is defined as a ≥ 70% decrease below baseline confirmed by 
a second consecutive value obtained 3 or more weeks later. An increase in PSA in the 
first 12 weeks does not preclude a response thereafter. Only subjects with measurable 
(i.e., > 0) baseline PSA will be evaluated for PSA response. 
PSA Response (PSA 90):  
A PSA response (PSA90) is defined as a ≥ 90% decrease below baseline confirmed by 
a second consecutive value obtained 3 or more weeks later. An increase in PSA in the 
first 12 weeks does not preclude a response thereafter. Only subjects with measurable 
(i.e., > 0) baseline PSA will be evaluated for PSA response. 
Time to PSA Progression:  
Time to PSA progression is defined as the interval from Study Day 1 to PSA 
progression; otherwise, time to PSA progression is censored based on the criteria in 
Appendix D.  
Time to Radiographic Progression:  
Time to radiographic progression is defined as the interval from Study Day 1 to 
radiographic progression; otherwise, time to radiographic progression is censored based 
on the criteria in Appendix D. 


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Duration of Response (DOR) per RECIST 1.1: 
DOR is defined as the time from the date of an initial objective response per RECIST 
1.1, which was subsequently confirmed, to the earlier of soft-tissue progression per 
RECIST 1.1 or death. Subjects who have not ended their response at the time of 
analysis will have DOR censored at their last evaluable tumor assessment by CT/MRI 
scan. This endpoint only applies to subjects with an objective response per RECIST 1.1. 
Duration of PSA Response (PSA DOR): 
PSA DOR is defined as the time from the date of initial PSA response (PSA 50), which 
was subsequently confirmed, to the earlier of PSA progression or death. Subjects who 
have not ended their response at the time of analysis will have PSA DOR censored on 
the date of their last PSA measurement. The endpoint only applies to subjects with a 
PSA response (PSA 50).  
Details about the censoring rules are included in Appendix D. 
Time to Symptomatic Skeletal Events: 
Time to SSE is defined as time from Study Day 1 to the first SSE. Otherwise, SSE is 
censored at the last dose date of investigational product (AMG 340) or end of safety 
follow-up date, whichever is later.  
A Symptomatic Skeletal Event (SSE) is defined as any of the following which is collected 
on the Adverse Events eCRF: 
For Part A of the study, a list of preferred terms will be identified at the time of analysis 
for what constitutes an SSE.  
For Part B: there is a separate event categories to identify them 
 
A symptomatic fracture which is any adverse event of fracture (ankle, hip, spinal, 
wrist or other) per CTCAE version 5.0.  
 
Radiation or surgery to bone. 
 
Spinal cord compression.  
5.2 
Study Time Points  
Study Day 1: 
Study Day 1 is defined as the date of the first dose of the AMG 340 administered to the 
subject.  


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End of Treatment: 
End of treatment is defined as the date the decision was made to end of AMG 340 as 
recorded on the End of Treatment Status eCRF page.  
End of Study for Individual Subject: 
End of study for individual subject is defined as the date of the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study eCRF page.  
End of Study: 
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 (i.e., Last subject last 
visit), following any additional parts in the study (e.g., long-term follow-up), as applicable. 
Safety follow-up Visit: 
Safety follow-up visit is defined as upon permanent discontinuation from the study 
treatment for any reason, a safety follow-up visit will be performed approximately  
90 (+7) days after the end of the last dose of AMG 340 and/or product required 
therapies. However if subject starts a new line of therapy before 90 (+7) days follow-up 
visit, safety follow-up will be performed through 30 days post last dose of AMG 340 or 
until the subject begins a new line of therapy, whichever occurs later. 
Long-term follow-up Visit: 
Subjects will be followed for survival and/or the commencement of subsequent therapy 
via clinic visit, telephone, or chart review call every 6 months from the SFU visit for up to 
a maximum 3 years.  
5.3 
Demographics and Baseline Related Definitions  
Age at enrollment: 
Subject age at enrollment will be collected in years reported in the Demographics eCRF. 
Baseline: 
The baseline is defined as the last non-missing value on or prior to the pre-dose of AMG 
340 assessments on cycle 1 day 1.  
Change from Baseline:  
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline.  
Change from Baseline = (Post-baseline Value – Baseline Value). 


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Percent Change from Baseline: 
Percent change from baseline is the arithmetic difference between post-baseline and 
baseline divided by baseline values times 100.  
Change (Percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline 
Value] x 100. 
6. 
Analysis Sets 
6.1 
Safety Analysis Set 
Safety analysis set defined as all subjects who have received at least 1 dose of AMG 
340. 
6.2 
Pharmacokinetic/
 Analyses Set 
The Pharmacokinetic (PK) Analysis Set will include all subjects who have received at 
least 1 dose of AMG 340 and have at least 1 PK sample drawn post dose. These 
subjects will be evaluated for PK Analysis unless the number of data points required for 
analysis is not enough, or significant protocol deviations have affected the data, or if key 
dosing or sampling information is missing. The PK Analysis set will be used to conduct 
the analysis of PK data, unless otherwise specified. 
6.3 
Study-specific Analysis Sets 
6.3.1 
RECIST 1.1 Evaluable Analysis Set 
RECIST 1.1 Evaluable Analysis Set is defined as all subjects who have received at least 
1 dose of AMG 340, have measurable disease per RECIST 1.1 at baseline, and have 
the opportunity to be followed for at least 6 weeks from start of AMG 340 treatment. 
Subjects who stopped disease assessments prior to 6 weeks will be included in this 
analysis set if the data snapshot date is at least 6 weeks after their first study dose 
date.  
This analysis set is used for the analysis of the radiographic-measured endpoints of 
objective response and duration of response (radiographic). 
6.3.2 
PSA Response Evaluable Analysis Set 
PSA Response Evaluable Analysis Set is defined as all subjects who have received at 
least 1 dose of AMG 340, have a measurable (i.e., > 0) PSA at baseline, and have the 
opportunity to be followed for at least 9 weeks from start of AMG 340 treatment. 
Subjects who stopped disease assessments prior to 9 weeks will be included in this 
analysis set if the data snapshot date is at least 9 weeks after their first study dose 
date.  


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This analysis set is used for the analysis of PSA-measured endpoints that are PSA 
responses, PSA duration of response. 
6.3.3 
DLT Evaluable Analysis Set  
DLT Evaluable Analysis Set defined as all subjects who are evaluable for DLTs. A 
subject is considered DLT evaluable if the subject has completed at least the first full 
treatment cycle or experienced a DLT during the first treatment cycle. This applies only 
for dose exploration part. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Amgen will conduct evaluations of the treatment and outcome of the CRS events treated 
with siltuximab on an ongoing basis to assess if the threshold for pausing siltuximab 
treatment has been reached as outlined in the table below. If these stopping rules are 
met, an adhoc DLRT will be triggered to review safety data and available PK, PD, and 
efficacy data. If recommended by DLRT, the use of siltuximab will resume. The stopping 
rules to trigger an adhoc DLRT to review siltuximab treatment use a Bayesian approach 
proposed by Thall, et al (1995); an adhoc DLRT will be triggered if the posterior 
probability that the CRS progression to grade 3 rate is greater than 30% is > 80% or the 
posterior probability that the CRS progression to grade 4 rate is greater than 10% is 
>80%; or observation of any grade 5 CRS after the event has been treated with 
siltuximab. The stopping boundaries presented below assume a prior distribution of Beta 
(0.6, 1.4) for progression to grade 3 CRS and a prior distribution of Beta (0.2, 1.8) for 
progression to grade 4 CRS. The evaluations could occur more frequently if necessary 
to address emerging safety concerns. If the triggered ad hoc DLRT coincide with regular 
DLRT, they may be combined. 


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Table 7-1. 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 the number of subjects with 
severity of CRS progressed to 
Grade 3 after being treated with 
siltuximab is 
Or the number of subjects with 
severity of CRS progressed to 
Grade 4 after being treated with 
siltuximab is 
5 
≥ 3 
≥ 2 
10 
≥ 5 
≥ 3 
15 
≥ 7 
≥ 3 
20 
≥ 8 
≥ 4 
25 
≥ 10 
≥ 5 
30 
≥ 12 
≥ 5 
35 
≥ 13 
≥ 6 
40 
≥ 15 
≥ 6 
CRS = cytokine release syndrome; DLRM = dose level review meeting 
7.2 
Primary Analysis 
The primary analysis will occur 6 months following the enrollment of the last subject in 
Arm B. The data will be analyzed once they have been entered, cleaned, and locked. If 
we do not proceed with Arm B of the study, the primary analysis will be combined 
with the final analysis. 
7.3 
Final Analysis 
The final analysis will occur after all subjects have ended the study. The data will be 
analyzed once they have entered, cleaned, and locked. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
receive and store all data to be used in the planned analyses. This study will use the 
RAVE database and pharmacokinetics, antibody, biomarkers, and central lab data 
outside of RAVE database. The database will be subjected to edit check outlined in the 
Data Management Plan (DMP). Additional details will be provided in the DMP and Data 
Acquisition Requirements Specification (DARS). 


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8.3 
Handling of Missing and Incomplete Data 
Subjects may miss specific data points for a variety of causes. In general, data could be 
missing due to a subject’s early withdrawal from the study, a missed visit or inability to 
evaluate an endpoint at a particular point in time.  
In general, the safety analysis set will be used without any imputation for missing data 
for the primary and secondary endpoints. Missing safety endpoints and antibody data 
will not be imputed, except for adverse events, concomitant medications, and death date 
as described in 
 
PK concentrations that are below the quantification limits will be set to zero when 
included in the non-compartmental model to compute PK parameters. 
Missing or incomplete dates will be listed unless imputed as follows. An incomplete start 
date of an adverse event or concomitant medication taken will be handled by rules 
mentioned in 
 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations. The clinical study 
team will identify and document the criteria for important protocol deviations. 
8.5 
Outliers 
Pharmacokinetic (PK) concentration data will be evaluated for outliers by visual 
inspection, and decision to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice.  
Descriptive statistics will be used to identify potential outliers in key variables. Suspected 
outliers will be included in the analyses unless there is sufficient scientific justification to 
exclude them.  
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   


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Tables, figures, and listings will be produced and validated in accordance with 
. Standard macros will be used when available.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety 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. 
9.2 
Subject Accountability 
The number and percent of subjects who were enrolled received AMG 340, completed 
AMG 340, discontinued from AMG 340 and reasons for discontinuing, completed study, 
discontinued study and reasons for discontinuing, will be summarized by cohort. 
The number of subjects who signed informed consent but were not enrolled into the 
study will be tabulated by reason.  
Key study dates for the first subject enrolled, last subject enrolled, last subject’s end of 
AMG 340 and last subject's end of study will be presented. 
The number and percent of subjects enrolled will be tabulated by study site. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study. The final IPD list is used to 
produce the summary of the IPDs table and list the subjects with IPDs. In addition, a 
separate listing of all inclusion and exclusion deviations will be provided. Important 
protocol deviations thought to potentially impact the safety of subjects or the 
interpretation of the analyses will be listed and tabulated using incidence and 
percentages by deviation type. 


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The number of subjects reporting Protocol Deviation due to COVID-19 will be 
summarized in a table. A protocol deviation listing of subjects impacted due to COVID-
19 will also be provided. 
9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of demographics and baseline characteristics will 
be summarized.  
Demographics: 
 
Age (years) at enrollment (continuous summary statistics)  
 
Age categories (number and percentages of subjects < 65, ≥ 65, ≥ 75, and ≥ 85 
years) 
 
Race (number and percentages of subjects in each category) 
 
Ethnicity (number and percentages of subjects in each category) 
Baseline characteristics: 
 
Height and Weight (continuous summary statistics) 
 
ECOG performance status (frequency and percentages) 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoints 
Not applicable to this study. 
9.5.2 
Analyses of Secondary Efficacy Endpoints 
Analyses of secondary efficacy endpoints are defined in Table 9-1. Listings may be 
provided instead if the number of subjects for analysis is small.  
Table 9-1.  Secondary Efficacy Endpoints Summary Table 
Endpoint 
Statistical Analysis  
Analysis Set 
Objective Response per 
RECIST 1.1 
The proportion and subjects with an 
objective response per RECIST 1.1 
along with the corresponding exact 
95% CI will be calculated using the 
Clopper-Pearson method (Clopper 
and Pearson, 1934).  
 
Waterfall plots for the maximum 
percent decrease from baseline in 
RECIST 1.1 Evaluable 
Analysis Set 
 
 
 
 
RECIST 1.1 Evaluable 
analysis set and 
applicable for all subjects 
with baseline measurable 


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Endpoint 
Statistical Analysis  
Analysis Set 
sums of longest diameter will also be 
provided.  
disease and with both a 
baseline at least one post-
baseline evaluable tumor 
response assessment.  
Overall Survival 
The overall survival will be estimated 
using the Kaplan-Meier curve and 
95% CI using Greenwood’s formula 
to estimate the standard error of the 
landmark estimates, see Kalbfleisch, 
J.D. and Prentice, R. L. (Kalbfleisch 
and Prentice, 1980). 
 
Safety Analysis Set 
Progression Free 
Survival PSA 
The median and other percentiles as 
appropriate, will be presented using 
the Kaplan-Meier curve and 95% CI 
using the Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) 
method.  
Safety Analysis Set 
Progression Free 
Survival Radiographic 
The median and other percentiles as 
appropriate, will be presented using 
the Kaplan-Meier curve and 95% CI 
using the Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) 
method. 
Safety Analysis Set 
PSA Response (30%, 
50%, 70%, and 90%) 
The proportion of subjects with PSA 
response (≥ 30%, ≥ 50%, ≥ 70%, 
and ≥ 90% decrease from baseline) 
and 95% CI calculated by Clopper 
and Pearson method (Clopper and 
Pearson, 1934) will be reported.  
 
Waterfall plot for maximum percent 
decrease from baseline PSA will be 
presented. 
PSA Response Evaluable 
Analysis Set 
 
 
 
 
PSA Response Evaluable 
analysis set and 
applicable to all subjects 
with a measurable 
baseline PSA and at least 
one post-baseline 
measurable PSA 
assessment 
6-month landmark rPFS 
A 6 month landmark rPFS will be 
provided as a 6 month estimate of 
rPFS. 
Safety Analysis Set 
Time to PSA Progression  The median and other percentiles as 
appropriate, will be presented using 
the Kaplan-Meier curve and 95% CI 
using the Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) 
method. 
Safety Analysis Set 


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Endpoint 
Statistical Analysis  
Analysis Set 
Time to Radiographic 
Progression  
The median and other percentiles as 
appropriate, will be presented using 
the Kaplan-Meier curve and 95% CI 
using the Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) 
method. 
Safety Analysis Set 
Duration of Response per 
RECIST 1.1 
Descriptive statistics will be 
presented. If more than 10 subjects 
experience a Radiographic 
response, then the following will be 
done.  
The median and other percentiles as 
appropriate, will be presented using 
the Kaplan-Meier curve and 95% CI 
using the Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) 
method. 
RECIST 1.1 Evaluable 
Analysis Set – Objective 
Responders  
Duration of Response 
PSA50 
Descriptive statistics will be 
presented. If more than 10 subjects 
experience a PSA response 
(PSA50), then the following will be 
done.  
The median and other percentiles as 
appropriate, will be presented using 
the Kaplan-Meier curve and 95% CI 
using the Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) 
method. 
PSA Response Evaluable 
Analysis Set – PSA 
Responders 
Time to Symptomatic 
Skeletal Events 
Descriptive statistics will be 
presented. If more than 10 subjects 
experience a Symptomatic Skeletal 
events, then the following will be 
done.  
The median and other percentiles as 
appropriate, will be presented using 
the Kaplan-Meier curve and 95% CI 
using the Brookmeyer and Crowley 
(Brookmeyer and Crowley, 1982) 
method. 
Safety Analysis Set 
 
9.5.3 
Analyses of Exploratory Efficacy Endpoint 
The analysis of exploratory efficacy endpoints are defined in Table 9-2.  


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Table 9-2.  Exploratory Efficacy Endpoints Summary Table  
Endpoint 
Statistical Analysis 
Incidence of anti-AMG 340 antibody 
formation 
If available, the incidence and percentage of 
subjects who develop binding anti-AMG 340 
antibodies at any time will be tabulated by planned 
dose level. 
 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoints 
 
Table 9-3.  Safety Endpoint Summary Table 
Endpoint 
Statistical Analysis Method 
Analysis Set 
Dose Limiting 
Toxicities 
(DLTs) 
Subject incidence of DLT will be 
tabulated by planned dose level. A table 
of DLTs will be provided.  
DLT Evaluable Analysis Set 
 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
Subject incidence of all treatment-emergent adverse events and treatment-related 
adverse events will be tabulated by system organ class, preferred term and CTCAE 
grade. Tables of fatal adverse events, serious adverse events and adverse events 
leading to withdrawal of AMG 340 by system organ class and preferred term will be 
summarized.  
The severity of each adverse event will be graded using CTCAE version 5.0 with the 
exception of CRS, TLS, and ICANS. 
CRS must be graded as per ASTCT referenced by Lee et al, 2019, TLS must be graded 
using the criteria referenced by Coiffier et al, 2008 and ICANS must be graded by using 
the criteria referenced by Lee et al, 2019. 


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The adverse events of interest (CRS) will be summarized by preferred term and 
worst grade. 
9.6.3 
Laboratory Test Results 
Clinical laboratory data will be reviewed and selected laboratory parameters of interest 
may be plotted. Depending on the size and scope of changes in laboratory data, the 
analyses of safety laboratory endpoints may include summary statistics over time and/or 
changes from baseline over time. Shifts in grades of safety laboratory values from 
baseline for selected laboratory values may also be provided. 
9.6.4 
Vital Signs 
Vital signs data will be reviewed for each subject. The analyses of vital signs for every 
subject will include summary statistics over time and/or changes from baseline over time 
will be provided. 
ECOG performance status scores will be summarized for each treatment group at each 
assessed timepoints. Shifts in scores for ECOG performance status scores between 
baseline and each assessed timepoint will be tabulated. 
9.6.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at baseline. 
9.6.6 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QT interval corrected (QTc) effect. Since these evaluations may 
not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data; summaries and statistical analyses of ECG 
measurements are not planned, and these data would not be expected to be useful for 
meta-analysis with data from other trials. 
9.6.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-AMG 340 antibodies at any 
time will be tabulated overall and by planned dose level. 
9.6.8 
Exposure to Investigational Product 
Details of AMG 340 administration will be listed for every subject. A listing of unique 
manufacturing lot numbers and a listing of the subjects administered each manufacturing 
lot number will be provided.  


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Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. 
Descriptive statistics of the duration of usage, number of cycles, cumulative (total) 
dose, duration of exposure (months), number and percentage of subjects with dose 
modifications and interruptions will be described. 
9.6.9 
Exposure to Other Protocol-required Therapy 
All other protocol-required therapies, including dexamethasone, diphenhydramine, 
acetaminophen, ranitidine, and tocilizumab (or siltuximab if tocilizumab is not available) 
that are commercially available are not provided by Amgen (except if required by local 
regulation).  
Descriptive statistics of total dose (mg) will be produced to describe the exposure to 
dexamethasone, tocilizumab, and siltuximab. 
Subject-level data may be provided instead of the summary if the subject incidence is 
low or single dose is given. 
9.6.10 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHO DRUG) dictionary. 
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/
 
Endpoints 
Nominal sampling times will be used for individual concentration-times plots and tables. 
Actual dose administered and actual sampling times will be used for the calculation of 
PK parameters for each subject. The reasons for excluding any sample from the 
analyses will be provided. 
Individual concentration-time data will be tabulated and presented graphically. Summary 
of PK concentration over time and PK parameters will be provided. Mean concentration-
time profiles for each dose will be provided. 
PK parameters will include, but are not limited to, maximum observed concentration 
(Cmax), time to maximum concentration (tmax) and area under the serum concentration-
time curve (AUC). Other PK parameters such as clearance and terminal half-life (t1/2) 
may be analyzed. Pharmacokinetic parameters will be estimated using standard non-
compartmental approaches based on the PK Analysis Set and summarized by dose 


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level using descriptive statistics including, but not limited to means, standard deviations, 
medians, minimums, and maximums. Additional analyses will be performed if useful and 
appropriate. 
 
 
10. 
Changes From Protocol-specified Analyses 
Analyses for adverse events related to other protocol required therapies will not 
be provided for part A of the study since this data was not collected in the eCRF. If 
we do not proceed with Arm B of the study, the primary analysis will be combined 
with the final analysis. 
11. 
Literature Citations / References 
Brookmeyer R, Crowley J.  A Confidence Interval for the Median Survival Time.  
Biometrics.  1982;38(1):29-41. 
Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
the binomial.  Biometricka.  1934;26:404-413. 
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS.  Guidelines for the management of 
pediatric and adult tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26:2767-2778. 
Kalbfleisch JD, Prentice RL.  The statistical analysis of failure time data.  John Wiley & 
Sons, New York; 1980. 
Lee DW, Gardner R, Porter DL, et al.  Current concepts in the diagnosis and 
management of cytokine release syndrome.  Blood.  2014;124:188-195. 
Lee DW, Santomasso BD, Locke FL, et al.  ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells.  Biol 
Blood Marrow Transplant.  2019;25(4):625-638. 
Scher HI, Morris MJ, Stadler WM, et al.  Trial design and objectives for 
castration-resistant prostate cancer:  updated recommendations from the Prostate 
Cancer Clinical Trials Working Group 3.  J Clin Oncol.  2016;34(12):1402. 
Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes.  Statist Med.  1995;14:357-379. 
12. 
Prioritization of Analyses 
There is no prioritization of analyses.  
13. 
Data Not Covered by This Plan 
Exploratory data not included in this plan may be analyzed later or may be analyzed by a 
different Amgen department. 


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14. 
Appendices 


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Appendix B.  RECIST 1.1 Assessment and Radiographic Progression 
The objective response (OR) and best overall response (BOR) will be derived as per 
RECIST 1.1. Radiographic progression will be derived as per RECIST 1.1 with PCWG3 
modifications. 
Table 14-1.  Confirmed BOR per RECIST 1.1 where Confirmation of CR/PR is 
Required  
Criterion Time 
point T1 
Response 
T1 ≥ 35 
days after 
Baseline? 
Time point 
T2 
Response 
T2 ≥ 35 
days after 
Baseline? 
T2 ≥ 28 
days after 
T1? 
Confirmation 
C1 
CR 
Yes 
CR 
- 
Yes 
CR 
C2 
 
CR 
- 
No 
SD 
C3 
PR, SD 
- 
- 
Query data* 
C4 
PD 
- 
- 
SD 
C5 
NE, No further evaluations 
SD 
C6 
No 
 
CR 
- 
Yes 
CR 
C7 
CR 
Yes 
No 
SD 
C8 
PR, SD 
- 
- 
Query data* 
C9 
PD 
- 
- 
PD 
C10 
NE, No further evaluations 
NE 
C11 
PR 
 
Yes 
CR, PR 
- 
Yes 
PR 


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C12 
CR, PR 
- 
No 
SD 
C13 
SD 
- 
- 
SD 
C14 
PD 
- 
- 
SD 
C15 
NE, No further evaluations 
SD 
C16 
No 
CR, PR 
- 
Yes 
PR 
C17 
CR, PR 
Yes 
No 
SD 
C18 
SD 
Yes 
- 
SD 
C19 
PD 
- 
- 
PD 
C20 
NE, No further evaluations 
NE 
C21 
SD 
Yes 
CR, PR, SD, PD, NE, no more evaluation 
SD 
C22 
No 
 
CR, PR, SD 
Yes 
- 
SD 
C23 
CR, PR, SD 
No 
- 
NE 
C24 
PD 
- 
- 
PD 
C25 
NE, No further evaluations 
NE 
C26 
PD 
 
- 
PD 
C27 
NE 
- 
NE, No further evaluations 
NE 
C28 
 
- 
CR, PR, SD 
Yes 
- 
SD 
C29 
 
- 
CR, PR, SD 
No 
- 
NE 
C30 
 
- 
PD 
- 
- 
PD 
CR = Complete Response; PR = Partial Response; SD = Stable Disease; PD = Progressive Disease; and 
NE = Not Evaluable. 
* If a CR is truly met at first time point, then any disease seen at subsequent timepoint, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD (35 days) was 
met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
still present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. If this response sequence occurs in the 
dataset, a data issue needs to be raised and resolved. 
Note: T1 could be any time point on study (best response) and does not necessarily indicate the first on-
treatment scan. 


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Table 14-3.  Bone Progression Status as per PCWG3 
Bone Lesion 
Response 
Definition 
NEB 
No evidence of Bone Lesion at screening.  
NE 
(Not Evaluable) 
No evaluable bone scan is available (i.e., not performed or issue with 
the quality of image) at that visit. 
Non-PD 
(1) For the first post-treatment bone scan (e.g., Week 8), if appearance 
of <2 new lesions relative to screening/baseline, then set to  Non-PD. 
(2) For scans after the first post-treatment scan, if appearance <2 new 
lesions relative to the first post-treatment scan, then set to Non-PD. 
PDu 
(Unconfirmed PD) 
(1) For the first post-treatment bone scan (e.g., Week 8), if appearance 
of ≥2 new lesions relative to screening/baseline, then set to PDu. 
(2) For scans after the first post-treatment scan, if appearance ≥2 new 
lesions relative to the first post-treatment scan, then set to PDu. 
PDc 
(Confirmed PD) 
(1) For the first post-treatment bone scan (e.g., Week 8), if appearance 
of ≥2 new lesions relative to screening/baseline and confirmed by the 
appearance of ≥2 additional new lesions at the next scan date, then set 
to PDc. 
(2) For scans after the first post-treatment scan, if appearance ≥2 new 
lesions relative to the first post-treatment scan and confirmed by the 
persistence of these new lesions at the next scan date, then set to PDc. 
Bone lesion status (Absent/Present) will be marked as follows: 


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Bone Lesion 
(Present/Absent) 
Definition 
Absent 
Total number of lesions related to metastatic disease for the specific 
timepoint is 0. 
Present 
Total number of lesions related to metastatic disease for the specific 
timepoint is more than 0. 
Table 14-4.  Radiographic Progression by RECIST 1.1 with PCWG3 Modifications 
RECIST 1.1 visit 
response (soft 
tissue/visceral)a 
Bone Progression 
Status 
Bone Lesion 
(Present/Absent) 
Radiographic 
Progression by 
RECIST 1.1 with 
PCWG3 
Modification 
PD 
Any 
Any 
PD 
Anyd 
PDc 
Any 
PDb 
Any except PD 
PDu 
Any 
Non-PD 
NE 
Non-PD, NEB, or NE 
Any 
NE 
SD 
Non-PD, NEB, or NE 
Any 
Non-PD 
Non-CR/Non-PDc 
Non-PD, NEB, or NE 
Any 
Non-PD 
PR 
Non-PD, NEB, or NE 
Any 
Non-PD 
CR 
Non-PD, NEB, or NE 
Any 
Non-PD 


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NED 
NE 
Any 
NE 
NED 
Non-PD 
Any 
Non-PD 
NED 
NEB 
Any 
NED 
CR = Complete Response; PR = Partial Response; SD = Stable Disease; PD = Progressive 
Disease; NE = Not Evaluable (if a scan is not performed at that visit, it will be considered NE); 
NEB = No Evidence of Bone Lesion at screening; NED = No Evidence of Disease (only relevant if 
there were no target lesions and non-target lesions at all visits), ‘Undefined’ in vendor data.   
a Collected time point responses  
b Following the confirmation of PD at the subsequent bone scan, the overall radiological visit response of 
progression for the visit will be programmatically derived as PD using the progression date (previous bone 
scan date where new lesion first seen) captured on the eCRF 
c For subjects with non-measurable disease only at baseline. 
d For subjects with RECIST 1.1 response of CR, PR, SD, PD, NE or Missing.  
 


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Appendix C.  Additional Definitions 
Information described below will be reported from eCRF  
Partial Response (PR) per RECIST 1.1: 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. Non-target lesions must be non-Partial Response (non-
PR)/non-Progressive Disease (non-PD).  
Complete Response (CR) per RECIST 1.1: 
The disappearance of all target lesions, non-target lesions, and normalization of tumor 
markers. Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Progressive Disease (PD) per RECIST 1.1: 
At least 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).  
Stable Disease (SD) per RECIST 1.1: 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum of diameters while on study.  
Non-CR/Non-PD per RECIST 1.1: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. This time point visit response is only valid for subjects who 
do not have measurable disease per RECIST 1.1 at baseline.  
Measurable baseline disease per RECIST 1.1: 
Measurable baseline disease is defined as “Lesions must be accurately measured in at 
least one dimension (longest diameter in the plane of measurement is to be recorded) 
with a minimum size of 10 mm by CT/MRI. To be measurable a lymph node must be  
15 mm in short axis when assessed by CT/MRI. All tumor measurements must be 
recorded in millimeters. Note: Previously irradiated lesions are non-measurable except in 
cases of documented progression of the lesion since the completion of radiation 
therapy.” 


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Evaluable tumor assessment per RECIST 1.1: 
Either of the following assessment must be performed for an evaluable tumor 
assessment (on or before subsequent anti-cancer therapy): 
 
CT/MRI scan to assess tumor response per RECIST 1.1 
 
Bone scan to assess bone disease progression status  
The results must be adequate to define a visit response, i.e., a visit overall response 
other than not evaluable (NE) for RECIST 1.1. 


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Appendix D.  Censoring Rules 
Censoring rules for radiographic PFS (rPFS): 
Situation up to DCO/EOS 
Date of Event or Censoring 
Outcome 
No evaluable post-baseline or on-
study disease assessment; on 
study without disease progression 
or death recorded 
Date of the first dose of 
Investigational product (AMG 340) 
Censored 
PD prior to new anti-cancer 
therapy 
Date of PD 
Event 
No PD, but death recorded without 
new anti-cancer therapy 
Date of Death 
Event 
Start of new anti-cancer therapy 
prior to PD or death, or prior to 
any other disease assessment if 
there is no PD or death recorded 
Date of last evaluable radiographic 
tumor assessment prior to the start 
of new anti-cancer therapy 
Censored 
No PD or death, no new anti-
cancer therapy 
Date of last evaluable radiographic 
tumor assessment 
Censored 
DCO: Data Cut-off; EOS: End of Study; PD: Progressive Disease  
Censoring rules for PSA PFS: 
Situation up to DCO/EOS 
Date of Event or Censoring 
Outcome 
No evaluable post-baseline or on-
study PSA assessment (on study 
without PSA progression or 
death); no evaluable baseline PSA 
assessment 
Date of the first dose of 
Investigational product (AMG 340) 
Censored 
PSA Progression 
Date of PSA Progression 
Event 
Death 
Date of Death 
Event 


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All other scenarios 
Date of last PSA assessment.  
Censored 
DCO: Data Cut-off; EOS: End of Study; PSA: Prostate Specific Antigen 
Censoring rules for Time to PSA Progression: 
Situation up to DCO/EOS 
Date of Event or Censoring 
Outcome 
No evaluable baseline or post-
baseline or on-study PSA 
assessment 
Date of the first dose of 
Investigational product (AMG 340) 
Censored 
PSA Progression 
Date of PSA Progression 
Event 
All other scenarios 
Date of last PSA assessment 
Censored 
DCO: Data Cut-off; EOS: End of Study; PSA: Prostate Specific Antigen 
Censoring rules for Time to Radiographic Progression: 
Situation up to DCO/EOS 
Date of Event or Censoring 
Outcome 
No evaluable post-baseline or on-
study disease assessment; on 
study without progressive disease 
or death 
Date of the first dose of 
Investigational product (AMG 340) 
Censored 
PD prior to new anti-cancer 
therapy 
Date of PD 
Event 
No PD, but death recorded without 
new anti-cancer therapy 
Date of last evaluable radiographic 
tumor assessment 
Censored 
Start of new anti-cancer therapy 
prior to PD or death, or prior to 
any other disease assessment if 
there is no PD or death recorded 
Date of last evaluable radiographic 
tumor assessment prior to the start 
of new anti-cancer therapy 
 
Censored 
No PD or death, no new anti-
cancer therapy 
Date of last evaluable radiographic 
tumor assessment 
Censored 
DCO: Data Cut-off; EOS: End of Study; PD: Progressive Disease  


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Censoring rules for DOR per RECIST 1.1 (CT/MRI assessment):  
 
Data for responders who are alive and without disease progression or new anti-
cancer therapy are censored at the time of last evaluable tumor assessment by 
CT/MRI scan. 
 
Data for responders who are alive and without disease progression but who started 
new anti-cancer therapy are censored at the time of last evaluable tumor 
assessment by CT/MRI scan before the start of new anti-cancer therapy.  
Situation up to DCO/EOS 
Date of Event or Censoring 
Outcome 
PD prior to new anti-cancer 
therapy 
Date of PD 
Event 
No PD, but death recorded without 
new anti-cancer therapy 
Date of Death 
Event 
Start of new anti-cancer therapy 
prior to PD or death, or prior to 
any other disease assessment if 
there is no PD or death recorded 
Date of last evaluable tumor 
assessment by CT/MRI prior to the 
start of new anti-cancer therapy 
Censored 
No PD or death, no new anti-
cancer therapy 
Date of last evaluable tumor 
assessment by CT/MRI 
Censored 
DCO: Data Cut-off; EOS: End of Study; PD: Progressive Disease  
Censoring rules for PSA Duration of Response: 
Situation up to DCO/EOS 
Date of Event or Censoring 
Outcome 
PSA progression after PSA 
response (PSA50). 
Date of PSA progression. 
Event 
Death after PSA response 
(PSA50). 
Date of Death. 
Event 
All other scenarios 
Date of last PSA assessment.  
Censored 
DCO: Data Cut-off; EOS: End of Study; PSA: Prostate Specific Antigen