Clinical trial NCT04727554
Conditions: Advanced Solid Tumors
Keywords: Mesothelin expression
Sponsor: Amgen
Start date: 2021-04-29; Completion date: 2023-06-05
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/maximum tolerated combination dose (MTCD) or recommended phase 2 dose (RP2D) of AMG 994 as monotherapy and AMG 994 in combination with AMG 404 in participants with advanced solid tumors.

Detailed description:
AMG 994 will be administered by short term intravenous (IV) infusion once weekly in each 28-day cycle and AMG 404 will be administered by short-term IV infusion once every 4 weeks (Q4W) in a 28 day cycle (on day 1 of cycle 2 and beyond). The study will be conducted in 2 parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion.

Arms: arm 1: Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404. arm 2: Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404. arm 3: Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404. arm 4: Participants will be administered with the MTD or RP2D of AMG 994 identified in the dose escalation part of the study, in combination with AMG 404.
Interventions: intervention 1: AMG 994 intervention 2: AMG 404
Intervention descriptions: intervention 1: Administered as an intravenous (IV) infusion. intervention 2: Administered as an intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 1 of 180 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Phase 1, Multicenter, Open-label, Dose 
Exploration and Dose Expansion Study Evaluating 
the Safety, Tolerability, Pharmacokinetics and 
Efficacy of AMG 994 Monotherapy and 
Combination of AMG 994 and AMG 404 in 
Subjects with Advanced Solid Tumors 
Short Protocol Title: 
AMG 994 Monotherapy and AMG 994 and 
AMG 404 Combination Therapy in Patients with 
Advanced Solid Tumors 
Protocol Number: 
20190136 
Investigational Product: 
AMG 994 and AMG 404  
Sponsor 
Name of Sponsor: 
Amgen 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone 
Number: 
+1 805-447-1000 
Protocol 
Approver 
Name: 
, MD 
Function: 
VP Early Development, TA Head Oncology 
Key 
Sponsor 
Contact 
Name: 
, MD PhD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91321 
USA 
Telephone 
Number: 
Email Address: 
EudraCT Number: 
2020-003937-40 
NCT Number: 
NCT04727554 
Protocol Version Date: 
Document Version 
Date 
Original 
03 September 2020 
Amendment 1 
14 October 2020 
Amendment 2 
22 October 2020 
Amendment 3 
03 December 2020 
Amendment 4 
16 June 2022 
Data Elements Standards 
Version: 
6.0 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6).  


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 2 of 180 
CONFIDENTIAL  
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics 
committee/institutional scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 3 of 180 
CONFIDENTIAL  
 
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1, Multicenter, Open-label, Dose 
Exploration and Dose Expansion Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of AMG 994 Monotherapy and Combination of AMG 994 
and AMG 404 in Subjects with Advanced Solid Tumors, dated 16 June 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) 
 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 4 of 180 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 10 
1.1 
Synopsis ................................................................................................... 10 
1.2 
Study Schema ........................................................................................... 15 
1.3 
Schedule of Activities (SoA) ...................................................................... 17 
2. 
Introduction ........................................................................................................... 65 
2.1 
Study Rationale ......................................................................................... 65 
2.2 
Background ............................................................................................... 67 
2.2.1 
Disease ..................................................................................... 67 
2.2.2 
Amgen Investigational Product Background:  
AMG 994 ................................................................................... 69 
2.2.2.1 
AMG 994 Toxicology ............................................... 69 
2.2.3 
Amgen Investigational Product Background:  
AMG 404 ................................................................................... 70 
2.3 
Benefit/Risk Assessment ........................................................................... 70 
2.3.1 
AMG 994 ................................................................................... 71 
2.3.1.1 
Therapeutic Context ................................................ 71 
2.3.1.2 
Key Benefits ............................................................ 71 
2.3.1.3 
Key Risks ................................................................ 71 
2.3.2 
AMG 404 ................................................................................... 72 
2.3.2.1 
Therapeutic Context ................................................ 72 
2.3.2.2 
Key Benefits ............................................................ 72 
2.3.2.3 
Key Risks ................................................................ 72 
2.3.3 
AMG 994 in Combination with AMG 404 ................................... 73 
3. 
Objectives and Endpoints ..................................................................................... 74 
4. 
Study Design ........................................................................................................ 75 
4.1 
Overall Design .......................................................................................... 75 
4.2 
Number of Subjects ................................................................................... 79 
4.2.1 
Replacement of Subjects ........................................................... 79 
4.2.2 
Number of Sites ......................................................................... 80 
4.3 
Justification for Investigational Product Dose ............................................ 80 
4.4 
End of Study ............................................................................................. 81 
4.4.1 
End of Study Definition .............................................................. 81 
4.4.2 
Study Duration for Subjects ....................................................... 81 
4.5 
Patient Input on Study ............................................................................... 81 
5. 
Study Population .................................................................................................. 82 
5.1 
Inclusion Criteria ....................................................................................... 82 
5.2 
Exclusion Criteria ...................................................................................... 84 
5.3 
Subject Enrollment .................................................................................... 86 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
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5.4 
Screen Failures ......................................................................................... 87 
6. 
Treatments ........................................................................................................... 87 
6.1 
Treatment(s) Administered ........................................................................ 87 
6.1.1 
Investigational Products ............................................................ 87 
6.1.2 
Non-investigational Products ..................................................... 89 
6.1.3 
Medical Devices ........................................................................ 89 
6.1.4 
Other Protocol-required Therapies ............................................ 89 
6.1.5 
Other Treatment Procedures ..................................................... 89 
6.1.6 
Product Complaints ................................................................... 89 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 90 
6.2 
Dose Modification ...................................................................................... 90 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 90 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 96 
6.2.2.1 
Dose Adjustment ..................................................... 96 
6.2.2.2 
Rules for Withholding or Restarting ......................... 97 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 98 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 98 
6.4 
Treatment Compliance .............................................................................. 98 
6.5 
Treatment of Overdose ............................................................................. 98 
6.6 
Prior and Concomitant Treatment ............................................................. 98 
6.6.1 
Prior Treatment ......................................................................... 98 
6.6.2 
Concomitant Treatment ............................................................. 98 
7. 
Discontinuation Criteria ......................................................................................... 98 
7.1 
Discontinuation of Study Treatment........................................................... 99 
7.2 
Discontinuation From the Study .............................................................. 100 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ............................................... 100 
7.2.2 
Reasons for Removal From Study ........................................... 100 
7.3 
Lost to Follow-up ..................................................................................... 100 
8. 
Study Assessments and Procedures .................................................................. 101 
8.1 
General Study Periods ............................................................................ 101 
8.1.1 
Screening, Enrollment and/or Randomization .......................... 101 
8.1.2 
Treatment Period ..................................................................... 102 
8.1.3 
Safety Follow-up ...................................................................... 102 
8.1.4 
Long-term Follow-up ................................................................ 102 
8.1.5 
End of Study ............................................................................ 102 
8.2 
Description of General Study Assessments and Procedures ................... 102 
8.2.1 
General Assessments ............................................................. 103 
8.2.1.1 
Informed Consent .................................................. 103 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
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CONFIDENTIAL  
 
 
8.2.1.2 
Demographics ....................................................... 103 
8.2.1.3 
Medical History ...................................................... 103 
8.2.1.4 
Physical Examination ............................................ 103 
8.2.1.5 
Physical Measurements ........................................ 103 
8.2.1.6 
Performance Status............................................... 103 
8.2.2 
Efficacy Assessments .............................................................. 103 
8.2.3 
Safety Assessments ................................................................ 105 
8.2.3.1 
Vital Signs ............................................................. 105 
8.2.3.2 
Electrocardiograms (ECGs) ................................... 105 
8.2.3.3 
Vital Status ............................................................ 106 
8.2.4 
Adverse Events and Serious Adverse Events .......................... 106 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information ................ 106 
8.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events ........................................ 107 
8.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ..................................................... 108 
8.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events ........................................ 108 
8.2.4.5 
Safety Monitoring Plan .......................................... 108 
8.2.4.6 
Pregnancy and Lactation ....................................... 109 
8.2.5 
Clinical Laboratory Assessments ............................................. 109 
8.2.6 
Pharmacokinetic Assessments ................................................ 110 
8.2.7 
Pharmacodynamic Assessments ............................................. 110 
8.2.8 
Pharmacogenetic Assessments............................................... 110 
9. 
Statistical Considerations .................................................................................... 113 
9.1 
Statistical Hypotheses ............................................................................. 113 
9.2 
Sample Size Determination ..................................................................... 113 
9.3 
Analysis Sets,
and Covariates .............................................. 114 
9.3.1 
Analysis Sets ........................................................................... 114 
9.3.2 
Covariates ............................................................................... 114 
9.3.4 
Handling of Missing and Incomplete Data ................................ 114 
9.4 
Statistical Analyses ................................................................................. 115 
9.4.1 
Planned Analyses .................................................................... 115 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................. 115 
9.4.1.2 
Primary Analysis ................................................... 117 
9.4.1.3 
Final Analysis ........................................................ 117 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 7 of 180 
CONFIDENTIAL  
 
 
9.4.2 
Methods of Analyses ............................................................... 117 
9.4.2.1 
General Considerations ......................................... 117 
9.4.2.2 
Efficacy Analyses .................................................. 118 
9.4.2.3 
Safety Analyses .................................................... 118 
9.4.2.4 
Other Analyses ...................................................... 120 
10. 
References ......................................................................................................... 121 
11. 
Appendices ......................................................................................................... 124 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 125 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 129 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 131 
Committee(s) .......................................................................................... 131 
Regulatory and Ethical Considerations .................................................... 132 
Recruitment Procedures .......................................................................... 133 
Informed Consent Process ...................................................................... 133 
Data Protection/Subject Confidentiality ................................................... 135 
Publication Policy .................................................................................... 135 
Investigator Signatory Obligations ........................................................... 136 
Data Quality Assurance ........................................................................... 136 
Source Documents .................................................................................. 138 
Study and Site Closure............................................................................ 139 
Compensation ......................................................................................... 139 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 140 
Definition of Adverse Event ..................................................................... 140 
Definition of Serious Adverse Event ........................................................ 141 
Recording Adverse Events and Serious Adverse Events ........................ 142 
Evaluating Adverse Events and Serious Adverse Events ........................ 143 
Reporting of Serious Adverse Event ........................................................ 144 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 149 
Collection of Pregnancy Information ........................................................ 151 
Collection of Lactation Information .......................................................... 152 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 155 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 157 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-
required Therapies Due to Potential Hepatotoxicity ................. 157 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 158 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 8 of 180 
CONFIDENTIAL  
 
 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 159 
11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse 
Events ..................................................................................................... 161 
11.9 
Appendix 9.  ECOG Performance Status and NYHA 
Classification ........................................................................................... 162 
11.10 Appendix 10.  Toxicity Management Guidelines ...................................... 163 
11.11 Appendix 11.  Modified Response Evaluation Criteria in Solid 
Tumors Version 1.1 (Modified RECIST 1.1) ............................................ 175 
 
List of Tables 
Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy 
Cycles .................................................................................................... 17 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of 
AMG 994 and AMG 404 Combination Therapy ....................................... 26 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 
Second Combination Therapy Cycle and Beyond ................................... 36 
Table 1-4.  Schedule of Activities:  Dose Expansion Cycle 1 - AMG 994 and 
AMG 404 Combination Therapy ............................................................. 48 
Table 1-5.  Schedule of Activities:  Dose Expansion AMG 994 and AMG 404 
Combination Therapy Cycle 2 and Beyond ............................................. 57 
Table 2-1.  Key Safety Risks for AMG 994 .................................................................... 72 
Table 2-2.  Key Safety Risks for AMG 404 .................................................................... 73 
Table 4-1:  MSLN Expression in Solid Tumors .............................................................. 76 
Table 6-1.  Study Treatments ........................................................................................ 88 
Table 9-1.  Stopping Boundary for Dose Expansion With Posterior Probability 
of 80 and Grade 4 or Higher Treatment-Related Adverse 
Event Limit of 20 ................................................................................ 117 
Table 9-2.  Operating Characteristics With Batch Size of 20 Subjects ......................... 117 
Table 11-1.  Analyte Listing ......................................................................................... 129 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 158 
Table 11-3.  Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Reactions Associated With 
AMG 404* ............................................................................................. 163 
Table 11-4.  Management of Infusion-related Reactions With AMG 994 or 
AMG 404 .............................................................................................. 173 
 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
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Page 9 of 180 
CONFIDENTIAL  
 
 
List of Figures 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) ...................................................................... 146 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 153 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 10 of 180 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1, Multicenter, Open-label, Dose Exploration and Dose 
Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of 
AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in Subjects with 
Advanced Solid Tumors 
Short Protocol Title:  AMG 994 Monotherapy and AMG 994 and AMG 404 Combination 
Therapy in Patients with Advanced Solid Tumors 
Study Phase:  1 
Indication:  Advanced solid tumors 
Rationale 
AMG 994 is a bivalent bispecific monoclonal immunoglobulin G1 (IgG1) stable effector 
functionless (SEFL2) directed against mesothelin (MSLN) and clusters of 
differentiation 40 (CD40) and AMG 404 is a fully human, monoclonal IgG1 SEFL2 
directed against programmed cell death protein 1 (PD-1) currently being evaluated by 
Amgen.  Nonclinical studies with an AMG 994 mouse surrogate alone showed a 
dose-dependent reduction in tumor growth and improvement in overall survival 
compared with treatment with an isotype control antibody, while the combination of the 
AMG 994 mouse surrogate plus an anti programmed death ligand 1 (PD-L1) molecule 
promoted increased complete tumor regression relative to either individual treatment 
alone.  A recent review by Vonderheide (2020) of clinical experience with CD40 agonist 
antibodies suggests limited monotherapy efficacy, but the potential to show increased 
efficacy in combination with other immunotherapies, such as PD-1 blockade. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety, tolerability, 
and maximum tolerated dose 
(MTD)/maximum tolerated 
combination dose (MTCD) or 
recommended phase 2 dose 
(RP2D) of AMG 994 as 
monotherapy and AMG 994 in 
combination with AMG 404 in 
subjects with advanced solid 
tumors 
 
Dose-limiting toxicities (DLTs) 
 
Treatment-emergent and 
treatment related adverse 
events (including all adverse 
events, grade  3, serious 
adverse events, fatal adverse 
events, adverse events 
requiring permanent 
discontinuation of study 
treatment, and immune-related 
events) 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 11 of 180 
CONFIDENTIAL  
 
 
 
Overall Design 
This is a First In Human (FIH), multicenter, non-randomized, open-label, phase 1 
study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, 
immunogenicity, and preliminary efficacy of AMG 994 monotherapy and evaluation of 
AMG 994 in combination with AMG 404 in subjects with advanced solid tumors with 
known MSLN expression, including mesothelioma, non-small cell lung cancer 
(NSCLC) squamous cell carcinoma [Part 2 only] and adenocarcinoma [Part 1 and 
Part 2], pancreatic adenocarcinoma, and high grade serous ovarian carcinoma 
(platinum resistant).  Study assessments will include measures of safety, tolerability, 
PK, and pharmacodynamics data, and preliminary anti-tumor activity. 
AMG 994 will be administered by 
 
 and AMG 404 will be administered by 
 
  The study 
will be conducted in 2 parts:  Part 1 – Dose Exploration and Part 2 – Dose Expansion.  
 
Changes in vital signs, 
electrocardiograms (ECGs), 
and clinical laboratory tests 
Secondary 
 
Preliminary evaluation of 
anti-tumor activity of AMG 994 as 
monotherapy and AMG 994 in 
combination with AMG 404 
 
Objective response (OR) per 
modified Response Evaluation 
Criteria in Solid Tumors 
(RECIST) 1.1 
 
Duration of response (per 
modified RECIST 1.1) 
 
Overall survival (OS) 
 
Progression-free survival (per 
modified RECIST 1.1) 
 
Time to progression (per 
modified RECIST 1.1) 
 
Time to subsequent therapy 
 
Characterize the PK of AMG 994 
monotherapy and AMG 994 in 
combination with AMG 404 
PK parameters 
 
Maximum serum concentration 
(Cmax) 
 
Minimum serum concentration 
(Cmin) 
 
Area under the concentration-
time curve (AUC) over the 
dosing interval 
 
Half-life (t1/2), if feasible 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 12 of 180 
CONFIDENTIAL  
 
 
Part 1 is aimed at evaluating the safety, tolerability, PK, and pharmacodynamics of 
AMG 994 monotherapy and AMG 994 in combination with AMG 404 using sequential 
and concurrent initiation of dosing:  
The maximum tolerated dose/maximum tolerated combination dose (MTD/MTCD) of the 
combination in subjects with advanced solid tumors will be determined using a Bayesian 
Logistics Regression Model (BLRM) design.  Part 2 will further evaluate the safety of the 
MTD/MTCD and/or a biologically active dose (eg, recommended phase 2 dose [RP2D]) 
of the combination in specific tumor types.  The dose expansion part of the study (Part 2) 
will be opened once the MTD/MTCD/RP2D of the combination has been determined in 
Part 1.   
The dose exploration part of the study will consist of approximately 94 subjects and the 
dose expansion will consist of approximately 120 additional subjects, 30 subjects in each 
of 4 tumor types (mesothelioma, NSCLC squamous cell carcinoma and adenocarcinoma 
[in Part 2, if upon screening found to be MSLN positive], pancreatic adenocarcinoma, 
and high grade serous ovarian carcinoma).  Dose escalation will be conducted in 
subjects with metastatic or locally advanced solid tumors of types known to express 
MSLN for which no standard systemic therapy exists and dose expansion will be 
conducted in subjects with specific tumor types.  The DLT evaluation period will be 
 for each cycle.  Administration of AMG 994 (in Part 1 and Part 2) may continue 
until evidence of disease progression; intolerance to study medication; withdrawal of 
consent; or, in the absence of the above, up to 12 months if subject achieves a complete 
response, and up to 24 months if partial response or stable disease. 
Number of Subjects 
Approximately 214 subjects with advanced solid tumors of types known to express 
MSLN will be enrolled in the study.  During Dose Exploration (Part 1), screening for 
MSLN expression will not occur and up to 94 evaluable subjects will be enrolled.  During 
Dose Expansion (Part 2), approximately 120 evaluable subjects, 30 subjects in each of 
4 tumor types (mesothelioma, NSCLC squamous cell carcinoma and adenocarcinoma [if 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 13 of 180 
CONFIDENTIAL  
 
 
upon screening are found to be MSLN positive], pancreatic adenocarcinoma, and high 
grade serous ovarian carcinoma) will be enrolled. 
Summary of Subject Eligibility Criteria 
Male or female subjects  18 years of age at the time of informed consent who have 
advanced solid tumors of known MSLN expression who have relapsed after and/or are 
refractory to established and available therapies with known clinical benefit.   
Once consented to the study, subjects will provide a medical history and undergo 
screening safety tests to confirm all eligibility requirements of the study have been met.   
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
AMG 994 is supplied as a sterile, single-use, preservative-free solution for
 
 AMG 994.  
 
 with AMG 994 doses administered
 and AMG 404 doses of 
 administered 
 in subjects 
with advanced solid tumors.  Planned AMG 994 dose levels for the dose exploration 
cohorts are as follows:  
, and 
  Based on emerging data and DLRM recommendation, intermediate and/or 
alternative dose levels and schedules (eg, dose dense) may be implemented. 
AMG 404 is supplied as a sterile, single-use, preservative-free solution for 
 
 AMG 404.  Taking into consideration cumulative preliminary 
safety, PK, pharmacodynamics, and immunogenicity data as of 14 February 2020, the 
AMG 404 recommended dose for evaluation in combination therapy is
 
in subjects with advanced solid tumors. 
Procedures 
Written informed consent must be obtained from all subjects before any study-specific 
screening procedures are performed.  Scans performed prior to consent may be used for 
screening provided they are accessed for study purposes after consent has been 
obtained.  Study-specific procedures will occur according to the Schedule of 
Assessments (Section 1.3).   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Section 1.3. 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
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CONFIDENTIAL  
 
 
Statistical Considerations 
This is a phase 1 study and no formal statistical hypotheses will be tested. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
This is a phase 1 study and no formal statistical hypotheses will be tested. 
 
Sponsor Name:  Amgen 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
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Page 15 of 180 
CONFIDENTIAL  
 
 
1.2 
Study Schema 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
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1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy Cycles  
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
end of infusion) 
GENERAL AND 
SAFETY 
ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
ECOG PS12 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Page 1 of 7 
Footnotes defined on last page of this table


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Protocol Number:  20190136 
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Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy Cycles  
 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
end of infusion) 
Medical history  
ECG triplicate 
measurement1 
X 
X  
X 
 
  
 
 (X) 
 
 
X 
 
X  
 
 
 
 (X) X 
 
X  
 
 
 
 
(X) X 
 
X  
 
 
 
 
X 
 
Vital signs, pulse ox2 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
review 
 
 
 
Serious adverse 
events 
 
Concomitant 
medication review 
 
Page 2 of 7 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 19 of 180 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy Cycles  
 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
end of infusion) 
LABORATORY 
ASSESSMENTS 
 
Pregnancy test 
(females of 
childbearing potential 
only)3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
X 
 
X  
 
 
 
 
X 
 
 
X 
 X 
 
 
 
 
 
X 
X 
 
X  
 
 
 
 
X X 
 X  
 
 
 
 
X 
 
Hematology 
X 
X 
 
X  
 
 
 
 
X 
 
 
X 
 X 
 
 
 
 
 
X 
X 
 
X  
 
 
 
 
X X 
 X  
 
 
 
 
X 
 
Chemistry4 
X 
X 
 
X  
 
 
 
 
X 
 
 
X 
 X 
 
 
 
 
 
X 
X 
 
X  
 
 
 
 
X X 
 X  
 
 
 
 
X 
 
Page 3 of 7 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 20 of 180 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy Cycles  
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
end of infusion) 
HIV, Hepatitis B and 
C screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ACTH5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, ANCA5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 7 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 21 of 180 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy Cycles  
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
end of infusion) 
RADIOLOGICAL 
ASSESSMENTS 
 
CT/MRI and Tumor 
Burden Assessment 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Brain MRI6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
 
AMG 9947 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
Hospitalization8 
 
X 
 
 
X 
X 
X 
 
Page 5 of 7 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 22 of 180 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy Cycles  
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
end of infusion) 
PHARMACOKINETI
C ASSESSMENTS 
AMG 9949 
 
X 
 X 
 
X 
 
X X X 
X 
X 
X 
 X  
 
 
 
 
 
X 
 X 
 
 
 
 
 
 
X 
 X  X  X X X 
 
ARCHIVAL TUMOR 
TISSUE10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRE-TREATMENT 
TISSUE/FRESH 
TUMOR BIOPSIES11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
WHOLE BLOOD 
FOR CYTOMETRY 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Page 6 of 7 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 23 of 180 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities:  Dose Exploration AMG 994 Monotherapy Cycles  
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
end of infusion) 
SERUM MARKERS  
 
X 
 
 
 
 
 
X 
 
X X 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PLASMA FOR ctDNA 
ANALYSIS 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC 
 
X 
 
 
 
 
 
 
 
X X 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 7 of 7 
(X)  conditional, refer to applicable footnote  
 
ACTH  adrenocorticotropic hormone; ALT  alanine aminotransferase; ANA  anti-nuclear antibody; ANCA  anti-neutrophil cytoplasmic antibodies; AST  aspartate 
aminotransferase; BUN  blood urea nitrogen; CNS  central nervous system; CR  complete response; CT  computed tomography; ECG  electrocardiogram; 
ECOG PS  Eastern Cooperative Oncology Group Performance Status; EOI  end of infusion; EOT  end of treatment; HIV  human immunodeficiency virus; 
MRI  magnetic resonance imaging; PBMC  peripheral blood mononuclear cells; PK  pharmacokinetics; PR  partial response; 
WOCBP  women of child bearing potential. 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 24 of 180 
CONFIDENTIAL  
 
 
1 ECGs are required in triplicate approximately 30 to 60 seconds apart and run consecutively for the first 3 cycles during Dose Exploration as described below for each 
cohort at the following time points ( 5 minutes):  
- 
  predose, EOI (AMG 994 and AMG 404, as applicable), and 24 hours after AMG 994 EOI (during cycles where hospitalization 
is required).   
- 
As clinically indicated 
No ECGs after cycle 3 for any cohort unless clinically indicated; ECGs at 24 hours after AMG 994 infusion only required for cycles in which hospitalization is 
required.   
2 Vital signs, pulse ox are required at the following time points ( 5 minutes):  
- 
Screening 
During exploration: 
During expansion: 
 
Note:  Vitals and pulse oximetry should be taken as close to the exact nominal time point as noted above.   
Note: 
 during infusion timepoint is relative to AMG 994 infusion.   
Note:  EOI and Post-EOI timepoints for all combination cycles are relative to AMG 404 infusion.   
3 WOCBP, an initial serum pregnancy test is required prior day 1 of cycle 1; a urine pregnancy test is required at least Q4W thereafter prior to day 1 dosing of all cycles 
4 Chemistry to include:  albumin, alkaline phosphatase, ALT, AST, BUN/total urea, calcium, chloride, creatinine, glucose, potassium, sodium, total bilirubin, total protein 
5 ACTH to be done once every cycle.  ANA and ANCA to be done at screening and then if clinically indicated. 
6 Radiological imaging and tumor assessments are required at screening, cycle 1
thereafter (C3
 C5
 
C
 and EOT 
  Every assessment must include the chest, abdomen, and pelvis and all other known sites of disease.  Tumor burden assessments will 
be performed based on RECIST 1.1 guidelines (Section 11.11).  Radiographic response (CR and PR) requires confirmation by a repeat assessment at least 4 weeks 
after the first detection of response.  All subjects must have MRI of the brain performed within 28 days prior to enrollment.  Only if MRI is contraindicated, then CT 
with contrast is acceptable.  Subsequently, MRI brain scans may be performed at any time if subject has history of CNS disease or as clinically indicated.  Any 
supplemental imaging used to evaluate or determine response by sites should be sent along with the required scans to the central imaging vendor promptly upon 
completion.   
7 AMG 994 will be administered
 
8 Subjects will be hospitalized for a minimum of 24 hours following each infusion during the first cycle of treatment on study and following the week 1 infusion of the 
second cycle of treatment on study.  Hospitalization should be extended if any adverse event, clinical change, or safety concern associated with the infusion is 
observed.  This will be based on investigator and Amgen Medical Monitor discretion.  Subjects will be observed for 6 hours following each remaining infusion 
(weeks 2, 3, and 4) during the second cycle of treatment on study and observed for 2 to 4 hours following each subsequent infusion for observation of any side 
effects. 
9 PK blood samples should be collected at the exact nominal time point as noted above [see hours (relative to end of infusion) row].  If unable to collect a blood sample 
at the specified nominal time point, collect it as close as possible to the nominal time point and record the actual collection time.  PK samples not collected at exact 
nominal time point will not be considered protocol deviations. 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 25 of 180 
CONFIDENTIAL  
 
 
10 If available, archived tumor tissue (archival within  6 months of enrollment) or recent acquisition will be collected prior to cycle 1, day 1 (during screening).   
11 A tumor biopsy is required at baseline if patient has received any pre-treatment prior to participating in this study.  Tumor tissue must be available for correlative 
studies.  Subjects must consent to allow the acquisition of formalin-fixed paraffin-embedded (FFPE) material (block or unstained slides) by study personnel for 
performance of correlative tissue studies.  Fresh tumor biopsies are required for subsequent time points. 
   
12 Physical exam is required on days
of each cycle.  Height will be measured at screening only.  Weight will be measured at screening and each study 
visit where a physical exam is also performed. 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 26 of 180 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
CYCLES 
WEEKS 
DAYS 
Hours (relative 
to AMG 994 end 
of infusion) 
Hours (relative 
to AMG 404 end 
of infusion) 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination, ECOG 
PS14 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 8 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 27 of 180 
CONFIDENTIAL  
 
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
 
CYCLES 
WEEKS 
DAYS 
Hours 
(relative to 
AMG 994 end 
of infusion) 
Hours 
(relative to 
AMG 404 end 
of infusion) 
ECG triplicate 
measurement1 
X 
X  
X 
 
 X 
 
  
 (X) 
 
 
X  
X  
 
 
 
 (X) X 
 
X 
 
 
 
 
 (X) X  X 
 
 
 
 
 
X 
 
Vital signs, pulse 
ox2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
review 
 
 
 
 
Serious adverse 
events 
 
 
Concomitant 
medication 
review 
 
 
Page 2 of 8 
Footnotes defined on last page of this table 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 28 of 180 
CONFIDENTIAL  
 
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
CYCLES 
WEEKS 
DAYS 
Hours (relative 
to AMG 994 end 
of infusion) 
Hours (relative 
to AMG 404 end 
of infusion) 
LABORATORY ASSESSMENTS 
Pregnancy test 
(females of 
childbearing 
potential only)3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
X 
 
 
 
 X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
  
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 X  
 
Hematology 
X 
X 
 
 
 
 X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 X  
 
Page 3 of 8 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 29 of 180 
CONFIDENTIAL  
 
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
CYCLES 
WEEKS 
DAYS 
Hours (relative 
to AMG 994 end 
of infusion) 
Hours (relative 
to AMG 404 end 
of infusion) 
Chemistry4 
X 
X 
 
 
  X  
 
 
 
X 
 
 
X 
 
X  
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
  
X 
 
HIV, Hepatitis B and 
C screening 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ACTH5 
X 
X 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, ANCA5 
X 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 8 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 30 of 180 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
CYCLES 
WEEKS 
DAYS 
Hours (relative 
to AMG 994 end 
of infusion) 
Hours (relative 
to AMG 404 end 
of infusion) 
RADIOLOGICAL ASSESSMENTS 
CT/MRI and Tumor 
Burden 
Assessment6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Brain MRI6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
AMG 9947 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
AMG 40413 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization8 
 
X 
X 
X 
 
Page 5 of 8 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 31 of 180 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
CYCLES 
WEEKS 
DAYS 
Hours (relative 
to AMG 994 end 
of infusion) 
Hours (relative 
to AMG 404 end 
of infusion) 
PHARMACOKINET
IC ASSESSMENTS 
AMG 9949 
 
X 
 X 
 
X 
 
 
X X X X X X X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
X  
 
 
X 
X 
X 
 
PHARMACOKINET
IC ASSESSMENTS 
AMG 4049 
 
X  
 
 
 
X 
 
X X X X X X  X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ARCHIVAL 
TUMOR TISSUE10 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Page 6 of 8 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 32 of 180 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
CYCLES 
WEEKS 
DAYS 
Hours (relative 
to AMG 994 end 
of infusion) 
Hours (relative 
to AMG 404 end 
of infusion) 
PRE-TREATMENT 
TISSUE/FRESH 
TUMOR 
BIOPSIES11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  X 
WHOLE BLOOD 
FOR CYTOMETRY 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
SERUM MARKERS  
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
X 
 
X X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
PLASMA FOR 
ctDNA ANALYSIS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Page 7 of 8 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 33 of 180 
CONFIDENTIAL  
 
 
Table 1-2.  Schedule of Activities:  Dose Exploration for First Cycle of AMG 994 and AMG 404 Combination Therapy 
CYCLES 
WEEKS 
DAYS 
Hours (relative 
to AMG 994 end 
of infusion) 
Hours (relative 
to AMG 404 end 
of infusion) 
PBMC 
 
X 
 
 
 
 
 
 
 
 
 
X X 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Page 8 of 8 
(X)  conditional, refer to applicable footnote  
 
ACTH  adrenocorticotropic hormone; ALT  alanine aminotransferase; ANA  anti-nuclear antibody; ANCA  anti-neutrophil cytoplasmic antibodies; AST  aspartate 
aminotransferase; BUN  blood urea nitrogen; CNS  central nervous system; CR  complete response; CT  computed tomography; ECG  electrocardiogram; 
ECOG PS  Eastern Cooperative Oncology Group Performance Status; EOI  end of infusion; HIV  human immunodeficiency virus;
MRI  magnetic resonance imaging; PBMC  peripheral blood mononuclear cells; PK  pharmacokinetic(s); PR  partial response; WOCBP  women of child bearing 
potential. 
 
1 ECGs are required in triplicate approximately 30 to 60 seconds apart and run consecutively for the first 3 cycles during Dose Exploration as described below for each 
cohort at the following time points ( 5 minutes):  


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 34 of 180 
CONFIDENTIAL  
 
 
- 
Days
:  predose, EOI (AMG 994 and AMG 404, as applicable), and 24 hours after AMG 994 EOI (during cycles where hospitalization 
is required).   
- 
As clinically indicated 
No ECGs after cycle 3 for any cohort unless clinically indicated; ECGs at 24 hours after AMG 994 infusion only required for cycles in which hospitalization is 
required.   
2 Evaluation of vital signs and pulse oximetry is required at the following time points ( 5 minutes):  
- 
Screening 
During exploration: 
During expansion: 
Note:  Vitals and pulse oximetry should be taken as close to the exact nominal time point as noted above.   
Note:  
 during infusion timepoint is relative to AMG 994 infusion.   
Note:  EOI and Post-EOI timepoints for all combination cycles are relative to AMG 404 infusion.   
3 WOCBP, an initial serum pregnancy test is required prior day 1 of cycle 1; a urine pregnancy test is required at least Q4W thereafter prior to day 1 dosing 
4 Chemistry to include:  albumin, alkaline phosphatase, ALT, AST, BUN/total urea, calcium, chloride, creatinine, glucose, potassium, sodium, total bilirubin, total protein 
5 ACTH to be done once every cycle.  ANA and ANCA to be done at screening and then if clinically indicated. 
6 Radiological imaging and tumor assessments are required at screening, cycle 1
  Every assessment must include the chest, abdomen, and 
pelvis and all other known sites of disease.  Tumor burden assessments will be performed based on RECIST 1.1 guidelines (Section 11.11).  Radiographic response 
(CR and PR) requires confirmation by a repeat assessment at least 4 weeks after the first detection of response.  All subjects must have MRI of the brain performed 
within
 prior to enrollment.  Only if MRI is contraindicated, then CT with contrast is acceptable.  Subsequently, MRI brain scans may be performed at any time 
if subject has history of CNS disease or as clinically indicated.  Any supplemental imaging used to evaluate or determine response by sites should be sent along with 
the required scans to the central imaging vendor promptly upon completion.   
7 AMG 994 will be administered
 
8 Subjects will be hospitalized for a minimum of 24 hours following each infusion during the first cycle of treatment on study and following the week 1 infusion of the 
second cycle of treatment on study.  Hospitalization should be extended if any adverse event, clinical change, or safety concern associated with the infusion is 
observed.  This will be based on investigator and Amgen Medical Monitor discretion.  Subjects will be observed for 6 hours following each remaining infusion 
(weeks 2, 3, and 4) during the second cycle of treatment on study and observed for 2 to 4 hours following each subsequent infusion for observation of any side 
effects. 
9 PK blood samples for AMG 994 and AMG 404 should be collected at the exact nominal time point relative to their respective end of infusions as noted above [see 
hours (relative to end of infusion) rows for AMG 994 and AMG 404].  If unable to collect a blood sample at the specified nominal time point, collect it as close as 
possible to the nominal time point and record the actual collection time.  PK samples not collected at exact nominal time point will not be considered protocol 
deviations.   
10 If available, archived tumor tissue (archival within  6 months of enrollment) or recent acquisition will be collected prior to cycle 1, day 1 (during screening). 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 35 of 180 
CONFIDENTIAL  
 
 
11 A tumor biopsy is required at baseline.  Tumor tissue (archival within  6 months of enrollment or recent acquisition) must be available for correlative studies.  
Subjects must consent to allow the acquisition of formalin-fixed paraffin-embedded (FFPE) material (block or unstained slides) by study personnel for performance of 
correlative tissue studies.  Fresh tumor biopsies are required for subsequent time points. 
tumor biopsy sample during 
combination therapy is only required for subjects on their first cycle of treatment
 
AMG 404 to be administered on
fter the end of infusion of AMG 994 if a  grade 2 infusion reaction is not observed.  The 
dose is
 
14 Physical exam is required on days
of each cycle.  Height will be measured at screening only.  Weight will be measured at screening and each study 
visit where a physical exam is also performed. 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 36 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
GENERAL AND SAFETY 
ASSESSMENTS 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 10 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 37 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
Physical examination, 
ECOG PS13 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X X 
 
Medical history  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG triplicate 
measurement1 
X  
X 
 X  
 
 
(X) 
X 
 
X 
 
 
 
 
 (X)  (X)  
 (X)  
 
 
 (X)  (X)  
 
 
 
 
 
 
 
 
Page 2 of 10 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 38 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
Vital signs, pulse ox2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Adverse events review 
 
 
Serious adverse events 
 
Page 3 of 10 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 39 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
Concomitant medication 
review 
 
LABORATORY 
ASSESSMENTS 
 
Pregnancy test (females 
of childbearing potential 
only)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Coagulation 
X 
 
 
 X  
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
  
 
X   
 
 
 
X 
 
X 
 
 
  
 
 
 
X 
X 
 
Page 4 of 10 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 40 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
Hematology 
X 
 
 
 X  
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
  
 
 X  
 
 
 
 
X 
 
X 
 
 
  
 
 
 
X 
X 
 
Chemistry4 
X 
 
 
 X  
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 X  
 
 
 
 
X 
 
X 
 
 
  
 
 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
ACTH5 
X 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
ANA, ANCA5 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Page 5 of 10 
Footnotes defined on last page of this table 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 41 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
RADIOLOGICAL 
ASSESSMENTS 
 
CT/MRI and Tumor 
Burden Assessment6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Brain MRI6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Page 6 of 10 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 42 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
DOSING 
AMG 9947 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
  
 
 
 
 
 
AMG 40415 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization/ 
Observation8 
(X) 
(X) 
 
(X) 
 
(X) 
 
 
 
 
 
 
Page 7 of 10 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
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CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
PHARMACOKINETIC 
ASSESSMENTS – 
AMG 9949 
X 
 
X X X  
X 
 
 
X 
 (X)  
 
 
 
 
X 
 X 
 
X 
 
 
X 
 
 
 
  
 
 
 
 
X 
 
X 
X 
 
PHARMACOKINETIC 
ASSESSMENTS – 
AMG 4049 
X 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 (X)  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
PRE-TREATMENT 
TISSUE/FRESH TUMOR 
BIOPSIES10 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
Page 8 of 10 
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Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 44 of 180 
CONFIDENTIAL  
 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
WHOLE BLOOD FOR 
CYTOMETRY 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SERUM MARKERS 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
PLASMA FOR ctDNA 
ANALYSIS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
PBMC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Page 9 of 10 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 45 of 180 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
Table 1-3.  Schedule of Activities:  Dose Exploration AMG 994 and AMG 404 Second Combination Therapy Cycle and Beyond 
CYCLES 
WEEKS 
DAYS 
Hours (relative to 
AMG 994 end of 
infusion) 
Hours (relative to 
AMG 404 end of 
infusion) 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 10 of 10 
(X)  conditional, refer to applicable footnote  
 
ACTH  adrenocorticotropic hormone; ALT  alanine aminotransferase; ANA  anti-nuclear antibody; ANCA  anti-neutrophil cytoplasmic antibodies; AST  aspartate 
aminotransferase; BUN  blood urea nitrogen; CNS  central nervous system; CR  complete response; CT  computed tomography; ECG  electrocardiogram; 
ECOG PS  Eastern Cooperative Oncology Group Performance Status; EOI  end of infusion; EOT  end of treatment; HIV  human immunodeficiency virus; 
 LTFU  long-term follow-up; MRI  magnetic resonance imaging; PBMC  peripheral blood mononuclear cells; PK  pharmacokinetic(s); 
PR  partial response; SFU  safety follow-up; WOCBP  women of child bearing potential. 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 46 of 180 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
 
1 ECGs are required in triplicate approximately 30 to 60 seconds apart and run consecutively for the first 3 cycles during Dose Exploration as described below for each 
cohort at the following time points ( 5 minutes): 
- 
Days 
:  predose, EOI (AMG 994 and AMG 404, as applicable), and 24 hours after AMG 994 EOI (during cycles where hospitalization 
is required).   
- 
As clinically indicated 
No ECGs after cycle 3 for any cohort unless clinically indicated; ECGs at 24 hours after AMG 994 infusion only required for cycles in which hospitalization is 
required.   
2 Vital signs, pulse ox are required at the following time points ( 5 minutes):  
- 
Screening 
During exploration: 
During expansion: 
Note:  Vitals and pulse oximetry should be taken as close to the exact nominal time point as noted above.   
Note:  
during infusion timepoint is relative to AMG 994 infusion.   
Note:  EOI and Post-EOI timepoints for all combination cycles are relative to AMG 404 infusion.   
3 WOCBP, a urine pregnancy test is required at least Q4W thereafter prior to day 1 dosing of all cycles 
4 Chemistry to include:  albumin, alkaline phosphatase, ALT, AST, BUN/total urea, calcium, chloride, creatinine, glucose, potassium, sodium, total bilirubin, total protein 
5 ACTH to be done once every cycle.  ANA and ANCA to be done at screening and then if clinically indicated. 
6 Radiological imaging and tumor assessments are required at screening, cycle 1 
thereafter (C3D
 C5D
 
C7D
 and EOT
  Every assessment must include the chest, abdomen, and pelvis and all other known sites of disease.  Tumor burden assessments will 
be performed based on RECIST 1.1 guidelines (Section 11.11).  Radiographic response (CR and PR) requires confirmation by a repeat assessment at least 4 weeks 
after the first detection of response.  All subjects must have MRI of the brain performed within 28 days prior to enrollment.  Only if MRI is contraindicated, then CT 
with contrast is acceptable.  Subsequently, MRI brain scans may be performed at any time if subject has history of CNS disease or as clinically indicated.  Any 
supplemental imaging used to evaluate or determine response by sites should be sent along with the required scans to the central imaging vendor promptly upon 
completion.   
7 AMG 994 will be administered
 
8 Subjects will be hospitalized for a minimum of 24 hours following each infusion during the first cycle of treatment on study and following the week 1 infusion of the 
second cycle of treatment on study.  Hospitalization should be extended if any adverse event, clinical change, or safety concern associated with the infusion is 
observed.  This will be based on investigator and Amgen Medical Monitor discretion.  Subjects will be observed for 6 hours following each remaining infusion 
(weeks 2, 3, and 4) during the second cycle of treatment on study and observed for 2 to 4 hours following each subsequent infusion for observation of any side 
effects. 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 47 of 180 
CONFIDENTIAL  
FORM-001520, v. 24, 21 May 2019 
 
9 PK blood samples for AMG 994 and AMG 404 should be collected at the exact nominal time point relative to their respective end of infusions as noted above [see 
hours (relative to end of infusion) rows for AMG 994 and AMG 404].  If unable to collect a blood sample at the specified nominal time point, collect it as close as 
possible to the nominal time point and record the actual collection time.  PK samples not collected at exact nominal time point will not be considered protocol 
deviations.  For cycles 3, AMG 404 PK samples should be collected at predose on day 1 of every cycle and at end of infusion at every other cycle on day 1 starting 
in cycle 3 (ie, day 1 of cycles 3, 5, 7 and so on). 
10 A tumor biopsy is required at baseline.  Tumor tissue (archival within  6 months of enrollment or recent acquisition) must be available for correlative studies. 
Subjects must consent to allow the acquisition of formalin-fixed paraffin-embedded (FFPE) material (block or unstained slides) by study personnel for performance of 
correlative tissue studies.  Fresh tumor biopsies are required for subsequent time points. 
 
11 Safety follow-up visit will occur 30 (7) days and 140 days (1 week) after the last dose of AMG 994 and AMG 404 combination therapy. 
12 Long-term follow-up phone call at 6 months (1 week) after the last dose to collect information on adverse events, serious adverse events, concomitant medications, 
start of new therapies, and disease status.  After end of study, serious adverse events suspected to be related to investigational products that the 
investigator becomes aware of, will be reported to Amgen.  As a study endpoint is overall survival, the investigator will also need to collect/report fatal 
serious adverse events (regardless of causality) to Amgen within 24 hours following the investigator’s awareness of the event. 
13 Physical exam is required on days 
 of each cycle.  Height will be measured at screening only.  Weight will be measured at screening and each study 
AMG 404 to be administered on
after the end of infusion of AMG 994 if a  grade 2 infusion reaction is not observed.  The 
dose is 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 48 of 180 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Dose Expansion Cycle 1 - AMG 994 and AMG 404 Combination Therapy  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 end 
of infusion) 
Hours (relative to AMG 404 end 
of infusion) 
GENERAL AND SAFETY 
ASSESSMENTS 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, ECOG PS13 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 49 of 180 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Dose Expansion Cycle 1 - AMG 994 and AMG 404 Combination Therapy  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 
994 end of infusion) 
Hours (relative to AMG 
404 end of infusion) 
ECG triplicate 
measurement1 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, pulse ox2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events review 
 
 
 
Serious adverse events 
 
Concomitant medication 
review 
 
Page 2 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 50 of 180 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Dose Expansion Cycle 1 - AMG 994 and AMG 404 Combination Therapy  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 end 
of infusion) 
Hours (relative to AMG 404 end 
of infusion) 
LABORATORY ASSESSMENTS 
Pregnancy test (females of 
childbearing potential only)3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
Hematology 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
Chemistry4 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
HIV, Hepatitis B and C screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 51 of 180 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Dose Expansion Cycle 1 - AMG 994 and AMG 404 Combination Therapy  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 
end of infusion) 
Hours (relative to AMG 404 
end of infusion) 
SP74 Ventana MSLN IHC 
assay5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
ACTH6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, ANCA6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RADIOLOGICAL 
ASSESSMENTS 
 
CT/MRI and Tumor Burden 
Assessment7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain MRI7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 6 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 52 of 180 
CONFIDENTIAL  
 
 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 53 of 180 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Dose Expansion Cycle 1 - AMG 994 and AMG 404 Combination Therapy  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 end 
of infusion) 
Hours (relative to AMG 404 end 
of infusion) 
DOSING 
 
AMG 9948 
 
  X  
 
 
 
 
 
 
 
 
 
 
 
  
X  
 
 
 
 
 
 
 
 
 
AMG 40415 
 
  
 
 
 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization/Observation9 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
 
PHARMACOKINETIC 
ASSESSMENTS AMG 99410 
 
X 
 
X 
 
X X  
X 
 
X 
X 
X 
X 
X 
(X) 
 
X  
 
 
 
 
X 
 
X 
 
PHARMACOKINETIC 
ASSESSMENTS AMG 40410 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X  
X 
 
 
 
 
 
 
 
 
 
 
Page 5 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 54 of 180 
CONFIDENTIAL  
 
 
Table 1-4.  Schedule of Activities:  Dose Expansion Cycle 1- AMG 994 and AMG 404 Combination Therapy  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 
end of infusion) 
Hours (relative to AMG 404 
end of infusion) 
ARCHIVAL TUMOR TISSUE11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRE-TREATMENT 
TISSUE/FRESH TUMOR 
BIOPSIES12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
WHOLE BLOOD FOR 
CYTOMETRY 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
SERUM MARKERS  
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
PLASMA FOR ctDNA 
ANALYSIS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PBMC 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Page 6 of 6 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 55 of 180 
CONFIDENTIAL  
 
 
(X)  conditional, refer to applicable footnote  
 
ACTH  adrenocorticotropic hormone; ALT  alanine aminotransferase; ANA  anti-nuclear antibody; ANCA  anti-neutrophil cytoplasmic antibodies; AST  aspartate 
aminotransferase; BUN  blood urea nitrogen; CNS  central nervous system; CR  complete response; CT  computed tomography; ECG  electrocardiogram; 
ECOG PS  Eastern Coopera
 Performance Status; EOI  end of infusion; EOT  end of treatment; HIV  human immunodeficiency virus; 
IHC  immunohistochemistry;
MRI  magnetic resonance imaging; MSLN  mesothelin; PBMC  peripheral blood mononuclear cells; 
PK  pharmacokinetic(s); PR  partial response; WOCBP  women of child bearing potential. 
 
1 For Dose Expansion, ECGs are required in triplicate approximately 30 to 60 seconds apart and run consecutively at the following time points ( 5 minutes):  
As clinically indicated 
2 Vital signs, pulse ox are required at the following time points ( 5 minutes):  
Screening 
During expansion: 
Note:  Vitals and pulse oximetry should be taken as close to the exact nominal time point as noted above.   
Note: 
during infusion timepoint is relative to AMG 994 infusion.   
Note:  EOI and Post-EOI timepoints for all combination cycles are relative to AMG 404 infusion.   
3 WOCBP, an initial serum pregnancy test is required prior day 1 of cycle 1; a urine pregnancy test is required at least Q4W thereafter prior to day 1 dosing. 
4 Chemistry to include:  albumin, alkaline phosphatase, ALT, AST, BUN/total urea, calcium, chloride, creatinine, glucose, potassium, sodium, total bilirubin, total protein 
5 SP74 Ventana MSLN IHC assay to be performed for NSCLC squamous cell carcinoma and adenocarcinoma patients only. 
6 ACTH to be done once every cycle.  ANA and ANCA to be done at screening and then if clinically indicated. 
7 Radiological imaging and tumor assessments are required at screening, cycle 1
.  Every assessment must include the chest, abdomen, and 
pelvis and all other known sites of disease.  Tumor burden assessments will be performed based on RECIST 1.1 guidelines (Section 11.11).  Radiographic response 
(CR and PR) requires confirmation by a repeat assessment at least 4 weeks after the first detection of response.  All subjects must have MRI of the brain performed 
within 28 days prior to enrollment.  Only if MRI is contraindicated, then CT with contrast is acceptable.  Subsequently, MRI brain scans may be performed at any time 
if subject has history of CNS disease or as clinically indicated.  Any supplemental imaging used to evaluate or determine response by sites should be sent along with 
the required scans to the central imaging vendor promptly upon completion.   
8 AMG 994 will be administered
. 
9 During dose expansion, subjects will be observed for 2 to 4 hours following each infusion for observation of any side effects.   
10 PK blood samples for AMG 994 and AMG 404 should be collected at the exact nominal time point relative to their respective end of infusions as noted above [see 
hours (relative to end of infusion) rows for AMG 994 and AMG 404].  If unable to collect a blood sample at the specified nominal time point, collect it as close as 
possible to the nominal time point and record the actual collection time.  PK samples not collected at exact nominal time point will not be considered protocol 
deviations. 
11 If available, archived tumor tissue (archival within  6 months of enrollment) or recent acquisition will be collected prior to cycle 1, day 1 during screening. 
12 A tumor biopsy is required at baseline.  Tumor tissue (archival within  6 months of enrollment or recent acquisition) must be available for correlative studies. 
Subjects must consent to allow the acquisition of formalin-fixed paraffin-embedded (FFPE) material (block or unstained slides) by study personnel for performance of 
correlative tissue studies.  Fresh tumor biopsies are required for subsequent time points.
13 Physical exam is required on days 
 of each cycle.  Height will be measured at screening only.  Weight will be measured at screening and each study 
visit where a physical exam is also performed. 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 56 of 180 
CONFIDENTIAL  
 
 
15 AMG 404 to be administered on
after the end of infusion of AMG 994 if a  grade 2 infusion reaction is not observed.  The dose is 
 
 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 57 of 180 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Dose Expansion AMG 994 and AMG 404 Combination Therapy Cycle 2 and Beyond  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 
994 end of infusion) 
Hours (relative to AMG 
404 end of infusion) 
GENERAL AND SAFETY ASSESSMENTS 
Physical examination, 
ECOG PS13 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
  
 
  
 
 
 
X 
X 
 
ECG triplicate 
measurement1 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, pulse ox2 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Page 1 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 58 of 180 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Dose Expansion AMG 994 and AMG 404 Combination Therapy Cycle 2 and Beyond  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 
end of infusion) 
Hours (relative to AMG 404 
end of infusion) 
Adverse events review 
 
 
Serious adverse events 
 
Concomitant medication 
review 
 
LABORATORY ASSESSMENTS 
Pregnancy test (females of 
childbearing potential only)3 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Coagulation 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Page 2 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 59 of 180 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Dose Expansion AMG 994 and AMG 404 Combination Therapy Cycle 2 and Beyond  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 
end of infusion) 
Hours (relative to AMG 404 
end of infusion) 
Hematology 
X 
 
 
 
 
X  
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Chemistry4 
X 
 
 
 
 
X  
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
HIV, Hepatitis B and C 
screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
ACTH5 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, ANCA5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 3 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 60 of 180 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Dose Expansion AMG 994 and AMG 404 Combination Therapy Cycle 2 and Beyond  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 
994 end of infusion) 
Hours (relative to AMG 
404 end of infusion) 
RADIOLOGICAL ASSESSMENTS 
CT/MRI and Tumor Burden 
Assessment6 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Brain MRI6 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
DOSING 
AMG 9947 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
AMG 40415 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
 
(X)  
 
 
 
 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
Hospitalization/Observation8 
(X) 
 
(X) 
 
(X) 
 
 
 
 
Page 4 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 61 of 180 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Dose Expansion AMG 994 and AMG 404 Combination Therapy Cycle 2 and Beyond  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 
994 end of infusion) 
Hours (relative to AMG 
404 end of infusion) 
PHARMACOKINETIC 
ASSESSMENTS AMG 9949 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X X 
 
PHARMACOKINETIC 
ASSESSMENTS AMG 4049 (X) 
 
 
 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
X X 
 
PRE-TREATMENT 
TISSUE/FRESH TUMOR 
BIOPSIES10 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 5 of 6 
Footnotes defined on last page of this table


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 62 of 180 
CONFIDENTIAL  
 
 
Table 1-5.  Schedule of Activities:  Dose Expansion AMG 994 and AMG 404 Combination Therapy Cycle 2 and Beyond  
CYCLES 
WEEKS 
DAYS 
Hours (relative to AMG 994 
end of infusion) 
Hours (relative to AMG 404 
end of infusion) 
WHOLE BLOOD FOR 
CYTOMETRY 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SERUM MARKERS 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
PLASMA FOR ctDNA 
ANALYSIS 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
PBMC 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Phone Call12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 6 of 6 
(X)  conditional, refer to applicable footnote  


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 63 of 180 
CONFIDENTIAL  
 
 
ACTH  adrenocorticotropic hormone; ALT  alanine aminotransferase; ANA  anti-nuclear antibody; ANCA  anti-neutrophil cytoplasmic antibodies; AST  aspartate 
aminotransferase; BUN  blood urea nitrogen; CNS  central nervous system; CR  complete response; CT  computed tomography; ECG  electrocardiogram; 
ECOG PS  Eastern Cooperative Oncology Group Performance Status; EOI  end of infusion; EOT  end of treatment; HIV  human immunodeficiency virus; 
LTFU  long-term follow-up; MRI  magnetic resonance imaging; PBMC  peripheral blood mononuclear cells; PK  pharmacokinetic(s); 
PR  partial response; SFU  safety follow-up; WOCBP  women of child bearing potential. 
 
1 For Dose Expansion, ECGs are required in triplicate approximately 30 to 60 seconds apart and run consecutively at the following time points:  
As clinically indicated 
2 Vital signs, pulse ox are required at the following time points:  
Screening 
During expansion: 
Note:  Vitals and pulse oximetry should be taken as close to the exact nominal time point as noted above, 5 minutes.   
Note: 
during infusion timepoint is relative to AMG 994 infusion.   
Note:  EOI and Post-EOI timepoints for all combination cycles are relative to AMG 404 infusion for combination therapy cycles and relative to AMG 994 for 
monotherapy cycles.   
3 WOCBP, a urine pregnancy test is required at least Q4W thereafter prior to day 1 dosing of all cycles 
4 Chemistry to include:  albumin, alkaline phosphatase, ALT, AST, BUN/total urea, calcium, chloride, creatinine, glucose, potassium, sodium, total bilirubin, total protein 
5 ACTH to be done once every cycle.  ANA and ANCA to be done at screening and then if clinically indicated. 
6 Radiological imaging and tumor assessments are required 
 (C3
C5
 C7
7 days) and EOT 
  Every assessment must include the 
chest, abdomen, and pelvis and all other known sites of disease.  Tumor burden assessments will be performed based on RECIST 1.1 guidelines (Section 11.11).  
Radiographic response (CR and PR) requires confirmation by a repeat assessment at least 4 weeks after the first detection of response.  All subjects must have MRI 
of the brain performed within 28 days prior to enrollment.  Only if MRI is contraindicated, then CT with contrast is acceptable.  Subsequently, MRI brain scans may be 
performed at any time if subject has history of CNS disease or as clinically indicated.  Any supplemental imaging used to evaluate or determine response by sites 
should be sent along with the required scans to the central imaging vendor promptly upon completion.   
7 AMG 994 will be administered 
 
8 During dose expansion, subjects will be observed for 2 to 4 hours following each infusion for observation of any side effects.   
9 PK blood samples for AMG 994 and AMG 404 should be collected at the exact nominal time point relative to their respective end of infusions as noted above [see 
hours (relative to end of infusion) rows for AMG 994 and AMG 404].  If unable to collect a blood sample at the specified nominal time point, collect it as close as 
possible to the nominal time point and record the actual collection time.  PK samples not collected at exact nominal time point will not be considered protocol 
deviations.  For AMG 404, PK samples should be collected at (1) predose on day 1 of every cycle and (2) end of infusion on day 1 of cycle 2 and day 1 of every other 
cycle starting in cycle 3 (ie, day 1 of cycles 3, 5, 7 and so on). 
10 Fresh tumor biopsies are required for subsequent time points. 
 
11 Safety follow-up visit will occur 
days after the last dose of AMG 994 and AMG 404 combination therapy. 
12 Long-term follow-up phone call at 6 months ( 1 week) after the last dose to collect information on adverse events, serious adverse events, concomitant medications, 
start of new therapies, and disease status.  After end of study, serious adverse events suspected to be related to investigational products that the 
investigator becomes aware of, will be reported to Amgen.  As a study endpoint is overall survival, the investigator will also need to collect/report fatal 
serious adverse events (regardless of causality) to Amgen within 24 hours following the investigator’s awareness of the event. 
13 Beginning with cycle 3 and subsequent cycles, physical exam is required on days 
 of each cycle.  Height will be measured at screening only.  Weight 
will be measured at screening and each study visit where a physical exam is also performed. 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 64 of 180 
CONFIDENTIAL  
 
 
15 AMG 404 to be administered on
after the end of infusion of AMG 994 if a  grade 2 infusion reaction is not observed.  The 
dose is
 


Product:  AMG 994 and AMG 404  
Protocol Number:  20190136  
Date:  16 June 2022 
Page 65 of 180 
CONFIDENTIAL  
 
 
2. 
Introduction 
2.1 
Study Rationale 
AMG 994 is a bivalent bispecific monoclonal IgG1 directed against MSLN and CD40.  
This study will evaluate AMG 994 monotherapy and in combination with AMG 404, an 
anti-PD-1 checkpoint monoclonal antibody (mAb), for the treatment of patients with 
locally-advanced or metastatic advanced solid tumors reported to express MSLN. 
Mesothelin is a cell-surface glycoprotein with normal expression limited to mesothelial 
cells lining the surface of several body cavities, including the pleura, peritoneum, and 
pericardium, and covering the surface of multiple internal organs.  Expression of MSLN 
is upregulated in many solid tumors during the tumorigenic process, with particularly 
high expression in NSCLC, mesothelioma, pancreatic cancer, and serous ovarian 
cancer.  Higher expression of MSLN has been correlated with poorer patient prognosis 
across multiple tumor types, including ovarian cancer, bile duct cancer, lung 
adenocarcinoma, triple-negative breast cancer, and resectable pancreatic cancer 
(Hassan et al, 2016).  Based on these findings, MSLN is an attractive target for cancer 
therapy with antibody-based approaches as well as tumor vaccines (Awuah et al, 2016). 
CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily that is 
preferentially expressed by antigen presenting immune cells, such as dendritic cells, 
B cells, and macrophages.  Interaction with its trimeric ligand, CD40L, expressed by 
activated T helper cells leads to CD40-mediated activation of antigen presenting cells, 
potentiating expression of antigen presentation machinery, T cell co-stimulatory 
molecules, and pro-inflammatory cytokines.  CD40 function is critical for the generation 
of robust and long-lasting cell-mediated immunity (Schaer et al, 2014; Bennett et al, 
1998; Ridge et al, 1998) and activation of CD40 has been widely explored as an 
immunotherapeutic approach for the treatment of cancer (Schaer et al, 2014; 
Vonderheide and Glennie, 2013). 
Systemic non-tumor targeted CD40 agonist monoclonal antibodies have been 
associated with dose-limiting, immune-mediated adverse events such as cytokine 
release syndrome (CRS), thrombocytopenia, and elevated liver function tests (Irenaeus 
et al, 2019; Vitale et al, 2019; Johnson et al, 2015; Vonderheide et al, 2007; 
Vonderheide et al, 2001).  To limit systemic CD40 activation and associated key safety 
risks and induce robust CD40 activation of antigen presenting immune cells locally in 
solid tumors, Amgen has developed AMG 994, a bispecific monoclonal immunoglobulin 
targeting MSLN and CD40 that has been shown to be a potent, MSLN‑dependent CD40 


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agonist in nonclinical studies.  Given the route of administration, an infusion-related 
reaction is still considered a key safety risk for AMG 994.  Another bispecific molecule 
targeting CD40 and MSLN, ABBV-428, has been shown to enhance tumor-specific 
immunity in nonclinical studies (Ye et al, 2019) and is being evaluated in a clinical 
program including a recently completed phase 1 dose escalation clinical study (Fang et 
al, 2020; Luke et al, 2019; National Library of Medicine, NCT02955251, 2019). 
Generation of productive anti-tumor immunity is a multi-step process consisting of 
tumor-specific T cell activation, differentiation, and expansion in tumor-draining lymph 
nodes, trafficking of tumor-specific T cells into tumor tissue, and direct interactions 
between tumor cells and T cells leading to T cell activation and tumor cell death (Chen 
and Mellman, 2013).  The PD-1 receptor functions as a dominant inhibitor of anti-tumor 
T cell responses.  Its expression is rapidly upregulated by T cells after activation and 
sustained at high levels by populations of tumor-specific T cells within the tumor 
microenvironment (Ribas and Wolchok, 2018).  Interactions between PD-1 expressed by 
T cells and its ligands PD-L1 and programmed death ligand 2 (PD-L2) expressed by 
tumor cells and antigen presenting cells of the immune system can inhibit generation of 
tumor-specific T cells in the lymph node and cytolytic killing activity of T cells in the 
tumor. 
Enhancement of anti-tumor immunity through inhibition of PD-1 has been effective in the 
treatment of many malignancies.  AMG 404 is a fully human mAb that binds human and 
cynomolgus monkey PD-1 and blocks the ability of these receptors to interact with 
human ligands, PD-L1, and PD-L2.  Anti-PD-1 and anti-PD-L1 therapies have 
demonstrated improved overall survival and/or objective responses in multiple advanced 
solid tumors; however, optimal therapy will likely require combining anti-PD-1 mAb 
treatment with other therapies.  AMG 404 is currently being evaluated in subjects with 
advanced solid tumors in Study 151001.  Clinical results to date indicate that AMG 404 
is well tolerated at doses up to 
 with 3 key safety risks:  infusion-
related reaction, immune-related toxicities, and embryofetal toxicity. 
A recent review by Vonderheide (2020) of clinical experience with CD40 agonist 
antibodies suggests limited monotherapy efficacy, but the potential to show increased 
efficacy with other immunotherapies, such as PD-1 blockade.  Amgen proposes that the 
novel-novel combination of AMG 994, a CD40 agonist designed to limit systemic 
toxicities by MSLN-dependent-activation, and AMG 404, a molecule that can block 


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PD-1-mediated T cell inhibition, may promote greater responses in multiple advanced 
solid tumor types than either therapy alone. 
Amgen plans to conduct a FIH phase 1 Study 20190136 in adult subjects with 
locally-advanced or metastatic advanced solid tumors reported to express MSLN, which 
includes evaluation of AMG 994 in combination with AMG 404 administered until 
evidence of disease progression; intolerance to study medication; withdrawal of consent; 
or, in the absence of the above, up to 12 months if subject achieves a complete 
response, and up to 24 months if partial response or stable disease.  Study 
assessments will include measures of safety, tolerability, PK, pharmacodynamics, 
immunogenicity, and preliminary anti-tumor activity. 
2.2 
Background 
2.2.1 
Disease 
Mesothelin is a cell-surface glycoprotein with normal expression limited to mesothelial 
cells lining the surface of several body cavities, including the pleura, peritoneum, and 
pericardium, and covering the surface of multiple internal organs.  Expression of MSLN 
is upregulated in many solid tumors during the tumorigenic process, with particularly 
robust expression in mesothelioma, serous ovarian cancer, NSCLC, and pancreatic 
cancer.  Higher expression of MSLN has been correlated with poorer patient prognosis 
across multiple tumor types, including ovarian cancer, bile duct cancer, lung 
adenocarcinoma, triple-negative breast cancer, and resectable pancreatic cancer 
(Hassan et al, 2016).  Five-year survival rates are as follows:  pancreatic 
adenocarcinoma 3, mesothelioma less than 10, lung adenocarcinoma less than 30, 
high grade ovarian cancer 25 .  Based on these findings, MSLN is an attractive target 
for cancer therapy with antibody-based approaches as well as tumor vaccines (Awuah 
et al, 2016). 
Interaction with its trimeric ligand, CD40L, expressed by activated T helper cells leads to 
CD40-mediated activation of antigen presenting cells potentiating expression of antigen 
presentation machinery, T cell co-stimulatory molecules, and pro-inflammatory 
cytokines.  CD40 function is critical for the generation of robust and long-lasting 
cell-mediated immunity critical for the generation of robust and long-lasting cell-mediated 
immunity (Schaer et al, 2014; Bennett et al, 1998; Ridge et al, 1998) and activation of 
CD40 has been widely explored as an immunotherapeutic approach for the treatment of 
cancer (Schaer et al, 2014; Vonderheide and Glennie, 2013).  


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AMG 994 (MSLN-dependent CD40 agonist) and AMG 404 (PD-1 inhibitor) target distinct 
steps in the anti-tumor immune response.  By activating the CD40 receptor on antigen 
presenting cells, AMG 994 promotes initiation of anti-tumor T-cell responses while 
AMG 404 further enhances these T-cell responses by blocking PD-1-mediated inhibitory 
signals.   
The combination of AMG 994 and AMG 404 is not predicted to result in synergistic 
increases or significant overlapping toxicity based on differing modes of action 
(Vonderheide, 2018; Piechutta and Berghoff, 2019), and differing safety profiles in 
nonclinical monotherapy toxicology studies (Study 151001; AMG 404:  Section 2.6.6, 
IND 140964).  By targeting orthogonal processes in the anti-tumor T cell response, 
AMG 994 and AMG 404 may synergize to promote efficacy.  
Clinical experience with CD40 agonist antibodies suggests limited monotherapy efficacy, 
as reviewed in Vonderheide (2020), but the potential to combine well with other 
immunotherapies, such as PD-1 blockade.  Activation of CD40 on antigen presenting 
cells leads to upregulation of antigen presenting cell machinery, T cell co-stimulatory 
molecules, and pro-inflammatory cytokines, all of which can serve to promote and 
sustain anti-tumor T cell responses.  Thus, by targeting orthogonal processes in the 
anti-tumor immune response, therapeutics designed to inhibit the function of PD-1 
(AMG 404) and promote the activity of CD40 (AMG 994) may synergize to potentiate 
generation of tumor-specific cytolytic T cells and promote therapeutic efficacy.   
Consistent with this hypothesis, in vivo studies in the huEPCAM-MC38 syngeneic mouse 
tumor model using the AMG 994 mouse surrogate (muCD40 BsAb) and an antibody that 
inhibits interaction between murine PD-1 and PD-L1 (anti-PD-L1; AMG 404 mouse 
surrogate) have demonstrated the ability of this combination to promote increased 
complete tumor regression relative to either individual treatment alone or the 
combination of a nontargeted systemic CD40 agonist (anti-CD40) with anti-PD-L1. 
Thus, the combination of AMG 994, a molecule that may promote CD40-mediated 
initiation of anti-tumor T cell responses with limited systemic toxicities, and AMG 404, a 
molecule that can block PD-1-mediated T cell inhibition downstream of these initiation 
events, may promote greater responses in multiple advanced solid tumor types than 
either therapy alone. 


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2.2.2 
Amgen Investigational Product Background:  AMG 994 
AMG 994 is a fully human bivalent bispecific monoclonal IgG1 SEFL2 directed against 
MSLN and CD40, expressed in a Chinese hamster ovary cell line with a molecular 
weight of approximately 196 kDa. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AMG 994 
is provided in the AMG 994 Investigator’s Brochure. 
2.2.2.1 
AMG 994 Toxicology 
The nonclinical safety assessment was performed in accordance with ICH Guideline S9, 
“Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH, 2010) and consisted of an 
exploratory 17-day repeat dose study in the cynomolgus monkey, a Good Laboratory 
Practice (GLP)-compliant 
 repeat dose study in the cynomolgus monkey, an in 
vitro human cytokine release assay, and an in vitro platelet activation assay.  The 
cynomolgus monkey was selected as the pharmacologically relevant species for 
nonclinical safety assessment based on similar binding and functional activity of the 
CD40 and MSLN arms of AMG 994 for human and cynomolgus monkey, but not mouse 
or rat.  
In the
 GLP study AMG 994 was administered intravenously to cynomolgus 
monkeys weekly for 4-weeks at doses of
mg/kg.  The doses were selected 
to appropriately characterize toxicity, toxicokinetic parameters, and establish a highest 
non-severely toxic dose (HNSTD) while ensuring maximum CD40 receptor occupancy 
(RO).  The 
 route of administration was chosen based on the intended clinical route of 
administration.  AMG 994-related changes in this study were limited to


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  The HNSTD was 
, the highest dose tested.  
The potential for AMG 994-mediated cytokine release was in a human cytokine release 
assay.  AMG 994 did not induce increases of measured cytokines above background 
levels in the absence of MSLN expressing cells as predicted based on the requirement 
for MSLN binding and CD40 crosslinking for AMG 994 mediated agonism.  Consistent 
with these in vitro results, AMG 994 did not cause cytokine release at any dose level in 
the cynomolgus monkey during the GLP toxicology study. 
Additionally, the potential for AMG 994-mediated platelet activation was assessed in a 
human platelet activation assay.  AMG 994 did not induce platelet activation in human 
whole blood at any of the concentrations tested in the absence of MSLN expressing cells 
as predicted based on requirement for MSLN binding and CD40 crosslinking for 
AMG 994 mediated agonism.  A lack of AMG 994-associated platelet activation is further 
supported by no platelet count changes in the cynomolgus monkey during the GLP 
toxicology study.   
2.2.3 
Amgen Investigational Product Background:  AMG 404 
AMG 404 is a fully human, monoclonal IgG1 SEFL2 directed against PD-1, expressed in 
a Chinese hamster ovary cell line.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AMG 404 
is provided in the AMG 404 Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
This is a FIH study with AMG 994 monotherapy and AMG 994 in combination with 
AMG 404.  Data from nonclinical toxicity studies of AMG 994 and clinical and nonclinical 
studies with AMG 404 suggest that the potential benefit/risk profile favors clinical 
development of AMG 994 in combination with AMG 404 for patients with advanced solid 


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tumors of types known to express MSLN.  Clinical signs and symptoms, along with other 
safety laboratory parameters, will be monitored during the study and at the appropriate 
time points to ensure subjects’ safety. 
2.3.1 
AMG 994 
2.3.1.1 
Therapeutic Context 
AMG 994 will be investigated with advanced solid tumors of types known to express 
MSLN.  Mesothelin is expressed by many solid tumors, with particularly high expression 
in NSCLC adenocarcinoma, mesothelioma, pancreatic adenocarcinoma, and high-grade 
serous ovarian cancer.  Higher expression of MSLN has been correlated with poorer 
prognosis for patients with ovarian cancer, cholangiocarcinoma, lung adenocarcinoma, 
triple negative breast cancer, and resectable adenocarcinoma.  The 5-year survival rates 
are as follows: 
 
Lung adenocarcinoma, less than 30 
 
Mesothelioma, less than 10 
 
Pancreatic adenocarcinoma, 3 
 
High grade ovarian cancer, 25 
2.3.1.2 
Key Benefits 
As AMG 994 is in early development and there is no human or clinical experience with 
AMG 994, key benefits are being investigated and will be described when the data 
become available. 
2.3.1.3 
Key Risks 
AMG 994 has not been administered to humans, there is no human or clinical 
experience with AMG 994.  Based on biological mechanism of action, nonclinical toxicity 
studies of AMG 994, and clinical experience with other CD40 agonists, the key safety 
risks for AMG 994 include infusion-related reactions (see Table 2-1). 
Systemic CD40 molecules have been associated with higher frequency of adverse 
events such as CRS, thrombocytopenia and elevations in liver enzymes, however since 
there is requirement for MSLN binding and CD40 crosslinking for AMG 994 mediated 
agonism it is unlikely these adverse events will be observed with AMG 994.  Overall, the 
results of the nonclinical safety studies support the initiation of AMG 994 clinical studies. 


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Table 2-1.  Key Safety Risks for AMG 994 
Safety Risk 
Description 
Infusion-related 
reactions 
Signs and symptoms may include pyrexia, chills, rigors, 
flushing, urticaria, hypotension, dyspnea, wheezing, 
headache, back pain, and abdominal pain.  
Clinical signs and symptoms of infusion-related reactions, along with safety laboratory 
parameters, will be monitored during the study to ensure subjects’ safety.  Refer to 
Section 11.10 for specific recommendations regarding the mitigation and management 
of infusion-related reactions.  
Refer to the AMG 994 Investigator’s Brochure for further description of key safety risks 
2.3.2 
AMG 404 
2.3.2.1 
Therapeutic Context 
AMG 404 is currently being investigated in subjects with advanced solid tumors as a 
monotherapy and in combination with other investigational agents and, in this study, will 
be investigated in combination with AMG 994 in subjects with advanced solid tumors of 
types known to express MSLN. 
2.3.2.2 
Key Benefits 
The PD-1 receptor-ligand interaction is a major pathway that tumors use to suppress 
immune control.  Programmed cell death-1 has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) and 
limit the efficacy of immune therapies.  Enhancement of anti-tumor immunity through 
inhibition of PD-1 has been effective in treatment of many malignancies.  AMG 404 is a 
mAb that binds to PD-1 and may provide clinical benefit in combination with AMG 994. 
2.3.2.3 
Key Risks 
AMG 404 is currently being tested as monotherapy for the first time in humans with 
advanced solid tumors in the Amgen-sponsored Study 20180143.  As of 04 May 2020, 
62 subjects have received AMG 404 at doses between 
 and has been 
well-tolerated.  Key safety risks for AMG 404 include immune-related toxicities, 
infusion-related reactions, and embryo-fetal toxicity (see Table 2-2).  Among immune 
related toxicities, more recently hypothyroidism has been identified as an adverse drug 
reaction (ADR). 


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Table 2-2.  Key Safety Risks for AMG 404 
Safety Risk 
Description 
Immune-related 
toxicities 
Immune-related adverse effects associated with PD-1 
blocking agents include pneumonitis, colitis, hepatitis, 
endocrinopathies including hypothyroidism, nephritis and 
renal dysfunction, skin reactions, encephalitis, and other 
immune-related adverse reactions.  
Infusion-related 
reactions 
Signs and symptoms may include pyrexia, chills, rigors, 
flushing, urticaria, hypotension, dyspnea, wheezing, 
headache, back pain, and abdominal pain.  
Embryofetal toxicity 
Blockade of PD-L1 signaling has been shown in animal 
models of pregnancy to disrupt tolerance to the fetus and to 
result in an increase in fetal loss; therefore, there is the 
possibility of fetal harm if administered during pregnancy 
(Poulet et al, 2016).  
Clinical signs and symptoms of immune-related toxicities and infusion-related reactions, 
along with safety laboratory parameters, will be monitored during the study to ensure 
subjects’ safety.  Refer to Section 11.10 for specific recommendations regarding the 
mitigation and management of immune-related toxicities and infusion-related reactions.  
Refer to the AMG 404 Investigator’s Brochure for further description of key safety risks.   
2.3.3 
AMG 994 in Combination with AMG 404 
AMG 994 will be used in combination with AMG 404.  Based on biological mechanism of 
action and initial clinical safety information from the ongoing FIH study with AMG 404 
(Study 20180143), the key safety risks described for AMG 404 monotherapy including 
immune related toxicities (with hypothyroidism now as an ADR) and embryofetal toxicity 
would also be expected. 
With the exception of infusion-related reactions, which is a key safety risk for both 
AMG 994 and AMG 404, the combination of AMG 994 and AMG 404 is not anticipated to 
have synergistic increases or additional overlapping toxicity based on differing 
mechanisms of action (Piechutta and Berghoff, 2019; Vonderheide, 2018) and differing 
adverse events reported in nonclinical monotherapy toxicology studies (AMG 994:  
ongoing; AMG 404:  Section 5 of Investigator’s Brochure, Appendix 2). 
Safety of combination therapy will be monitored by routine safety parameters (adverse 
events, laboratory data, etc.) collected during the study.  The risk of synergistic toxicity is 
anticipated to be low due to different modes of clearance and modes of action.  Refer to 
the protocol schedule of assessments for specific information regarding the safety 
monitoring parameters. 


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Finally, sucrose-mediated renal toxicity is an additional risk which may increase during 
combination therapy and will be monitored during the study.   
The drug product for AMG 994 and AMG 404 contains 9 sucrose as a stabilizer.  In 
accordance with the dosing schedule, using the anticipated maximum doses of 
AMG 994 (
) in combination with AMG 404 (
), the estimated 
toxicology-based limit for parenteral administration of sucrose or per dose limit of  3.5 g 
of sucrose is not expected to be exceeded. 
Monitoring of renal function (eg, serum creatinine, electrolytes) and any potential renal 
dysfunction associated adverse events will be conducted during the study.  Subject 
eligibility criteria, monitoring, and dose modification guidelines pertaining to renal 
function are provided in the clinical study protocol. 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the respective Investigator’s Brochure for further data on AMG 994 
and AMG 404. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety, tolerability, 
and maximum tolerated dose 
(MTD)/maximum tolerated 
combination dose (MTCD) or 
recommended phase 2 dose 
(RP2D) of AMG 994 as 
monotherapy and AMG 994 in 
combination with AMG 404 in 
subjects with advanced solid 
tumors 
 
Dose-limiting toxicities (DLTs) 
 
Treatment-emergent and 
treatment related adverse 
events (including all adverse 
events, grade  3, serious 
adverse events, fatal adverse 
events, adverse events 
requiring permanent 
discontinuation of study 
treatment, and immune-related 
events) 
 
Changes in vital signs, 
electrocardiograms (ECGs), 
and clinical laboratory tests 
Secondary 
 
Preliminary evaluation of 
anti-tumor activity of AMG 994 as 
monotherapy and AMG 994 in 
combination with AMG 404 
 
Objective response (OR) per 
modified Response Evaluation 
Criteria in Solid Tumors 
(RECIST) 1.1 
 
Duration of response (per 
modified RECIST 1.1) 


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Exploratory 
 
4. 
Study Design 
4.1 
Overall Design 
This is a FIH, multicenter, non-randomized, open-label, phase 1 study to evaluate the 
safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary efficacy of 
multiple doses of AMG 994 monotherapy and multiple doses of AMG 994 in combination 
with AMG 404 in subjects with locally-advanced or metastatic solid tumors reported in 
the literature to express MSLN including mesothelioma, NSCLC squamous cell 
carcinoma (Part 2 only) and adenocarcinoma (Part 1 and Part 2), pancreatic 
adenocarcinoma, and high grade serous ovarian carcinoma (platinum resistant).  
Table 4-1 summarizes tumor histologies known to express MSLN (Hassan et al 2016), 
and will be used as a reference for eligibility to enroll to Dose Escalation (Part 1).  
Except for NSCLC subjects enrolled to Dose Expansion (Part 2), subjects will not be 
 
Overall survival (OS) 
 
Progression-free survival (per 
modified RECIST 1.1) 
 
Time to progression (per 
modified RECIST 1.1) 
 
Time to subsequent therapy 
 
Characterize the PK of AMG 994 
monotherapy and AMG 994 in 
combination with AMG 404 
PK parameters 
 
Maximum serum concentration 
(Cmax) 
 
Minimum serum concentration 
(Cmin) 
 
Area under the concentration-
time curve (AUC) over the 
dosing interval 
 
Half-life (t1/2), if feasible 


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required to undergo testing to confirm tumor MSLN expression to be enrolled into the 
study.   
Table 4-1:  MSLN Expression in Solid Tumors 
Tumor Type 
Patients with MSLN Expression – 
Positive Disease () 
Mesothelioma 
82 
 
Epithelioid 
95 
 
Sarcomatoid 
0 
Pancreatic adenocarcinoma 
85 
Epithelial ovarian cancer 
70 
 
High-grade serous 
75 
 
Endometrioid 
69 
 
Mucinous 
11 
 
Clear cell 
52 
NSCLC 
57 
 
Adenocarcinoma 
64 
 
Squamous 
21 
SCLC 
0 
Esophageal cancer 
28 
Gastric cancer 
47 
Biliary cancer 
 
 
Extrahepatic 
95 
 
Intrahepatic 
10 
 
Other or unspecified 
42 
Colorectal cancer 
30 
Cervical cancer 
25 
Endometrial cancer 
59 
Breast cancer 
 
 
Triple negative 
66 
 
Other 
1.6 
 
Unspecified 
9 
MSLN  mesothelin, NSCLC  nonsmall-cell lung cancer 
Study assessments will include measures of safety, tolerability, PK, and 
pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. 
AMG 994 will be administered by 
cycle 
(on days
) and AMG 404 will be administered by 
cycle.  The study will be 
conducted in 2 parts:  Part 1 – Dose Exploration and Part 2 – Dose Expansion.  Part 1 is 
aimed at evaluating the safety, tolerability, PK, and pharmacodynamics of AMG 994 and 
AMG 404 combination using sequential and concurrent initiation of dosing:  (a) 1 cycle of 
AMG 994 monotherapy followed by combination of AMG 994 and AMG 404 from cycle 2 
onwards and (b) AMG 994 and AMG 404 dosing starting on cycle 1 day 1.  The 
MTD/MTCD of the combination in subjects with locally advanced or metastatic solid 
tumors will be determined using a Bayesian Logistics Regression Model (BLRM) design.  
Part 2 will further evaluate the safety of the MTD/MTCD and/or a biologically active dose 
(eg, recommended phase 2 dose [RP2D]) of the combination in specific tumor types.  


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The dose expansion part of the study (Part 2) will be opened once the 
MTD/MTCD/RP2D of the combination has been determined in Part 1.   
During Dose Exploration (Part 1), 94 subjects will be enrolled with metastatic or locally 
advanced solid tumors of types known to express MSLN for which no standard systemic 
therapy exists; screening for MSLN expression will not occur.  During Dose Expansion 
(Part 2), approximately 120 additional subjects, up to 30 subjects in each of 4 tumor 
types (mesothelioma, NSCLC squamous cell carcinoma and adenocarcinoma [if upon 
screening found to be MSLN positive], pancreatic adenocarcinoma, and high grade 
serous ovarian carcinoma) will be enrolled; screening for MSLN expression will be 
required for subjects with NSCLC.  The DLT evaluation period will be
 for each 
cycle.  Administration of AMG 994 (in Part 1 and Part 2) may continue until evidence of 
disease progression; intolerance to study medication; withdrawal of consent; or, in the 
absence of the above, up to 12 months if subject achieves a complete response, and up 
to 24 months if partial response or stable disease.   
Part 1 - Dose Exploration 
Dose exploration cohorts will estimate the safety, tolerability, PK, and 
pharmacodynamics of different doses of AMG 994 in combination with AMG 404 in 
subjects with advanced solid tumors of types known to express MSLN.  The dose 
exploration will be conducted in 2 parts (Section 1.2):  
Part 1a will include 
 of 3 to 6 subjects each.   


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Part 1b:   
Part 1c:   
The decision to advance to the next dose level will be recommended by the DLRT using 
the dose level recommendation from BLRM model, as appropriate, and by evaluating 
available safety data, laboratory, and PK information.  For each DLT or suspected DLT, 
the BLRM model will be updated and reviewed by Amgen safety and the medical 
monitor and, as appropriate, an ad hoc DLRM may be called.   
To ensure the safety of all subjects, risk mitigation plans will be followed (see 
Section 6.2.1). 
Dose exploration will continue until any of the following events: 
 
The highest planned dose level is determined to be safe and tolerable (minimum of 
6 DLT-evaluable subjects) 
 
The MTD/MTCD is identified, BLRM recommends a dose level which already has 
6 DLT-evaluable subjects 


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Part 2 – Dose Expansion 
Upon completing the dose exploration phase of the study, and depending on data 
obtained, dose expansion may proceed in subjects with certain advanced solid tumors of 
types known to express MSLN:  
 
Mesothelioma 
 
NSCLC squamous cell carcinoma and adenocarcinoma, if upon screening found to 
be MSLN positive 
 
Pancreatic adenocarcinoma 
 
High grade ovarian carcinoma (platinum resistant) 
AMG 994 plus AMG 404 combination will be administered from cycle 1, day 1. 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.2 
Number of Subjects 
Approximately 214 subjects with advanced solid tumors of types known to express 
MSLN will be enrolled in the study.  Up to 94 evaluable subjects will be enrolled in dose 
escalation (Part 1) and approximately 120 evaluable subjects will be enrolled in dose 
expansion (Part 2), up to 30 subjects in each of 4 tumor types (mesothelioma, NSCLC 
squamous cell carcinoma and adenocarcinoma [if upon screening are found to be MSLN 
positive], pancreatic adenocarcinoma, and high grade serous ovarian carcinoma). 
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
Ineligible subjects (ie, subjects who were exposed to investigational product but post hoc 
were found to be ineligible) may be replaced.  During Part 1, subjects who are not 
DLT-evaluable may be replaced (see Section 6.2.1 for a definition of DLT-evaluable).  All 
available safety data for subjects who are not DLT evaluable will still be evaluated and 
considered in DLRT recommendations.  Refer to Section 7.2.2 for information regarding 
replacement of subjects who receive AMG 994 in combination with AMG 404.  Subjects 
who are withdrawn or removed from treatment or the study during Part 2 will not be 
replaced.  


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4.2.2 
Number of Sites 
Approximately 30 investigative sites in Australia, Canada, China, Japan, the United 
States, and some countries of the European Union (EU) will be included in the study.  
Sites that do not enroll subjects within 6 months of site initiation may be closed. 
4.3 
Justification for Investigational Product Dose 
The proposed starting dose of AMG 994 in the FIH study is 
 per dose.  This was 
based on the predicted human dose necessary to provide a maximum serum 
concentration (Cmax) approximating the minimum anticipated biological effect level 
(MABEL).  The RO on CD40 was identified as the key in vitro parameter of AMG 994 
activity used to estimate the MABEL because the binding of CD40 to the anti-CD40 
domain in AMG 994 (dissociation constant [Kd] for binding, Kd
) is the primary 
event that triggers the pharmacological activity of AMG 994.  It is worth noting that a 
similar Kd was measured for MSLN RO of AMG 994 in humans.  Based on 80 CD40 
RO of AMG 994, the MABEL was estimated to be
Use of 80 RO as the MABEL and basis for the FIH starting dose is supported by the 
toxicological and pharmacological data of AMG 994 and external clinical data from a 
MSLN-dependent CD40 agonist with a similar mechanism of action as AMG 994 
demonstrating that AMG 994 is a low risk immune activating agent. 
Specifically, data from a 1-month GLP-compliant study in cynomolgus monkeys showed 
that AMG 994 is well tolerated at doses up to 
 with no concerning safety 
findings.  At a starting dose of 
 the predicted human exposure based on the area 
under the curve (AUC) and Cmax is 
-fold and 
-fold lower than the observed AUC 
and Cmax exposure in cynomolgus monkeys at the HNSTD of 
.  The lack of 
concerning safety findings observed in cynomolgus monkeys at approximately 
 fold 
higher exposures than the proposed starting dose in humans is clinically relevant due to 
cross reactivity of AMG 994 in cynomolgus monkeys further supporting the lack of safety 
concerns at the proposed starting dose. 
AMG 404 will be administered at a fixed dose of 
 (RP2D) as part 
of the AMG 994 plus AMG 404 combination.  This dose is supported with data from 
59 subjects with advanced or metastatic solid tumors that have been exposed to 
AMG 404 monotherapy in the ongoing Study 20180143.  As a monotherapy, AMG 404 
was well tolerated across the 
 dose range with no 
dose‑related increases in frequency or severity of adverse events in the population 


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studied and preliminary RO results confirm PD-1 target coverage in peripheral blood 
T-cell subsets and are consistent with AMG 404 achieving saturating PD-1 occupancy 
on total CD3+ T cells, CD4+ T cells, and CD8+ T cells by 4 hours postinfusion with 
maintenance of saturation. 
The combination of AMG 994 plus AMG 404 is not anticipated to have increases or 
significant overlapping toxicity based on differing mechanisms of action (Piechutta and 
Berghoff, 2019; Vonderheide, 2018).  
4.4 
End of Study 
4.4.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up, 
additional antibody testing), as applicable. 
4.4.2 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for up to 
approximately 2.5 years.  This includes the screening period lasting up to
, a 
treatment period up to 2 years, and a follow-up period of 6 months after end of 
treatment.  
The actual duration for individual subjects will vary depending upon tolerability of 
AMG 994 and AMG 404, evidence of clinical and radiologic progression, and willingness 
to participate in the study. 
4.5 
Patient Input on Study 
Patient input on the design of the study was not obtained. 


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5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided.  
Minor variations to these inclusion and exclusion criteria may be allowed on the basis of 
agreement reached by the Investigator and Amgen Study Physician, such that 
recruitment does not compromise either the safety of the study subject involved or the 
integrity of the study data.  Such agreements are to be documented in accordance with 
Amgen SOPs.  The Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
is required to be notified that an allowance to the criteria had been made.   
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
 
101 
Subject has provided informed consent/assent prior to initiation of any study 
specific activities/procedures. 
102 
Age  18 years at the time of signing informed consent. 
103 
Life expectancy of  3 months, in the opinion of the investigator. 
104 
Dose Exploration (Part 1) and Dose Expansion (Part 2):  Subject must have 
histologically or cytologically proven metastatic or locally advanced solid tumors 
of known MSLN expression (Table 4-1) who have relapsed after and/or are 
refractory to established and available therapies with known clinical benefit, for 
which: 
 
No standard systemic therapy exists; or 
 
Standard systemic therapy has failed or is not available. 
Note:  testing to confirm MSLN expression is not required for study inclusion 
within Dose Exploration (Part 1).  During Dose Expansion (Part 2), subjects with 
NSCLC will be screened and enrolled if MSLN positive. 


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105 
Dose Expansion (Part 2):  Subject must have 1 of the following malignancies:  
mesothelioma, pancreatic adenocarcinoma, MSLN positive NSCLC squamous 
cell carcinoma or adenocarcinoma, high grade serous ovarian carcinoma. 
106 
At least 1 measurable or evaluable lesion as defined by modified 
RECIST 1.1 guidelines. 
107 
Subjects must be willing to undergo a biopsy prior to enrollment and during 
treatment with AMG 994. 
108 
Subjects with treated brain metastases are eligible provided they meet the 
following criteria: 
 
Definitive therapy was completed at least 2 weeks prior to enrollment. 
 
No evidence of radiographic central nervous system (CNS) progression or 
CNS disease following definitive therapy and by the time of study screening.  
Patients manifesting progression in lesions previously treated with 
stereotactic radiosurgery may still be eligible if pseudoprogression can be 
demonstrated by appropriate means and after discussion with the medical 
monitor. 
 
Any CNS disease is asymptomatic, any neurologic symptoms due to CNS 
disease have returned to baseline, or non-serious CNS diseases that are 
asymptomatic and deemed irreversible (eg, peripheral neuropathy), the 
patient is off steroids for at least 7 days (physiologic doses of steroids are 
permitted), and the patient is off or on stable doses of anti-epileptic drugs for 
malignant CNS disease and has not had a seizure within 1 month prior to the 
screening visit. 
109 
Eastern Cooperative Oncology Group (ECOG) Performance Status of  2. 
110 
Hematologic function, as follows (transfusions or growth factor support must not 
be administered within 7 days prior to obtaining screening labs): 
 
Absolute neutrophil count (ANC)  1.5 x 109/L 
 
Platelet count  75 x 109/L 
 
Hemoglobin  9 g/dL 
111 
Adequate renal laboratory assessments, as follows:  
 
Estimated glomerular filtration rate based on Modification of Diet in Renal 
Disease (MDRD) calculation  45 mL/min/1.73 m2 
112 
Hepatic function, as follows:  
 
Total bilirubin (TBL)  1.5 x upper limit of normal (ULN) or  3 x ULN for 
subjects with liver metastasis 


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 
Aspartate transaminase (AST)  3 x ULN or  5 x ULN for subjects with liver 
metastasis 
 
Alanine aminotransferase (ALT)  3 x ULN or  5 x ULN for subjects with liver 
metastasis 
 
Alkaline phosphatase  2.5 x ULN or  5 x ULN for subjects with liver 
metastasis  
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Primary brain tumor, untreated or symptomatic brain metastases and 
leptomeningeal disease.   
Other Medical Conditions 
202 
History of other malignancy within the past 2 years, with the following 
exception[s]: 
- 
Malignancy treated with curative intent and with no known active disease 
present for  3 years before enrollment and felt to be at low risk for recurrence 
by the treating physician. 
- 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
- 
Adequately treated cervical carcinoma in situ without evidence of disease. 
- 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
- 
Prostatic intraepithelial neoplasia without evidence of prostate cancer. 
- 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ. 
227 
Subjects with NSCLC squamous cell carcinoma (Part 1), MSLN negative NSCLC 
squamous cell carcinoma (Part 2), or MSLN negative NSCLC adenocarcinoma 
(Part 2) once the subject has been screened for MSLN expression. 
228 
Subjects with sarcomatoid mesothelioma and small cell lung cancer will be 
excluded from both the Dose Exploration (Part 1) and Dose Expansion (Part 2) 
parts of the study. 
203 
History of solid organ transplantation.  
204 
Major surgery within 28 days of study day 1.  
Prior/Concomitant Therapy 
205 
Anti-tumor therapy (radiotherapy, chemotherapy, antibody therapy, molecular 
targeted therapy, or investigational agent) within 21 days prior to study day 1. 
Note:  Palliative radiotherapy is permitted.  
206 
Treatment with a checkpoint inhibitor within 9 weeks prior to study day 1. 
207 
Live vaccine therapy within 4 weeks prior to study drug administration. 


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208 
Current treatment or within 14 days of day 1 with immunosuppressive 
corticosteroid defined as  10 mg prednisone daily or equivalent.  Steroids with 
no minimal systemic effect (such as topical or inhalation) are permitted. 
Prior/Concurrent Clinical Study Experience 
209 
Currently receiving treatment in another investigational device or drug study, or 
less than 21 days prior to study day 1 since ending treatment on another 
investigational device or drug study(ies). 
Diagnostic Assessments 
210 
Evidence of active or radiological sequelae of non-infectious pneumonitis. 
211 
History of any immune-related colitis.  Infectious colitis is allowed if evidence of 
adequate treatment and clinical recovery exists and at least 3 months interval 
observed since diagnosis of colitis. 
212 
History of allergic reactions or acute hypersensitivity reaction to antibody 
therapies. 
213 
Positive/non-negative test results for human immunodeficiency virus (HIV) 
214 
Hepatitis B and C based on the following results: 
 
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 
Active infection requiring oral or intravenous therapy. 
216 
Active or history of any autoimmune disease or immunodeficiencies.  Subjects 
with diabetes Type 1, vitiligo, psoriasis, hypo- or hyper-thyroid disease not 
requiring immunosuppressive treatment are permitted.  
217 
Myocardial infarction within 6 months of study day 1, symptomatic congestive 
heart failure (New York Heart Association  class II), unstable angina, or cardiac 
arrhythmia requiring medication. 
218 
Unresolved toxicities from prior anti-tumor therapy, defined as not having 
resolved to Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 grade 1, or are stable and well controlled with minimal, local, or non-
invasive intervention AND there is agreement to allow by both the investigator 
and the Amgen Medical Monitor.  
- 
Any history of grade 3 or higher colitis, pneumonitis, or neurological toxicity OR 
- 
Unresolved toxicities from prior checkpoint inhibitor therapy, defined as not 
having resolved to CTCAE v5.0 grade 1.   


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- 
Exception:  - clinically stable hypothyroid status managed with hormone 
replacement therapy, is permitted 
Other Exclusions 
219 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 6 months after the last dose of 
AMG 994 and/or AMG 404.   
220 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 6 months after the 
last dose of AMG 994 and/or AMG 404.  Refer to Section 11.5 for additional 
contraceptive information. 
221 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at day 1 by a serum pregnancy test.  
222 
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 8 months after the last dose 
of AMG 994 and/or AMG 404.  Refer to Section 11.5 for additional contraceptive 
information. 
223 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 8 months after the last dose of AMG 994 and/or AMG 404. 
224 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
225 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
226 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 


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Each subject who enters into the screening period for the study (beginning from time of 
consent) receives a unique subject identification number before any study-related 
activities/procedures are performed.  This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened.  Refer to Section 8.1.1. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Modular Investigational Product Instruction Manual (IPIM), a document external to 
this protocol, contains detailed information regarding the storage, preparation, 
destruction, and administration of each treatment shown in Table 6-1 below. 
6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
 


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Table 6-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational 
Product:a 
AMG 994 
Amgen Investigational 
Product:a 
AMG 404 
Dosage Formulation 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
Doses will vary across 
treatment cohorts and will 
 
Planned AMG 994 dose 
levels for the dose 
exploration cohorts are as 
follows: 
  Based on 
emerging data and DLRM 
recommendation, 
intermediate and/or 
alternative dose levels 
and schedules (eg, dose 
dense) may be 
implemented.   
Route of Administration 
Accountability 
The start date, start time, 
stop date, stop time, dose 
administered, reason for 
dose change, and 
package lot number are to 
be recorded on each 
subject's CRF(s). 
The start date, start time, stop 
date, stop time, dose 
administered, reason for dose 
change, and package lot 
number are to be recorded on 
each subject’s CRF(s).   
Dosing Instructions 
AMG 994 will be 
administered as an 
 
 at a constant flow 
rate over 
AMG 404 will be administered 
as an
 at a 
constant flow rate over 
AMG 994 infusion if a 
 grade 2 infusion reaction is 
not observed. 
Device 
Infusion Pump 
Infusion Pump 
CRF = case report form; DLRM = dose level review meeting;
a AMG 994 and AMG 404 will be manufactured and packaged by Amgen and distributed using Amgen 
clinical study drug distribution procedures. 
 


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6.1.2 
Non-investigational Products 
This study will not use non-investigational products. 
6.1.3 
Medical Devices 
There are no investigational medical devices in this study.   
Amgen investigational products must be administered using infusion pumps approved 
for use by the appropriate regulatory authorities for the country in which the subject is 
undergoing treatment.  Investigational product solutions for infusion will be prepared in 
bags for 
 and delivered through infusion lines that are both compatible with 
the investigational products.  Other non-investigational medical devices may be used in 
the conduct of this study as part of standard care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.   
6.1.4 
Other Protocol-required Therapies 
There are no other protocol-required therapies in this study 
6.1.5 
Other Treatment Procedures 
There are no other protocol-required treatment procedures in this study. 
6.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s), combination product, or device(s) 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, labelling, and 
inserts. 
This includes any investigational product(s) provisioned and/or repackaged/modified by 
Amgen:   
 
AMG 994 
 
AMG 404 
Any product complaint(s) associated with an investigational product supplied by Amgen 
are to be reported according to the instructions provided in the Modular IPIM. 


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6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Any anti-tumor therapy other than the investigational product, including cytotoxic and/or 
cytostatic drugs, hormonal therapy, systemic corticosteroids (except for subjects who 
were receiving  10 mg prednisone or equivalent at the time of enrollment are permitted 
to remain on it), immunotherapy or any biological response modifiers, any other 
investigational agent, and other immunosuppressive therapies are excluded.  
Primary prophylactic use of hematopoietic growth factors such as granulocyte-colony 
stimulating factor is not encouraged during the DLT-evaluation period.  Once the DLT 
evaluation period is complete, the use of growth factors can be allowed after discussion 
with the Amgen medical monitor.   
Administration of systemic corticosteroids, immunomodulators, and hormonal 
replacement therapy for the management of toxicities (eg, immune-related adverse 
events) is allowed; however, AMG 994 and AMG 404 must be discontinued if  10 mg 
per day prednisone or equivalent is continued for more than 12 weeks.  Corticosteroids 
with no or minimal systemic effect (eg, topical, inhalation) are allowed.  
Any live vaccine therapies for the prevention of infectious disease are not allowed 
(except administration of the inactive influenza vaccine). 
Radiotherapy is not permitted except for palliation of symptoms and should be discussed 
with the sponsor’s Medical monitor first.  Investigators should ensure that the need for 
radiation does not indicate progressive disease and that for subjects with measurable 
disease, radiation is not to the sole site of measurable disease.  
The following procedures should also not be undertaken within the timeframes specified 
prior to enrollment and during the study:   
 
Participation in any investigational study (drug or device) within 
 
Major surgery within 
 
 
Enrollment into another investigational drug or device study 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
Sentinel Dosing 
During the dose-exploration part of the study, there will be at least a 1-week interval 
between start of treatment of the first and second subject, in each cohort (ie, at the same 


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dose for AMG 994 monotherapy and AMG 994 in combination with AMG 404).  Prior to 
start of a new subject, the site investigator of the previous subject will evaluate all 
available safety and laboratory data for the treated subject and will send written 
confirmation on occurrence/non-occurrence of a DLT to the sponsor.  The sponsor will 
only be able to approve treatment start for the next subject in the cohort after receipt of 
this confirmation.  If deemed necessary, the 1-week interval may be extended until 
sufficient data are available to allow an assessment of the feasibility of treatment start of 
the next subject.  In addition to the 1-week interval between treatment start of the first 
and second subject in each cohort, there will be a 72-hour interval between treatment 
start of the second and third subject, then all subsequent subjects in each cohort may 
start treatment.  Sentinel dosing may apply during cohort extension, at the Sponsor’s 
discretion, based on available safety data.  The same process as described above will 
apply for determining if subsequent subjects may start treatment. 
DLT-evaluable Periods (DLT Windows) 
Part 1a will include 
 of 3 to 6 subjects each.   


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Part 1b:   
Part 1c:   
Dose Level Determination 
A recommendation to escalate to a higher dose cohort will only occur when the previous 
dose regimen has been found to be reasonably tolerated based on available study data 
through study
 of cycle 1 for all evaluable subjects and upon unanimous 
agreement of the DLRT members.  Available data from previous cohorts will also be 
considered.  Dose level recommendations will be made on a treatment cohort basis (not 
on an individual basis).  After receiving the DLRT recommendation, Amgen will render a 
final decision and will issue a written notification of the dose change decision to 


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investigators.  Further information on dose level review meetings is provided in 
Appendix 3 (Section 11.3). 
After all DLT-evaluable subjects have completed the monotherapy DLT window, the first 
DLRM will be held to review data, monitor safety, and recommend dose changes, if 
applicable.  
 
 
. 
The review team will be composed of the investigators, Amgen Medical Monitor, Amgen 
Global Safety Officer (GSO) or designated safety scientist, Amgen Early Clinical 
Development Manager, and Biostatistics representative.  Additional members may be 
added as needed (eg, Clinical Pharmacologist).  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 investigators. 
A quorum, defined as the majority (defined as greater than or equal to 50) of actively 
screening and enrolling investigators or their qualified designee (ie, sub-investigator), 
must be in attendance for DLRM to proceed.  The DLRM will be rescheduled if a quorum 
is not reached.   
Voting members of the DLRM will include the Amgen Medical Monitor, the Amgen GSO 
or designated safety scientist, and all actively screening and enrolling investigators or 
their qualified sub-investigator designee.  The team may recommend escalation to the 
next planned dose, escalation to an intermediate dose (a dose lower or higher than the 
next planned dose), continuation or delay in dosing, repetition or expansion of a cohort, 
de-escalation to a lower dose, or termination of the study.  One or more dosing regimens 
may be selected based on clinical findings including safety, tolerability, and PK results 
from previous cohorts; after DLRT review, the DLRT may make recommendations for 
the next cohort dose and frequency.  
 
 
.  The Amgen Medical 
Monitor and GSO or designee and the majority (defined as greater than or equal to 50) 
of actively screening and enrolling investigators participating in the DLRM must cast a 
positive vote indicating an acceptable safety profile was observed for AMG 994 to allow 
the dose level modification and/or cohort continuation/expansion to proceed.  All 
available study data including demographics, medical history, concomitant medications, 


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AEs, ECGs, vital signs, laboratory results, and emerging PK or pharmacodynamics data 
will be reviewed.  Data to be reviewed may be unqueried.   
The dosing schedule is described by the Study Schema in the protocol synopsis (see 
Section 1.2). 
Dose Cohort Stopping Rules 
The DLRT will recommend escalation to the next planned dose, escalation to an 
intermediate dose (a dose lower or higher than the next planned dose), continuation or 
delay in dosing, repetition or expansion of a cohort, de-escalation to a lower dose, or 
termination of the study.  One or more dosing regimens may be selected based on 
clinical findings including safety, tolerability, and PK results from previous cohorts; after 
DLRT review, the DLRT may make recommendations for the next cohort dose and 
frequency.  
 
 
  All available study data including 
demographics, medical history, concomitant medications, AEs, ECGs, vital signs, 
laboratory results, and emerging PK or pharmacodynamics data will be reviewed.  
The Amgen Medical Monitor may suspend dosing and convene a DLRM at any time 
based on emerging safety data.   
The study may be terminated at any point at the discretion of the sponsor.   
Dose-Limiting Toxicity 
All events will be graded using the CTCAE version 5.0.  The occurrence of any of the 
following events during the first or second DLT evaluation period will be considered a 
DLT, excluding events clearly related to disease progression or intercurrent illness:   
 
Any grade 5 event 
 
Grade 4 neutropenia or thrombocytopenia of any duration  
 
Grade 3 thrombocytopenia with clinically significant bleeding or lasting  7 days 
 
Febrile neutropenia 
 
Grade 4 anemia 
 
Grade 3 or 4 non-hematologic toxicity, with the following exceptions: 
o DLT Exemption:  Grade 3 nausea/vomiting or diarrhea  72 hours in the 
absence of maximal medical therapy 
o DLT Exemption:  Grade 3 fatigue  1 week 


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o DLT Exemption:  Asymptomatic grade 3 electrolyte abnormalities that 
last  72 hours, are not clinically complicated, and resolve spontaneously or 
respond to conventional medical interventions 
o DLT Exemption:  Grade 3 amylase or lipase elevations, as per 
CTCAE version 5.0, grade 4 elevations in amylase and lipase are defined as 
being associated with signs or symptoms of pancreatitis 
o DLT Exemption:  Other laboratory parameters of grade 3, not considered 
clinically relevant, and improved to grade  2 within 72 hours.  
 
Any grade 3 event requiring hospitalization 
 
Recurrent grade 2 pneumonitis 
 
Delay in cycle 2 treatment for  14 days due to an adverse event in the dose 
escalation portion of the study due to study drug-related toxicity, except for 
immune-mediated toxicities as outlined in Table 11-3 where a longer timeframe is 
specified 
 
Any other event requiring permanent discontinuation of AMG 994 (for example, as 
specified in Table 11-4, Infusion-Related Reactions)   
The cumulative adverse event profile will be taken into consideration when making 
decisions on dose escalation and on any other dose-level or safety review.   
Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver injury) 
will be considered a DLT.  A Hy’s Law case is defined as:  AST or ALT values 
of  3 x ULN AND with serum TBL of  2 x ULN without signs of cholestasis and with no 
other clear alternative reason to explain the observed liver-related laboratory 
abnormalities (see Section 6.2.3 for hepatotoxicity management and Section 11.7 for 
further explanation of Hy’s law case and Management of Hepatic Function).   
Clinically or medically significant suspected adverse drug reactions, and serious adverse 
events considered to be related to study procedures will be followed until resolved or 
considered stable.   
The study may be terminated at any point at the discretion of the sponsor. 
The DLT window (ie, DLT-evaluable period) during dose exploration will start on day 1 
(start of the administration of the first infusion).  The duration of the DLT windows and 
definition of DLT-evaluable subjects are shown below (Table 6-2).   


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All available safety data for subjects who are not DLT evaluable will still be evaluated 
and considered in DLRT recommendations. 
A DLT will be defined as any of the events described above occurring in a subject during 
the DLT window excluding events clearly related to disease progression or intercurrent 
illness.  The CTCAE version 5.0 (see Section 11.4) will be used to grade adverse 
events. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Dose Adjustment 
A given subject should continue on the same dose level of AMG 994 throughout the 
study.   
An exception to this may be considered when a given subject experiences a DLT or 
other intolerable AMG 994-related adverse event, but shows evidence of clinical benefit.  
The medical monitor and investigator, in consultation with the GSO, may deem it 
appropriate for such subjects to have a dose reduction to the immediate next lower 
dose.  Each subject is only allowed 1 dose reduction.   
No dose modifications for AMG 404 are recommended.  Based on established 
preclinical and clinical data available from AMG 404 and other anti-PD1 therapies and 


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also on preclinical data from AMG 994, immune-mediated adverse reactions are 
expected to be associated to AMG 404 and emerging study safety data will inform any 
necessary revision of this initial expectation.  Guidelines for withholding or discontinuing 
AMG 404 for immune-mediated reactions are listed in Table 11-3.  If AMG 404 has been 
withheld, treatment with AMG 404 may be resumed after the adverse event (or 
associated signs/symptoms/laboratory parameters) has been reduced to grade  1 and 
corticosteroid has been tapered to prednisone  10 mg or equivalent (per Table 11-3, 
myocarditis must be resolved to grade  1).   
6.2.2.2 
Rules for Withholding or Restarting 
 
AMG 994, and AMG 404 if the subject is on combination therapy, should be withheld 
for any DLT or any adverse event that meets the criteria of a DLT but occurs outside 
of the DLT windows 
 
AMG 994, and AMG 404 if the subject is on combination therapy, should be withheld 
for potential hepatotoxicity as detailed in Table 11-2 
 
AMG 404 alone should be withheld for immune-mediated adverse reactions as 
detailed in Table 11-3 
 
AMG 994 and/or AMG 404 should be withheld for infusion-related reactions as 
specified in Table 11-4 
For adverse events not addressed by Table 11-2, Table 11-3 and Table 11-4, AMG 994 
and AMG 404 dosing can be resumed if the applicable event resolves to grade  1 or 
otherwise resolves to subject’s baseline grade within 2 weeks.  The restarting of therapy 
should be deemed appropriately safe by the investigator and Medical Monitor.  For 
restart criteria following hepatotoxicity, immune-mediated reactions, and infusion-related 
reactions, refer to Table 11-2, Table 11-3 and Table 11-4, respectively.  For 
immune-mediated hepatitis, if Table 11-2 and Table 11-3 are both applicable, Table 11-2 
is to take precedence.  
Subjects should not be restarted with AMG 994 and/or AMG 404 if the following 
treatment-related adverse events occur: 
 
Any grade 4 adverse events except those not considered DLT, OR 
 
Adverse event criteria are met for permanent withholding of AMG 994 and/or 
AMG 404 due to potential hepatotoxicity, immune-mediated reaction or infusion 
related reaction (Table 11-2, Table 11-3, or Table 11-4, respectively).  For 
immune-mediated hepatitis, if Table 11-2 and Table 11-3 are both applicable, Table 
11-2 is to take precedence.   
If a subject experiences an adverse event meeting withholding or discontinuation criteria 
above from AMG 404, and if the subject is experiencing clinical benefit with AMG 994 
monotherapy, a decision to have the subject continue with AMG 994 monotherapy 
alone, may be considered by the Amgen medical monitor in consultation with the 
investigator. 


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The reason for dose change of AMG 994 and/or AMG 404 is to be recorded on each 
subject’s CRF. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the Modular IPIM. 
6.4 
Treatment Compliance 
Compliance to treatment and the corresponding assessments should be followed 
according to the Schedule of Activities (Section 1.3) and the Study Assessments and 
Procedures (Section 8). 
6.5 
Treatment of Overdose 
The effects of overdose of AMG 994 and AMG 404 are not known. 
6.6 
Prior and Concomitant Treatment 
6.6.1 
Prior Treatment 
Prior therapies that were being taken/used from initial diagnosis through the time of 
consent will be collected. 
6.6.2 
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 
study. 
7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 


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study as a whole at any time prior to study completion for the reasons listed in 
Section 7.1, Section 7.2.1, and Section 7.2.2. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see 
Section 1.3) including different options of follow-up (eg, in person, by phone/mail, 
through family/friends, in correspondence/communication with other treating physicians, 
from the review of medical records) and collection of data, including endpoints and 
adverse events, and must document this decision in the subject’s medical records.  
Subjects who have discontinued investigational product and/or other protocol-required 
therapies or procedures should not be automatically removed from the study.  Whenever 
safe and feasible, it is imperative that subjects remain on-study to ensure safety 
surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 
 
Disease progression 
 
Pregnancy 


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7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.  
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
This section is not applicable. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
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 


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mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 1.3).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, 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 screen the subject in order to assess 
eligibility for participation.  The screening window is up to 28 days prior to day 1. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening up to 3 additional times.  
Rescreen subjects must first be registered as screen failures and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28 day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 


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after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (see Section 1.3).  On-study visits may be 
completed within 1 day/week.  The date of the first dose of AMG 994 or AMG 404 is 
defined as day 1.  All subsequent doses and study visits will be scheduled based on the 
day 1 date.  Administration of AMG 994 and/or AMG 404 is to be administered after all 
safety assessments have been completed and reviewed during each visit that it is 
required. 
8.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, a safety 
follow-up visit will be performed at 30 (7) days and 140 days (1 week) after the last 
dose of protocol required therapies.  These visits include adverse event/serious adverse 
event assessment, a physical exam, blood work (chemistry; coagulation; complete blood 
count [CBC]; adrenocortiocopic hormone [ACTH]; anti-neutrophil cytoplasmic antibodies 
[ANCA], anti-nuclear antibodies [ANA], pregnancy test), and urinalysis. 
The chemistry includes albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen 
(BUN)/total urea, calcium, chloride, creatinine, glucose, potassium, sodium, total 
bilirubin, total protein, thyroid stimulating hormone (TSH), and free T4. 
8.1.4 
Long-term Follow-up 
Long-term follow-up phone call at 6 months (1 week) after last dose of protocol 
required therapies to collect information on serious adverse events, survival, start of new 
therapies, and disease status.   
8.1.5 
End of Study 
The end of study will be the day of the last scheduled long-term follow-up call.   
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 


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8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarkers variability 
and PK of the protocol-required therapies.  
8.2.1.3 
Medical History 
The Investigator or designee will collect a complete medical and surgical history that 
started prior to screening through start of treatment.  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, the condition under study 
history must date back to the original diagnosis.  The current toxicity grade will be 
collected for each condition that has not resolved. 
8.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.5 
Physical Measurements 
Height [in centimeters] should be measured without shoes.  Weight [in kilograms] should 
be measured without shoes. 
8.2.1.6 
Performance Status  
Subjects will be graded according to the Eastern Cooperative Oncology Group (ECOG) 
Performance Status.  The ECOG criteria for this protocol are further defined in 
Section 11.9. 
8.2.2 
Efficacy Assessments 
Tumor evaluations (by contrast-enhanced computed tomography [CT] or magnetic 
resonance imaging [MRI]) and tumor markers, if applicable, are to be collected at time 
points specified in the Schedule of Activities (see Section 1.3).  Imaging may also be 
performed more frequently if clinically necessitated at the discretion of the managing 
physician.   


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All radiological imaging will be performed as indicated in the Site Imaging Manual 
provided by the central imaging core laboratory.  In order to reduce radiation exposure 
for subjects, low dose CT should be utilized whenever possible.   
The screening scans must be performed within 28 days prior to enrollment and will be 
used as baseline.  All subsequent scans will be performed in the same manner as at 
screening, with the same contrast, preferably on the same scanner.  Radiological 
assessments must include MRI/CT of the chest, abdomen and pelvis, as well as 
assessment of all other known sites of disease as detailed within the Site Imaging 
Manual.   
All subjects must have MRI of the brain performed within 28 days prior to first dose of 
AMG 994.  Subsequently, MRI brain scans may be performed at any time if subject has 
a history of CNS disease, or if signs or symptoms suggestive of central nervous system 
metastases are present.  All brain scans on protocol are required to be MRI unless MRI 
is contraindicated, and then CT with contrast is acceptable.   
The same imaging modality, MRI field strength and intravenous and oral contrast agents 
used at screening should also be used for all subsequent assessments.  Liver specific 
MRI contrast agents should not be used.  To reduce potential safety concerns, 
macrocyclic gadolinium contrast agents are recommended per National Health Institute 
guidelines, or follow local standards if more rigorous.   
Eligibility and determination of disease response for clinical management of subjects will 
be assessed at the clinical sites per Modified RECIST 1.1 (Section 11.11).  Scans will be 
submitted to a central imaging core laboratory for archival and response assessment 
including Modified RECIST 1.1.   
Detailed information regarding submission of images to the central imaging core 
laboratory is found in the Site Imaging Manual.   
Radiographic response (Complete Response, Partial Response) requires confirmation 
by a repeat, consecutive scan at least 4 weeks after the first documentation of response 
and may be delayed until the next scheduled scan to avoid unnecessary procedures.  
Radiographic progression (Progressive Disease) requires confirmation by a repeat, 
consecutive assessment 4 to 6 weeks after the first detection of radiological progression.  
Upon discussion with the Sponsor, in the absence of clinical deterioration, subjects may 
continue to receive AMG 994 and AMG 404 combination treatment after confirmation of 
radiographic progressive disease as long as they continue to derive clinical benefit, until 


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clinical disease progression, or intolerance of study treatment, or clinically significant 
deterioration of health status requiring discontinuation, or the subject withdrawal of 
consent, whichever occurs first; or, in the absence of the above, up to 12 months if the 
subject achieves a complete response, and up to 24 months if partial response or stable 
disease. 
If a subject discontinues treatment for reasons other than progression, tumor evaluations 
should continue according to the Schedule of Activities (see Section 1.3) until 
progression or start of a new treatment regimen. 
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(see Section 1.3). 
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, pulse oximetry, and temperature.  Subject must be in a rested and 
calm state for at least 5 minutes before blood pressure assessments are conducted.  
The position selected for a subject should be the same that is used throughout the study 
and documented on the vital sign CRF.  The temperature location selected for a subject 
should be the same that is used throughout the study and documented on the vital signs 
CRF.  Record all measurements on the vital signs CRF.  Oxygen saturation will be 
measured using a standard pulse oximeter.  The temperature location selected for a 
subject should be the same that is used throughout the study and documented on the 
vital signs CRF.  Record all measurements on the vital signs CRF. 
8.2.3.2 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  ECGs should be 
performed in a standardized method, in triplicate, and run consecutively (all 3 ECGs 
should be completed within a total of 5 minutes from the start of the first to the 
completion of the third), prior to blood draws or other invasive procedures.  Each ECG 
must include the following measurements:  QRS, QT, QTc, RR, and PR intervals.  
 
3 baseline ECGs collected  30 minutes apart, with each baseline ECG in triplicate 
run consecutively (all 3 ECGs should be completed within a total of 5 minutes from 
the start of the first to the completion of the third) (total 9 ECGs)  
 
Triplicate ECGs at time points after dosing  


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Baseline is defined as at screening.  The PI or designated sub-investigator will review all 
ECGs.  ECGs will be transferred electronically to an ECG central reader for analysis per 
Amgen instructions.  Once signed, the original ECG tracing will be retained with the 
subject's source documents.  At the request of the sponsor, a copy of the original ECG 
will be made available to Amgen.  Standard ECG machines should be used for all 
study-related ECG requirements.   
8.2.3.3 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
8.2.4 
Adverse Events and Serious Adverse Events  
The method of recording, evaluating, and assessing causality of adverse events, 
and serious adverse events and the procedures for completing and transmitting 
serious adverse event reports are provided in Section 11.4.  
8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 and is described in 
Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of protocol-required 
therapies through the end of study are reported using the Events CRF. 
8.2.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through end of study visit are reported using the Events CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 


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Since the criteria for the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 CTCAE toxicity 
grading scale criteria (eg, laboratory abnormality reported as grade 4 without 
manifestation of life-threatening status), it will be left to the investigator’s judgment to 
also report these abnormalities as serious adverse events.  For any adverse event that 
applies to this situation, comprehensive documentation of the event’s severity 
must be recorded in the subject medical records. 
8.2.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events suspected to be related 
to the investigational product after the protocol-required reporting period (as defined 
in Section 11.4) is complete, then these serious adverse events will be reported to 
Amgen within 24 hours following the investigator’s awareness of the event. 
Since a study endpoint is overall survival, the investigator will need to 
collect/report fatal serious adverse events (regardless of causality) to Amgen 
within 24 hours following the investigator’s awareness of the event.  
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 within 24 hours following the investigator’s awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.   
If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study. 
8.2.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 


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8.2.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following 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 Event CRF. 
8.2.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
8.2.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 


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8.2.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 6 months (for 
female subjects) or 8 months (for female partners of male subjects) after the last 
dose of protocol required therapies. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.2.5 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities (see 
Section 1.3).  
Pregnancy Testing 
A highly sensitive serum pregnancy test should be completed at screening and within 
7 days of initiation of investigational product for females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 


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male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional pregnancy testing should be performed at monthly intervals during treatment 
with protocol-required therapies and at the 30 day and 140 day follow-up visit 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.2.6 
Pharmacokinetic Assessments 
All subjects enrolled will have pharmacokinetic samples assessed. 
Blood samples of approximately 5 and 3 mL will be collected for measurement of serum 
concentrations of AMG 994 and AMG 404, respectively 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. 
8.2.7 
Pharmacodynamic Assessments 
Biopsy tissue will be collected for evaluation of pharmacodynamic changes as specified 
in the Schedule of Activities (Section 1.3).   
8.2.8 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of advanced solid tumors 
and/or to identify subjects who may have positive or negative response to AMG 994 and 
AMG 404 combination therapy.  No additional samples are collected for this part of the 
study.  For subjects who consent to this/these analysis/analyses, DNA may be extracted. 
The final disposition of samples will be described in Section 11.6.  


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
This is a phase 1 study and no formal statistical hypotheses will be tested. 
9.2 
Sample Size Determination 
It is anticipated that approximately 214 subjects will be enrolled in this study. 
Approximately 94 subjects will be enrolled in the dose-exploration cohorts (Part 1).  Up 
to 120 subjects will be enrolled in the dose-expansion cohorts (Part 2), 30 subjects in 
each of 4 tumor types (mesothelioma, NSCLC squamous cell carcinoma and 
adenocarcinoma [if upon screening found to be MSLN positive], pancreatic 
adenocarcinoma, and high grade serous ovarian carcinoma). 
The sample size in the dose-escalation phase is based on practical consideration and is 
consistent with conventional oncology studies with the objective to estimate the 
MTD/MTCD.  With 3 subjects in a cohort, there is a 27 to 70 probability of observing 
at least 1 DLT if the true DLT rate is 10 to 33 and with 6 subjects in a cohort, there is 
a 47 to 91 probability.  
In the dose-expansion cohorts, a total subject sample size of 120 will provide a 
91 probability of observing at least 1 adverse event with 2 incidence rate.  An exact 
95 binomial Cl will be provided for overall response rate.  With the 30 subjects in a 
cohort of subjects with a particular tumor type and a 20 overall response rate, the 
expected 95 Cl would be 8 to 39.  Under certain circumstances, the sample size 
dose expansion will be smaller due to early stopping; see Section 9.4.1.1 for details. 


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9.3 
Analysis Sets,
 and Covariates 
9.3.1 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 994 or AMG 404.  
The analysis of DLT in the initial safety review period 
 will be conducted 
on the Early DLT Analysis set defined as all subjects that are enrolled and receive at 
least 1 dose of AMG 994 with an evaluable early DLT endpoint (evaluable in AMG 994 
monotherapy cohort per Table 6-2).   
The analysis of DLT in the cumulative safety review period will be conducted on the 
Cumulative DLT Analysis set defined as all subjects that are enrolled and receive at 
least 1 dose of AMG 994 or AMG 404 with an evaluable cumulative DLT endpoint 
(experience a DLT during monotherapy cohort or evaluable in combination therapy 
cohort per Table 6-2).   
The analysis of objective response will be conducted on the Efficacy Evaluable Analysis 
set defined as all subjects that are enrolled to a dose expansion cohort and receive at 
least 1 dose of AMG 994 or AMG 404 with at least 1 tumor lesion that is measurable in 
contrast-enhanced CT as defined by modified RECIST 1.1, with the following 
exceptions.  The following subjects will be excluded from the Efficacy Evaluable Analysis 
set:  1) subjects who are lost to follow-up and have no on study radiological 
assessments and 2) subjects who have been on study less than 8 weeks and have no 
on study radiological assessments.  
9.3.2 
Covariates 
The relationship of covariates to efficacy endpoints will be explored as appropriate.  
9.3.4 
Handling of Missing and Incomplete Data 
The handling of missing and incomplete data is described in the statistical analysis plan. 


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9.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  Based on accumulating safety data, 
BLRM will be used to make dosing recommendations.  In DLRMs, Amgen, in 
consultation with the site investigators, will review the BLRM recommended dose level 
and will review all available cumulative data by cohort prior to making dose escalation 
recommendations.  As a sensitivity analysis, a 1-parameter Continual Reassessment 
Method model may be used to estimate the dose-toxicity relationship and in particular to 
estimate the dose level with a 25 DLT rate in order to help make dose escalation 
decisions.  Adverse events, including late onset immune-mediated toxicities, and DLTs 
observed in all subjects will be evaluated continually and fully integrated into all DLRMs 
and considered in all enrollment and dosing decisions.  If during the study there is any 
grade 5 adverse event (or any 2 of the same grade 4 adverse events) at least possibly 
related to AMG 994 or AMG 404, further accrual will be suspended; Amgen will conduct 
a safety analysis and submit to the regulatory authority for review prior to resuming 
enrollment.  
Given that a fixed-dose administration of AMG 404 
 is used as part of the 
AMG 994 plus AMG 404 combination, the 2-parameter BLRM for single agent AMG 994 
will be used.  Key details of the BLRM model as used in this study are as follows.  A bi-
variate normal prior distribution (parameters “a” and “b”) is used for the BLRM model 
with bi-variate normal prior are as follows:  the mean natural log (ln) of “a” ln(a) 
, 
SD of “a” SD(ln(a)) 
, mean ln(b) 
, SD(ln(b))  
 and correlation 
  
The target toxicity probability interval (TPI) is defined as a rate at least 
and less 
than
; an excessive or unacceptable TPI is a rate of 
 or higher.  The prior 
distribution is specified such that probability of DLT is 
 for the starting dose 
 
and 
 for the reference dose 
 where the probability that the true DLT rate is 
at the lowest planned dose is 
 and the probability the true DLT rate is 
at the reference dose is 
.  The BLRM will be used 
 
 to recommend the next dose level and at the end of dose 


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exploration the recommended MTD will be the level with the highest probability of the 
target TPI, but with a less than 
 probability of an excessive or unacceptable TPI. 
During dose expansion, if the observed rate of responses in a particular tumor type is 
less than 10 after n  10 and n  20 subjects in that tumor type, then enrollment to that 
tumor type will be terminated due to futility.  For purposes of assessing futility, a 
response is defined as an objective response per modified RECIST 1.1.  The guidelines 
for early termination of enrollment for a tumor type due to futility are as follows:  
Number of Treated Subjects in a Tumor 
Type 
Enrollment Stopping Rule 
10 
0 responders 
20 
1 or fewer responders 
30 
Enrollment complete 
If the true response rate is 5 then these termination guidelines result in a 
78.7 probability of terminating tumor type enrollment at or prior to n  20 subjects.  If 
the true response rate is 20 then there is an 86.4 probability of continuing enrollment 
past n  20 subjects.  
During dose expansion, Amgen will conduct evaluations of the ongoing grade 4 or 
higher treatment-related adverse event rate to assess if the threshold for possible early 
trial termination has been reached.  If this threshold is met, enrollment to dose 
expansion will be halted pending review of safety data by the DLRT.  After receiving 
the DLRT recommendation, Amgen will choose to take 1 of the following actions.  
 
Terminate the trial 
 
Amend the protocol to potentially improve the benefit/risk for subjects (eg, increase 
safety monitoring, modify dose/schedule, mandate premedication) 
 
Continue dose expansion without any changes 
The stopping rules use a Bayesian approach proposed by Thall, Simon, and Estey 
(1995) to terminate the study if the posterior probability that the grade 4 or higher 
treatment-related adverse event rate is greater than 20 is  80.  The stopping 
boundaries assume a prior distribution of Beta (0.40, 1.60) are presented in Table 9-1 
and the operating characteristics with pre-specified batch size of 10 new subjects per 
batch are presented in Table 9-2.  The operating characteristics in Table 9-2 provide the 
probability of stopping the trial early for given hypothetical true rate of grade 4 or higher 
treatment-related adverse events, whereas the stopping criteria in Table 9-1 are based 


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on situations where the empirical evidence would result in the posterior probability of 
 80 that the true grade 4 or higher treatment-related adverse event rate is  20. 
Table 9-1.  Stopping Boundary for Dose Expansion With Posterior Probability of 
80 and Grade 4 or Higher Treatment-Related Adverse Event Limit of 20 
Number of subjects 
Hold enrollment if observing this many grade 4 or 
higher treatment adverse events 
20 
 6 
40 
 11 
60 
 15 
80 
 20 
100 
 24 
120 
Dose Expansion Complete 
Table 9-2.  Operating Characteristics With Batch Size of 20 Subjects 
True grade 4 or higher 
treatment-related 
adverse event rate 
Probability of early 
stopping of dose 
expansion 
Average dose expansion 
sample size 
0.10 
1.2 
118.8 
0.15 
9.6 
111.5 
0.20 
37.6 
90.1 
0.25 
76.0 
59.9 
0.30 
95.7 
38.0 
9.4.1.2 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject 
either completes 6 months on study or withdraws from the study.  
9.4.1.3 
Final Analysis 
The final analysis will occur when target enrollment is complete for all study parts and all 
subjects have ended the study.  Primary and final analysis may be combined in case all 
subjects have ended study close to the time point of the primary analysis.  
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, 
pharmacodynamic and biomarker data.  Unless otherwise specified, descriptive 
summaries will be presented by planned dose level and schedule.  Descriptive statistics 


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on continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages.  Graphical 
summaries of the data may also be presented.  
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Pearson (1934).  Kaplan-Meier methods will be used to estimate 
the median and percentiles for time to event endpoints with CL calculated using the 
Brookmeyer and Crowley (1982) method.  Kaplan-Meier methods will be used to 
estimate landmarks for time to event endpoints (eg, 1-year progression-free survival) 
with the Greenwood formula (Kalbfleisch and Prentice, 1980) used to estimate the 
standard error used in Cl calculation.  
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Listings of secondary efficacy endpoints will be produced for all 
subjects in the dose-escalation cohorts and the dose-expansion 
cohorts.  
For all subjects in the Efficacy Analysis Set, the proportion of subjects 
and 95 CL with an objective response (complete or partial response 
per modified RECIST 1.1) will be tabulated by tumor type and planned 
dose level and schedule.  
For all subjects in the Efficacy Analysis Set, Kaplan-Meier methods will 
be used to estimate the time of event curve, median time to event, and 
percentiles with 95 Cl for 1) duration of response (DOR, per modified 
RECIST 1.1); 2) overall survival (OS); 3) progression-free survival 
(PFS, per modified RECIST 1.1); 4) time to progression (TTP, per 
modified RECIST 1.1) and 5) time to subsequent therapy.  
Kaplan-Meier methods will be used to estimate appropriate landmarks 
for DOR, OS, PFS and TTP (eg, 1-year PFS).   
Exploratory 
Will be described in the statistical analysis plan finalized before 
database lock 
 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Unless otherwise specified, statistical analyses on safety endpoints will 
be done using subjects from the safety analysis set, which includes 
subjects that are enrolled and received AMG 994 or AMG 404.  The 


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analysis of early DLTs will be conducted on the Early DLT Analysis Set 
and the analysis of cumulative DLTs will be conducted on the 
Cumulative DLT Analysis Set.  Subject incidence of both early and 
cumulative DLT will be tabulated by planned dose level.  A table of 
both early and cumulative DLTs will be provided.  The probability of a 
subject having an early and cumulative DLT by dose level will be 
estimated using a 2-parameter BLRM model.   
The statistical analysis methods for other safety endpoints are 
described in Section 9.  
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies, and significant treatment emergent adverse events will also 
be provided.  Subject incidence of device-related events, if applicable, will be tabulated 
by system organ class and preferred term. 
9.4.2.3.3 
Laboratory Test Results 
Clinical chemistry, hematology, and urinalysis data will be reviewed for each subject. 
Depending on the size and scope of changes in laboratory data the analyses of safety 
laboratory endpoints will include summary statistics over time and/or changes from 
baseline over time may be provided.  Shifts in grades of safety laboratory values from 
baseline for selected laboratory values may also be provided.  
9.4.2.3.4 
Vital Signs 
Vital signs data will be reviewed for each subject.  The analyses of vital signs will include 
summary statistics over time and/or changes from baseline over time may be provided.  
9.4.2.3.5 
Physical Measurements 
Physical measurements will be reviewed for each subject.  
9.4.2.3.6 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.  Subjects’ maximum change from baseline in QTcF will be categorized 
and the number and percentage of subjects in each group will be summarized.  
Subjects’ maximum post baseline values will also be categorized and the number and 
percentage of subjects in each group will be summarized.  All on-study ECG data will be 
listed and select parameters of interest plotted.  


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9.4.2.3.8 
Exposure to Investigational Product 
Details of AMG 994 and AMG 404 administration will be listed for every subject.  
9.4.2.3.9 
Exposure to Non-investigational Product 
Not applicable 
9.4.2.3.10 
Exposure to Other Protocol-required Therapy 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each treatment group as coded by the World Health Organization 
Drug dictionary.  
9.4.2.3.11 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each treatment group as coded by the World Health Organization 
Drug dictionary.  
9.4.2.4 
Other Analyses 
The PK parameters of AMG 994 and AMG 404 including, but not limited to, Cmax, tmax, 
and AUC will be estimated using non-compartmental methods and summarized by dose 
level using means, geometric means, standard deviations, coefficients of variation, 
medians, minimums, and maximums.  Individual concentration-time profiles will be 
summarized by dose level.  Serum AMG 994 and AMG 404 concentrations at each time 
point along with PK parameter values may be listed for each subject.  Summary 
statistics will be computed for each sampling time and parameter as appropriate.  The 
relationship between AMG 994 exposure and efficacy/safety may be conducted. 


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10. 
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AMG 404 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
AMG 994 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
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Mesothelin Improves Efficacy of Mesothelin-Targeting Recombinant Immunotoxins.  Mol 
Cancer Ther.  2016;15(7):1648-1655. 
Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR.  Help for 
cytotoxic-T-cell responses is mediated by CD40 signalling.  Nature.  
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Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. in 
collaboration with the National Comprehensive Cancer Network.  Management of 
Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor 
Therapy:  American Society of Clinical Oncology Clinical Practice Guideline.  Journal of 
Clinical Oncology, 36:1714-1768. © 2018 American Society of Clinical Oncology and 
National Comprehensive Cancer Network. 
Brookmeyer R, Crowley J.  (1982) A Confidence Interval for the Median Survival Time, 
Biometrics, 38, 29 – 41. 
Chen DS, Mellman I.  Oncology meets immunology:  the cancer-immunity cycle. 
Immunity.  2013;39(1):1-10 
Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
the binomial.  Biometricka.  1934;26:404-413. 
Fang H, Ye S, Reddy A, Turan T, Woolley A, Chao DT et al.  Pharmacodynamics and 
potential predictive biomarkers of ABBV-428, a first-in-class mesothelin (MSLN)-CD40 
bispecific, in patients with advanced solid tumors Abstract 5672.  Presented at: 
VMS.CL11.01 - Predictive Biomarkers for Immunotherapeutics at the AACR Virtual 
Annual Meeting I (April 27-28, 2020).  Available at 
https://www.abstractsonline.com/pp8/#!/9045/presentation/10537https://www.abstractso
nline.com/pp8/#!/9045/presentation/10537 accessed on 14 May 2020. 
Gonzalez NK, Wennhold K, Balkow S, et al.  In vitro and in vivo imaging of initial B-T-cell 
interactions in the setting of B-cell based cancer immunotherapy.  Oncoimmunology.  
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Hassan R, Thomas A, Alewine C, Le DT, Jaffee EM, Pastan I.  Mesothelin 
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Harmonised Tripartite Guideline:  Nonclinical Evaluation for Anticancer Pharmaceuticals 
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Irenaeus SMM, Nielsen D, Ellmark P, et al.  First-in-human study with intratumoral 
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Int J Cancer.  2019;145(5):1189-1199. 
Johnson P, Challis R, Chowdhury F, et al.  Clinical and biological effects of an agonist 
anti-CD40 antibody:  a Cancer Research UK phase I study.  Clin Cancer Res. 
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Kalbfleisch and Prentice, 1980 Kalbfleisch JD and Prentice JL.  The Statistical Analysis 
of Failure Time Data.  New York.  John Wiley & Sons; 1980. 
Liu L, Jacobsen FW, Everds N, et al.  Biological Characterization of a Stable Effector 
Functionless (SEFL) Monoclonal Antibody Scaffold in Vitro.  J Biol Chem. 
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Luke JJ, Fong L, Chun K, et al.  Phase 1 Study Evaluating Safety, Pharmacokinetics, 
Pharmacodynamics, and Preliminary Efficacy Of Abbv-428, First-in-class 
Mesothelin-CD40 Bispecific, in Patients With Advanced Solid Tumors.  Annals of 
Oncology 2019:30 (suppl_5):  v475-v532.  Poster presented at:  ESMO Congress 2019; 
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National Library of Medicine (US).  ClinicalTrials.gov [Internet].  Bethesda (MD):  2000 
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With Advanced Solid Tumors.  Available from: 
https://clinicaltrials.gov/ct2/show/study/NCT02955251https://clinicaltrials.gov/ct2/show/st
udy/NCT02955251.  Last update posted 07 November 2019.  Accessed 14 April 2020. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649-655. 
Piechutta M, Berghoff AS.  New emerging targets in cancer immunotherapy:  the role of 
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1-5. 
Poulet FM, Wolf JJ, Herzyk DJ, et al.  An evaluation of the impact of PD-1 pathway 
blockade on reproductive safety of therapeutic PD-1 inhibitors.  Birth Defects Res B Dev 
Reprod Toxicol.  2016;107:108-119. 
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade.  Science. 
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Ridge JP, Di Rosa F, Matzinger P.  A conditioned dendritic cell can be a temporal bridge 
between a CD4+ T-helper and a T-killer cell.  Nature.  1998;393(6684):474-478. 
Saber H, Gudi R, Manning M, Wearne E, Leighton JK.  An FDA oncology analysis of 
immune activating products and first-in-human dose selection.  Regul Toxicol 
Pharmacol. 2016, 81:448-456. 
Schaer DA, Hirschhorn-Cymerman D, Wolchok JD.  Targeting tumor-necrosis factor 
receptor pathways for tumor immunotherapy.  J Immunother Cancer.  2014;2:7:9 pages 
Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes.  Statistics in Medicine.  1995;14:357-379. 
Vitale LA, Thomas LJ, He LZ, et al.  Development of CDX-1140, an agonist CD40 
antibody for cancer immunotherapy.  Cancer Immunol Immunother.  2019;68(2):233-
245. 
Von Bergwelt-Baildon M, Shimabukuro-Vornhagen A, Popov A, et al.  CD40-activated B 
cells express full lymph node homing triad and induce T-cell chemotaxis:  potential as 
cellular adjuvants.  Blood.  2006;107:2786-2789. 
Vonderheide RH.  CD40 Agonist Antibodies in Cancer Immunotherapy.  Annu Rev Med. 
2020;71:47-58. 
Vonderheide RH, Burg JM, Mick R, et al.  Phase I study of the CD40 agonist antibody 
CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid 
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Vonderheide RH, Dutcher JP, Anderson JE, et al.  Phase I study of recombinant human 
CD40 ligand in cancer patients.  J Clin Oncol.  2001;19(13):3280-3287. 
Vonderheide RH, Flaherty KT, Khalil M, et al.  Clinical activity and immune modulation in 
cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.  J 
Clin Oncol.  2007;25(7):876-883. 
Vonderheide RH, Glennie MJ.  Agonistic CD40 antibodies and cancer therapy.  Clin 
Cancer Res.  2013;19(5):1035-1043. 
Vonderheide RH.  The Immune Revolution:  A Case for Priming, Not Checkpoint.  
Cancer Cell.  2018;33(4):563-569.   
Ye S, Cohen D, Belmar NA et al.  A Bispecific Molecule Targeting CD40 and Tumor 
Antigen Mesothelin Enhances Tumor-Specific Immunity.  Cancer Immunol Res.  2019; 
7(11):1864-1875. 
 
 


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11. 
Appendices 
 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibodies 
ADR 
adverse drug reaction 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibody 
ANCA 
anti-neutrophil cytoplasmic antibodies 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-14d 
AUC from 0 to 14 days postdose 
AUC0-28d 
AUC from 0 to 28 days postdose 
BLRM 
Bayesian Logistics Regression Model 
BUN 
blood urea nitrogen 
CD40 
cluster of differentiation 40 
CD40L 
CD40 trimeric ligand 
CH2 
heavy chain constant domain 2 
CFR 
U.S. Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DES 
Amgen data element standard 
DILI 
drug induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose-limiting toxicity 


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ECG 
electrocardiogram 
Echo 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic 
record used for the reconstruction and evaluation of a trial. 
Exposure-Response  
Analysis 
mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic (PK) 
exposure (eg, population pharmacokinetic modeling) and 
response, which may include biomarkers, 
pharmacodynamic effects, efficacy and safety endpoints. 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures 
are conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for 
the primary endpoint(s), for the purposes of conducting the 
primary analysis, whether the study concluded as planned 
in the protocol or was terminated early  
End of Study (end of trial) defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the 
study (ie, last subject last visit), following any additional 
parts in the study (eg, long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HC 
Heavy chain 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


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ICJME 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IgG1 
immunoglobulin G1 
IHC 
immunohistochemistry 
Il 
interleukin 
IND 
Investigational New Drug 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
Kd 
equilibrium dissociation constant 
KPS 
Karnofsky Performance Status 
Lansky PFS 
Lansky Play-Performance Scale 
LC 
light chain 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MABEL 
minimum anticipated biological effect level 
MRI 
magnetic resonance imaging 
MSLN 
mesothelin 
MTD/MTCD 
maximum tolerated dose/maximum tolerated combination 
dose 
MUGA scan 
multigated acquisition scan 
NCT 
National Clinical Trials 
NSCLC 
nonsmall-cell lung cancer 
OR 
objective response 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death ligand 1 
PD-L2 
programmed death ligand 2 
PK 
Pharmacokinetics 
PR 
partial response 


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RO 
receptor occupancy 
SAT 
safety assessment team 
scFv 
single chain variable fragments 
SEFL2 
stable effector functionless 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in 
clinical research.  The information may include, but is not 
limited to, clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and 
evaluation of the trial.  Source data are contained in source 
documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and 
Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified 
investigational product(s)/protocol-required therapies is/are 
administered to the subject 
TBL 
total bilirubin 
TMF 
trial master file 
TPI 
toxicity probability interval 
TSH 
thyroid stimulating hormone 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory and/or by the 
local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.1 to Section 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 11-1.  Analyte Listing 
Local 
Laboratory:  
Chemistry 
Local 
Laboratory:  
Coagulation 
Local 
Laboratory:  
Urinalysis 
Local 
Laboratory:  
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Calcium 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
TSH 
Free T4 
PT/INR 
PTT/APTT 
Fibrinogen 
Fibrin split 
products 
D-dimer 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Nucleated RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Total neutrophils 
• Segmented 
neutrophils  
• Bands/stabs 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Myeloblasts 
• Promyelocytes 
• Myelocytes 
• Metamyelocytes 
• Atypical 
lymphocytes 
Central 
Laboratory:  
Tumor biopsya 
SP74 Ventana 
MSLN IHC 
assayb 
AMG 994 and 
AMG 404 Pharm
acokinetic 
Assessments  
 
Local Laboratory: 
Hep B surface 
antigen 
Hep C antibody 
HIVc 
Serum 
Pregnancy 
ACTH 
ANA 
ANCA 
(cytoplasmic and 
perinuclear) 
a.Archived tumor tissue acceptable for the screening sample only. 
b.NSCLC squamous cell carcinoma and adenocarcinoma patients only, Part 2 only. 
c HIV assessment is required. 
ACTH  adrenocorticotropic hormone; ALP  alkaline phosphatase; ALT  alanine aminotransferase; 
APTT  activated partial thromboplastin time; AST  aspartate aminotransferase; BUN  blood urea 
nitrogen; HDL  high density lipoprotein; Hep  hepatitis; HIV  human immunodeficiency virus; 
HLA  human leukocyte antigen; IHC  immunohistochemistry; INR  international normalized ratio; 
LDH  lactate dehydrogenase; LDL  low density lipoprotein; MCH  mean corpuscular hemoglobin; 


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MCHC  mean corpuscular hemoglobin concentration; MCV  mean corpuscular volume; 
MSLN  mesothelin; 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; TSH  thyroid stimulating hormone; WBC  white blood cell count 
 


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11.3 
Appendix 3.  Study Governance Considerations 
Committee(s) 
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, cohort continuation, or cohort expansion; 
making recommendations about non-dose escalation cohorts (eg, expanded, highest 
dose and/or final cohort); and evaluating safety signals for purposes of applying Dose 
Cohort Stopping Rules.  The required Dose Level Review Team (DLRT) members are 
the Medical Monitor, Global Safety Officer (GSO), and Site Investigators.  The DLRT will 
include all Site Investigators.  The Medical Monitor, GSO, and Site Investigators are the 
only voting DLRT members.  The following non-voting Amgen representatives may also 
be part of the DLRT:  safety scientist, global study manager, biostatistician, PK scientist. 
The Medical Monitor must be in attendance and cannot be represented by a voting 
designee or delegate.  Voting designees can be identified as appropriate by the GSO or 
Site Investigator(s).  A Site Investigator may identify a delegate (eg, sub-Investigator) 
who is listed in the Delegation of Authority.  If a Site Investigator does this, the Site 
Investigator must provide written agreement with the designee or delegate’s vote.   
For a DLRM to occur, the Medical Monitor must attend, and the GSO or delegate must 
attend.  In addition, a quorum of Site Investigators must be present.  A quorum is defined 
as more than 50 of the participating investigators or their qualified designee.  The 
DLRM will be rescheduled if these requirements are not met.  
All available study data, including demographics, IP administration, medical history, 
concomitant medications, adverse events, ECG, vital signs, and laboratory results will be 
reviewed.  Data to be reviewed will be unqueried.   
DLRM voting will occur as follows:  there will be a total of 3 votes, 1 for the Medical 
Monitor, 1 for the GSO or delegate, and 1 for all of the Site Investigators or delegates 
combined.  Regardless of how many Site Investigators there are, all of the Site 
Investigators combined will have a total of 1 vote decided by a majority of the 
investigators (defined as greater than or equal to 50). 
DLRM recommendations to escalate to the next planned cohort, or to an intermediate 
cohort, must be by unanimous vote.  If the voting members of the DLRT are not able to 
reach a unanimous recommendation on whether to escalate to the next planned cohort 


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or to an intermediate cohort, then this should be reflected in the DLRM Memo.  Other 
recommendations, such as expanding a cohort or lowering a dose will be made by a 
majority vote. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 


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Recruitment Procedures 
Site staff may identify potential subjects from their existing patient population and/or may 
seek referral patients through existing professional networks or other community 
sources.  All patient-facing materials must be reviewed/approved by the sponsor (Amgen 
Inc.) and the local IRB/IEC prior to use. 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative (defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study) will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
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 


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physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 7. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 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. 


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Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 


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


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


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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 CRF entries 
if the CRF is the site of the original recording (ie, there is no other written or electronic 
record of data, such as paper questionnaires for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the [IRB/IEC] 
and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 


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 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable] 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
 


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


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


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


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 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor in lieu of completion of the Event CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events, version 5.0 which is available 
at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies, and/or study-mandated procedure and each 
occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 


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 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper based Serious Adverse Event 
Contingency Report Form (also referred to as the electronic Serious Adverse 
Event (eSAE) Contingency Report Form) (see Figure 11-1) within 24 hours of the 
investigator’s knowledge of the event. 


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 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line 
to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC system has been taken off-line, then the site can report this information on 
the paper-based Serious Adverse Event Contingency Report Form 
(see Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen if the investigator becomes 
aware of a serious adverse event.  The investigator should use the paper-based 
Serious Adverse Event Contingency Report Form to report the event. 


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency 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 male and female subjects of childbearing 
potential are outlined in Section 5.2.  Contraceptive use and methods should be 
consistent with local regulations for subjects participating in clinical studies.   
Male and female subjects of childbearing potential should be advised of the pregnancy 
prevention requirements and the potential risk to the fetus if they become pregnant or 
father a child during treatment and for 6 months (for female subjects) or 8 months (for 
female partners of male subjects) after the last dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  1) review 
of subject’s medical records; 2) subject’s medical examination; or 3) subject’s medical 
history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment 


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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of 1 per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Contraception Methods for Male Subjects  
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject)  
 
Use a condom during treatment and for an additional 8 months after the last dose of 
protocol-required therapies 
The female partner should consider using an acceptable method of effective 
contraception such as:  hormonal, IUD, IUS, female barrier method (diaphragm, cap, 
sponge [a female condom is not an option because there is a risk of tearing when both 
partners use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 


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 
Spermicides only 
 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 6 months after the last 
dose of protocol-required therapies 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety within 24 hours of 
learning of a subject’s pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws). 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through6 months after 
the last dose of the study drug.  This information will be forwarded to Amgen Global 
Patient Safety.  Generally, infant follow-up will be conducted up to 12 months after 
the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
 


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Male Subjects With Partners Who Become Pregnant 
 
In the event a male subject fathers a child during treatment, and for an additional 
8 months after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) must be 
submitted to Amgen Global Patient Safety within 24 hours of the site’s awareness of 
the pregnancy.  (Note:  Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
 
The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 6 months after discontinuing 
protocol-required therapies. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 219. 
 
With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 6 months after discontinuing protocol-
required therapies. 


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Figure 11-2.  Pregnancy and Lactation Notification Forms 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood biomarker, pharmacokinetics (PK), and biopsy 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 
advanced solid tumors, the dose response and/or prediction of response to AMG 994, 
characterize antibody response, and characterize aspects of the molecule (eg, 
mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study. 
Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood, serum, and 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-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, 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 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
 3 x ULN  
at any time 
 2 x ULN 
 
 
OR 
INR 
-- 
 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
 8 x ULN at any time 
 5 x ULN but  8 x ULN for  2 weeks 
 5 x ULN but  8 x ULN and unable to 
adhere to enhanced monitoring 
schedule 
 3 x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, 
vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 3 x ULN (when baseline was  ULN) 
 
OR 
 
ALP 
 8 x ULN at any time 
-- 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
INR  international normalized ratio; TBL  total bilirubin; ULN  upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product is to be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Table 11-2) are never to be rechallenged. 


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Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 11-2 or who experience AST or ALT elevations  3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL  2 x ULN or INR  1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


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


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11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse Events 
Anticipated serious adverse events are events that are anticipated to occur in the study 
population at some frequency independent of investigational product exposure and do 
not need to be reported individually as an FDA IND safety report by the sponsor.  
Identification and reporting of anticipated serious adverse events is the responsibility of 
the sponsor; the investigator is responsible for reporting adverse events and serious 
adverse events as described in Appendix 11.4. 
Anticipated Serious Adverse Events for Study 20190136 
Preferred Term1 
N/A 
1 MedDRA Version 22.1 


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11.9 
Appendix 9.  ECOG Performance Status and NYHA Classification 
Eastern Cooperative Oncology Group Performance Status Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (eg, light 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. 
5 
Dead. 
Source:  Oken et al, 1982 
ECOG  Eastern Cooperative Oncology Group 
New York Heart Association Functional Classification 
Class I  
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation or dyspnea. 
Class II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea. 
Class III 
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation or dyspnea. 
Class IV 
Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency may be present even at rest.  If any physical activity 
is undertaken, discomfort is increased. 


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11.10 
Appendix 10.  Toxicity Management Guidelines 
Table 11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dos
e Modification 
Management with 
Corticosteroids and/or Other 
Therapies 
Monitor & Follow-
up 
Pneumonitis 
Grade 2  (symptomatic, involves more 
than 1 lobe of the lung of 25 - 50 of 
lung parenchyma, medical intervention 
indicated, limiting instrumental ADL) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper.  Consider additional 
immunosuppressive agent (eg, 
infliximab, mycophenolate, 
cyclophosphamide) if refractory to 
corticosteroids. 
Monitor subjects for 
signs and symptoms 
of pneumonitis.  
Evaluate subjects with 
suspected 
pneumonitis with 
radiographic imaging.  
Add prophylactic 
antibiotics for 
opportunistic 
infections. 
Grade 3  (severe symptoms, 
hospitalization required, involves all lung 
lobes or  50 of lung parenchyma, 
limiting self-care ADL, oxygen indicated)  
OR 
Grade 2 recurrent 
Permanently 
discontinue 
Grade 4 (life-threatening respiratory 
compromise, urgent intervention indicated 
[intubation]) 
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Table 11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with 
Corticosteroids and/or Other 
Therapies 
Monitor & Follow-
up 
Colitis/Diarrhea 
Grade 2  (increase of 4-6 stools per 
day over baseline; moderate increase 
in ostomy output compared with 
baseline) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper.  Consider infliximab if 
symptoms refractory to 
corticosteroids within 2-3 days. 
Monitor subjects for 
signs and symptoms 
of enterocolitis (eg, 
diarrhea, abdominal 
pain, blood or mucus 
in stool with or without 
fever) and of bowel 
perforation (eg, 
peritoneal signs and 
ileus). For subjects 
with grade 
 2 diarrhea 
suspecting colitis, 
consider  
GI consultation and 
endoscopy to rule out 
colitis. 
Grade 3 (increase of 7 or more stools 
per day over baseline, incontinence; 
hospitalization indicated, severe 
increase in ostomy output compared 
with baseline, limiting self-care ADL) 
Grade 4 (life-threatening 
consequences; urgent intervention 
indicated) 
Permanently 
discontinue 
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Table11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 
Dose 
Modification 
Management with 
Corticosteroids and/or Other 
Therapies 
Monitor & 
Follow-up 
Hepatitis 
Grade 2 (asymptomatic, AST or ALT 
 3.0 to  5 x ULN and/or 
total bilirubin  1.5 to  3 x ULN [for 
patients with values  ULN at 
baseline]) 
Withhold 
Administer corticosteroids at an initial 
dose of 0.5 to 1 mg/kg/d prednisone 
(or equivalent) followed by taper. 
Monitor with liver 
function tests more 
frequently until 
returned to 
baseline or stable. 
Grade 3 (symptomatic liver 
dysfunction, fibrosis by biopsy, 
compensated cirrhosis, reactivation of 
chronic hepatitis  
[AST or ALT 5-20 x ULN and/or 
total bilirubin 3-10 x ULN]) 
Permanently 
discontinue 
Administer corticosteroids at an initial 
dose of 1 to 2 mg/kg/d prednisone (or 
equivalent) followed by taper.  
Consider mycophenolate mofetil if 
refractory to corticosteroids or no 
improvement after 3 days. 
Grade 4 (decompensated liver 
function eg, ascites, coagulopathy, 
encephalopathy, coma [AST or ALT  
 20 x ULN and/or total bilirubin 
  10 x ULN]) 
Administer corticosteroids at an initial 
dose of 2 mg/kg/d prednisone (or 
equivalent) followed by taper.  
Consider mycophenolate mofetil if 
refractory to corticosteroids or no 
improvement after 3 days. 
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Table 11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse 
Reactions 
Severity (CTCAE Grade 
Version 5.0 or Specific 
Conditions) 
AMG 404 
Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & Follow-
up 
Hypophysitis 
Grade 3 or 4 not responsive to 
therapy within 2 days  
Permanently 
discontinue 
Administer corticosteroids at an initial 
dose of 1 mg/kg/d prednisone (or 
equivalent) followed by taper.  In addition, 
initiate hormonal replacement therapy as 
clinically indicated. 
Monitor for signs 
and symptoms of 
hypophysitis. 
Consider endocrine 
consultation. 
Adrenal 
Insufficiency 
Grade 3 or 4 not responsive to 
therapy within 2 days 
Permanently 
discontinue 
Initiate IV stress-dose corticosteroids on 
presentation (hydrocortisone  
100 mg or dexamethasone 4 mg [if the 
diagnosis is not clear and ACTH 
stimulation testing will be needed]).  
Taper stress-dose corticosteroids down to 
maintenance doses (prednisone 5 to 10 
mg daily) over  
1-2 weeks after discharge. 
Monitor for signs 
and symptoms of 
adrenal 
insufficiency.  
Consider endocrine 
consultation. 
Hypothyroidism 
Grade 3 or 4 not responsive to 
therapy within 2 days 
Permanently 
discontinue 
Initiate thyroid hormone supplementation. 
Monitor subjects for 
signs and symptoms 
of hypothyroidism.  
Consider endocrine 
consultation. 
Hyperthyroidism 
Grade 3 or 4 not responsive to 
therapy within 2 days 
Permanently 
discontinue 
Initiate -Blocker (eg, atenolol, 
propranolol) for symptomatic relief.  For 
severe symptoms or concern for thyroid 
storm, initiate prednisone 1-2 mg/kg/d (or 
equivalent) tapered over 1-2 weeks.  
Consider use of potassium iodide (SSKI) 
Monitor subjects for 
signs and symptoms 
of hyperthyroidism.  
Consider endocrine 
consultation. 


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or thionamide (methimazole or 
propylthiouracil [PTU]). 
Page 4 of 8  
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Table 11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 
Dose 
Modification 
Management with 
Corticosteroids and/or Other 
Therapies 
Monitor & Follow-
up 
Diabetes Mellitus 
Grade 3 not responsive to therapy 
within 2 days 
Permanently 
discontinue 
Initiate insulin therapy. 
Monitor subjects for 
hyperglycemia or 
other signs and 
symptoms of diabetes.  
Consider endocrine 
consultation. 
Grade 4 hyperglycemia ( 500 mg/dL 
[ 27.8 mmol/L]) 
Nephritis and Renal 
Dysfunction 
Grade 2 (serum creatinine  1.5 - 3.0 
x baseline;  1.5 - 3.0 x ULN) 
Withhold 
Administer corticosteroids at an 
initial dose of 0.5 to 1 mg/kg/d 
prednisone (or equivalent) followed 
by taper.  If worsening or no 
improvement occurs, increase dose 
of corticosteroids to 1 to 2 mg/kg/d 
prednisone (or equivalent). 
Monitor changes in 
renal function.  
Evaluate for other 
causes of renal 
dysfunction (eg, 
recent IV contrast, 
medications, fluid 
status, etc) 
Grade 3 (serum creatinine  3.0 x 
baseline;  3.0 - 6.0 x ULN) lasting 
greater than 3 days 
Permanently 
discontinue 
Administer corticosteroids at an initial 
dose of 1 to 2 mg/kg/d prednisone (or 
equivalent) followed by taper. 
Grade 4 (serum creatinine  6 x ULN; 
dialysis indicated) 
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Table 11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 
Dose 
Modification 
Management with 
Corticosteroids and/or Other 
Therapies 
Monitor & Follow-
up 
Skin 
Grade 3 rash or suspected  
Stevens-Johnson syndrome (SJS) or 
toxic epidermal necrolysis (TEN) 
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper.  Treat with topical 
emollients, oral antihistamines, and 
high-potency topical corticosteroids 
as indicated. 
Monitor subjects for 
suspected severe skin 
reactions and exclude 
other causes (eg 
infection, an effect of 
another drug, a skin 
condition linked to 
another systemic 
disease, etc).  For 
signs or symptoms of 
SJS or TEN, withhold 
study drug and refer 
the patient for 
specialized care for 
assessment and 
treatment. 
Grade 4 rash or confirmed SJS or TEN 
Permanently 
discontinue 
Encephalitis 
Any Grade (if immune related) 
Permanently 
discontinue 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper.  Consider empirical antiviral 
(IV acyclovir) and antibacterial 
therapy until CSF results obtained 
and negative for aseptic meningitis. 
Monitor subjects for 
neurologic symptoms 
and exclude other 
etiologies (eg, 
infectious).  Evaluation 
of patients with 
neurologic symptoms 
may include, but not 
be limited to, 
consultation with a 


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neurologist, brain MRI, 
and lumbar puncture. 
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Table 11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 Dose 
Modification 
Management with 
Corticosteroids and/or Other 
Therapies 
Monitor & Follow-
up 
Myocarditis 
Grade 1 (abnormal cardiac biomarker 
testing, including abnormal ECG)  
Withhold 
Administer corticosteroids at an 
initial dose of 1 to 2 mg/kg/d 
prednisone (or equivalent) followed 
by taper. 
Monitor patients with 
cardiovascular 
symptoms.  Ensure 
adequate evaluation to 
confirm etiology and/or 
exclude other causes. 
Grade 2 (abnormal screening tests 
with mild symptoms) 
Grade 3 (moderately abnormal testing 
or symptoms with mild activity) 
Permanently 
discontinue 
Grade 4 (moderate to severe 
decompensation, IV medication or 
intervention required, life-threatening 
conditions) 
All Other 
Immune-Related 
Adverse Reactions 
Grade 3 adverse reaction involving a 
major organ 
Withhold 
Based on type and severity of 
adverse reaction, administer 
corticosteroids.  Refer to ASCO 
Clinical Practice Guidelines for 
additional recommendations. 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes. 
Life-threatening or Grade 4 adverse 
reaction involving a major organ 
Permanently 
discontinue 
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Table 11-3.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Reactions Associated With 
AMG 404* 
Immune-related 
Adverse 
Reactions 
Severity (CTCAE Grade Version 
5.0 or Specific Conditions) 
AMG 404 
Dose 
Modification 
Management with Corticosteroids 
and/or Other Therapies 
Monitor & 
Follow-up 
Recurrent or 
Persistent Immune-
Related Adverse 
Reactions 
Recurrence of same Grade 3 or Grade 
4 adverse reaction 
Permanently 
discontinue 
Based on type and severity of adverse 
reaction, administer corticosteroids.  
Additional immunosuppressive 
treatment may be required. 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude other 
causes. 
Requirement for  10 mg/day 
prednisone (or equivalent) for more 
than 12 weeks 
Persistent grade 2 or 3 adverse 
reactions lasting 12 weeks or longer 
after last dose (ie, does not resolve to 
grade 0 or 1 within 12 weeks) 
 
General considerations:  
 
Corticosteroid taper should be initiated upon improvement of signs/symptoms and/or laboratory values to Grade 1 or less.  Continue 
corticosteroid taper over the course of at least 4 to 6 weeks.  
 
If AMG 404 has been withheld, treatment with AMG 404 may be resumed after adverse event (or associated signs/symptoms/laboratory 
parameters) has been reduced to Grade 1 or less and corticosteroid has been tapered to prednisone  10 mg (or equivalent).  
 
For severe and life-threatening immune-related adverse reactions, IV corticosteroids should be initiated first followed by oral corticosteroids.  
Other immunosuppressive treatment should be initiated if the event cannot be controlled by corticosteroids.  
Page 8 of 8 
ACTH  adrenocorticotropic hormone; ADL  activities of daily living; ALT  alanine aminotransferase; ASCO  American Society of Clinical Oncology; AST  aspartate 
aminotransferase; CSF  cerebrospinal fluid; CTCAE  Common Terminology Criteria for Adverse Events; ECG  electrocardiogram; GI  gastrointestinal; 
IV  intravenous; MRI  magnetic resonance imaging; PTU  propylthiouracil; SSKI  potassium iodide; SJS  Stevens-Johnson syndrome; TEN  toxic epidermal 
necrolysis; ULN  upper limit of normal. 
* Recommendations adapted from the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines for the Management of Immune-Related Adverse 
Events in Patients Treated with Immune Checkpoint Inhibitor Therapy (Brahmer et al, 2018) 
.


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Table 11-4.  Management of Infusion-related Reactions With AMG 994 or AMG 404 
Severity (CTCAE 
Grade Version 5.0) 
AMG 404 or 
AMG 994 Dose 
Modification 
Management 
Premedication at 
Subsequent 
Dosing 
Grade 1 (mild transient 
reaction; infusion 
interruption not 
indicated; intervention 
not indicated) 
Interrupt 
AMG 404 or 
AMG 994 or 
slow the rate of 
the infusion to 
50 or less of 
the standard 
rate. 
 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 If the infusion is 
interrupted, then after 
all symptoms have 
resolved, consider 
rechallenge with a 
reduced infusion rate 
(50 or less of 
standard rate) and 
additional 
premedication (such as 
corticosteroids and 
antihistamines). 
 Treat per institutional 
guidelines. 
None 
Grade 2 (therapy or 
infusion interruption 
indicated but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDS,  
narcotics, IV fluids); 
prophylactic medications 
indicated for  24 hours) 
Interrupt 
AMG 404 or 
AMG 994 or 
slow the rate of 
the infusion.  
For subjects 
who develop 
grade 2 
infusion-related 
reaction despite 
adequate 
premedication, 
permanently 
discontinue 
AMG 404 or 
AMG 994. 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 If the infusion is 
interrupted, then after 
all symptoms have 
resolved, consider 
rechallenge with a 
reduced infusion rate 
(50 or less of 
standard rate) and 
additional 
premedication (such as 
corticosteroids and 
antihistamines). 
 Treat per institutional 
guidelines.  Additional 
appropriate medical 
therapy may include but 
is not limited to IV 
fluids, antihistamines, 
NSAIDs, 
acetaminophen, and 
narcotics. 
Subject may be 
premedicated 
1.5 hours  
( 30 minutes) 
prior to infusion of 
AMG 994 or 
AMG 404 with:  
 Diphenhydramine 
50 mg orally (or 
equivalent dose 
of antihistamine). 
 Acetaminophen 
500-1000 mg 
orally (or 
equivalent dose 
of antipyretic). 


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Grade 3 (prolonged [eg, 
not rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion]; recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae) 
 
OR 
 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
Permanently 
discontinue 
study drug. 
 Increase monitoring of 
vital signs as medically 
indicated until the 
subject is deemed 
medically stable.  
 Hospitalization may be 
indicated. 
 Treat per institutional 
guidelines.  Additional 
appropriate medical 
therapy may include but 
is not limited to IV 
fluids, antihistamines, 
NSAIDs, 
acetaminophen, 
narcotics, oxygen, 
vasopressors, 
corticosteroids, and 
epinephrine.  In cases 
of anaphylaxis, 
epinephrine should be 
used immediately. 
No subsequent 
dosing 
CTCAE  Common Terminology Criteria for Adverse Events; IV  intravenous; NSAIDS  nonsteroidal 
anti-inflammatory drugs. 


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11.11 
Appendix 11.  Modified Response Evaluation Criteria in Solid 
Tumors Version 1.1 (Modified RECIST 1.1) 
This study utilizes modified RECIST 1.1 criteria, which includes required confirmation of 
disease progression, and the following modification to RECIST 1.1: 
 
Up to 5 target lesions per organ and 10 total are allowed (compared to 2 per organ 
and 5 total for standard RECIST 1.1) to increase lesion sampling and reduce 
assessment error. 
Definitions 
 
Measurable Lesions 
1 Measurable Tumor Lesions – Non-nodal lesions with clear borders that can 
be accurately measured in at least 1 dimension with longest diameter 
 10 mm in CT/MRI scan with slice thickness no greater than 5 mm.  When 
slice thickness is greater than 5 mm, the minimum size of measurable lesion 
should be twice the slice thickness. 
2 Nodal Lesions - Lymph nodes are to be considered pathologically enlarged 
and measurable, a lymph node must be  15 mm in short axis when assessed 
by CT/MRI (scan slice thickness recommended to be no greater than 5 mm).  
At baseline and in follow-up, only the short axis will be measured and 
followed. 
▪ 
Nodal size is normally reported as two dimensions in the axial plane.  
The smaller of these measures is the short axis (perpendicular to the 
longest axis). 
3 Irradiated Lesions - Tumor lesions situated in a previously irradiated area, or 
in an area subjected to other loco-regional therapy, are not measurable unless 
there has been demonstrated progression in the lesion prior to enrollment. 
 
Non-measurable Lesions 
4 All other lesions, including small lesions (longest diameter  10 mm or 
pathological lymph nodes with  10 mm but to  15 mm short axis with 
CT scan slice thickness no greater than 5 mm) are considered 
non-measurable and characterized as non-target lesions. 
5 Other examples of non-measurable lesions include: 
▪ 
Lesions with prior local treatment:  tumor lesions situated in a previously 
irradiated area, or an area subject to other loco-regional therapy, should 
not be considered measurable unless there has been demonstrated 
progression in the lesion. 
▪ 
Biopsied lesions 
▪ 
Categorially, clusters of small lesions, bone lesions, inflammatory breast 
disease, and leptomeningeal disease are non-measurable. 


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


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


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


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


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 180 of 180 
CONFIDENTIAL  
 
 
 
New lesions – The term “new lesion” always refers to the presence of a new finding 
that is definitely tumor.  New findings that only may be tumor, but may be benign 
(infection, inflammation, etc.) are not selected as new lesions, until that time when 
the review is certain they represent tumor.   
 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
 
A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression, regardless of any response that may be seen in target or non-target 
lesions present from baseline. 
 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.”  Every effort should be made to 
document the objective progression with an additional imaging assessment even 
after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from scar or 
normal tissue.  When the evaluation of complete response (CR) depends on this 
determination, the residual lesion may be further investigated by additional scans to 
be discussed with Sponsor, or possibly fine needle aspirate/biopsy, to confirm the 
CR status 
Confirmation Measurement / Duration of Response 
 
Response Confirmation - In non-randomized trials where response is the 
primary endpoint, confirmation of PR and CR is required to ensure 
responses identified are not the result of measurement error. 
 
Duration of overall response – The duration of overall response is 
measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date the recurrent or progressive 
disease is objectively documented. 
 
Duration of Stable Disease - SD is measured from the start of the 
treatment until the criteria for disease progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 1 of 13 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Phase 1, Multicenter, Open-label, Dose Exploration and Dose 
Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and 
Efficacy of AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in 
Subjects with Advanced Solid Tumors 
 
Amgen Protocol Number:  AMG 994 and AMG 404, 20190136 
EudraCT Number:  2020-003937-40 
NCT Number:  NCT04727554 
 
Amendment Date: 
16 June 2022 
 
Rationale: 
This protocol is being amended to update long-term follow-up (LTFU) safety reporting 
language in accordance with Amgen processes for ongoing interventional studies with a 
LTFU period.  Changes including, but not limited to, the following were incorporated into 
the protocol: 
 
Added language to schedule of activities (SoA) to clarify that after end of study, 
serious adverse events suspected to be related to investigational product need to be 
reported to Amgen if the investigator becomes aware of the event. 
 
Language in serious adverse events section was added to clarify that it is up to the 
investigator’s judgment to report grade 4 abnormalities by Common Terminology 
Criteria for Adverse Events (CTCAE) as serious adverse events, and that 
comprehensive documentation of the event severity must be recorded in the subject 
medical record. 
 
Updated product complaints language to make clear that all components distributed 
with the drugs can be included in communications with regard to product complaints; 
and to clarify that AMG 994 and AMG 404 are the investigational products 
provisioned and/or repackaged/modified by Amgen. 
 
Updated language in adverse events and serious adverse events section to maintain 
consistency with clinical trial (CT) protocol template language.  


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  16 June 2022 
Page 2 of 13 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Language in serious adverse events after the protocol-required reporting period 
section was updated to clarify that all serious adverse events suspected to be related 
to the investigational product needs to be reported to Amgen within 24 hours following 
the investigator’s awareness of the event; investigators need to collect/report fatal 
serious adverse events (regardless of causality) to Amgen within 24 hours following 
the investigator’s awareness of the event; that there is no requirement to actively 
monitor study subjects after end of study (EOS), this in regard to study subject 
treatment by the investigator; and to clarify that additional information may need to be 
collected from the subject’s records after the subject EOS, that if further safety related 
data is needed to fulfill any regulatory reporting requirements for a reportable event.  
 
Updated pregnancy and lactation language to clarify that details on all pregnancies 
and/or lactation in female subjects and female partners of male subjects will be 
collected until 6 months or 8 months, respectively.  
 
Language in Appendix 4 was added to clarify that SAE suspected to be related to 
investigational products will be reported to Amgen if the investigator becomes aware 
of a serious adverse event. 
 
Updated Appendix 5 pregnancy and lactation section to clarify language on the 
pregnancy prevention requirements and the potential risk to the fetus if the female 
subjects or female partners of male subjects become pregnant 6 months or 8 months, 
respectively, after the last dose of protocol-required therapies. 
 
Administrative and editorial changes including typographical, grammatical, and 
formatting have been made throughout the protocol for clarification. 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  03 December 2020 
Page 1 of 99 
Amgen Proprietary - Confidential 
Amendment 3 
Protocol Title:  A Phase 1, Multicenter, Open-label, Dose Exploration and 
Dose Expansion Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of AMG 994 Monotherapy and Combination 
of AMG 994 and AMG 404 in Subjects with Advanced Solid Tumors 
 
Amgen Protocol Number AMG 994 and AMG 404, 20190136 
EudraCT number 2020-003937-40 
NCT number:  TBD 
 
Amendment Date: 
03 December 2020 
 
Rationale: 
This protocol is being amended to address feedback from the Food and Drug 
Administration (FDA) during the pre-Investigational New Drug meeting to expand 
the inclusion criterion related to renal function, allowing enrollment of subjects 
with moderate renal impairment.  Additional clarifications and updates are being 
made to the Schedule of Activities (SOA) tables to ensure all activities are 
accurately reflected within the tables and the associated footnotes.  The following 
changes were incorporated into the study: 
 
Inclusion criterion 111 has been updated to allow subjects with moderate 
renal impairment to be enrolled into the study.   
 
The SOA tables were updated to more accurately and more clearly reflect 
the timepoints for vital sign collection and ensure consistency with the 
associated footnotes.   
 
End of Infusion safety laboratory collections were added (hematology, 
chemistry, and coagulation tests) to all cohorts in the Dose Exploration 
SOA tables.   


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  03 December 2020 
Page 2 of 99 
Amgen Proprietary - Confidential 
 
Updated timing and number of electrocardiogram (ECG) assessments to 
include consistent timepoints for ECGs to allow/enable monitoring of 
patient cardiac safety at appropriate timepoints during the first few cycles 
of therapy.   
 
Schedule of Assessments Table 1-3 was reformatted to show all 
timepoint collections more accurately.   
 
Biopsy samples were deleted from the Dose Exploration and Dose 
Expansion SOA tables at the End of Treatment timepoints as they will not 
be collected.   
 
Updated language in Section 8.2.2 related to continuation of AMG 994 
and AMG 404 combination treatment after confirmation of disease 
progression to be consistent with Section 4.   
 
Standard deviation calculations for the Bayesian Logistic Regression 
Model were update in Section 9.4.1.1.   
 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  22 October 2020 
Page 1 of 30 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 1, Multicenter, Open-label, Dose Exploration and Dose 
Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and 
Efficacy of AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in 
Subjects with Advanced Solid Tumors 
Amgen Protocol Number AMG 994 and AMG 404 20190136 
 
Amendment Date: 
22 October 2020 
 
Rationale: 
This protocol is being amended to: 
 
Update protocol to reflect Adverse Event collection from first dose of protocol 
required therapies through end of study.   
 
Update protocol to accurately reflect collection of Serious Adverse Event 
information and performance of Concomitant Medication Review from screening 
through end of study.   
 
Update protocol to correctly reflect intended coagulation, hematology, and 
chemistry assessments.   
 
Delete duplicated exclusion criterion related to male subjects with female 
partners of reproductive potential and renumbered accordingly.   
 
Updated inclusion/exclusion criteria numbering to coincide with numbering used 
in study database and case report forms.   
 
Update exclusion criterion 208 to align with requirements for AMG 404 by adding 
“
   
 
Revise the number/frequency of Whole Blood for Cytometry samples required for 
the study.   
 
Update the protocol to provide a window for tumor evaluation scans.   
 
Revise the protocol to further clarify the hospitalization requirements for the 
study.   
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  22 October 2020 
Page 2 of 30 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 accurately reflect Hep B surface antigen, Hep C 
antibody, and HIV as local laboratory tests; clarify that HIV testing is a required 
test; and clarify that IHC testing for NSCLC patients is only required in Part 2 of 
the study.   
 
Administrative, typographical and formatting changes were made throughout the 
protocol.  Updates to safety language have been implemented throughout the 
protocol to align with the current template. 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  14 October 2020 
Page 1 of 27 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020, Version:  6.0 
Amendment 1 
Protocol Title:  A Phase 1, Multicenter, Open-label, Dose Exploration and Dose 
Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and 
Efficacy of AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in 
Subjects with Advanced Solid Tumors 
 
Amgen Protocol Number (AMG 994 and AMG 404) 20190136  
EudraCT Number 2020-003937-40 
 
Amendment Date: 
14 October 2020 
 
Rationale: 
This protocol is being amended to include changes as described in Amgen’s response to 
Food and Drug Administration’s 23 September 2020 information request.  Changes 
include:   
 
Remove “…in the investigator’s opinion, standard therapy does not exist” from 
Inclusion Criteria language 
 
Modify the dose limiting toxicity (DLT) definition to remove the criterion that “an 
adverse event will be considered related to study treatment (possibly, probably, or 
definitely related to the study treatment) if there is a suspected ‘reasonable causal 
relationship’ to the study treatment (ICH E2A), and not only a lack of an alternative 
explanation for the toxicity.” 
 
Update dose modification and discontinuation guidelines to provide clarity and 
consistency  
 
Revise Exclusion Criteria to clarify that patients with sarcomatoid mesothelioma and 
small cell lung cancer will not be enrolled into Study 20190136 
 
Clarify and correct discrepancies in the protocol regarding the enrollment of patients 
with squamous non-small cell lung cancer (NSCLC) who express mesothelin (MSLN) 
into Part 2 of the study 
 
Add MSLN (SP74) Ventana immunohistochemistry (IHC) assay to assess mesothelin 
expression in patients with squamous NSCLC during dose expansion 
 
Delete Table 6-2 to ensure consistency throughout the protocol on management of 
adverse events of AMG 404 and AMG 994 
 
Revise Dose Modification and Discontinuation Guidelines for AMG 404 
 
Revise Toxicity Management Guidelines for both AMG 994 and AMG 404 
 
Remove the Amgen Standard Grading Scale that had previously been inadvertently 
included in the protocol 

SAP_001.pdf: 
Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
Page 1 of 38 
CONFIDENTIAL 
FORM-008180 v. 17.0, 29 April 2020 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1, Multicenter, Open-label, Dose 
Exploration and Dose Expansion Study Evaluating 
the Safety, Tolerability, Pharmacokinetics and 
Efficacy of AMG 994 Monotherapy and Combination 
of AMG 994 and AMG 404 in Subjects with 
Advanced Solid Tumors 
Short Protocol Title: 
AMG 994 Monotherapy and AMG 994 and AMG 404 
Combination Therapy in Patients with Advanced 
Solid Tumors 
Protocol Number: 
20190136 
NCT Number: 
TBD 
Authors: 
 
Biostatistician II, IQVIA 
 
Biostatistics Sr.Director, Amgen Inc 
Sponsor: 
Amgen 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Original (v[1.0]) 
10MAR2021 
NCT Number: NCT04727554
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
Page 2 of 38 
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Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
10MAR2021 
Not applicable for first version 
 
 
 
 
 
 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
Page 3 of 38 
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Table of Contents 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints/Estimands .......................................................... 7 
2.2 
Hypotheses and/or Estimations ................................................................... 9 
3. 
Study Overview ...................................................................................................... 9 
3.1 
Study Design ............................................................................................... 9 
3.2 
Sample Size .............................................................................................. 10 
3.3 
Adaptive Design ........................................................................................ 10 
4. 
Covariates
 ................................................................................... 11 
4.1 
Planned Covariates ................................................................................... 11 
 
5. 
Definitions ............................................................................................................. 11 
6. 
Analysis Sets ........................................................................................................ 17 
6.1 
Efficacy Evaluable Analysis Set ................................................................ 17 
6.2 
Safety Analysis Set ................................................................................... 17 
6.3 
Early DLT Evaluable Analysis Set ............................................................. 18 
6.4 
Cumulative DLT Evaluable Analysis Set ................................................... 18 
7. 
Planned Analyses ................................................................................................. 18 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 18 
Table 7.1.1.  Stopping Boundary for Dose Expansion With Posterior 
Probability of 80 and Grade 4 or Higher Treatment-Related 
Adverse Event Limit of 20 ...................................................................... 20 
Table 7.1.2.  Operating Characteristics With Batch Size of 20 Subjects ................ 20 
7.2 
Primary Analysis ....................................................................................... 21 
7.3 
Final Analysis ............................................................................................ 21 
8. 
Data Screening and Acceptance ........................................................................... 21 
8.1 
General Principles ..................................................................................... 21 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 21 
8.3 
Handling of Missing and Incomplete Data ................................................. 21 
8.4 
Detection of Bias ....................................................................................... 22 
8.5 
Outliers ..................................................................................................... 22 
8.6 
Distributional Characteristics ..................................................................... 22 
8.7 
Validation of Statistical Analyses ............................................................... 22 
9. 
Statistical Methods of Analysis.............................................................................. 22 
9.1 
General Considerations ............................................................................. 22 
9.2 
Subject Accountability ............................................................................... 23 
9.3 
Important Protocol Deviations ................................................................... 23 
9.4 
Demographic and Baseline Characteristics ............................................... 23 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
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9.5 
Efficacy Analyses ...................................................................................... 23 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 23 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 23 
9.6 
Safety Analyses ........................................................................................ 24 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 24 
9.6.2 
Adverse Events ......................................................................... 24 
9.6.3 
Laboratory Test Results ............................................................ 25 
9.6.4 
Vital Signs ................................................................................. 26 
9.6.5 
Electrocardiogram ..................................................................... 27 
9.6.7 
Exposure to Investigational Product .......................................... 27 
9.6.8 
Exposure to Non-investigational Product ................................... 27 
9.6.9 
Exposure to Concomitant Medication ........................................ 28 
9.7 
Other Analyses ......................................................................................... 28 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 28 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 28 
9.7.3 
Analyses of Health Economic Endpoints ................................... 28 
10. 
Changes From Protocol-specified Analyses.......................................................... 28 
11. 
Literature Citations / References ........................................................................... 28 
12. 
Prioritization of Analyses....................................................................................... 31 
13. 
Data Not Covered by This Plan............................................................................. 31 
14. 
Appendices ........................................................................................................... 32 
 
List of Appendices 
Appendix A.  Reference Values/Toxicity Grades ........................................................... 17 
Appendix B.  Concomitant Medications ......................................................................... 18 
Appendix C.  Clinical Outcome Assessment Forms/Instruments .................................... 19 
Appendix D.  Health Economic Forms/Instruments ........................................................ 20 
Appendix E.  Details of PK or PK/PD Methods for Modeling .......................................... 21 
Appendix F.  Analytical Windows ................................................................................... 22 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
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List of Abbreviations 
 
Abbreviation or Term 
Definition/Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BLRM 
Bayesian Logistics Regression Model 
BUN 
blood urea nitrogen 
Cmax 
maximum concentration 
CRF 
case report form 
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DES 
Amgen data element standard 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
Echo 
echocardiogram 
Exposure-Response  
Analysis 
mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic (PK) 
exposure (eg, population pharmacokinetic modeling) and 
response, which may include biomarkers, 
pharmacodynamic effects, efficacy and safety endpoints. 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures 
are conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for 
the primary endpoint(s), for the purposes of conducting the 
primary analysis, whether the study concluded as planned 
in the protocol or was terminated early  
End of Study (end of trial) defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the 
study (ie, last subject last visit), following any additional 
parts in the study (eg, long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
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FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
F/U 
follow-up 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
MRI 
magnetic resonance imaging 
MSLN 
mesothelin 
MTD/MTCD 
maximum tolerated dose/maximum tolerated combination 
dose 
MUGA scan 
multigated acquisition scan 
NSCLC 
nonsmall-cell lung cancer 
OR 
objective response 
OS 
overall survival 
PD 
progressive disease 
PK 
Pharmacokinetics 
PR 
partial response 
SAT 
safety assessment team 
SD 
stable disease 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in 
clinical research.  The information may include, but is not 
limited to, clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and 
evaluation of the trial.  Source data are contained in source 
documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and 
Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified 
investigational product(s)/protocol-required therapies is/are 
administered to the subject 
TBL 
total bilirubin 
TMF 
trial master file 
TPI 
toxicity probability interval 
ULN 
upper limit of normal 
 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20190136, AMG 994 and 
AMG 404 dated 03 December 2020. The scope of this plan includes the primary analysis 
and the final analysis that are planned and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety, tolerability, 
and maximum tolerated dose 
(MTD)/maximum tolerated 
combination dose (MTCD) or 
recommended phase 2 dose 
(RP2D) of AMG 994 as 
monotherapy and AMG 994 in 
combination with AMG 404 in 
subjects with advanced solid 
tumors 
 
Dose-limiting toxicities (DLTs) 
 
Treatment-emergent and 
treatment related adverse 
events (including all adverse 
events, grade  3, serious 
adverse events, fatal adverse 
events, adverse events 
requiring permanent 
discontinuation of study 
treatment, and immune-related 
events) 
 
Changes in vital signs, 
electrocardiograms (ECGs), 
and clinical laboratory tests 
Secondary 
 
Preliminary evaluation of 
anti-tumor activity of AMG 994 as 
monotherapy and AMG 994 in 
combination with AMG 404 
 
Objective response (OR) per 
modified Response Evaluation 
Criteria in Solid Tumors 
(RECIST) 1.1 
 
Duration of response (per 
modified RECIST 1.1) 
 
Overall survival (OS) 
 
Progression-free survival (per 
modified RECIST 1.1) 
 
Time to progression (per 
modified RECIST 1.1) 
 
Time to subsequent therapy 
 
Characterize the PK of AMG 994 
monotherapy and AMG 994 in 
combination with AMG 404 
PK parameters 
 
Maximum serum concentration 
(Cmax) 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
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 
Minimum serum concentration 
(Cmin) 
 
Area under the concentration-
time curve (AUC) over the 
dosing interval 
 
Half-life (t1/2), if feasible 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
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2.2 
Hypotheses and/or Estimations 
This is a phase 1 study and no formal statistical hypotheses will be tested. 
3. 
Study Overview 
3.1 
Study Design 
This is a First In Human (FIH), multicenter, non-randomized, open-label, phase 1 
study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, 
immunogenicity, and preliminary efficacy of AMG 994 monotherapy and evaluation of 
AMG 994 in combination with AMG 404 in subjects with advanced solid tumors with 
known MSLN expression, including mesothelioma, non-small cell lung cancer 
(NSCLC) squamous cell carcinoma [Part 2 only] and adenocarcinoma [Part 1 and 
Part 2], pancreatic adenocarcinoma, and high grade serous ovarian carcinoma 
(platinum resistant).  Study assessments will include measures of safety, tolerability, 
PK, and pharmacodynamics data, and preliminary anti-tumor activity. 
AMG 994 will be administered by
and AMG 404 will be administered by 
  The study 
will be conducted in 2 parts:  Part 1 – Dose Exploration and Part 2 – Dose Expansion.  
Part 1 is aimed at evaluating the safety, tolerability, PK, and pharmacodynamics of 
AMG 994 monotherapy and AMG 994 in combination with AMG 404 using sequential 
and concurrent initiation of dosing:  
The maximum tolerated dose/maximum tolerated combination dose (MTD/MTCD) of the 
combination in subjects with advanced solid tumors will be determined using a Bayesian 
Logistics Regression Model (BLRM) design.  Part 2 will further evaluate the safety of the 
MTD/MTCD and/or a biologically active dose (eg, recommended phase 2 dose [RP2D]) 
of the combination in specific tumor types.  The dose expansion part of the study (Part 2) 
will be opened once the MTD/MTCD/RP2D of the combination has been determined in 
Part 1.   
The dose exploration part of the study will consist of approximately 94 subjects and the 
dose expansion will consist of approximately 120 additional subjects, 30 subjects in each 


Product:  AMG 994 and AMG 404 
Protocol Number:  20190136 
Date:  10MAR2021 
Page 10 of 38 
CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020 
 
of 4 tumor types (mesothelioma, NSCLC squamous cell carcinoma and adenocarcinoma 
[in Part 2, if upon screening found to be MSLN positive], pancreatic adenocarcinoma, 
and high grade serous ovarian carcinoma).  Dose escalation will be conducted in 
subjects with metastatic or locally advanced solid tumors of types known to express 
MSLN for which no standard systemic therapy exists and dose expansion will be 
conducted in subjects with specific tumor types.  The DLT evaluation period will be 
 for each cycle.  Administration of AMG 994 (in Part 1 and Part 2) may continue 
until evidence of disease progression; intolerance to study medication; withdrawal of 
consent; or, in the absence of the above, up to 12 months if subject achieves a complete 
response, and up to 24 months if partial response or stable disease. 
3.2 
Sample Size 
It is anticipated that approximately 214 subjects will be enrolled in this study. 
Approximately 94 subjects will be enrolled in the dose-exploration cohorts (Part 1). Up to 
120 subjects will be enrolled in the dose-expansion cohorts (Part 2), 30 subjects in each 
of 4 tumor types (mesothelioma, NSCLC squamous cell carcinoma and adenocarcinoma 
[if upon screening found to be MSLN positive], pancreatic adenocarcinoma, and high 
grade serous ovarian carcinoma). 
The sample size in the dose-escalation phase is based on practical consideration and is 
consistent with conventional oncology studies with the objective to estimate the 
MTD/MTCD. With 3 subjects in a cohort, there is a 27 to 70 probability of observing 
at least 1 DLT if the true DLT rate is 10 to 33 and with 6 subjects in a cohort, there is 
a 47 to 91 probability.  
In the dose-expansion cohorts, a total subject sample size of 120 will provide a 
91 probability of observing at least 1 adverse event with 2 incidence rate. An exact 
95 binomial Cl will be provided for overall response rate. With the 30 subjects in a 
cohort of subjects with a particular tumor type and a 20 overall response rate, the 
expected 95 Cl would be 8 to 39. Under certain circumstances, the sample size 
dose expansion will be smaller due to early stopping; see protocol section 9.4.1.1 for 
details. 
3.3 
Adaptive Design 
Not applicable 


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4. 
Covariates 
 
4.1 
Planned Covariates 
The relationship of covariates if applicable, to efficacy endpoints will be explored as 
appropriate.  
5. 
Definitions 
Adverse Event (AE)     
 
 
 
 
 
 
 
         
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment. 
 
      
Age at Enrollment 
Subject age at enrollment will be determined using the age in years reported in the clinical 
database. 
Area under the Curve (AUC) 
Area under the plasma concentration-time curve reflects the actual body exposure to drug 
after administration of a dose of the drug.  
Baseline  
For any variable, unless otherwise specified the baseline is the last non-missing 
assessment taken prior to the first administration of AMG 994 and for cohorts with 
concurrent administration of AMG 994 and AMG 404 first administration of AMG 994 and 
AMG 404.  Where baseline measurements are taken on the same day as the study 
specified treatment and no times are present, it will be assumed that these measurements 
are taken prior to the study specified treatment being administered. 
Baseline ECG Values in Triplicate 
The mean of the triplicate ECG results should be calculated for Baseline.  For all post-
baseline ECG, the mean of triplicate ECG results at the same assessment will be 
calculated and used in the analysis. When an ECG is missing within a triplicate, all 
available data will be averaged for that time point. 
Best Overall Response (BOR) 


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The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment or disease progression/recurrence (taking as 
reference for PD the smallest measurements recorded since the treatment started). 
Overall response assessments occurring after the start of the first subsequent anticancer 
therapy will not be included. 
In general, the subject's best response assignment will depend on the findings of both 
target and non-target disease and will also take into consideration the appearance of new 
lesions. 
BOR for a subject is the best observed disease response per modified RECIST 1.1 in the 
following order: Complete response (CR), Partial response (PR), Stable disease (SD), 
Progressive disease (PD) and Not evaluable (NE). A best overall response of CR and PR 
require confirmation by a repeat, consecutive scan at least 4 weeks after the first 
documentation of response.   
A best overall response of SD requires an on-study imaging of SD or better no earlier than 
7 weeks after cycle 1 day 1; otherwise the best overall response will be not evaluable (NE) 
unless PD is identified. 
Evaluation of overall response details provided in protocol appendix 11. 
Change from Baseline  
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline value.  
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value)  
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value)/Baseline  
Value] x 100 
Cmax 
Maximum observed plasma drug concentration. 
Dose Limiting Toxicity (DLT) 
DLTs are the severe toxicities during the first cycle of cancer therapy. A Dose Limiting 
Toxicity (DLT) is defined as any AE (meeting the criteria listed in section 6.2.1.5 of 
protocol) occurring during the first treatment cycle of AMG 994 
 
where relationship to AMG 404 cannot be ruled out.  


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The DLT window (DLT-evaluable period) will be the first 
 of AMG 994 treatment 
(starting cycle 1, day 1). A subject is evaluable if subject experiences a DLT or completes 
 of treatment. DLT window will begin from Cycle 2 through study 
 
 for combination of AMG 994 and AMG 404. 
Duration of Response (DOR) 
The duration of response is defined as time from first evidence of PR or CR to disease 
progression or death due to any cause.  . 
DOR will be calculated only for subjects who achieve a confirmed best overall response 
of PR or better. 
DOR (in months) = (Earliest date of disease progression, death, censor - Date of first 
                                observation of PR or better + 1)/30.4 
Dates of progression and censoring will be determined as described below in table 5.1. 
End of Study (End of Trial) 
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 (e.g., last subject last visit), 
following the final protocol-specified visit (e.g. SFU) or any additional parts in the study (e.g., 
long-term follow-up, additional antibody testing) whichever is later. 
End of Study (Individual Subject) 
End of study for each subject is defined as the date the subject last completed a protocol-
specified procedure. The date will be recorded on the End of Study CRF page. 
End of Study (Primary Completion) 
It is defined as when the last subject is assessed or receives an intervention for the 
purposes of final collection of data for the primary endpoint(s), whether the study was 
conducted as planned in the protocol or was terminated early.  
End of Treatment (EOT) 
Defined as the last assessment for the protocol-specified treatment of the study for an 
individual subject. 
Enrollment  
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria. 
Fridericia-corrected QT Interval (QTcF)  


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The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows:  
QTcF=QT/(RR/1000)1/3 
Investigational Product 
The term ‘Investigational product’ is used in reference to AMG 994 and combination of 
AMG994 and AMG 404. 
Last IP Dose Date  
The last IP dose date for each subject is defined as the latest date IP administered. 
Objective Response Rate (ORR) 
Objective response rate is defined as the proportion of patients with a Best Overall 
Response (BOR) of confirmed CR or PR.  
Overall Survival (OS) 
Overall survival (OS) is defined as the time from the start of treatment until event of death 
due to any cause.  Subjects still alive will be censored at the date last known to be alive.  
If the date last known to be alive is after the date that triggers the analysis (i.e., the data 
cutoff date), the subject will be censored at the analysis trigger date. 
For subjects not known to have died, their last date known to be alive will be determined 
as the latest date associated with clinic visits before data cutoff date including, for 
example, but not limited to the following: 
o Survival status: Last contact date if status of subject is “Alive” 
o End of study date if the subject’s primary reason for ending study is not 
“Lost to follow-up” 
o Any subsequent anti-tumor therapy initialization date 
o AE start or end date 
o Procedure and concomitant medication start/end date 
o Date of lesions assessments 
o Visit date of vital signs; physical exam; ECOG; sample collection for labs 
o Date of last investigational product administration 
Progression Free Survival (PFS) 
The PFS is defined as interval from the start of treatment to disease progression or death 
due to any cause (whichever comes first). 


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PFS (in months) = (Earliest date of disease progression, death, censor – Date of first 
                            dose + 1)/30.4  
Subjects who are alive and have not progressed, whether on-study or lost to follow-up, 
will be censored at their last evaluable tumor assessment date. Censoring rules for 
progression-free survival analysis are given below in Table 5-1.  


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Safety Follow-Up (SFU) 
A safety follow-up visit will be performed approximately 
30 (7) days and 
140 days (1 week) days after the end of the last dose of AMG 994 and AMG 404 
combination therapy. 
Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, meets at 
least 1 of the following serious criteria: 
 
Results in death (fatal) 
 
Immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Other medically important serious event 
 
Is a congenital anomaly/birth defect 
Study Day  
Post study day: study day= (date - date of Study Day 1) + 1  
Pre-study day: study day= (date – date of Study Day 1) 
Study Day 1  
It is defined as the first day that investigational product is administered to the subject. The 
day before Day 1 is referenced as Day -1. 
Treatment-emergent Adverse Event (TEAE) 
A treatment-emergent adverse event is any adverse event starting on or after the first 
administration of any study drug, as determined by the flag indicating if the adverse event 
started prior to the first dose on the Events CRF, and 140 days (1 week) after the last 
dose of AMG 994 or AMG 404 whichever is later. The severity of each adverse event will 
be graded using the CTCAE version 5.0.  Adverse events will be coded using MedDRA 
v23.0 or later. 
Treatment-emergent Treatment-related Adverse Event 


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A treatment-emergent treatment-related AE is any treatment-emergent AE that per 
investigator review has a reasonable possibility of being caused by the investigational 
product. 
Time to Progression (TTP) 
Time to progression is defined as time from the start of treatment until the disease starts 
to get worse or spread to other parts of the body. 
TTP (in months) = (Earliest date of disease progression, censor – Date of first 
                            dose + 1)/30.4  
Table 5-2.  Censoring Rules for TTP  
 
Situation 
Date of Event or Censoring Outcome 
PD, no prior new 
anticancer therapy or prior 
to start of new anticancer 
therapy 
PD 
Event 
No PD, no 
new anticancer treatment 
Last visit; otherwise, first 
IP dose date 
Censored 
No PD and new anticancer 
therapy or PD after start of 
new anticancer therapy 
Last visit prior to new 
treatment; otherwise, first 
IP dose date 
Censored 
No PD, but death recorded 
Date of death 
Censored 
 
Time to Subsequent Therapy 
Time to subsequent therapy is defined as time from the start of treatment until the first 
subsequent therapy. 
TTST (in months) = (Earliest date of subsequent therapy, censor – Date of first 
                            dose + 1)/30.4  
Table 5-3.  Censoring Rules for Time to subsequent therapy 
Situation 
Date of Event or Censoring Outcome 
No new anti-cancer 
therapy 
Last visit; otherwise, first IP 
dose date 
Censored 
New anti-cancer therapy 
started 
Start date of new anti-
cancer therapy 
Event 
 


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6. 
Analysis Sets 
6.1 
Efficacy Evaluable Analysis Set 
The analysis of objective response will be conducted on the Efficacy Evaluable Analysis 
set defined as all subjects that are enrolled to a dose expansion cohort and receive at 
least 1 dose of AMG 994 or AMG 404 with at least 1 tumor lesion that is measurable in 
contrast-enhanced CT as defined by modified RECIST 1.1, with the following 
exceptions.   
The following subjects will be excluded from the Efficacy Evaluable Analysis set:   
1) Subjects who are lost to follow up and have no on study radiological assessments and 
2) Subjects who have been on study less than 8 weeks and have no on study 
radiological assessments.  
6.2 
Safety Analysis Set 
Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose 
of AMG 994 or AMG 404. 
6.3 
Early DLT Evaluable Analysis Set 
The analysis of DLT in the initial safety review period (through 
) will be conducted 
on the Early DLT Analysis set defined as all subjects that are enrolled and receive at 
least 1 dose of AMG 994 with an evaluable early DLT endpoint (evaluable in AMG 994 
monotherapy cohort per Table 6.4.1).   
6.4 
Cumulative DLT Evaluable Analysis Set 
The analysis of DLT in the cumulative safety review period will be conducted on the 
Cumulative DLT Analysis set defined as all subjects that are enrolled and receive at 
least 1 dose of AMG 994 or AMG 404 with an evaluable cumulative DLT endpoint 
(experience a DLT during monotherapy cohort or evaluable in combination therapy 
cohort per Table 6.4.1).   


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7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  Based on accumulating safety data, 
BLRM will be used to make dosing recommendations.  In DLRMs, Amgen, in 
consultation with the site investigators, will review the BLRM recommended dose level 
and will review all available cumulative data by cohort prior to making dose escalation 
recommendations.  As a sensitivity analysis, a 1-parameter Continual Reassessment 
Method model may be used to estimate the dose-toxicity relationship and in particular to 
estimate the dose level with a 25 DLT rate in order to help make dose escalation 
decisions.  Adverse events, including late onset immune-mediated toxicities, and DLTs 
observed in all subjects will be evaluated continually and fully integrated into all DLRMs 
and considered in all enrollment and dosing decisions.  If during the study there is any 
grade 5 adverse event (or any 2 of the same grade 4 adverse events) at least possibly 
related to AMG 994 or AMG 404, further accrual will be suspended; Amgen will conduct 
a safety analysis and submit to the regulatory authority for review prior to resuming 
enrollment.  
Given that a fixed-dose administration of AMG 404 
 is used as part of the 
AMG 994 plus AMG 404 combination, the 2-parameter BLRM for single agent AMG 994 
will be used.  Key details of the BLRM model as used in this study are as follows.


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During dose expansion, if the observed rate of responses in a particular tumor type is 
less than 10 after n  10 and n  20 subjects in that tumor type, then enrollment to that 
tumor type will be terminated due to futility.  For purposes of assessing futility, a 
response is defined as an objective response per modified RECIST 1.1.  The guidelines 
for early termination of enrollment for a tumor type due to futility are as follows:  
Number of Treated Subjects in a Tumor Type 
Enrollment Stopping Rule 
10 
0 responders 
20 
1 or fewer responders 
30 
Enrollment complete 
If the true response rate is 5 then these termination guidelines result in a 
78.7 probability of terminating tumor type enrollment at or prior to n  20 subjects. If 
the true response rate is 20 then there is an 86.4 probability of continuing enrollment 
past n  20 subjects.  
During dose expansion, Amgen will conduct evaluations of the ongoing grade 4 or 
higher treatment-related adverse event rate to assess if the threshold for possible early 
trial termination has been reached. If this threshold is met, enrollment to dose 
expansion will be halted pending review of safety data by the DLRT.  After receiving 
the DLRT recommendation, Amgen will choose to take 1 of the following actions.  
 
Terminate the trial 
 
Amend the protocol to potentially improve the benefit/risk for subjects (eg, increase 
safety monitoring, modify dose/schedule, mandate premedication) 
 
Continue dose expansion without any changes 


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The stopping rules use a Bayesian approach proposed by Thall, Simon, and Estey 
(1995) to terminate the study if the posterior probability that the grade 4 or higher 
treatment-related adverse event rate is greater than 20 is  80. The stopping 
boundaries assume a prior distribution of Beta (0.40, 1.60) are presented in Table 7.1.1 
and the operating characteristics with pre-specified batch size of 10 new subjects per 
batch are presented in Table 7.1.2. The operating characteristics in Table 7.1.12 provide 
the probability of stopping the trial early for given hypothetical true rate of grade 4 or 
higher treatment-related adverse events, whereas the stopping criteria in Table 7.1.1 are 
based on situations where the empirical evidence would result in the posterior probability 
of  80 that the true grade 4 or higher treatment-related adverse event rate is  20. 
Table 7.1.1.  Stopping Boundary for Dose Expansion With Posterior Probability of 
80 and Grade 4 or Higher Treatment-Related Adverse Event Limit of 20 
Number of subjects 
Hold enrollment if observing this many grade 4 or higher 
treatment adverse events 
20 
 6 
40 
 11 
60 
 15 
80 
 20 
100 
 24 
120 
Dose Expansion Complete 
Table 7.1.2.  Operating Characteristics With Batch Size of 20 Subjects 
True grade 4 or higher 
treatment-related adverse 
event rate 
Probability of early 
stopping of dose expansion 
Average dose expansion 
sample size 
0.10 
1.2 
118.8 
0.15 
9.6 
111.5 
0.20 
37.6 
90.1 
0.25 
76.0 
59.9 
0.30 
95.7 
38.0 
 
7.2 
Primary Analysis 
The primary analysis will occur when target enrollment is complete and each subject 
either completes 6 months on study or withdraws from the study. 


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7.3 
Final Analysis 
The final analysis will occur when target enrollment is complete for all study parts and all 
subjects have ended the study. Primary and final analysis may be combined in case all 
subjects have ended study close to the time point of the primary analysis. 
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. The 
database will be subject to edit checks outlined in the data management plan (DMP) by 
Amgen Clinical Data Management (CDM) department. Data inconsistencies and 
suspicious values will be reviewed and resolved before the database is locked 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
The following imputation for missing or incomplete data will be performed if required: 
Incomplete adverse event and concomitant medication dates missing data will be 
imputed as described in Appendix A. 
Non-pharmacokinetic measurements (e.g. biomarker data) that are below the lower limit 
of quantification will be considered equal to half of the lower limit of quantification for all 
analyses unless specified otherwise. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort.  
The clinical study team will identify and document the criteria for important protocol 
deviations. 
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified. 
Pharmacokinetic (PK) serum concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice 


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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. 
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs. 
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Unless otherwise specific, all described analyses will be conducted on the Safety 
Analysis Set.  Descriptive statistics will be provided for selected demographics, safety, 
PK, PD, and biomarker data by dose, dose schedule, and time as appropriate.  
Descriptive statistics on continuous data will include means, medians, standard 
deviations, and ranges, while categorical data will be summarized using frequency 
counts and percentages.  Graphical summaries of the data may also be presented. 
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Pearson (Clopper & Pearson, 1934).  Kaplan-Meier methods will 
be used to estimate the median and percentiles for time to event endpoints with CI 
calculated using the Brookmeyer and Crowley method (Brookmeyer & Crowley, 1982).  
Kaplan-Meier methods will be used to estimate landmarks for time to event endpoints 
(e.g., 1-year OS) with the Greenwood formula (Kalbfleisch & Prentice, 1980) used to 
estimate the standard error used in CI calculation 
9.2 
Subject Accountability 
The following subject disposition information will be summarized as follows 
 
Number of screened subjects 
 
Number (%) of subjects who completed IP 
 
Number (%) of subjects who discontinued IP 
 
Number (%) of subjects who discontinued IP 


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 
Number (%) of subjects who discontinued the study 
 
Primary reason for ending IP 
 
Primary reason for study discontinuation 
The percentages are based on the number of subjects enrolled in the study. 
9.3 
Important Protocol Deviations 
Imported Protocol Deviations (IPDs) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD reviews throughout the study prior 
to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. 
9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of the demographic and baseline characteristics will 
be produced: Demographic (i.e., age, sex, race, ethnicity), and baseline characteristics 
(height, weight, Eastern Cooperative Oncology Group (ECOG) Performance Status will 
be summarized using descriptive statistics. If multiple races have been reported for a 
subject, the subject will be categorized as multiple. 
9.5 
Efficacy Analyses 
 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
No efficacy parameter is considered in primary endpoints. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Listings of secondary efficacy endpoints will be produced for all subjects in the dose-
escalation cohorts and the dose-expansion cohorts.  
For all subjects in the Efficacy Analysis Set, the proportion of subjects and 95 CL with 
an objective response (complete or partial response per modified RECIST 1.1) will be 
tabulated by tumor type and planned dose level and schedule.  
For all subjects in the Efficacy Analysis Set, Kaplan-Meier methods will be used to 
estimate the time of event curve, median time to event, and percentiles with 95 Cl for 
1) Duration of response (DOR, per modified RECIST 1.1), 
2) Overall survival (OS) 
3) Progression-free survival (PFS, per modified RECIST 1.1) 
4) Time to progression (TTP, per modified RECIST 1.1) and 


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5) Time to subsequent therapy.   
Kaplan-Meier methods will be used to estimate appropriate landmarks for DOR, OS, 
PFS and TTP (eg, 1-year PFS) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
 
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 994 or AMG 404.  The analysis of early DLTs will be conducted on the 
Early DLT Analysis Set and the analysis of cumulative DLTs will be conducted on the 
Cumulative DLT Analysis Set.  Subject incidence of both early and cumulative DLT will 
be tabulated by planned dose level.  A table of both early and cumulative DLTs will be 
provided.  The probability of a subject having an early and cumulative DLT by dose level 
will be estimated using a 2-parameter BLRM model. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or later will be 
used to code all adverse events to a system organ class and a preferred term.  
Where appropriate the tables will also be presented by worst grade. 
  
Treatment-emergent adverse events will be summarized based on the number (%) of 
subjects experiencing events by MedDRA SOC and PT. The denominator for the 
percentage will be based on the number of subjects in the safety analysis set. 
 
The subject incidence of adverse events will be summarized for 
 
TEAE 
o All treatment-emergent AEs 
o Grade 3 or higher treatment-emergent AEs 
o Treatment-emergent SAEs 
o Treatment-emergent AEs leading to interruption of investigational product 
o Treatment-emergent AEs leading to withdrawal of investigational product 
o Fatal treatment-emergent AEs 
 
Treatment-related AEs 
o All treatment-related AEs 
o Grade 3 or higher treatment-related AEs 


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o Treatment-related SAEs 
o Treatment-related AEs leading to interruption of investigational product 
o Treatment-related AEs leading to withdrawal of investigational product 
o Fatal treatment-related AEs 
The summaries that are displayed by SOC, PT and grade will be ordered by descending 
order of incidence of SOC, PT and grade with in each SOC for the total group. 
The above adverse event tables will not be created if two or fewer subjects experience 
the adverse event.  
Dose Limiting Toxicities  
The analysis of the probability of DLTs will include data from DLT-evaluable subjects 
The primary analysis will only include DLTs that occur during the DLT evaluation period.  
If DLTs occur outside the DLT evaluation period, a sensitivity analysis will be performed 
where DLTs occurring outside of the specified time interval are included.  The number 
and percentage of subjects evaluated by tumor type and planned dose level. 
9.6.3 
Laboratory Test Results 
Chemistry, Hematology and Coagulation 
Actual values and change from baseline for selected chemistry and hematology 
parameters will be summarized descriptively for each scheduled visit based on the 
safety analysis set. 
Local 
Laboratory: 
Chemistry 
Local 
Laboratory: 
Coagulation 
Local 
Laboratory: 
Urinalysis 
Local 
Laboratory: 
Hematology 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Calcium 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
TSH 
Free T4 
PT/INR 
PTT/APTT 
Fibrinogen 
Fibrin split 
products 
D-dimer 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Nucleated RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Total neutrophils 
• Segmented 
neutrophils  
• Bands/stabs 
• Eosinophils 
• Basophils 
• Lymphocytes 


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Local 
Laboratory: 
Chemistry 
Local 
Laboratory: 
Coagulation 
Local 
Laboratory: 
Urinalysis 
Local 
Laboratory: 
Hematology 
• Monocytes  
• Myeloblasts 
• Promyelocytes 
• Myelocytes 
• Metamyelocytes 
• Atypical 
lymphocytes 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; APTT  activated partial thromboplastin time; 
AST  aspartate aminotransferase; BUN  blood urea nitrogen; INR  international normalized ratio; MCH  
mean corpuscular hemoglobin; MCHC  mean corpuscular hemoglobin concentration; MCV  mean 
corpuscular volume; MSLN  mesothelin; 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; TSH  thyroid stimulating hormone; WBC  white blood cell 
count 
Shift tables will be presented for the baseline toxicity grade by the worst on-study toxicity 
grade in a table form for selected parameters mentioned above if applicable. CTCAE 
version 5.0 will be used for toxicity grading for the above mentioned parameters 
excluding Total bilirubin, ALT (SGPT), AST (SGOT) and Alkaline phosphatase (CTCAE 
version 4.03 will be used for toxicity grading). 
Potential Hy’s law cases may be summarized. 
9.6.4 
Vital Signs 
The analysis of vital signs systolic blood pressure, diastolic blood pressure, heart rate, 
respiratory rate and temperature include summary statistics over time and/or changes 
from baseline over time. 
9.6.5 
Electrocardiogram 
The summaries over time and/or changes from baseline over time will be provided for 
the ECG parameters QRS, QT, QTc, RR, PR and QTcF. Subjects' maximum post 
baseline values will be categorized and the number and percentage of subjects in each 
group will be summarized for QTcF. Subjects maximum change from baseline in QTcF 
will be categorized and the number and percentage of subjects in each group will be 
summarized. 
In addition, the relationship between AMG 994 exposure and change from baseline in 
QTcF will be explored graphically. 


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9.6.7 
Exposure to Investigational Product 
The average dose administration (g), cumulative dose (g), number of cycles, duration 
of treatment, number and percentage of subjects with dose modifications, reasons for 
modification will be summarized using descriptive statistics. Subject-level data may be 
provided instead of the summary if the subject incidence is low or single dose is given. 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. 
Extent of exposure to study treatments will be summarized for Safety population 
 
Duration of treatment (days) 
o Defined as the duration (in weeks) from the date of the first dose to the date of 
the last dose of study drug + 1 
 
Total number of treatment cycles started  
o Defined as the total number of treatment cycles in which at least one dose of 
study drug is administered. 
 
Cumulative dose received of AMG 994 and AMG 404 across all cycles, defined as 
the cumulative dose of AMG 994 and AMG 404. 
Average dose of AMG 994 and AMG 404, defined as the total dose received divided by 
the number of days on treatment administered. 
In addition, dose-exposure proportionality assessment will be performed for AMG994. 
9.6.8 
Exposure to Non-investigational Product  
Not applicable 
9.6.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each treatment group as coded by the World Health Organization 
Drug dictionary.  
9.7 
Other Analyses 
The PK parameters of AMG 994 and AMG 404 including, but not limited to Cmax, Cmin, 
AUC and half-life (if feasible) will be estimated using non-compartmental methods and 
summarized by dose level using means, geometric means, standard deviations, 


Product:  AMG 994 and AMG 404 
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coefficients of variation, medians, minimums, and maximums.  Individual concentration-
time profiles will be summarized by dose level.  Serum AMG 994 and AMG 404 
concentrations at each time point along with PK parameter values may be listed for each 
subject.  Summary statistics will be computed for each sampling time and parameter as 
appropriate. The relationship between AMG 994 exposure and efficacy/safety may be 
conducted. 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Not applicable 
9.7.2 
Analyses of Clinical Outcome Assessments 
Not applicable 
9.7.3 
Analyses of Health Economic Endpoints 
Not applicable 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
Literature Citations / References 
AMG 404 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
AMG 994 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Awuah P, Bera TK, Folivi M, Chertov O, Pastan I.  Reduced Shedding of Surface 
Mesothelin Improves Efficacy of Mesothelin-Targeting Recombinant Immunotoxins.  Mol 
Cancer Ther.  2016; 15(7):1648-1655. 
Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR.  Help for 
cytotoxic-T-cell responses is mediated by CD40 signalling.  Nature.  
1998;393(6684):478-480. 
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. in 
collaboration with the National Comprehensive Cancer Network. Management of 
Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor 
Therapy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of 
Clinical Oncology, 36:1714-1768. © 2018 American Society of Clinical Oncology and 
National Comprehensive Cancer Network. 
Brookmeyer R, Crowley J. (1982) A Confidence Interval for the Median Survival Time, 
Biometrics, 38, 29 – 41. 
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. 
Immunity. 2013;39(1):1-10 
Clopper CJ, Person ES.  The use of confidence or fiducial limits illustrated in the case of 
the binomial.  Biometricka.  1934;26:404-413. 


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Fang H, Ye S, Reddy A, Turan T, Woolley A, Chao DT et al.  Pharmacodynamics and 
potential predictive biomarkers of ABBV-428, a first-in-class mesothelin (MSLN)-CD40 
bispecific, in patients with advanced solid tumors Abstract 5672.  Presented at: 
VMS.CL11.01 - Predictive Biomarkers for Immunotherapeutics at the AACR Virtual 
Annual Meeting I (April 27-28, 2020).  Available at 
https://www.abstractsonline.com/pp8/#!/9045/presentation/10537https://www.abstractso
nline.com/pp8/#!/9045/presentation/10537 accessed on 14 May 2020. 
Gonzalez NK, Wennhold K, Balkow S, et al.  In vitro and in vivo imaging of initial B-T-cell 
interactions in the setting of B-cell based cancer immunotherapy.  Oncoimmunology.  
2015;4:e1038684. 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 
2009. 
Hassan R, Thomas A, Alewine C, Le DT, Jaffee EM, Pastan I.  Mesothelin 
Immunotherapy for Cancer: Ready for Prime Time?  J Clin Oncol.  
2016;34(34):41714179. 
International Council for Harmonisation.  International Council for Harmonisation (ICH) 
Harmonised Tripartite Guideline: Nonclinical Evaluation for Anticancer Pharmaceuticals 
S9, 2010. 
Irenaeus SMM, Nielsen D, Ellmark P, et al.  First-in-human study with intratumoral 
administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies.  
Int J Cancer. 2019;145(5):1189-1199. 
Johnson P, Challis R, Chowdhury F, et al.  Clinical and biological effects of an agonist 
anti-CD40 antibody: a Cancer Research UK phase I study.  Clin Cancer Res. 
2015;21(6):1321-1328.  
Kalbfleisch and Prentice, 1980 Kalbfleisch JD and Prentice JL.  The Statistical Analysis 
of Failure Time Data.  New York.  John Wiley & Sons; 1980. 
Liu L, Jacobsen FW, Everds N, et al.  Biological Characterization of a Stable Effector 
Functionless (SEFL) Monoclonal Antibody Scaffold in Vitro.  J Biol Chem. 
2017;292(5):1876-1883. 
Luke JJ, Fong L, Chun K, et al.  Phase 1 Study Evaluating Safety, Pharmacokinetics, 
Pharmacodynamics, and Preliminary Efficacy Of Abbv-428, First-in-class 
Mesothelin-CD40 Bispecific, in Patients With Advanced Solid Tumors.  Annals of 
Oncology 2019:30 (suppl_5): v475-v532.  Poster presented at: ESMO Congress 2019; 
30 September 2019; Barcelona, Spain. 
National Library of Medicine (US).  ClinicalTrials.gov [Internet].  Bethesda (MD): 2000 
Feb 29.  Identifier NCT02955251, A Study of ABBV-428, an Immunotherapy, in Subjects 
With Advanced Solid Tumors.  Available from: 
https://clinicaltrials.gov/ct2/show/study/NCT02955251https://clinicaltrials.gov/ct2/show/st
udy/NCT02955251.  Last update posted 07 November 2019.  Accessed 14 April 2020. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649-655. 
Piechutta M, Berghoff AS.  New emerging targets in cancer immunotherapy: the role of 
Cluster of Differentiation 40 (CD40/TNFR5).  ESMO Open. 2019 Jun 12;4(Suppl 3): 1-5. 
Poulet FM, Wolf JJ, Herzyk DJ, et al.  An evaluation of the impact of PD-1 pathway 
blockade on reproductive safety of therapeutic PD-1 inhibitors.  Birth Defects Res B Dev 
Reprod Toxicol.  2016;107:108-119. 


Product:  AMG 994 and AMG 404 
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Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 
2018;359(6382):1350-1355. 
Ridge JP, Di Rosa F, Matzinger P.  A conditioned dendritic cell can be a temporal bridge 
between a CD4+ T-helper and a T-killer cell.  Nature.  1998;393(6684):474-478. 
Saber H, Gudi R, Manning M, Wearne E, Leighton JK. An FDA oncology analysis of 
immune activating products and first-in-human dose selection. Regul Toxicol Pharmacol. 
2016, 81:448-456. 
Schaer DA, Hirschhorn-Cymerman D, Wolchok JD.  Targeting tumor-necrosis factor 
receptor pathways for tumor immunotherapy.  J Immunother Cancer.  2014;2:7:9 pages 
Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes.  Statistics in Medicine.  1995;14:357-379. 
Vitale LA, Thomas LJ, He LZ, et al.  Development of CDX-1140, an agonist CD40 
antibody for cancer immunotherapy.  Cancer Immunol Immunother. 2019;68(2):233-245. 
Von Bergwelt-Baildon M, Shimabukuro-Vornhagen A, Popov A, et al.  CD40-activated B 
cells express full lymph node homing triad and induce T-cell chemotaxis: potential as 
cellular adjuvants.  Blood.  2006;107:2786-2789. 
Vonderheide RH.  CD40 Agonist Antibodies in Cancer Immunotherapy.  Annu Rev Med. 
2020;71:47-58. 
Vonderheide RH, Burg JM, Mick R, et al.  Phase I study of the CD40 agonist antibody 
CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid 
tumors.  Oncoimmunology.  2013;2:e23033. 
Vonderheide RH, Dutcher JP, Anderson JE, et al.  Phase I study of recombinant human 
CD40 ligand in cancer patients.  J Clin Oncol.  2001;19(13):3280-3287. 
Vonderheide RH, Flaherty KT, Khalil M, et al.  Clinical activity and immune modulation in 
cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.  J 
Clin Oncol. 2007;25(7):876-883. 
Vonderheide RH, Glennie MJ.  Agonistic CD40 antibodies and cancer therapy.  Clin 
Cancer Res.  2013;19(5):1035-1043. 
Vonderheide RH.  The Immune Revolution: A Case for Priming, Not Checkpoint.  Cancer 
Cell. 2018;33(4):563-569.   
Ye S, Cohen D, Belmar NA et al.  A Bispecific Molecule Targeting CD40 and Tumor 
Antigen Mesothelin Enhances Tumor-Specific Immunity.  Cancer Immunol Res.  2019; 
7(11):1864-1875. 
12. 
Prioritization of Analyses 
No prioritization will be planned.  
13. 
Data Not Covered by This Plan 
Not applicable 


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14. 
Appendices 


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Appendix A.  Reference Values/Toxicity Grades 
The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 is available at the 
following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Technical Detail and Supplemental Information Regarding Statistical Procedures 
and Programs 
Imputation Rules for Partial or Missing Stop Dates 
If the month and year are present, impute the last day of the month. If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing. 
 Imputation Rules for Partial or Missing Start Dates 
 
Stop Date 
 
 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start Date 
 
<1st 
Dose 
1st 
Dose 
<1st Dose 
yyyymm 
1st Dose 
yyyymm 
<1st 
Dose 
yyyy 
1st 
Dose 
yyyy 
Partial: 
yyyymm 
=1st Dose 
yyyymm 
N/A 
1 
N/A 
1 
N/A 
1 
1 
 1st Dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
=1st Dose 
yyyy 
N/A 
1 
N/A 
1 
N/A 
1 
1 
 1st Dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute the date of first dose 
2 = Impute the first day of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
 
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month. 
 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 


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Imputation rules for stop date: 
For partial stop date mmyyyy, impute the last day of the month. 
For partial stop date yyyy, impute December 31 of the year. 
For completely missing stop date, do not impute. 
If the stop date imputation leads to a stop date that is after the death date, then 
impute the stop date as the death date. 
If the stop date imputation leads to a stop date that is before the start date, then 
there is a data error and do not impute the stop date. (ie. set the stop date as 
missing). 
 


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Appendix B.  Concomitant Medications 
Not applicable 
 


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Appendix C.  Clinical Outcome Assessment Forms/Instruments 
Not applicable 
 


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Appendix D.  Health Economic Forms/Instruments 
Not applicable 
 


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Appendix E.  Details of PK or PK/PD Methods for Modeling 
CPMS group will perform the modeling.