A Phase 1, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 510 in Subjects of Chinese Descent With Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation (CodeBreaK 105)
Phase: PHASE1
Conditions: Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation
Sponsor: Amgen

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 1 of 109 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Phase 1, Open-label Study Evaluating the 
Safety, Tolerability, Pharmacokinetics, and 
Efficacy of AMG 510 in Subjects of Chinese 
Descent With Advanced/Metastatic Solid 
Tumors With KRAS p.G12C Mutation 
(CodeBreaK 105) 
Short Protocol Title: 
AMG 510 Ethnic Sensitivity Study 
Protocol Number: 
20190147 
Investigational Product: 
AMG 510  
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
+1 805 447-1000 
 
Key 
Sponsor 
Contacts 
Name: 
 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
 
Email Address: 
 
Name: 
 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number 
Email Address: 
 
 
NCT Number: 
NCT04380753 
Protocol Version Date: 
Document Version 
Date 
Original 
06 August 2019 
Amendment 1 (v2.0) 
04 February 2020 
Amendment 2 
18 September 2020 
Amendment 3 
16 December 2020 
Amendment 4 
05 January 2022 
Data Elements Standards 
Version: 
DES v6.2 
 
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 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 2 of 109 
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; for all other countries, Amgen’s general number in the US, 
1-805-447-1000. 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 3 of 109 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1, Open-label Study Evaluating the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 510 in Subjects of Chinese 
Descent With Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation 
(CodeBreaK 105), dated 05 January 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 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 4 of 109 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary .................................................................................................. 9 
1.1 
Synopsis ..................................................................................................... 9 
1.2 
Study Schema ........................................................................................... 14 
1.3 
Schedule of Activities (SoA) ...................................................................... 15 
2. 
Introduction ........................................................................................................... 20 
2.1 
Study Rationale ......................................................................................... 20 
2.2 
Background ............................................................................................... 20 
2.2.1 
Disease ..................................................................................... 20 
2.2.2 
Amgen Investigational Product Background:  
AMG 510 ................................................................................... 21 
2.2.2.1 
AMG 510 Preclinical Experience ............................. 22 
2.2.2.2 
Pharmacokinetics .................................................... 22 
2.2.2.3 
Toxicology ............................................................... 23 
2.3 
Benefit/Risk Assessment ........................................................................... 24 
3. 
Objectives and Endpoints ..................................................................................... 26 
4. 
Study Design ........................................................................................................ 26 
4.1 
Overall Design .......................................................................................... 26 
4.2 
Number of Subjects ................................................................................... 27 
4.2.1 
Replacement of Subjects ........................................................... 27 
4.2.2 
Number of Sites ......................................................................... 27 
4.3 
Justification for Investigational Product Dose ............................................ 27 
4.4 
End of Study ............................................................................................. 28 
4.4.1 
End of Study Definition .............................................................. 28 
4.4.2 
Study Duration for Subjects ....................................................... 29 
5. 
Study Population .................................................................................................. 29 
5.1 
Inclusion Criteria ....................................................................................... 29 
5.2 
Exclusion Criteria ...................................................................................... 30 
5.3 
Subject Enrollment .................................................................................... 33 
5.4 
Screen Failures ......................................................................................... 33 
6. 
Treatments ........................................................................................................... 34 
6.1 
Treatment(s) Administered ........................................................................ 35 
6.1.1 
Investigational Products ............................................................ 35 
6.1.2 
Non-investigational Products ..................................................... 36 
6.1.3 
Medical Devices ........................................................................ 36 
6.1.4 
Other Protocol-required Therapies ............................................ 36 
6.1.5 
Other Treatment Procedures ..................................................... 36 
6.1.6 
Product Complaints ................................................................... 36 

Product:  AMG 510 
Protocol Number:  20190147 
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6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 36 
6.2 
Dose Modification ...................................................................................... 37 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 37 
6.2.2 
Dose-limiting Toxicity Definition ................................................. 38 
6.2.3 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 39 
6.2.3.1 
Amgen Investigational Product:  AMG 510 .............. 39 
6.2.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 41 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 43 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 43 
6.4.1 
Method of Treatment Assignment .............................................. 43 
6.4.2 
Blinding ..................................................................................... 43 
6.5 
Treatment Compliance .............................................................................. 43 
6.6 
Treatment of Overdose ............................................................................. 43 
6.7 
Prior and Concomitant Treatment ............................................................. 43 
6.7.1 
Prior Treatment ......................................................................... 43 
6.7.2 
Concomitant Treatment ............................................................. 44 
7. 
Discontinuation Criteria ......................................................................................... 44 
7.1 
Discontinuation of Study Treatment........................................................... 45 
7.2 
Discontinuation From the Study ................................................................ 46 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 46 
7.2.2 
Reasons for Removal From Study ............................................. 46 
7.3 
Lost to Follow-up ....................................................................................... 46 
8. 
Study Assessments and Procedures .................................................................... 47 
8.1 
General Study Periods .............................................................................. 47 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 47 
8.1.2 
Treatment Period ....................................................................... 49 
8.1.3 
End of Treatment Visit ............................................................... 49 
8.1.4 
Safety Follow-up ........................................................................ 49 
8.1.5 
End of Study .............................................................................. 50 
8.2 
Description of General Study Assessments and Procedures ..................... 50 
8.2.1 
General Assessments ............................................................... 51 
8.2.1.1 
Informed Consent .................................................... 51 
8.2.1.2 
Demographics ......................................................... 51 
8.2.1.3 
Medical History ........................................................ 51 
8.2.1.4 
Physical Examination .............................................. 51 
8.2.1.5 
Physical Measurements .......................................... 51 
8.2.1.6 
Substance Abuse History ........................................ 51 
8.2.1.7 
Performance Status................................................. 51 

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8.2.2 
Efficacy Assessments ................................................................ 51 
8.2.3 
Safety Assessments .................................................................. 53 
8.2.3.1 
Vital Signs ............................................................... 53 
8.2.3.2 
Electrocardiograms (ECGs) ..................................... 53 
8.2.4 
Adverse Events and Serious Adverse Events ............................ 54 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 54 
8.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 55 
8.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 55 
8.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 56 
8.2.4.5 
Safety Monitoring Plan ............................................ 56 
8.2.4.6 
Pregnancy and Lactation ......................................... 56 
8.2.5 
Clinical Laboratory Assessments ............................................... 57 
8.2.6 
Pharmacokinetic Assessments .................................................. 58 
8.2.7 
Biomarkers ................................................................................ 58 
9. 
Statistical Considerations ...................................................................................... 59 
9.1 
Statistical Hypotheses ............................................................................... 59 
9.2 
Sample Size Determination ....................................................................... 59 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 59 
9.3.1 
Analysis Sets ............................................................................. 59 
9.3.1.1 
Safety Analysis Set ................................................. 59 
9.3.1.2 
Pharmacokinetic Analysis Set ................................. 60 
9.3.2 
Covariates ................................................................................. 60 
9.3.3 
Subgroups ................................................................................. 60 
9.3.4 
Handling of Missing and Incomplete Data .................................. 60 
9.4 
Statistical Analyses ................................................................................... 60 
9.4.1 
Planned Analyses ...................................................................... 60 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 60 
9.4.1.2 
Primary Analysis ..................................................... 62 
9.4.1.3 
Final Analysis .......................................................... 62 
9.4.2 
Methods of Analyses ................................................................. 62 
9.4.2.1 
General Considerations ........................................... 62 
9.4.2.2 
Efficacy Analyses .................................................... 62 
9.4.2.3 
Safety Analyses ...................................................... 63 
9.4.2.4 
Other Analyses ........................................................ 64 
10. 
References ........................................................................................................... 65 
11. 
Appendices ........................................................................................................... 66 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 67 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
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11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 70 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 72 
Regulatory and Ethical Considerations ...................................................... 73 
Informed Consent Process ........................................................................ 74 
Investigator Signatory Obligations ............................................................. 77 
Data Quality Assurance ............................................................................. 77 
Source Documents .................................................................................... 79 
Study and Site Closure.............................................................................. 80 
Compensation ........................................................................................... 80 
11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 81 
Definition of Adverse Event ....................................................................... 81 
Definition of Serious Adverse Event .......................................................... 82 
Recording Adverse Events and Serious Adverse Events .......................... 83 
Evaluating Adverse Events and Serious Adverse Events .......................... 83 
Reporting of Serious Adverse Event .......................................................... 85 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 91 
Definition of Females of Childbearing Potential ......................................... 91 
Collection of Pregnancy Information .......................................................... 92 
Collection of Lactation Information ............................................................ 94 
11.6 
Appendix 6.  Sample Storage and Destruction .......................................... 97 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments...................................................................... 99 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity............................................................................ 99 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 100 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 101 
11.8 
Appendix 8.  Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1) ...................................................................... 103 
11.9 
Appendix 9.  Eastern Cooperative Oncology Group Performance 
Status ...................................................................................................... 108 
11.10 Appendix 10.  Examples of Excluded Treatments ................................... 109 
 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
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List of Tables 
Table 1-1.  Schedule of Activities:  Daily Dosing ............................................................ 15 
Table 6-1.  Study Treatments ........................................................................................ 35 
Table 6-2.  Dose Decrements for AMG 510 ................................................................... 40 
Table 6-3.  AMG 510 Dose Modification Guidelines for Hematologic and 
Non-hematologic Toxicities ..................................................................... 40 
Table 6-4.  AMG 510 Hepatotoxicity Guidelines ............................................................ 42 
Table 11-1.  Analyte Listing ........................................................................................... 70 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 100 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 14 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ....................................................................................................... 86 
Figure 11-2.  Pregnancy and Lactation Notification Forms ............................................. 95 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
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CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1, Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 510 in Subjects of Chinese Descent With 
Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation (CodeBreaK 105)   
Short Protocol Title:  AMG 510 Ethnic Sensitivity Study 
Study Phase:  1 
Indication:  Advanced/Metastatic Solid Tumors with KRAS p.G12C Mutation 
Rationale 
AMG 510 is a small molecule that specifically and irreversibly inhibits the Kirsten rat 
sarcoma viral oncogene homolog (KRAS)G12C mutant protein.  AMG 510 binds to the P2 
pocket of KRAS, adjacent to the mutant cysteine at position 12 and the 
nucleotide-binding pocket.  The inhibitor contains a thiol-reactive portion that covalently 
modifies the cysteine residue and locks KRASG12C in the inactive 
guanosine diphosphate (GDP)-bound conformation.  
Preclinical studies of AMG 510 have demonstrated inhibition of growth and regression of 
cells and tumors harboring the KRAS p.G12C mutation.  These data suggest that 
inhibition of KRASG12C may have therapeutic benefit for patients with 
KRAS p.G12C-driven cancers.  The aim of this study is to evaluate the safety, 
tolerability, pharmacokinetics (PK), and preliminary efficacy of AMG 510 in subjects of 
Chinese descent with advanced/metastatic solid tumors with the KRAS p.G12C 
mutation.  The data from this study, in comparison with data from the global phase 1, 
first-in-human (FIH) study of AMG 510 (Study 20170543), will allow for an assessment of 
any ethnicity associated differences with AMG 510 treatment in subjects of Chinese 
descent, and subsequently enable China to participate in a global, phase 3 study of 
AMG 510. 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
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Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability of 
AMG 510 in adult subjects of Chinese 
descent with KRAS p.G12C-mutant 
advanced/metastatic solid tumors 
 
Subject incidence of dose-limiting toxicity 
(DLT), treatment-emergent adverse events, 
treatment-related adverse events, and 
changes in vital signs, electrocardiograms 
(ECGs), and clinical laboratory tests 
 
To characterize the pharmacokinetics 
(PK) of AMG 510 in subjects of Chinese 
descent when administered orally (PO) 
 
PK parameters of AMG 510 including, but 
not limited to, maximum observed plasma 
concentration (Cmax), time to achieve Cmax 
(tmax), and area under the plasma 
concentration time curve (AUC) 
Secondary 
 
To evaluate the preliminary efficacy of 
AMG 510 as a monotherapy in subsets 
of solid tumors with the KRAS p.G12C 
mutation 
 
Objective response, duration of response, 
progression-free survival (PFS), disease 
control, time to response (TTR), and 
duration of stable disease measured by 
computed tomography (CT) or magnetic 
resonance imaging (MRI) and assessed per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 guidelines 
 
Overall Design 
This is a non-randomized, open-label, multi-center phase 1 study to evaluate the safety, 
tolerability, PK, and preliminary efficacy of AMG 510 administered orally (PO) once daily 
(QD) in subjects of Chinese descent with KRAS p.G12C-mutant advanced/metastatic 
solid tumors.  This study will be conducted at sites in Hong Kong and Taiwan. 
Up to 18 subjects will be enrolled into the study.  Enrollment into the first dose level 
cohort (cohort 1) may be from any eligible KRAS p.G12C-mutant advanced/metastatic 
solid tumor type.  Six initial subjects will be enrolled into cohort 1 and will receive 960 mg 
of AMG 510 PO QD.  If  1 dose-limiting toxicity (DLT) is observed in the first 6 subjects, 
up to 6 additional subjects may be enrolled in cohort 1 to collect additional PK, safety, 
and preliminary efficacy at the 960 mg dose.  If  2 DLTs are observed in the first 6 
subjects in cohort 1, an additional 6 subjects will be enrolled into a second dose level 
cohort (cohort 2), wherein the dose will be reduced to 720 mg AMG 510 PO QD.  If  1 
DLT is observed in the first 6 subjects in cohort 2, up to 6 additional subjects may be 
enrolled in cohort 2 to gather additional PK, safety, and preliminary efficacy at the 720 
mg dose. 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
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The safety and tolerability data from the first 6 subjects at the 960 mg dose level will be 
reviewed by a Dose Level Review Team (DLRT) 21 days after receiving the first dose of 
AMG 510.  The DLRT will recommend whether cohort 1 should be continued at 960 mg 
or be modified and whether an additional 6 subjects could be enrolled in cohort 1 or if 
the 720 mg dose cohort (cohort 2) should be opened.  If the DLRT makes the 
recommendation to enroll the next 6 subjects at the 720 mg AMG 510 dose in cohort 2, 
the DLRT will again review safety and tolerability data when the sixth enrolled subject at 
the 720 mg dose has the opportunity to receive AMG 510 for 21 days.  The DLRT will 
recommend whether cohort 2 should be continued at 720 mg or be modified and 
whether an additional 6 subjects could be enrolled in cohort 2.  The dose modification 
strategy for this study is described in Section 6.2. 
Administration of AMG 510 may continue until there is evidence of disease progression, 
intolerance to study medication, or withdrawal of consent.  Subjects will have a safety 
follow-up (SFU) visit approximately 30 (7) days after the last dose of AMG 510 or 
before any new anticancer treatment is started, whichever occurs first.  The SFU visit will 
be the end of study visit for each subject. 
Number of Subjects 
Up to 18 subjects will be enrolled in the study.   
Summary of Subject Eligibility Criteria 
Adult subjects ( 18 years old) with pathologically documented, previously treated, 
advanced/metastatic solid tumors will be eligible for this study.  Enrollment will be 
restricted to subjects with advanced/metastatic solid tumors with the KRAS p.G12C 
mutation identified through local or central screening.  
After providing informed consent, 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 510 PO QD will be administered daily for 21-day cycles, with no drug holidays 
between each cycle.  The planned dose level(s) for AMG 510 will be dispensed at the 
research facility by a qualified staff member.   
Procedures 
Written informed consent must be obtained from all subjects before any study-specific 
screening procedures are performed.  After written informed consent has been obtained, 

Product:  AMG 510 
Protocol Number:  20190147 
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all screening tests and procedures will be performed within 28 days of administration of 
the first dose of AMG 510 (day 1), unless otherwise noted.  Any procedures, 
assessments, and laboratory tests obtained or performed as part of standard of 
care treatment prior to signing of informed consent may be used for screening 
requirements as long as they were within the allowed 28-day screening window 
prior to cycle 1 day 1.  Subjects will be seen in the clinic where clinical safety and study 
evaluations will be performed including physical examination, vital signs, clinical 
laboratory tests, electrocardiograms (ECGs), PK sample collections, and tumor imaging. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Table 1-1. 
Statistical Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, and 
preliminary efficacy data by dose, and time as appropriate.  Descriptive statistics on 
continuous data will include means, medians, standard deviations and ranges, while 
categorical data will be summarized using frequency counts and percentages.  Graphical 
summaries of the data may also be presented. 
The primary analysis will occur after all subjects (6 to 12 subjects) enrolled in cohort 1 
and after all 6 to 12 subjects enrolled in cohort 2 (if 2 DLTs are observed in the first 6 
subjects in cohort 1) have had the opportunity to complete 6 months on study or have 
been withdrawn from the study.   
A final analysis is planned after all cohorts 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. 
Listings of secondary efficacy endpoints will be produced for all subjects.  The proportion 
of subjects with an objective response, defined as complete response (CR)  partial 
response (PR) (assessed per RECIST version 1.1) will be described.  Additionally, the 
95% CI will be tabulated by planned dose level, and similarly for subjects with disease 
control, defined as CR  PR  stable disease (SD) will be described.  For all subjects 
treated at the planned dose, the Kaplan-Meier method will be used for time-to-event 
endpoints to estimate the survival curve, quartiles, and rates at selected timepoints with 
95% CI for 1) duration of response, 2) progression-free survival, and 3) duration of 
stable disease.  Event free rates at 3-month intervals will be estimated using the 
Kaplan-Meier method for progression-free survival (PFS).  Time to response will be 

Product:  AMG 510 
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CONFIDENTIAL  
 
 
summarized by the nonmissing sample size (n), standard deviation, median, minimum, 
and maximum for responders.  Subject listings for time-to-event endpoints may be 
provided instead of Kaplan-Meier estimates or Clopper Pearson exact confidence 
interval if the analysis set has fewer than 10 subjects.   
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
No statistical hypothesis will be tested. 
Sponsor Name: 
 Amgen Inc. 

Product:  AMG 510 
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Date:  05 January 2022 
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1.2 
Study Schema 
Figure 1-1.  Study Schema 
Cohort 1: 960 mg PO QD
(6 subjects)
Cohort 2: 720 mg PO QD
(6 subjects)
SFUd
DLRMc
Screening
Screening
D -28
D -28
D1
D1
EOS
D21
EOS
D21
If ≥ 2 DLT, start 
cohort 2 enrollment
SFUd
treat until progressiona
treat until progressiona
EOTb
EOTb
If ≤ 1 DLT in the first 6 
subjects,  Cohort 1 
may be expanded (up 
to 6 additional 
subjects)
DLRMe
If ≤ 1 DLT in the first 6 
subjects,  Cohort 2 
may be expanded (up 
to 6 additional 
subjects)
 
DLRM  dose level review meeting; DLT  dose limiting toxicity; EOS  end of study; EOT  end of treatment; PO  orally; QD  once daily; SFU  safety follow-up.  
a Administration of AMG 510 may continue until there is evidence of disease progression, intolerance to study medication, or withdrawal of consent.   
b For subjects who discontinue investigational product, the EOT visit should occur as soon as possible (within 14 days) after the last dose of investigational product. 
c The first DLRM will occur after the sixth study subject has received 21 days of AMG 510 in Cohort 1.   
d The SFU visit should occur approximately 30 (7) days after the last dose of AMG 510 or before any new anticancer treatment is started, whichever occurs first.  The 
SFU visit will be the end of study visit for each subject.   
e The second DLRM will occur after the sixth subject enrolled in Cohort 2 has received 21 days of AMG 510. 

Product:  AMG 510 
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1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities:  Daily Dosing 
 
Screena 
Treatment 
EOTb SFUc 
Cycle 
 
1 
2 
3,5 ( 2 days) 
4,6 ( 2 days) 
QC Q2C 
 
 
Day 
-28 to 1 
1 
2 
8 
9 
15 
( 1 day) 
1 
8 ( 1 
day) 
1 
1 
1 
1 
 
 
Hours (relative to 
dosing) 
 
pre 0.25 0.5 1 2 4 6 
pre 
pre 
0.25 0.5 1 2 4 6 pre 
pre 
pre 0.25 0.5 1 pre pre pre pre pre 
 
 
GENERAL & SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & 
height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam & 
weightd 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
 
 
X 
ECOGd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
Vital signse 
X 
X 
X 
X X X X X 
X 
X 
X 
X X X X X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
 
 
X 
ECGe, f 
X 
X 
X 
X X X X X 
X 
X 
X 
X X X X X 
X 
X 
X 
X 
X X 
 
X 
X 
X 
 
 
X 
Prior therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 3 
Footnotes defined following last page of the table 
 

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Table 1-1.  Schedule of Activities:  Daily Dosing 
Screena 
Treatment 
EOTb SFUc 
Cycle 
 
1 
2 
3,5 ( 2 days) 
4,6 ( 2 days) 
QC Q2C 
 
 
Day 
-28 to 1 
1 
2 
8 
9 
15 
( 1 day) 
1 
8 ( 1 
day) 
1 
1 
1 
1 
 
 
Hours (relative to 
dosing) 
 
pre 0.25 0.5 1 2 4 6 pre 
pre 
0.25 0.5 1 2 4 6 pre 
pre 
pre 0.25 0.5 1 pre pre pre pre pre 
 
 
GENERAL & SAFETY ASSESSMENTS (continued) 
Concomitant 
medications 
 
X 
==============================================================================================➔ 
Adverse events 
 
 
==============================================================================================➔ 
Serious adverse 
eventso 
===========================================================================================================➔ 
Patient diaries 
 
 
====================================================================================➔ 
 
 
LABORATORY ASSESSMENTS 
Chemistrye 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panelg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Thyroid panele 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
X 
Hematologye 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
X 
Coagulatione 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
X 
Urinalysise, h 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
 
 
X 
Serum or urine 
pregnancy testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
X 
Page 2 of 3 
Footnotes defined following last page of the table 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 17 of 109 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities:  Daily Dosing 
Screena 
Treatment 
EOTb SFUc 
Cycle 
 
1 
2 
3,5 ( 2 days) 
4,6 ( 2 days) 
QC Q2C 
 
 
Day 
-28 to 1 
1 
2 
8 
9 
15 
( 1 day) 
1 
8 ( 1 
day) 
1 
1 
1 
1 
 
 
Hours (relative to 
dosing) 
 
pre 0.25 0.5 1 2 4 6 
pre 
pre 
0.25 0.5 1 2 4 6 pre 
pre 
pre 0.25 0.5 1 pre pre pre pre pre 
 
 
LABORATORY ASSESSMENTS (continued) 
Hepatitis serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TUMOR SAMPLE (if KRAS p.G12C status is not known) 
Archived tumor 
tissue (FFPE) or 
tumor biopsy 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMAGING/EFFICACY ASSESSMENTS 
Radiological imaging 
(CT/MRI) and tumor 
assessmentk, l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
MRI brainl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK ASSESSMENTS 
AMG 510 PKm 
 
X 
X 
X X X X X 
X 
X 
X 
X X X X X 
X 
 
X 
X 
X X 
 
X (X)m
 
 
 
 
STUDY DRUG ADMINISTRATION 
AMG 510n 
 
 
====================================================================================➔ 
 
 
Page 3 of 3 
Footnotes defined following last page of the table 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 18 of 109 
CONFIDENTIAL  
 
 
CR = complete response; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FFPE = 
formalin-fixed paraffin-embedded; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; HIV = human immunodeficiency virus; KRAS = Kirsten rat sarcoma; 
LDL = low-density lipoprotein; MRI = magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetics; PR = partial response; QC = every 
cycle from cycle 7 and beyond (cycles 7, 8, 9, etc), Q2C = every other cycle from cycle 7 and beyond (cycles 7, 9, 11, etc); RECIST = Response Evaluation Criteria in 
Solid Tumors;  
Screen = screening; SFU = safety follow-up. 
(X) = Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes.  
a KRAS p.G12C testing results must be available prior to starting all other screening procedures; 
b For subjects who discontinue investigational product, the EOT visit should occur as soon as possible (within 14 days) after the last dose of investigational product.  
c The SFU visit should occur approximately 30 (7) days after the last dose of AMG 510 or before any new anticancer treatment is started, whichever occurs first.  The 
SFU visit will be the end of study visit for each subject.  
d Can be performed within a -1 day window (ie, 1 day prior to visit).  Height is only required at screening.   
e For laboratory assessments, every effort should be taken to perform assessments on the indicated study day.  However, a window of  1 day is allowable for cycle 1 
and cycle 2 (except for cycle 1 day 1 and cycle 1 day 8 where the window is -1 day).  A window of  2 days is allowable after cycle 2.  The same laboratory result 
should not be used for multiple assessments (for example using cycle 1 day 1 labs for both cycle 1 day 1 and cycle 1 day 2).  For electrocardiograms and vital signs 
(including pulse oximetry):   5-minute window (for time points of 0.25 hr and 0.5 hr postdose),  15-minute window for all other postdose time points.  On days of 
clinic visits, all predose assessments performed must be completed prior to dose administration (there is no allowance window, only that predose assessments must 
occur prior to dose administration). 
f A single ECG must be performed at screening to fulfill inclusion criteria.  In addition, 3 triplicate ECGs must be performed prior to the first dose of AMG 510 to serve as 
baseline.  For all other visits, 1 triplicate ECG must be performed (See Section 8.2.3.2).  
g Assessments to be performed on day 1 of every other cycle starting in cycle 3 (eg, C3, C5, C7, etc).  Laboratory assessments may be performed within 24 hours 
before day 1 of cycle 1.  Lipid panel may include total cholesterol, HDL, and LDL depending on local standard practice for cholesterol testing, and 
triglycerides.   
h Microscopic exam to be performed at the discretion of the investigator. 
i For female subjects of childbearing potential only.  At screening, a highly sensitive serum pregnancy test is required.  For all other time points, a highly sensitive serum 
or urine pregnancy test is required.  
j If KRAS p.G12C status is not available in the subject’s medical record, archived FFPE tissue (collected within 5 years) may be used for KRAS p.G12C screening by 
local or central testing (as applicable).  If archived FFPE tissue is unavailable, a tumor biopsy may be performed. 
k Radiological imaging and tumor assessments are required at screening and every 6 1 weeks for the first 4 response assessments.  After four 6-week response 
assessments, radiological imaging and tumor assessments will be performed every 12  1 weeks.  Imaging and tumor assessments will continue until disease 
progression, start of new anticancer treatment, death, withdrawal of consent, or until end of study.  MRI/CT scans can be obtained earlier if clinical deterioration 
necessitates an earlier scan at the discretion of the managing physician.  End of treatment CT/MRI should be performed only for subjects that discontinue treatment 
for a reason other than disease progression per RECIST 1.1 criteria.  Every assessment must include the chest, abdomen, pelvis, and all other known sites of 
disease.  Tumor burden assessments will be performed based on RECIST 1.1 guidelines (Section 11.8).  Radiographic response (CR and PR) requires confirmation 
by a repeat assessment at least 4 weeks after the first detection of response. 
l 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 should be performed for all subjects with brain metastases or history of brain metastases and can also be performed at any time if 
clinically indicated or per standard of care.  Any additional imaging used to evaluate or determine response (eg, PET, CT/PET, bone scan, etc) should be sent along 
with the required imaging to the central imaging vendor promptly upon completion. 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 19 of 109 
CONFIDENTIAL  
 
 
 m Pharmacokinetic blood samples should be collected at the exact nominal time point as noted above (see hour postdose column).  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.  Pharmacokinetic samples not 
collected at exact nominal time point will not be considered protocol deviations.  Predose PK samples should be performed prior to AMG 510 dosing.  (X):  only cycle 
4 to be collected. 
n AMG 510 will be administered daily on a repeated basis with no planned off treatment days.  AMG 510 must be administered in the fasted state (no food or liquids, 
except water, 2 hours before to 1 hour after dosing) until cycle 2 day 2 and beyond at which time they may take AMG 510 with or without food. 
o After end of study serious adverse events suspected to be related to investigational product will be reported to Amgen.  Please refer to Section 8.2.4.1.3 
for additional details. 
 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 20 of 109 
CONFIDENTIAL  
 
 
2. 
Introduction 
2.1 
Study Rationale 
AMG 510 is a small molecule that specifically and irreversibly inhibits the Kirsten rat 
sarcoma viral oncogene homolog (KRAS)G12C mutant protein.  AMG 510 binds to the P2 
pocket of KRAS, adjacent to the mutant cysteine at position 12 and the 
nucleotide-binding pocket.  The inhibitor contains a thiol-reactive portion that covalently 
modifies the cysteine residue and locks KRASG12C in the inactive guanosine diphosphate 
(GDP)-bound conformation.  
Preclinical studies of AMG 510 have demonstrated inhibition of growth and regression of 
cells and tumors harboring the KRAS p.G12C mutation.  These data suggest that 
inhibition of KRASG12C may have therapeutic benefit for patients with KRAS 
p.G12C-driven cancers.  Accordingly, the first-in-human (FIH) Study 20170543 is 
evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of 
AMG 510 in subjects with KRAS p.G12C-mutant advanced non-small cell lung cancer 
(NSCLC), colorectal cancer (CRC), and other solid tumors.  The aim of this study is to 
evaluate the safety, tolerability, PK, and preliminary efficacy of AMG 510 in subjects of 
Chinese descent with advanced/metastatic solid tumors with the KRAS p.G12C 
mutation.   
The data from this study, in comparison with data from the global phase 1, FIH study of 
AMG 510 (Study 20170543), will allow for an assessment of any ethnicity associated 
differences with AMG 510 treatment in subjects of Chinese descent, and subsequently 
enable China to participate in a global, phase 3 study of AMG 510. 
2.2 
Background 
2.2.1 
Disease 
Advanced/metastatic cancer remains a leading cause of death for both men and women 
globally, with lung (small cell and non-small cell) and CRC among the most common 
causes of cancer death (WHO statistics, 2018).  In 2018 there were approximately 
234 030 new cases of lung cancer and 140 250 new cases of CRC in the United States 
alone (American Cancer Society, 2018).  Despite significant progress over the last few 
decades, the prognosis for patients with advanced/metastatic solid tumors remains poor.  
The 5-year survival rates for advanced NSCLC and advanced CRC are approximately 
5% and 14%, respectively (American Cancer Society, 2019).  The poor prognosis in 
patients with advanced/metastatic solid tumors highlights a critical unmet medical need. 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 21 of 109 
CONFIDENTIAL  
 
 
The KRAS guanosine triphosphate (GTP)-ase is involved in cell signalling pathways that 
regulate growth, division, and differentiation.  A relationship between KRAS mutations 
and oncogenesis has been established in cancers with solid tumors such as NSCLC and 
CRC (Smith et al, 2010; Der et al, 1982;).  Specifically, the KRAS p.G12C point mutation 
encodes an oncoprotein product with a structural change that prevents the association of 
GTPase-activating proteins, thereby reducing the hydrolysis of GTP by KRAS.  
Accumulation of the constitutively active, GTP-bound form of KRAS results in enhanced 
proliferative and survival signaling in tumor cells (Jones et al, 2017). 
AMG 510 is being developed by Amgen Inc., a for profit pharmaceutical company.  
AMG 510 (sotorasib) was granted accelerated approved by the United States Food 
and Drug Administration (FDA) for the treatment of adult patients with 
KRAS p.G12C-mutated locally advanced or metastatic NSCLC, as determined by 
an FDA-approved test, who have received at least one prior systemic therapy.   
Subjects with metastatic or unresectable NSCLC, CRC, and other solid tumors 
(including pancreatic, endometrial, bladder, ovarian, endometrial, appendiceal, 
ampullary, and small intestine) with the KRAS p.G12C mutation are commonly 
treated with combinations of chemotherapy, immunotherapy, or antiangiogenic agents.  
In NSCLC, until recently, most subjects with a KRAS p.G12C mutation would have 
received platinum containing doublets, typically cisplatin/pemetrexed as standard 
first line options (NCCN, 2018), followed by second line therapy with a taxane with 
or without a vascular endothelial growth factor (VEGF) inhibitor.   
Amgen has initiated a global phase 1, FIH study of AMG 510 (Study 20170543) to 
evaluate the safety, tolerability, PK, and preliminary efficacy of orally-administered (PO) 
AMG 510 in adult subjects with KRAS p.G12C-mutant advanced solid tumors.  To permit 
China’s future participation in AMG 510 clinical development, including an anticipated 
phase 3 study, the aim of this study is to evaluate the safety, tolerability, PK, and 
preliminary efficacy of AMG 510 in subjects of Chinese descent with 
advanced/metastatic solid tumors with the KRAS p.G12C mutation.  This study may be 
amended to include sites in China and seamlessly expand to phase 2 to further evaluate 
anti-tumor efficacy of AMG 510 in subjects of Chinese descent. 
2.2.2 
Amgen Investigational Product Background:  AMG 510 
AMG 510 is a small molecule that specifically and irreversibly inhibits the KRASG12C 
oncoprotein encoded by the KRAS p.G12C mutation.  AMG 510 binds to the P2 pocket 
of KRAS adjacent to the mutant cysteine at position 12 and the nucleotide-binding 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 22 of 109 
CONFIDENTIAL  
 
 
pocket.  The inhibitor contains a thiol-reactive portion which covalently modifies the 
cysteine residue and locks KRASG12C in the inactive GDP-bound conformation.  This 
blocks the normal interaction between KRAS and the rapidly accelerated fibrosarcoma 
(RAF) protein kinase, and consequently prevents downstream signaling events including 
the phosphorylation of extracellular signal-regulated kinase (ERK) 
(Simanshu et al, 2017; Ostrem et al, 2013). 
2.2.2.1 
AMG 510 Preclinical Experience 
In vitro, AMG 510 inhibited son-of-sevenless homolog 1 (SOS1)-catalyzed nucleotide 
exchange of recombinant mutant KRASG12C/C118A (half-maximal inhibitory concentration 
[IC50] = 0.09 µM), but had minimal effect on KRASC118A (KRAS protein with a C118A 
mutation at the protein level), which is wildtype at G12.  AMG 510 inhibited KRASG12C 
signaling only in KRAS p.G12C-mutant cell lines tested.  AMG 510 also impaired viability 
in all but one p.G12C-mutant cell line (IC50 values from 0.004 to 0.032 µM), but did not 
affect the viability of cell lines with other mutations in KRAS or with mutations in genes 
other than KRAS.  The kinetic efficiency of AMG 510, defined as the rate of enzyme 
inactivation divided by the inhibitory constant for reversible enzyme inhibition, was within 
the reported range of values for covalent epidermal growth factor receptor (EGFR) 
inhibitors.  In vivo pharmacodynamic analyses demonstrated that covalent modification 
of KRASG12C by AMG 510 tracked with inhibition of ERK1/2 phosphorylation.  Maximal 
inhibition and modification occurred within 2 to 4 hours and significant inhibition and 
modification of KRASG12C persisted for 48 hours after a single dose of AMG 510.  In 
tumor xenograft studies, AMG 510 significantly inhibited the growth of KRAS p.G12C 
tumors at doses as low as 3 mg/kg and achieved near complete regression at 
100 mg/kg.  Notably, AMG 510 had no effect in non-KRAS p.G12C tumor xenografts and 
did not affect body weight in any study.  
2.2.2.2 
Pharmacokinetics 
AMG 510 exhibited moderate to high clearance and moderate volume of distribution at 
steady state in mice, rats, dogs, and cynomolgus monkeys.  The terminal half-life 
associated with z (t1/2,z) of the compound in all the test species ranged between  
0.34 and 0.71 hours.  Following AMG 510 PO as a suspension or solution, the time to 
reach maximum observed plasma concentration (tmax) of AMG 510 was observed 
between 0.25 and 1.2 hours across the species tested.  The oral bioavailability ranged 
from 3.3% to 47% across the species tested.  The in vivo elimination of AMG 510 in 
nonclinical species suggests oxidative and conjugative metabolism as the primary routes 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 23 of 109 
CONFIDENTIAL  
 
 
of elimination.  AMG 510 has a potential to cause cytochrome P450 (CYP)3A-mediated 
drug-drug interactions (DDI) due to reversible and time-dependent inhibition of CYP3A, 
and induction of CYP3A4 in vitro.  The M24 metabolite (AMG3368167) also has the 
potential to contribute to CYP3A-mediated DDI.  The potential for AMG 510 to cause 
transporter-mediated DDIs is low except for multidrug and toxin extrusion protein 1 
(MATE1) transport inhibition.  In vitro, AMG 510 was shown to be a substrate of 
P-glycoprotein (P-gp) but not of breast cancer resistance protein (BCRP). 
2.2.2.3 
Toxicology 
Nonclinical, repeat-dose toxicology studies of 7- and 28-day duration have been 
completed in the rat and dog at daily doses of AMG 510 up to 300 mg/kg.  The key 
AMG 510-related finding of concern consisted of kidney tubular epithelial 
degeneration/necrosis which occurred in the rat only.  In the 28-day rat study, renal 
tubular injury partially reversed after a 28-day recovery period, with evidence of ongoing 
resolution/repair; however, a few tubules were surrounded by fibroplasia.  Additional 
findings were reversible and included increased spleen weight (rat only), increased 
leukocytes (rat only) and a decrease in red blood cell (RBC) mass (hemoglobin, RBC 
count, and hematocrit) that was associated with changes in reticulocytes and RBC 
indices.  There were no AMG 510-related changes in either the rat or dog repeat-dose 
toxicology studies that were considered severely toxic; thus, the severely toxic dose in 
10% (STD10) in rats was  200 mg/kg and the highest nonseverely toxic dose (HNSTD) 
in dogs was  300 mg/kg. 
The 3-month dog and rat toxicology studies did not identify any new target organs 
compared to the previous 1-month studies.  In rats, the same renal change progressed 
to a chronic change that involved more of the renal tubule and was attributed to higher 
exposures and longer dosing duration.  The STD10 in the rat was 180 mg/kg.  In dogs, 
AMG 510-related changes including minimal to mild changes in hematology and clinical 
chemistry parameters, abnormal content in the gall bladder, and microscopic changes in 
the liver, pituitary, or thyroid were considered to be either non-severely toxic and/or 
adaptive or secondary responses to hepatocellular enzyme induction.  No renal toxicity 
was identified in the dog.  The HNSTD in the dog was 1000 mg/kg/day. 
Mean observed AMG 510 clinical exposures from 180, 360, 720, and 960 mg once daily 
(QD) dosing in subjects were lower than the exposures observed at the STD10 of 
180 mg/kg in rats in the 3-month Good Laboratory Practice (GLP) repeated-dose 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 24 of 109 
CONFIDENTIAL  
 
 
toxicology study, but similar to or higher than the exposures observed at the HNSTD of 
1000 mg/kg/day in dogs in the 3-month GLP repeated-dose toxicology study.   
AMG 510 preclinical safety studies have not identified cardiovascular, respiratory, or 
nervous system concerns.  Genotoxicity studies indicate an absence of significant 
genotoxic risk for AMG 510.  AMG 510 was not phototoxic in vitro.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of AMG 510 
is provided in the AMG 510 Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
Based on preclinical data, nonclinical toxicity studies, and the clinical experience with 
AMG 510, the overall benefit/risk profile favors clinical development of AMG 510 for 
subjects with KRAS p.G12C-driven cancers. 
As of 17 July 2019, 76 subjects with KRAS p.G12C advanced or metastatic tumors were 
enrolled in the study.  Of these 76 subjects, 34 (44.7) had NSCLC, 35 (46.0) had 
CRC, and 7 (9.2) had other solid tumors.  Fifty-five subjects were evaluable (ie, had 
6-week response data or early progression).  Of the 55 enrolled subjects with all cancer 
types who were evaluable, 13 subjects had partial response (PR) and 34 subjects had 
stable disease; the response was not evaluable for 1 subject. 
Based on nonclinical toxicity studies of AMG 510, the key safety information to be 
monitored in clinical studies includes renal toxicity, anemia, leukocytosis, thyroid 
abnormalities, and splenomegaly.  Based on clinical study data, the key risks to be 
monitored includes increases of AST and ALT, and interstitial lung disease 
(ILD)/pneumonitis.  Clinical signs and symptoms of the key safety information, along 
with safety laboratories, will be monitored during the study to ensure the subjects’ safety. 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure for further data on AMG 510. 
COVID-19 Related Benefit/Risk Assessment 
Amgen closely monitors the coronavirus disease-2019 (COVID-19) pandemic 
around the world.  As part of this effort, Amgen performs a rigorous assessment, 
considering the study design, patient safety, public health risk, benefit-risk 
assessment, as well as the burden on country healthcare systems.  Decisions are 
made on a study-by-study and country-by-country basis to minimize risk to 
patients and avoid undue burden on healthcare facilities. 

Product:  AMG 510 
Protocol Number:  20190147 
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Patients who display symptoms consistent with COVID-19 infections or who have 
tested positive for COVID-19, should contact the investigator to ensure 
appropriate care as well as documentation and management of study activities. 
Amgen considers that it is important to continue the proposed development of 
AMG 510 in this study in order to advance potential therapy options for patients 
as rapidly as possible, while balancing this with appropriate measures to monitor 
and mitigate the potential impact of COVID-19. 
Subjects enrolled in this study are permitted to receive vaccinations for COVID-19.   

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 26 of 109 
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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability of 
AMG 510 in adult subjects of Chinese 
descent with KRAS p.G12C-mutant 
advanced/metastatic solid tumors 
 
Subject incidence of dose-limiting toxicity 
(DLT), treatment-emergent adverse events, 
treatment-related adverse events, and 
changes in vital signs, electrocardiograms 
(ECGs), and clinical laboratory tests 
 
To characterize the pharmacokinetics 
(PK) of AMG 510 in subjects of Chinese 
descent when administered orally (PO) 
 
PK parameters of AMG 510 including, but 
not limited to, maximum observed plasma 
concentration (Cmax), time to achieve Cmax 
(tmax), and area under the plasma 
concentration time curve (AUC) 
Secondary 
 
To evaluate the preliminary efficacy of 
AMG 510 as a monotherapy in subsets 
of solid tumors with the KRAS p.G12C 
mutation 
 
Objective response, duration of response, 
progression-free survival (PFS), disease 
control, time to response (TTR), and 
duration of stable disease measured by 
computed tomography (CT) or magnetic 
resonance imaging (MRI) and assessed per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 guidelines 
 
 
4. 
Study Design 
4.1 
Overall Design 
This is a non-randomized, open-label, multi-center phase 1 study to evaluate safety, 
tolerability, PK, and preliminary efficacy of AMG 510 PO QD in subjects of Chinese 
descent with KRAS p.G12C-mutant advanced/metastatic solid tumors.  This study will be 
conducted at sites in Hong Kong and Taiwan. 
Up to 18 subjects will be enrolled into the study.  Enrollment into the first dose level 
cohort (cohort 1) may be from any eligible KRAS p.G12C-mutant advanced/metastatic 
solid tumor type.  Six initial subjects will be enrolled into cohort 1 and will receive 960 mg 
of AMG 510 PO QD.  If  1 dose-limiting toxicity (DLT) is observed in the first 6 subjects, 
up to 6 additional subjects will be enrolled in cohort 1 to collect additional PK, safety, and 
preliminary efficacy at the 960 mg dose.  If  2 DLTs are observed in the first 6 subjects 
in cohort 1, an additional 6 subjects may be enrolled into a second dose level cohort 
(cohort 2), wherein the dose will be reduced to 720 mg AMG 510 PO QD.  If  1 DLT is 
observed in the first 6 subjects in cohort 2, up to 6 additional subjects may be enrolled in 
cohort 2 to gather additional PK, safety, and preliminary efficacy at the 720 mg dose. 

Product:  AMG 510 
Protocol Number:  20190147 
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The safety and tolerability data from the first 6 subjects at the 960 mg dose level will be 
reviewed by a Dose Level Review Team (DLRT) 21 days after receiving the first dose of 
AMG 510.  The DLRT will recommend whether cohort 1 should be continued at 960 mg 
or be modified and whether an additional 6 subjects could be enrolled in cohort 1 or if 
the 720 mg dose cohort (cohort 2) should be opened.  If the DLRT makes the 
recommendation to enroll the next 6 subjects at the 720 mg AMG 510 dose in cohort 2, 
the DLRT will again review safety and tolerability data when the sixth enrolled subject at 
the 720 mg dose has the opportunity to receive AMG 510 for 21 days.  The DLRT will 
recommend whether cohort 2 should be continued at 720 mg or be modified and 
whether an additional 6 subjects could be enrolled in cohort 2.  The dose modification 
strategy for this study is described in Section 6.2.   
Administration of AMG 510 may continue until there is evidence of disease progression, 
intolerance to study medication, or withdrawal of consent.  Subjects will have a safety 
follow-up (SFU) visit approximately 30 (7) days after the last dose of AMG 510 or 
before any new anticancer treatment is started, whichever occurs first.  The SFU visit will 
be the end of study visit for each subject.   
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 
Up to 18 subjects will be enrolled in the study. 
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 
For the purpose of assessing the primary endpoints, subjects may be replaced if they 
withdraw from the study prematurely.  A subject who discontinues from the study for 
reasons other than DLT after receiving investigational product may be replaced at the 
discretion of Amgen in consultation with the investigator or their designee. 
4.2.2 
Number of Sites 
Approximately 2 to 4 investigative sites in Hong Kong and Taiwan 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 
In the global phase 1/2 study of AMG 510 (Study 20170543), mean observed clinical 
exposures from 180, 360, 720, and 960 mg QD dosing in subjects were lower than the 

Product:  AMG 510 
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CONFIDENTIAL  
 
 
exposures observed at the STD10 of 180 mg/kg in rats in the 3-month GLP 
repeated-dose toxicology study, but similar to or higher than the exposures observed at 
the HNSTD of 1000 mg/kg/day in dogs in the 3-month GLP repeated-dose toxicology 
study, (see the Investigator’s Brochure).  At these exposures, no DLTs were observed in 
subjects. 
A dose level review meeting (DLRM) was held on 27 June 2019 to review the available 
safety and preliminary anti-tumor activity of AMG 510 in all subjects as of the 
12 June 2019 data cut off.  Following review of the aggregate safety data for all subjects 
and the available anti-tumor activity and PK data in Study 20170543, the Principal 
Investigators and the Amgen voting members unanimously agreed to propose 960 mg 
daily as the recommended phase 2 dose (RP2D).  Thus, the 960 mg PO QD dose is 
considered to be safe and well tolerated and is proposed as the clinical starting dose of 
AMG 510 for this phase 1 study in subjects of Chinese descent.  The proposed 
de-escalated dose for this study of 720 mg PO QD (if applicable) is one dose level below 
the 960 mg RP2D; based on available data from Study 20170543, this dose is also 
expected to be safe and tolerable in subjects of Chinese descent. 
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). 
The study-specific primary completion date is the date when the last subject has 
completed the assessments for the SFU visit. 
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, as applicable. 

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4.4.2 
Study Duration for Subjects 
Subject participation in this study is expected to last approximately 1 year and includes a 
28-day screening period and an estimated 6 to 12 months of treatment.  However, this 
may vary depending on tolerability and response to treatment. 
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).  However, any procedures, assessments, and 
laboratory tests obtained or performed as part of standard of care prior to signing 
of informed consent may be used for screening requirements as long as they were 
performed within the allowed 28-day screening window prior to cycle 1 day 1.   
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Male or female subjects  18 years old 
103 
Subject is of Chinese ancestry (ie, both parents and 4 grandparents are/were of 
Chinese descent; it is not a necessity for the subject, the subject’s parents, or 
grandparents to be born and raised in Hong Kong/Taiwan to participate in this 
study). 
104 
Pathologically documented, advanced/metastatic solid tumor with KRAS p.G12C 
mutation identified through local or central screening. 
 
For NSCLC:  subjects must have received anti-programmed cell death 
protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) immunotherapy 
(unless contraindicated) and/or platinum-based combination therapy and 
targeted therapy (if actionable oncogenic driver mutations were identified [ie, 
EGFR, ALK, and ROS1]). 
 
For CRC:  subjects must have received at least 2 prior systemic regimes for 
advanced or metastatic CRC including fluoropyrimidine, oxaliplatin, and 
irinotecan-based regimens.  For those CRC subjects with tumors that are 
microsatellite instability-high (MSI-H), at least 1 of the prior systemic 
regimens must have included an anti-PD-1 therapy if they were clinically able 

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to receive inhibitors and 1 of these agents is approved for that indication in 
the region or country. 
 
For advanced/metastatic solid tumor types other than NSCLC or CRC:  
subjects must have received at least 1 prior systemic therapy or be intolerant 
or ineligible for available therapies known to provide clinical benefit. 
 
If KRAS p.G12C status is not available in the subject’s medical record, an 
archived formalin-fixed paraffin-embedded (FFPE) tissue (collected within 
5 years) may be used for KRAS p.G12C screening by local or central testing 
(as applicable).  If archived tissue is not available, a tumor biopsy may be 
performed. 
105 
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 criteria  
106 
Eastern Cooperative Oncology Group (ECOG) Performance Status of  2 
107 
Life expectancy of  3 months, in the opinion of the investigator 
108 
Ability to take oral medications and willing to record daily adherence to 
investigational product utilizing a sponsor-provided dosing diary 
109 
Corrected QT interval (QTc)  470 msec for females and  450 msec for males 
110 
Adequate hematological laboratory assessments, as follows: 
 
absolute neutrophil count (ANC)  1.5 x 109/L 
 
platelet count  75 x 109/L 
 
hemoglobin  9 g/dL (90 g/L) 
111 
Adequate renal assessments, as follows: 
 
estimated glomerular filtration rate based on Modification of Diet in Renal 
Disease (MDRD) calculation  60 mL/min/1.73 m2 
112 
Adequate hepatic laboratory assessments, as follows: 
 
aspartate aminotransferase (AST)  2.5 x upper limit of normal (ULN) (if liver 
metastases are present,  5 x ULN) 
 
alanine aminotransferase (ALT)  2.5 x ULN (if liver metastases are present, 
 5 x ULN) 
 
total bilirubin (TBL)  1.5 x ULN ( 2.0 x ULN for subjects with documented 
Gilbert’s syndrome or  3.0 x ULN for subjects for whom the indirect bilirubin 
level suggests an extrahepatic source of elevation) 
113 
Adequate coagulation laboratory assessments, as follows 
 
prothrombin time (PT) or partial thromboplastin time (PTT)  1.5 x ULN, or 
international normalized ratio (INR)  1.5 or within target range if on 
prophylactic anticoagulation therapy 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 

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201 
Active brain metastases from non-brain tumors.  Subjects who have had brain 
metastases resected or have received radiation therapy ending at least 4 weeks 
prior to study day 1 are eligible if they meet all of the following criteria:  a) residual 
neurological symptoms grade  2; b) on stable doses of dexamethasone for at 
least 2 weeks, if applicable; and c) follow-up magnetic resonance imaging (MRI) 
performed within 30 days shows no new lesions appearing 
202 
History or presence of hematological malignancies unless curatively treated with 
no evidence of disease 2 years 
203 
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 
204 
Gastrointestinal (GI) tract disease causing the inability to take oral medication, 
malabsorption syndrome, requirement for intravenous (IV) alimentation, 
uncontrolled inflammatory GI disease (eg, Crohn’s disease, ulcerative colitis) 
205 
Active infection requiring IV antibiotics within 1 week of study enrollment (day 1) 
206 
Exclusion of hepatitis infection based on the following results and/or criteria:   
 
Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic 
Hepatitis B or recent acute hepatitis B) 
 
Negative HepBsAg with a positive for hepatitis B core antibody (Hepatitis B 
core antibody testing is not required for screening, however if this is done and 
is positive, then hepatitis B surface antibody [Anti-HBs] testing is necessary.  
Undetectable anti-HBs in this setting would suggest unclear and possible 
infection and needs exclusion). 
 
Positive Hepatitis C virus antibody:  Hepatitis C virus RNA by polymerase 
chain reaction is necessary.  Detectable Hepatitis C virus RNA suggests 
chronic hepatitis C and renders the subject ineligible 
207 
Known positive for human immunodeficiency virus (HIV) 
208 
Unresolved toxicities from prior anti-tumor therapy, defined as not having 
resolved to Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the 
exception of alopecia (grade 2 or 3 toxicities from prior anti-tumor therapy that are 
considered irreversible [defined as having been present and stable 
for  6 months], such as ifosfamide related proteinuria, may be allowed if they are 
not otherwise described in the exclusion criteria and there is agreement to allow 
by both the investigator and sponsor) 
209 
Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, 
retinoid therapy, hormonal therapy [except for subjects with breast cancer], or 
investigational agent) within 28 days of study day 1; concurrent use of hormone 
deprivation therapy for hormone-refractory prostate cancer or breast cancer is 
permitted 
210 
Therapeutic or palliative radiation therapy within 2 weeks of study day 1.  
Subjects must have recovered from all radiotherapy-related toxicity. 
211 
Currently enrolled in another investigational device or drug study, or less than 
28 days since ending another investigational device or drug study(s), or receiving 
other investigational agent(s) 
212 
Other investigational procedures are excluded 

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213 
Major surgery within 28 days of study day 1 
214 
Female subjects of childbearing potential who are unwilling to use 1 highly 
effective method of contraception during treatment of AMG 510 and for an 
additional 7 days after receiving the last dose of AMG 510.  Refer to Section 11.5 
for additional contraceptive information. 
215 
Female subjects who are lactating/breast feeding or who plan to breastfeed while 
on study and for an additional 7 days after receiving the last dose of study drug 
216 
Female subjects with a positive pregnancy test assessed at screening by a highly 
sensitive serum pregnancy test 
217 
Female subjects planning to become pregnant while on study and for an 
additional 7 days after receiving the last dose of AMG 510 
218 
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 7 days after the last dose of 
AMG 510.  Refer to Section 11.5 for additional contraceptive information. 
219 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional 7 days after the last dose of 
AMG 510 
220 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 7 days after the last dose of AMG 510 
221 
Subject has known sensitivity to any of the products to be administered during 
dosing 
222 
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 
223 
Subject has any kind of disorder that, in the opinion of the investigator, may 
compromise the ability of the subject to give written informed consent and/or to 
comply with all required study procedures 
224 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician would pose a risk to subject safety or interfere 
with the study evaluation, procedures or completion 
225 
Use of known CYP3A4 and P-gp-sensitive substrates (with a narrow therapeutic 
window), within 14 days or 5 half-lives of the drug or its major active metabolite, 
whichever is longer, prior to study day 1 that was not reviewed and approved by 
the Principal Investigator and the Amgen Medical Monitor 
227 
Use of strong inducers of CYP3A4 (including herbal supplements such as 
St. John’s wort) within 14 days or 5 half-lives (whichever is longer) prior to study 
day 1 that was not reviewed and approved by the Principal Investigator and the 
Amgen Medical Monitor. 
228 
History of other malignancy within the past 2 years, with the following exceptions: 
 
Malignancy treated with curative intent and with no known active disease 
present for  2 years before enrollment and felt to be at low risk for 
recurrence by the treating physician. 

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 
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 non-invasive carcinoma or carcinoma 
in situ without evidence of disease. 
229 
Previous treatment with a KRASG12C inhibitor  
230 
Leptomeningeal disease 
5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment electronic case report form (eCRF). 
Each subject who enters into the screening period for the study receives a unique 
subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned manually.  This number 
will be used to identify the subject throughout the clinical study and must be used on all 
study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 

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Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened up to 2 times.  Refer to Section 8.1.1. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, combination product, or medical device(s) intended to be 
administered to a study subject according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment (Table 6-1). 

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6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
Table 6-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
AMG 510 
Dosage Formulation 
120 mg tablets 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
960 mg QD, or 720 mg QD if dose modification is required 
(See Section 6.2) 
Route of Administration 
Oral 
Accountability 
The planned dose, start date/time, stop date, quantity 
administered, unit, planned frequency, reason for dose 
change/withheld, package lot number to be recorded on 
each subject’s eCRF(s). 
Dosing Instructions 
AMG 510 will be administered orally QD for 21-day cycles, 
with no drug holidays between each cycle.  The planned 
dose level(s) for AMG 510 will be dispensed at the 
research facility by a qualified staff member.  Subjects are 
required to take AMG 510 at the research facility on clinic 
visit days as described in Table 1-1.  Subjects will take 
AMG 510 at home on non-clinic visit days at approximately 
the same time(s) every day.  The AMG 510 dose should 
also not be taken more than 2 hours earlier than the target 
time based on previous day’s dose.  AMG 510 must be 
administered in the fasted state (no food or liquids, except 
water, 2 hours before to 1 hour after dosing) until cycle 2 
day 2 and beyond at which time they may take AMG 510 
with or without food.  Subjects will receive AMG 510 with 
approximately 240 mL (8 ounces) of water. 
The AMG 510 dose should not be taken more than 
6 hours after the dosing time.  Take the next dose as 
prescribed the next day.  If vomiting occurs after 
taking AMG 510, do not take an additional dose.  Take 
the next dose as prescribed the next day.   
Administration to patients who have difficulty 
swallowing solids:  disperse tablets in 120 mL 
(4 ounces) of non-carbonated, room-temperature 
water without crushing.  No other liquids should be 
used.  Stir until tablets are dispersed into small pieces 
(the tablets will not completely dissolve) and drink 
immediately or within 2 hours.  The appearance of the 
mixture may range from pale yellow to bright yellow.  
Swallow the tablet dispersion.  Do not chew pieces of 
the tablet.  Rinse the container with an additional 
120 mL (4 ounces) of water and drink.  If the mixture is 
not consumed immediately, stir the mixture again to 
ensure that tablets are dispersed.   
eCRF = electronic case report form; QD = once daily. 

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a AMG 510 will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
6.1.2 
Non-investigational Products 
There will be no non-investigational products administered in this study. 
6.1.3 
Medical Devices 
Investigational medical devices will not be used in this study.   
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.   
6.1.4 
Other Protocol-required Therapies 
There are no other protocol-required therapies for this study. 
6.1.5 
Other Treatment Procedures 
Not applicable to the study. 
6.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either (1) Amgen or (2) distributors or partners for whom Amgen manufactures 
the material.  This includes all components distributed with the drug, such as 
packing drug containers, delivery systems, labeling, and inserts.   
This includes any investigational products provisioned and/or repackaged/modified by 
Amgen.  AMG 510 is the investigational product in this study. 
Any product complaint(s) associated with an investigational product supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following medications and supplements to be avoided for 14 days prior to enrollment 
and during the study period unless reviewed and approved by the Principal Investigator 
and the Amgen Medical Monitor: 

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 
Known strong inducers of CYP3A4 including herbal supplements, such as St. John’s 
wort 
 
Known CYP3A4 and P-gp-sensitive substrates with a narrow therapeutic window 
unless approved by Amgen medical monitor 
 
Proton pump inhibitors (PPI) and H2-receptor antagonists unless approved by 
Amgen medical monitor  
If a subject needs palliative radiotherapy for pain control during the course of the study, 
all study drugs should be discontinued, and the investigator or designee should notify 
the sponsor as soon as possible.  A subject may be allowed to resume study drug after 
discussion between the Amgen Medical Monitor and the investigator to determine the 
appropriateness of treatment resumption. 
Subjects must not schedule any major elective surgeries during the treatment period, 
and for at least 28 days after the last administration of AMG 510.  Minor elective surgery 
may be allowed after discussion with the Amgen Medical Monitor.  If a subject 
undergoes any unexpected surgery during the course of the study, AMG 510 must be 
discontinued, and the investigator or designee should notify the sponsor as soon as 
possible.  A subject may be allowed to resume AMG 510 only if both the investigator and 
Amgen Medical Monitor agree to restart study therapy. 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
Dose Level Determination 
Up to 18 subjects will be enrolled into the study to evaluate the safety, tolerability, PK, 
and preliminary efficacy of AMG 510 PO QD in subjects of Chinese descent with KRAS 
p.G12C-mutant advanced/metastatic solid tumors.  Enrollment into the first dose level 
cohort (cohort 1) may be from any eligible KRAS p.G12C-mutant advanced/metastatic 
solid tumor type.  Six initial subjects will be enrolled into cohort 1 and will receive 960 mg 
of AMG 510 PO QD.  If  1 DLT (defined in Section 6.2.2) is observed in the first 
6 subjects, up to 6 additional subjects may be enrolled in cohort 1 to collect additional 
PK, safety, and preliminary efficacy at the 960 mg dose.  If  2 DLTs are observed in the 
first 6 subjects in cohort 1, an additional 6 subjects may be enrolled into a second dose 
level cohort (cohort 2), wherein the dose will be reduced to 720 mg AMG 510 PO QD.  If 
 1 dose-limiting toxicity (DLT) is observed in the first 6 subjects in cohort 2, up to 6 
additional subjects may be enrolled in cohort 2 to gather additional PK, safety, and 
preliminary efficacy at the 720 mg dose. 

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After 6 DLT evaluable subjects in cohort 1 and after 6 DLT evaluable subjects in cohort 2 
(if applicable) have completed the 21-day DLT window, a DLRM will be held to review 
data, monitor safety, and to provide recommendations related to dose change and 
further enrollment.  If the DLRT makes the recommendation to enroll the next 6 subjects 
at the 720 mg AMG 510 dose in cohort 2, the DLRT will again review safety and 
tolerability data when sixth enrolled subject at the 720 mg dose has the opportunity to 
receive AMG 510 for 21 days.  The DLRT will recommend whether cohort 2 should be 
continued at 720 mg or be modified and whether an additional 6 subjects could be 
enrolled in cohort 2.  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 and 
enrollment decision to investigators.  Further information on DLRMs is provided in 
Section 11.3. 
Dose Cohort Stopping Rules 
The DLRT will recommend stopping or modifying dosing if suspected adverse drug 
reactions, changes in vital signs, electrocardiogram (ECG), or clinical laboratory results 
are observed, and these changes pose a significant health risk.  The Amgen Medical 
Monitor may suspend dosing and convene a DLRM at any time based on emerging 
safety data.   
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. 
6.2.2 
Dose-limiting Toxicity Definition 
A DLT is defined as any adverse event meeting the criteria listed below occurring during 
the first treatment cycle of AMG 510 (day 1 through day 21) where a relationship to 
AMG 510 cannot be ruled out. 
The grading of adverse events will be based on the guidelines provided in the CTCAE 
(version 5.0).  A DLT is defined as any of the following events during the first treatment 
cycle and attributable to AMG 510: 
 
Hematological toxicity 
 
febrile neutropenia 
 
neutropenic infection 

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 
grade 4 neutropenia 
 
grade  3 thrombocytopenia for  7 days 
 
grade 3 thrombocytopenia with grade  2 bleeding 
 
grade 4 thrombocytopenia 
 grade 4 anemia 
 
Non-hematological toxicity 
 
grade  4 vomiting or diarrhea 
 
grade 3 diarrhea or grade 3 vomiting lasting more than 3 days despite optimal 
medical support 
 
grade  3 nausea for 3 days or more despite optimal medical support 
 
any other grade  3 adverse event 
Dose-limiting toxicity-evaluable is defined as completion of 80% of AMG 510 doses 
within the first treatment cycle (ie, 21 days).  A subject who experiences a DLT within the 
first cycle is DLT-evaluable regardless of number of doses taken.  If a subject is 
withdrawn from the study for any reason other than a DLT prior to completion of the 
21-day safety observation period, a replacement subject (if applicable) will be assigned 
the same dose as the replaced subject.   
6.2.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.3.1 
Amgen Investigational Product:  AMG 510 
Subjects experiencing any treatment-related toxicity meeting the DLT definition will not 
receive additional AMG 510 treatment and will be followed until resolution of the event or 
toxicity.  Subjects will be withdrawn from AMG 510 treatment and will be treated as 
deemed appropriate by the investigator or treating physician.  In subjects who received 
the 960 mg dose level with a favorable response to treatment, an option to continue at 
the same dose level or the lower dose of 480 mg according to the dose modification 
guidelines in Table 6-2 can be considered.   
The reason for dose modification of AMG 510 is to be recorded on each subject’s eCRF.  
Dose reduction levels of AMG 510 for toxicity management of individual subjects are 
provided in Table 6-2.  Up to 2 dose reductions are allowed.  Dose reductions below 
240 mg are not allowed.   

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Table 6-2.  Dose Decrements for AMG 510 
AMG 510 Doses (mg QD) 
Starting Dose 
Dose -1 
Dose -2 
960 
480 
240 
QD = once daily 
AMG 510 will be discontinued, or dosage reduced in the event of toxicity that, in the 
opinion of the investigator, warrants the discontinuation, or dose reduction as indicated 
in Table 6-3.  Subjects who experience an adverse event requiring dose reductions 
below 240 mg should be permanently discontinued from AMG 510 treatment.  
If day 1 of a cycle is delayed, day 1 of subsequent cycles should be adjusted accordingly 
to maintain the 21-day cycle duration.  However, if a within-cycle dose is held the missed 
dose will not be made up and day 1 of subsequent cycles should not be adjusted. 
Table 6-3.  AMG 510 Dose Modification Guidelines for Hematologic and 
Non-hematologic Toxicities 
Toxicity 
Recommended Action 
Hold Until: 
Restart Dose: 
Grade  3 nausea, vomiting, or 
diarrhea lasting longer than 
3 days despite optimal medical 
support 
Recovery to grade 1 or less or to 
baseline grade 
Resume dosing at 1 dose 
lowera 
Suspected interstitial lung 
disease (ILD)/pneumonitis 
ILD/pneumonitis confirmed or 
excluded 
 
If confirmed, 
permanently 
discontinue 
AMG 510 
 
If excluded, restart 
at same dose if no 
other AMG 510 dose 
modification 
guidelines are 
applicable 
Any other drug-related toxicity 
 grade 3b 
Recovery to grade 1 or less or to 
baseline grade  
Resume dosing at 1 dose 
lowera 
a Subjects may be resumed at a dose lower than the recommended restarting dose after discussion with the 
medical monitor. 
b For suspected hepatotoxicity, refer to Section 6.2.4 and Section 11.7. 

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6.2.4 
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.  
Guidelines for management and monitoring of subjects with increased AST, ALT, or 
alkaline phosphatase are outlined in Table 6-4.   

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Table 6-4.  AMG 510 Hepatotoxicity Guidelines 
 If the conditions for permanent discontinuation are met (below):  Subject to be permanently discontinued 
 AST or ALT > 3 x ULN and INR > 1.5 x ULN (for subjects not on anticoagulation therapy) in the presence of no important alternative causes for elevated 
AST/ALT values 
OR 
 AST or ALT > 3 x ULN and TBL > 2 x ULN in the presence of no important alternative causes for elevated AST/ALT and/or TBL values 
 If conditions are not met:  Exclude other causesa 
 Upon failure to identify any other causes and AMG 510 relation to increase in LFTs cannot be excluded, proceed with guidelines below: 
CTCAE Grade 
AMG 510 Action 
Medical Management 
Monitoring and Follow-up 
Grade 2 AST or ALT and ALP ≤ 8 x ULN with 
no clinical symptoms consistent with hepatitis 
(right upper quadrant pain/tenderness, fever, 
nausea, vomiting, and jaundice) 
Continue 
Consider steroidsb 
 
Closely monitor liver function tests 
Grade 2 AST or ALT 
with symptoms 
Or 
Grade 3 or 4 
AST or ALT 
Or 
8x ULN ALPd 
First Occurrence 
Initiate steroidsb 
 
Closely monitor liver function tests 
 
Await resolution to baseline or grade 1 and resolution 
or improvement of hepatitis symptoms  
 
Restart at 1 dose level reductionc, e 
Withhold 
Second Occurrence 
Initiate steroidsb 
 
Closely monitor liver function tests 
 
Await resolution to baseline or grade 1 and resolution 
or improvement of hepatitis symptoms 
 
Resume at an additional 1 dose level reduction only 
with MEDICAL MONITOR approvalc, e 
Withhold 
Third Occurrence 
NOT APPLICABLE 
Permanently 
discontinue AMG 510 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; 
INR = international normalized ratio; LFT = liver function test; TBL = total bilirubin; ULN = upper limit of normal 
a If increase in AST/ALT is likely related to alternative agent, discontinue causative agent and await resolution to baseline or grade 1 prior to resuming AMG 510. 
b For example:  prednisone 1.0 to 2.0 mg/kg/day, dexamethasone equivalent, or methylprednisolone equivalent, followed by a taper.  The taper may occur after 
restarting AMG 510.   
c Close monitoring at restart (eg, daily LFTs x 2, then weekly x 4).  AMG 510 dose may be increased after discussion with medical monitor. 
d There is no limit to the number of AMG 510 re-challenges for isolated alkaline phosphatase elevations that resolve to baseline or grade 1. 
e Dose decrements below 240 mg are not allowable.

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6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be assigned to treatment with AMG 510. 
6.4.2 
Blinding 
This is an open-label study that is not blinded. 
6.5 
Treatment Compliance 
A paper diary will be provided to subjects at the beginning of each cycle and the study 
staff will provide guidance to the subjects on how to complete the diary. 
Compliance with treatment and the corresponding assessments should be followed 
according to the Schedule of Activities (Section 1.3) and the treatment procedures 
(Section 8.2). 
6.6 
Treatment of Overdose 
Neither the effects of overdose of AMG 510 nor an antidote to overdose are known. 
For this study, any dose of AMG 510 greater than 960 mg QD within an 18-hour 
time period will be considered an overdose.   
In the event of an overdose, the investigator/treating physician should:  
 
Contact Amgen medical monitor immediately. 
 
Closely monitor the participant for any adverse event/serious adverse event 
and laboratory abnormalities for at least 7 days. 
 
Document the quantity of the excess dose as well as the duration of the 
overdose in the Case Report Form (CRF).   
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior therapies that were being taken/used from the original diagnosis through 
enrollment will be collected.  For prior anticancer therapies, collect line of therapy, 
regimen/agent, type of therapy, setting, start date, stop date, reason for stopping 
therapy, dose, unit, route, frequency, best response, date of best response, and date of 
progression documented.  For prior radiotherapy for current malignancy, collect body 

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site, sub site, setting, type, start date, stop date, total dose, unit, best response, was 
chemotherapy part of concurrent therapy, did documented progression occur in this 
area, date progression documented.  For prior surgeries for current malignancies collect 
date of surgery, surgery, reason for surgery, body site, subsite, intent of surgery, 
residual disease. 
All other prior therapies that were being taken 28 days before enrollment through 
enrollment should be collected on each subject’s eCRF(s).  Collect therapy name, 
indication, dose, unit, frequency, route, start date, and stop date. 
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.7. 
Concomitant administration of AMG 510 with PPI (eg, Omeprazole) or H2-receptor 
antagonists (eg, famotidine) decreased AMG 510 concentrations, which may 
reduce AMG 510 efficacy.  Avoid use of PPI or H2-receptor antagonists with 
AMG 510.  If antacid therapy is considered medically necessary, administer 
AMG 510 4 hours before or 10 hours after administration of a local antacid.   
Breast cancer resistance protein substrates should be used with caution when 
co-administered with AMG 510 which may increase the circulating concentration 
of BCRP substrates.   
Amgen will review all concomitant medications with the investigators prior to dosing with 
AMG 510 to ensure patient safety. 
All concomitant therapies (including all prescription, over-the-counter medications) are to 
be collected from enrollment through the end of the SFU period and will be recorded on 
the eCRF. 
For concomitant therapies, collect therapy name, indication, dose, unit, frequency, route, 
start date and stop date. 
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. 

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The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 7.1, 7.2.1, and 7.2.2. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 1-1) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints 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 
 
protocol deviation 
 
non-compliance 
 
requirement for alternative therapy 

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 
disease progression as defined by RECIST version 1.1 criteria (Section 11.8) 
 
pregnancy  
7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Table 1-1) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Not applicable to the study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
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. 

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 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 1-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
Ongoing patients who are unable or unwilling to attend protocol-specified trial 
visits and procedures should generally remain on study even if AMG 510 is 
interrupted, as continued collection of even limited clinical information is valuable 
for safety and efficacy assessments.  In cases where the patient is unable to visit 
the site, Amgen has explored alternative methods for safety assessments and 
continuation of study medication (eg, phone contact, virtual visit, alternative 
location for assessment including local labs or radiological assessment, direct to 
patient shipment of investigational product where possible).  Each case should be 
discussed with the medical monitor before temporary adjustments are made to 
the subject’s schedule of activities.   
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 written consent 
has been obtained, subjects will be screened in order to assess eligibility for study 
participation.  Laboratory assessments that were performed as standard of care 
prior to signing the informed consent may be used for screening assessments if 

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they were performed within the allowed 28-day screening window prior to cycle 1 
day 1.  All screening procedures must be performed within 28 days prior to start of 
investigational product administration, unless otherwise noted.   
Subjects who meet the inclusion and exclusion criteria will be eligible to be enrolled in 
the study.  If a subject has not met all eligibility criteria at the end of the 28-day window, 
the subject will be registered as a screen failure.  Subjects who screen fail may be 
eligible for re-screening at the investigator’s discretion after consultation with Amgen 
(see also below for details on re-screening). 
Laboratory assessments used to determine subject eligibility may be repeated once for 
confirmation during the 28-day screening period before the subject is considered a 
screen failure.  If laboratory assessments are repeated during the screening period, the 
result of the last sample taken prior to start of treatment with AMG 510 will be taken into 
account for determination of subject eligibility. 
The following procedures are to be completed during the screening period at the time 
points designated in the Schedules of Activities (Table 1-1). 
Assessments that were performed as standard of care prior to signature of informed 
consent, but within the allowed 28-day screening window prior to start of treatment 
with AMG 510 can be used as screening assessments and do not need to be repeated 
to confirm subject eligibility. 
Rescreening: 
Subjects may be rescreened up to 2 times at the discretion of the investigator, after 
consultation with Amgen.  The subject must be reconsented if a rescreening attempt 
occurs more than 30 days after the original signing of the ICF. 
Rescreened subjects must be documented as screen-failed in the subject’s medical 
record and subsequently documented as rescreened.  Subjects will retain the same 
subject identification number assigned at the time of initial screening.  Once the subject 
is recorded as rescreened, a new 28-day screening window will begin.  The following 
assessments do not have to be repeated during rescreening, if they were performed as 
standard of care or during the initial screening attempt within the time frames specified 
below: 
 
Hepatitis serology does not need to be repeated if it was performed within 6 weeks 
prior to start of treatment with AMG 510. 

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 
Imaging assessments do not need to be repeated if they were performed within 
4 weeks prior to start of treatment with AMG 510. 
 
Central confirmation of KRAS p.G12C status (if applicable) 
Any other assessments do not need to be repeated if they were performed within the 
allowed 28-day screening window prior to start of treatment with AMG 510. 
8.1.2 
Treatment Period 
Treatment begins on day 1 of cycle 1 when the first dose of investigational product is 
administered to a subject.  AMG 510 will be administered orally QD for 21-day cycles, 
with no drug holidays between each cycle. 
During clinic visit days all protocol-required predose assessments have to be performed 
prior to administration of AMG 510.  Predose is defined as a time before dosing.   For 
laboratory assessments, predose assessments may be performed within  1 day for 
cycle 1 (except cycle 1 day 1 and cycle 1 day 8 where the window is -1 day) and cycle 2 
and  2 days after cycle 2.   
Results of any predose laboratory tests will not have to be available before the 
administration of AMG 510.  Laboratory assessments that were done within 24 hours 
prior to AMG 510 administration do not need to be repeated. 
AMG 510 will be dispensed to subjects at the beginning of each cycle and the subjects 
are required to bring the bottle of AMG 510 to clinic during clinic visit days.  AMG 510 
administration should be done in the clinic after all pre-dose assessments have been 
performed during clinic visit days. 
A paper diary will be provided to subjects at the beginning of each cycle and the study 
staff will provide guidance to the subjects on how to complete the diary. 
Administration of AMG 510 may continue until there is evidence of disease progression, 
intolerance to study medication, or withdrawal of consent. 
8.1.3 
End of Treatment Visit 
For subjects who discontinue investigational product, the end of treatment visit should 
occur as soon as possible (within 14 days) after the last dose of investigational product. 
8.1.4 
Safety Follow-up 
The SFU visit should occur approximately 30 ( 7) days after the last dose of AMG 510 
or before any new anticancer treatment is started, whichever occurs first.  The SFU visit 
will be the end of study visit for each subject.   

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8.1.5 
End of Study 
The end of study visit is defined as last subject last visit (eg, SFU) when assessments 
and/or procedures are performed. 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points.  Every effort should be taken to perform assessments on the indicated study 
day as described in the Schedule of Activities.  However, below are the accepted 
deviation windows for study visits.  This should be documented and will not be 
considered a deviation from the protocol. 
 
± 1 day for cycle 1 day 15 and cycle 2 day 8 visits 
 
± 2 days for visits during cycle 3 and beyond 
 
+ 7 days for safety follow-up visit 
Other general procedure windows: 
 
Screening assessments:  Day -28 to Day 1 
 
For laboratory assessments, every effort should be taken to perform 
assessments on the indicated study day.  However, a window of ± 1 day is 
allowable for cycle 1 and cycle 2 (except for cycle 1 day 1 and cycle 1 day 8 
where the window is -1 day).  A window of ± 2 days is allowable after cycle 2.  
The same laboratory result should not be used for multiple assessments (for 
example using cycle 1 day 1 labs for both cycle 1 day 1 and cycle 1 day 2). 
 
ECGs and vital signs:  ± 5 minute window (for time points of 0.25 hour and 
0.5 hour postdose), ± 15-minute window for all other postdose time points.   
 
On days of clinic visits, all predose assessments performed must be completed 
prior to dose administration (there is no allowance window, only that predose 
assessments must occur prior to dose administration). 
 
Pharmacokinetic:  blood samples should be collected at the exact nominal time 
point as noted in the SOA.  If it is not possible to collect a blood sample at the 
specified nominal time point, it should be collected it as close as possible to the 
nominal time point and the actual collection time recorded.  Pharmacokinetic 
samples not collected at exact nominal time point will not be considered protocol 
deviations.  Predose PK samples should be performed prior to AMG 510 dosing.  

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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. 
8.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started prior to screening and through screening until start of treatment.  Medical history 
will include information on the subject’s concurrent medical conditions.  Record all 
findings on the medical history eCRF.  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 eCRF (eg, medical history, event). 
8.2.1.5 
Physical Measurements 
Height (in centimeters) is only required at screening and weight (in kilograms) should 
be measured without shoes. 
8.2.1.6 
Substance Abuse History  
Obtain a detailed history of prior and concurrent use of tobacco. 
8.2.1.7 
Performance Status  
The performance status of each subject will be assessed using the ECOG Performance 
Status (Section 11.9) and per the time points listed in the Schedule of Activities  
(Table 1-1). 
8.2.2 
Efficacy Assessments 
Radiological Imaging Assessment 
The extent of disease will be evaluated by contrast-enhanced MRI/computed 
tomography (CT) according to RECIST version 1.1 (Section 11.8).  All radiological 
imaging will be performed as indicated in the Site Imaging Manual provided by the 

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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 
assessment 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 (refer to separate Brain MRI section for details regarding MRI of the brain).   
The same imaging modality, MRI field strength and IV and oral contrast agents should 
be used at screening should 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.  
During treatment and follow-up radiological imaging of the chest, abdomen, pelvis, as 
well as all other known sites of disease, will be performed independent of treatment 
cycle every 6  1 weeks for the first 4 response assessments, with the first post-baseline 
scan to occur 6  1 weeks after cycle 1 day 1.  After four 6-week response assessments, 
radiological imaging and tumor assessment will be performed every 12  1 weeks.  
Radiologic imaging and tumor assessment will be performed until disease progression, 
start of new anticancer treatment, death, withdrawal of consent or until end of study.  
Imaging may also be performed earlier/more frequently if clinically necessitated at the 
discretion of the managing physician.  Radiographic response (complete response [CR], 
PR) requires confirmation by a repeat scan at least 4 weeks after the first documentation 
of response and may be delayed until the next scheduled scan to avoid unnecessary 
procedures.  The minimum time interval for determination of stable disease 
is   5 weeks.   
Radiological imaging assessment during the end of treatment visit should be performed 
only for subjects that discontinue treatment for a reason other than disease progression 
per RECIST version 1.1 guidelines. 
Determination of disease response for clinical management of subjects will be assessed 
at the clinical sites per RECIST version 1.1.  Scans will be submitted to a central imaging 
core laboratory for archival, response assessment including RECIST version 1.1, and/or 
exploratory analysis (eg, volumetric and viable tumor measurements).  Detailed 

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information regarding submission of images to the central imaging core laboratory is 
found in the Site Imaging Manual. 
Brain MRI 
All subjects must have MRI of the brain performed within 28 days prior to first dose of 
AMG 510.  Subsequently, brain scans should be performed for all subjects with brain 
metastases or history of brain metastases and can also be performed at any time if 
necessary in the judgement of the managing physician.  All brain scans on protocol are 
required to be MRI unless MRI is contraindicated, and then CT with contrast is 
acceptable. 
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(see Table 1-1). 
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, pulse oximetry, and temperature.  The subject must be in a supine 
position in a rested and calm state for at least 5 minutes before blood pressure 
assessments are conducted.  If the subject is unable to be in the supine position, the 
subject should be in most recumbent position as possible.  The position selected for a 
subject should be the same that is used throughout the study and documented on the 
vital signs eCRF.  The temperature location selected for a subject should be the same 
that is used throughout the study and documented on the vital signs eCRF.  Record all 
measurements on the vital signs eCRF. 
8.2.3.2 
Electrocardiograms (ECGs) 
The 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.  
Electrocardiograms 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. 
 
single ECG collected during screening  

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 
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) (ie, total  9 ECGs)  
 
one triplicate ECG at time points after dosing  
Baseline is defined as prior to dosing on cycle 1 day 1.  The Principal Investigator or 
central reader will review all ECGs.  Electrocardiograms 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.  In certain 
circumstances Amgen may be able to provide a standard ECG machine if a site is 
unable to provide one. 
8.2.4 
Adverse Events and Serious Adverse Events  
8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the 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 the first dose of investigational 
product/study treatment through the SFU (end of study) visit are reported using the 
Events eCRF.  All other adverse events possibly related to any study procedures will be 
reported from the signing of the ICF through the SFU (end of study) visit using the 
Events eCRF. 
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 ICF through the 
safety follow-up visit or 30 days after the last day of dosing interval of investigational 
product(s)/protocol-required therapies, whichever occurs later, are reported using 
the Events CRF.   
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s 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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The criteria for grade 4 in the CTCAE version 5.0 grading scale differs from the 
regulatory criteria for serious adverse events.  It is left to the investigator’s judgment to 
report these grade 4 abnormalities as serious adverse events. 
8.2.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
After end-of study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  
However, if the investigator becomes aware of serious adverse events suspected to 
be related to the 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 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. 
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. 
8.2.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care should be taken not to introduce bias when detecting adverse events and/or 
serious adverse events.  Open-ended and non-leading verbal questioning of the subject 
is the preferred method to inquire about adverse event occurrence. 
8.2.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following 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.  

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Information provided about the serious adverse event must be consistent with that 
recorded on the Events eCRF. 
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. 
8.2.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and male subjects’ female 
partners will be collected after the start of study treatment and until 7 days after the last 
dose of AMG 510.  Female subjects who become pregnant while on study or within 
7 days after receiving the last dose of AMG 510 will not receive subsequent scheduled 
doses and will be followed for safety until the end of study visit. 
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. 

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Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.2.5 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-1) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event eCRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator’s 
judgment) are not to be recorded as adverse events.  However, laboratory value 
changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-1).  
Pregnancy Testing 
A highly sensitive serum pregnancy test should be completed at screening and a highly 
sensitive serum or urine pregnancy test should be completed within 7 days of initiation of 
investigational product and within 7 days of day 1 of each cycle for females of 
childbearing potential. 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional serum or urine pregnancy testing should be performed as outlined in the 
Schedule of Activities (Table 1-1). 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 

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8.2.6 
Pharmacokinetic Assessments 
All subjects will have PK samples assessed.  AMG 510 must be administered in the 
fasted state (no food or liquids, except water, 2 hours before to 1 hour after dosing) until 
cycle 2 day 2 and beyond at which time AMG 510 may be administered with or without 
food.  Subjects will receive AMG 510 with approximately 240 Ml (8 ounces) of water.  In 
the case of vomiting, refer to Table 6-1. 
On days in which PK samples are collected, food status will be recorded on each 
subject’s eCRF(s).  Subjects will be asked to record the date, time, and number of 
capsules consumed in a subject drug diary that must be brought to each study visit.  The 
dates of any missed doses or instances of emesis and diarrhea associated with capsule 
administration will also be recorded in the subject drug diary. 
Plasma samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of AMG 510 at time points as specified in the Schedule of Activities 
(Table 1-1).  A maximum of 3 samples may be collected at additional time points during 
the study if warranted and agreed upon between the investigator and the sponsor.  
Instructions for the collection and handling of biological samples will be provided by the 
sponsor.  The actual date and time (24-hour clock time) of each sample will be recorded. 
8.2.7 
Biomarkers 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  In this study, a specific genomic biomarker (KRAS p.G12C) needs to be 
identified as part of the screening process. 
Genomic Biomarker Assessment to Determine Eligibility (KRAS p.G12C) 
Tumor Tissue 
If KRAS p.G12C status is not available in the subject’s medical record, tumor tissue may 
be required to identify KRAS p.G12C status.  Tumor samples may be collected after 
informed consent is obtained.  Tumor tissue may be tested locally or submitted to the 
central laboratory either as FFPE blocks or unstained slides (see study laboratory 
manual for details).  Tissue should be submitted along with the corresponding pathology 
report. 
If archived FFPE tumor samples are not available, subjects will have the option to 
undergo a tumor biopsy to identify KRAS p.G12C status.  When a tumor biopsy is 
needed to screen for KRAS p.G12C, collection of tumor tissue following local standard of 

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care is not expected to present any additional risk to the health, safety, and welfare of 
the subject.  Screening for KRAS p.G12C may be conducted at a central or local 
laboratory as described in Appendix 2 (Section 11.2). 
The tumor block submitted is to be carefully selected by a pathologist or a skilled, 
experienced histology associate to include generous tumor tissue using the Pathology 
Report as a guide.  In lieu of a block, 20 unstained sections on charged slides from the 
same block can be submitted. 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
No statistical hypothesis will be tested. 
9.2 
Sample Size Determination 
Up to 18 evaluable subjects will be enrolled in this study.  Six DLT-evaluable subjects 
will be enrolled in cohort 1.  If the 960 mg dose (cohort 1) is recommended to be safe 
and tolerable by the DLRT, up to 6 additional subjects may be enrolled in cohort 1 to 
gather additional safety, PK, and preliminary efficacy data (up to 12 subjects total 
enrolled in the study) at the 960 mg dose.  Alternatively, if the DLRT recommends to 
open cohort 2 (720 mg dose), 6 DLT-evaluable subjects will be enrolled in cohort 2.  If 
the DLRT then makes the recommendation to continue cohort 2 at 720 mg, up to 6 
additional subjects (up to 18 subjects total enrolled in the study) may be enrolled in 
cohort 2 to gather additional PK, safety, and preliminary efficacy at the 720 mg dose. 
The sample size of 6-DLT evaluable subjects in the dose exploration phase for DLRM is 
based on practical considerations and is consistent with conventional oncology studies.  
With 6-DLT evaluable subjects, there is a 47% to 91% probability of observing at least 
1 DLT if the true DLT rate is 10% to 33%.   
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
9.3.1.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects that are enrolled and receive at least 1 
dose of AMG 510. 
The analysis of all endpoints, unless noted otherwise, will be conducted on the safety 
analysis set. 
The analysis of DLT will be restricted to DLT-evaluable subjects, which consists of 
subjects if either:  1) the subject experiences a DLT, or 2) the subject does not 

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experience a DLT and 3) subject received at least 80% of the planned doses of 
investigational product within the 21-day DLT window. 
9.3.1.2 
Pharmacokinetic Analysis Set 
The PK Analysis Set will contain all subjects who have received at least 1 dose of 
AMG 510 and have at least 1 PK sample collected.  These subjects will be evaluated for 
PK analysis unless the number of data points required for analysis is not enough, or 
significant protocol deviations have affected the data, or if key dosing or sampling 
information is missing. 
9.3.2 
Covariates 
There are no planned covariates for this study. 
9.3.3 
Subgroups 
Potential subgroups may be pre-specified in the statistical analysis plan. 
9.3.4 
Handling of Missing and Incomplete Data 
Descriptive statistics will be used to identify the extent of missing data.  Missing or 
incomplete dates that are critical for the analysis (eg, date of death, adverse event start 
date) will be imputed.  Detailed imputation rules will be documented in the statistical 
analysis plan. 
9.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
9.4.1.1.1 
Cohort 1 (Dose Exploration – first 6 DLT-evaluable subjects in 
cohort) 
Safety data will be reviewed on an ongoing basis.  The first DLRM will occur after the 
first 6 DLT-evaluable subjects enrolled in cohort 1 have the opportunity to receive 
21 days treatment.  In the dose level review meetings, Amgen, in consultation with the 
site investigators, will review all available cumulative data by cohort prior to making dose 
determination recommendations.  Adverse events and DLTs observed in all subjects will 
be evaluated continually and fully integrated into all dose level review meetings and 
considered in all enrollment and dosing recommendations.  Additional details regarding 
the dose review meeting are providing in Section 11.3. 

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The DLRT will be composed of the investigators, Amgen Medical Monitor, Amgen Global 
Safety Officer (GSO), Amgen Early Clinical Development Manager, and Biostatistics 
representative.  Additional members may be added as needed (eg, PK Scientist).  A 
quorum, defined as the majority of actively screening and enrolling investigators or their 
qualified designee (ie, sub-investigator possessing hard copy documentation [eg, email] 
of the investigator’s recommendation regarding the dose level review), 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, and all actively screening and enrolling investigators or their qualified 
sub-investigator designee. 
The team may recommend de-escalation to a lower dose, or termination of the study.  
The Amgen Medical Monitor and GSO and the majority of actively screening and 
enrolling investigators participating in the DLRM must cast a positive vote indicating an 
acceptable safety profile was observed for AMG 510 to allow the dose level modification 
and/or cohort continuation/expansion to proceed.  Available study data including 
demographics, smoking status (prior and current), medical history, concomitant 
medications, adverse events, ECGs, vital signs, laboratory results, emerging PK or 
pharmacodynamics, and emerging efficacy data will be reviewed. 
The following recommendations will be made by the DLRT: 
 
dose de-escalation recommendations 
 
number of subjects per cohort 
 
continuation, delay or termination of dosing 
 
change of the dosing schedule 
 
termination of the study 
9.4.1.1.2 
Cohort 2 (Dose Exploration – first 6 DLT-evaluable subjects in 
cohort) 
If in cohort 1, DLRT makes the recommendation to open cohort 2 (720 mg), the second 
dose level review meeting will occur after the sixth subject enrolled in cohort 2 has had 
the opportunity to receive 21 days of treatment.  
The same DLRT will be responsible for reviewing all cumulative available data by cohort.  
The same procedure and principal described in cohort 1 dose level review meeting will 
be applied in cohort 2 as well.   

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9.4.1.2 
Primary Analysis 
The primary analysis will occur after all subjects (6 to 12 subjects) enrolled in cohort 1 
and after all 6 to 12 subjects enrolled in cohort 2 (if  2 DLTs are observed in the first 6 
subjects in cohort 1) have had the opportunity to complete 6 months on study or have 
been withdrawn from study.   
9.4.1.3 
Final Analysis 
A final analysis is planned after all cohorts 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, PK, and 
preliminary efficacy data by dose, 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.  Subject 
listings for time-to-event endpoints may be provided instead of Kaplan-Meier estimates 
or Clopper Pearson exact confidence interval if the analysis set has fewer than 
10 subjects.  Graphical summaries of the data may also be presented. 
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable to the study 
Secondary 
Listings of secondary efficacy endpoints will be produced for all subjects.  
The proportion of subjects with an objective response, defined as CR  PR 
(assessed per RECIST version 1.1) will be described.  Similarly for 
proportion of subjects with disease control, defined as CR  PR  SD will 
be described. 
 
For all subjects treated at the planned dose, the Kaplan-Meier method will 
be used for time-to-event endpoints to estimate the survival curve, 
quartiles, and rates at selected timepoints with 95% CI for 1) duration of 
response, 2) progression-free survival, and 3) duration of stable disease.  
Event-free rates at 3-month intervals will be estimated using the 
Kaplan-Meier method for progression-free survival (PFS).   
 
Time to response will be summarized by the nonmissing sample size (n), 
standard deviation, median, minimum, and maximum for responders.  For 
secondary endpoint definitions, refer to the statistical analysis plan. 
 

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9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Unless otherwise specified, statistical analyses on safety endpoints will be 
done using subjects from the safety analysis set, which includes subjects that 
are enrolled and received AMG 510.  The statistical analysis methods are 
described in Section 9.4.2.3.2 through Section 9.4.2.3.5. 
 
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, and adverse events 
of interest (if applicable) will also be provided.   
9.4.2.3.3 
Laboratory Test Results 
Summaries of laboratory data over time and/or changes from baseline over time will be 
provided.  Tables of maximum shifts from baseline to the worst on-study value will be 
provided for selected laboratory values with National Cancer Institute-CTCAE grades. 
9.4.2.3.4 
Vital Signs 
Summaries of vital signs data over time and/or changes from baseline over time will be 
provided.  
9.4.2.3.5 
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. 
9.4.2.3.6 
Exposure to Investigational Product 
Descriptive statistics of cumulative dose, number of cycles, duration of usage, number 
and percentage of subjects with dose modifications and reasons will be produced to 
describe the exposure to AMG 510. 
Subject-level data may be provided instead of the summary if the subject incidence is 
low or single dose is given. 

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9.4.2.3.7 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving concomitant medication will be summarized 
by preferred term as coded by the World Health Organization Drug Dictionary. 
9.4.2.4 
Other Analyses 
For AMG 510, PK parameters including, but not limited to Cmax, tmax, and AUC will be 
determined from the concentration-time profile using standard non-compartmental 
approaches and considering the profile over the complete sampling interval.  Based on 
the review of the data, analyses to describe the relationship between AMG 510 exposure 
and either pharmacodynamic effect and/or clinical outcome may also be performed. 

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10. 
References 
American Cancer Society.  Cancer Statistics Center.  Atlanta, Ga:  American Cancer 
Society; 2019.  Accessed at:  
https://cancerstatisticscenter.cancer.org/?_ga=2.231006559.1584449027.1563387628-
1207406634.1563387628&_gac=1.251316914.1563387628.EAIaIQobChMIwPSG28i84
wIVSmoqCh0i7A_EEAAYASAAEgLkLPD_BwE#!/ on 17 July 2019. 
American Cancer Society.  Cancer Facts & Figures.  Atlanta, Ga:  American Cancer 
Society; 2018.  Accessed at:  https://www.cancer.org/research/cancer-facts-statistics/all-
cancer-facts-figures/cancer-facts-figures-2018.html on 12 July 2019. 
AMG 510 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Der CJ, Krontiris TG, Cooper GM.  Transforming genes of human bladder and lung 
carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma 
viruses.  Proc Natl Acad Sci USA.  1982;79(11):3637-3640. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/. 
Jones RP, Sutton PA, Evans JP, et al.  Specific mutations in KRAS codon 12 are 
associated with worse overall survival in patients with advanced and recurrent colorectal 
cancer.  Br J Cancer.  2017;116(7):923-929. 
National Comprehensive Cancer Network.  NCCN Clinical Practice Guidelines in 
Oncology:  Non-Small Cell Lung Cancer.  Version 3.2018.  February 2018.  
Accessed at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.  
Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM.  K-Ras (G12C) inhibitors 
allosterically control GTP affinity and effector interactions.  Nature.  2013;503:548. 
Simanshu DK, Nissley DV, McCormick F.  RAS proteins and their regulators in human 
disease.  Cell.  2017;170:17-33. 
Smith G, Bounds R, Wolf H, et al.  Activating K-ras mutations outwith ‘hotspot’ codons in 
sporadic colorectal tumours – implications for personalized cancer medicine.  Br J 
Cancer.  2010;102:693-703. 
World Health Organization.  2018 Statistics.  Accessed at:  
https://www.who.int/news room/fact-sheets/detail/cancer on 12 July 2019. 

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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 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
Anti-HBs 
hepatitis B surface antibody 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration time curve 
BCRP 
breast cancer resistance protein 
CFR 
U.S. Code of Federal Regulations 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
Case Report Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interactions 
DES 
Amgen data element standard 
DILI 
drug induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
EMR 
Electronic Medical Record 
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  

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Abbreviation or Term 
Definition/Explanation 
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, as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
ERK 
extracellular signal-regulated kinase 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GDP 
guanosine diphosphate 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GSO 
Global Safety Officer 
GTP 
guanosine triphosphate 
Hep 
hepatitis  
HepBsAg 
hepatitis B surface antigen 
HbA1c 
hemoglobin A1c 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
HRT 
hormonal replacement therapy 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
ILD 
interstitial lung disease  
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IV 
intravenous 
KRAS 
Kirsten rat sarcoma  
MATE1 
multidrug and toxin extrusion protein 1 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high 

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Abbreviation or Term 
Definition/Explanation 
NCT 
National Clinical Trials 
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PO 
administered orally 
PPI 
proton pump inhibitor 
PR 
partial response 
Q2C 
every other cycle from cycle 7 and beyond 
QC 
every cycle from cycle 7 and beyond 
QD 
once daily 
QTc 
corrected QT interval 
RAF 
rapidly accelerated fibrosarcoma 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rSDR/V  
remote Source Data Review and Verification 
Screen 
screening  
SD 
stable disease 
SFU 
safety follow-up 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SOS1 
son-of-sevenless homolog 1 
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. 
STD10 
severely toxic dose in 10% 
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 

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Abbreviation or Term 
Definition/Explanation 
t1/2,z 
terminal half-life associated with z 
tmax 
time to achieve Cmax 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor  
WBC 
white blood cell 
 
 
11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory and/or by the 
local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 11-1.  Analyte Listing 
Local Laboratory:  
Chemistry 
Local Laboratory:  
Coagulation 
Local Laboratory:  
Urinalysis 
Local 
Laboratory:  
Hematology 
Central 
Laboratory 
sodium 
potassium 
chloride 
bicarbonate  
total protein 
albumin 
calcium 
magnesium 
phosphorus 
glucose 
BUN or urea 
creatinine 
total creatine 
kinase 
total bilirubin 
direct bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
Glomerular filtration 
rate (derived) 
PT/INR 
PTT/aPTT 
fibrinogen 
(optional) 
D-dimer 
(optional) 
specific gravity 
pH 
blood 
protein 
glucose 
bilirubin 
ketones 
sodium  
(optional) 
potassium 
(optional) 
Microscopic examc: 
 cellular casts 
 granular casts 
 hemoglobin casts 
 hyaline casts 
 mixed casts 
 WBC 
 RBC 
 epithelial cells 
 bacteria 
 urine casts 
RBC 
hemoglobin 
hematocrit 
MCV  
platelets 
calculated 
absolute 
neutrophil 
count (derived) 
WBC 
differential: 
 total 
neutrophils 
 eosinophils 
 basophils 
 lymphocytes 
 monocytes  
PK 
sampling 
tumor 
biopsyb 
Local Laboratory: 
Serology 
 Hep B surface 
antigen 
Hep C antibody 
Anti-HBs 
Local Laboratory:  
Thyroid Panel 
TSH 
Total T3 (or free 
T3 per local 
standard) 
Free T4 
Local Laboratory: 
Lipid Panel  
total cholesterol 
LDL 

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Local Laboratory:  
Chemistry 
Local Laboratory:  
Coagulation 
Local Laboratory:  
Urinalysis 
Local 
Laboratory:  
Hematology 
Central 
Laboratory 
HDL 
triglycerides 
Local Laboratory:  
Other 
HbA1c 
Serum or urine 
pregnancya 
Footnotes defined on next page 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; HbA1c = hemoglobin A1c; HDL = high 
density lipoprotein; Hep = hepatitis; HIV = human immunodeficiency virus; INR = international normalized 
ratio; LDL = low density lipoprotein; MCV = mean corpuscular volume; PK = pharmacokinetics; 
PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell count; SGOT = serum 
glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cell count. 
Note:  For creatinine clearance calculation, Modification of Diet in Renal Disease formula should be used:  
GFR (mL/min/1.73 m2) = 175 x SCr (mg/dL)-1.154 x age-0.203 x 0.742 (if female) x 1.21 (if African American) x 
0.763 (if Japanese) x 1.233 (if Chinese). 
a For female subjects of childbearing potential only.  At screening, a highly sensitive serum pregnancy test is 
required.  For all other time points, a highly sensitive serum or urine pregnancy test is required. 
b Only applicable if KRAS p.G12C status is unknown at screening.  Archived FFPE tumor tissue is 
acceptable.  If archived tumor tissue is not available, a tumor biopsy may be performed.  Testing for KRAS 
p.G12C can be performed locally or centrally. 
c Microscopic exam to be performed at the discretion of the investigator.   
 

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11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings (DLRM)  
A DLRM is conducted to review and interpret safety data for the purposes of making 
recommendations 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.  Additional members may be added as needed (eg, 
Pharmacokinetics [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 the majority of actively screening and enrolling investigators or their qualified 
designees (ie, sub-investigator possessing hard copy documentation [eg, email] of the 
investigator’s recommendation regarding the dose level review).  The DLRM will be 
rescheduled if these requirements are not met.  
Available study data, including demographics, smoking status (prior and current), 
medical history, concomitant medications, adverse events, electrocardiograms (ECGs), 
vital signs, laboratory results, emerging PK or pharmacodynamics, and emerging 
efficacy data will be reviewed. 
Dose Level Review Meeting 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 (if applicable), must be 
by unanimous vote.  If the voting members of the DLRT are not able to reach a 

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unanimous recommendation on whether to escalate to the next planned cohort or to an 
intermediate cohort, then this should be reflected in the DLRM Memo (FORM-115760).  
Other recommendations, such as expanding a cohort or lowering a dose will be made by 
a majority vote. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and ICF must be received by Amgen before recruitment of 
subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 

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

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and/or procedures must also be documented in the subject’s medical records; refer to 
Section 7. 
Subjects must be re-consented to the most current version of the ICF (s) during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional future research.  The investigator or authorized designee will 
explain to each subject the objectives of the future research.  Subjects will be told that 
they are free to refuse to participate and may withdraw their specimens at any time and 
for any reason during the storage period.  A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for future 
research.  Subjects who decline to participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 

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Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 

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data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.   Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 

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any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with national and/or local regulations, remote Source Data Review 
and Verification (rSDR/V) can be implemented.  The clinical monitor should be 
provided with a secure, read-only access to the Electronic Medical Record (EMR) 
system, including all modules relevant for review.  This access should be 
restricted to the records of only those patients who participate in the trial and who 
did not object to remote access to their medical records.  A list of the monitors to 
whom remote access has been granted should be maintained.  In order to prevent 
unauthorized access, access rights should be revoked once rSDR/V tasks have 
been completed for the trial.  The EMR system should have an audit trail and be 
able to log information on who accessed data and when.  Remote access to the 
EMR should only be possible using a two-factor authentication.   
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 must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.   
Consult the country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 

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Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the 
interactive response technology system (if used, such as subject ID and randomization 
number) and CRF entries if the CRF is the site of the original recording (ie, there is no 
other written or electronic record of data, such as paper questionnaires for a clinical 
outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 

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In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
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 statistical analysis plan. 
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/metastatic 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.  
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. 

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

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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 CRF. 
 
The investigator must assign the following adverse event attributes: 
 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
 
dates of onset and resolution (if resolved); 
 
Did the event start prior to first dose of investigational product; 
 
assessment of seriousness; 
 
severity (or toxicity defined below); 
 
assessment of relatedness to investigational product (AMG 510), other protocol-
required therapies, and/or study-mandated activity and/or procedures and; 
 
action taken and 
 
outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of resolution, 
record as a single event with the highest grade on the Events electronic CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical records 
to the sponsor in lieu of completion of the Events CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to Amgen. 
 
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. 
 

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Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational product, 
protocol-required therapies, and/or study-mandated activity and/or procedure and each 
occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and has 
provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Amgen to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully 
as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of a serious 
adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide Amgen with a copy of any post-mortem findings including 
histopathology. 
 
New or updated information will be recorded in the originally completed Events CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen within  
24 hours of receipt of the information. 

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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 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 
awareness of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on 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 
 

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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 must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant or father a 
child during treatment and for an additional 7 days after the last dose of AMG 510.  
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and/or for an increased length of time.  In addition, male 
subjects may also be required to use contraception.  The investigator must discuss 
these contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Females with 
documented permanent infertility due to an alternate medical cause (eg, Mullerian 
agenesis, androgen insensitivity, gonadal dysgenesis), can be considered not of 
childbearing potential. 
Note: Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of ≥ 55 years with no menses for 12 months without an alternative medical 
cause OR   
 
A woman age < 55 years with no menses for at least 12 months and with a follicle-
stimulating hormone (FSH) level within the definition of “postmenopausal range” for 
the laboratory involved.  In the absence of 12 months of amenorrhea, confirmation 
with more than one FSH measurement is required.  
Contraception Methods for Female Subjects 

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Highly Effective Contraceptive Methods 
Note: Failure rate of < 1% per year when used consistently and correctly. 
 
Intrauterine device  
 
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 7 days after the last dose of 
protocol-required therapies 
The female partner should consider using an acceptable method of effective 
contraception such as: hormonal, intrauterine device, intrauterine hormonal-releasing 
system, female barrier method (diaphragm, cap, sponge [a female condom is not an 
option because there is a risk of tearing when both partners use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
withdrawal (coitus interruptus) 
 
spermicides only 
 
lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through an additional 7 days after 
the last dose of AMG 510. 

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 
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 the 
site's awareness of a subject’s pregnancy.  (Note: Sites are not required to provide 
any information on the Pregnancy Notification Form that violates the country or 
regions local privacy laws). 
 
After obtaining the female subject’s signed 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 through the end of 
study visit.  This information will be forwarded to Amgen Global Patient Safety.  
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an adverse event or serious adverse event.  
Abnormal pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, 
congenital anomalies) will be reported as an adverse event or serious adverse 
event.  Note that an elective termination with no information on a fetal congenital 
malformation or maternal complication is generally not considered an adverse 
event, but still must be reported to Amgen as a pregnancy exposure case. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
Male Subjects With Partners Who Become Pregnant 
 
In the event a male subject fathers a child during treatment, and for an additional 
7 days 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 consent for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed consent for release of pregnancy and 
infant health information, the investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 

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 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through an additional 7 days after the last 
dose of AMG 510. 
 
Information will be recorded on the Lactation Notification Form (see Figure 11-2 
below) and submitted to Amgen Global Patient Safety within 24 hours of the 
investigator’s awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 215. 
 
With the female subjects signed consent for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through the end of study visit 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 or tissue samples collected according to the Schedule of Activities (Table 1-1) 
can be analyzed for any of the tests outlined in the protocol and for any tests necessary 
to minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can perform additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
solid tumors, the dose response and/or prediction of response to AMG 510, 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 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 
samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 

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

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

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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and/or 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 
-- 
> 1.5 x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 5 x ULN at any time 
> 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. 
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 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 > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
complete blood count with differential to assess for eosinophilia 
 
serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
serum acetaminophen (paracetamol) levels 

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

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11.8 
Appendix 8.  Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1) 
Quick Reference 
Definitions 
 
Measurable Lesions 
 
Measurable Tumor Lesions – Non-nodal lesions with clear borders that can be 
accurately measured in at least 1 dimension with longest diameter  10 mm in 
computed tomography/magnetic resonance imaging (CT/MRI) scan with slice 
thickness no greater than 5 mm.  When slice thickness is greater than 5 mm, the 
minimum size of measurable lesion should be twice the slice thickness. 
 
Nodal Lesions - Lymph nodes are to be considered pathologically enlarged and 
measurable, a lymph node must be  15 mm in short axis when assessed by 
CT/MRI (scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
▪ 
Nodal size is normally reported as 2 dimensions in the axial plane.  
The smaller of these measures is the short axis (perpendicular to the 
longest axis). 
 
Irradiated Lesions - Tumor lesions situated in a previously irradiated area, or in 
an area subjected to other loco-regional therapy, are not measurable unless there 
has been demonstrated progression in the lesion prior to enrollment. 
 
Non-measurable Lesions 
 
All other lesions, including small lesions (longest diameter  10 mm or pathological 
lymph nodes with  10 mm but to  15 mm short axis with CT scan slice thickness 
no greater than 5 mm) are considered non-measurable and characterized as  
non-target lesions. 
 
Other examples of non-measurable lesions include: 
▪ 
Lesions with prior local treatment:  tumor lesions situated in a 
previously irradiated area, or an area subject to other loco-regional 
therapy, should not be considered measurable unless there has been 
demonstrated progression in the lesion. 
▪ 
Biopsied lesions 
▪ 
Categorially, clusters of small lesions, bone lesions, inflammatory 
breast disease, and leptomeningeal disease are non-measurable. 
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 

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consistent administration (dose and rate) of intravenous (IV) contrast as well as timing 
of scanning.  Computed tomography 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 2 lesions per organ and 
5 lesions in total, representative of all involved organs should be identified as target 
lesions and recorded and measured at baseline. 
 
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and suitability for accurate repeated measurements. 
 
Pathologic lymph nodes (with short axis  15 mm) may be identified as target 
lesions.  All other pathological nodes (those with short axis  10 mm but 
 15 mm) should be considered non-target lesions. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum of 
diameters.  The baseline sum of diameters will be used as reference by which to 
characterize objective tumor response. 
 
Non-Target Lesions - All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be recorded 
at baseline.  Measurements of these lesions are not required, and these lesions 
should be followed as “present”, “absent”, or “unequivocal progression” throughout 
the study.  In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the CRF (eg, “multiple enlarged pelvic lymph nodes” 
or “multiple liver metastases”).  
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to  10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum of 
diameters. 
Progressive Disease (PD) 
At least a relative 20% increase and an absolute increase 
of 5 mm in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study, or the 
appearance of 1 or more new lesions. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum of diameters since the treatment started. 

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Evaluation of Non-target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be  
non-pathological in size ( 10 mm short axis). 
Incomplete Response/Stable 
Disease (SD) 
Persistence of one or more non-target lesions(s) and/or 
maintenance of I’ level above the normal limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions 
and/or appearance of one or more new lesionsa. 
a To achieve “unequivocal progression” on the basis of the non-target disease, there must be an overall level 
of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. 
Evaluation of Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment 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. 
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; PD = progressive disease; PR = partial response; NE = not evaluable; 
SD = stable disease. 

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Time Point Response:  Subjects with Non-target Disease Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “SD” for non-target disease since SD is increasingly used as endpoint 
for assessment of efficacy in some trials, so to assign this category when no lesions can be measured is 
not advised. 
Overall Response:  Confirmation of Complete Response (CR) and Partial 
Response (PR) required 
Overall Response First 
Time Point 
Overall Response 
Second Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
CR = complete response; PD = progressive disease; PR = partial response; NE = not evaluable; 
SD = stable disease. 
a If a CR is truly met at first time point, then any disease at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared 
after CR).  Best response would depend on whether minimum duration for SD was met.  However, 
sometimes “CR” may be claimed when subsequent scans suggest small lesions were likely still present 
and in fact that subject had PR, not CR at the first time point.  Under these circumstances, the original CR 
should be changed to PR and the best response is PR. 

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Special Notes on Response Assessment 
 
Nodal lesions – Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded, even if the nodes regress to below 10 mm 
on study.  In order to qualify for complete response (CR), each node must achieve a 
short axis  10 mm, NOT total disappearance.  Nodal target lesion short axis 
measurements are added together with target lesion’ longest diameter 
measurements to create the sum of target lesion diameters for a particular 
assessment (timepoint). 
 
Target lesions that become “too small to measure” – While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their measurements recorded at 
each subsequent evaluation.  If a lesion becomes less than 5 mm, the accuracy of the 
measurement becomes reduced.  Therefore, lesions less than 5 mm are considered as 
being “too small to measure” and are not measured.  With this designation, they are 
assigned a default measurement of 5mm.  No lesion measurement less than 5 mm 
should be recorded, unless a lesion totally disappears and “0” can be recorded for the 
measurement. 
 
New lesions – The term “new lesion” always refers to the presence of a new finding 
that is definitely tumor.  New findings that only may be tumor, but may be benign 
(infection, inflammation, etc.) are not selected as new lesions, until that time when 
the review is certain they represent tumor.   
 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
 
A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression, regardless of any response that may be seen in target or non-target 
lesions present from baseline. 
 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.”  Every effort should be made to 
document the objective progression with an additional imaging assessment even 
after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from scar or 
normal tissue.  When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be further investigated by 
fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET/CT, or 
possibly fine needle aspirate/biopsy, to confirm the CR status. 
Confirmation Measurement / Duration of Response 
 
Response Confirmation - In non-randomized trials where response is the primary 
endpoint, confirmation of PR and CR at least 4 weeks after the initial assessment 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 PD 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 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 108 of 109 
CONFIDENTIAL  
 
 
11.9 
Appendix 9.  Eastern Cooperative Oncology Group Performance 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
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 selfcare, but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3  Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4  Completely disabled.  Cannot carry out any selfcare.  Totally confined to bed or chair 
5  Dead 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 109 of 109 
CONFIDENTIAL  
 
 
11.10 
Appendix 10.  Examples of Excluded Treatments 
Examples of sensitive clinical substrates for CYP3A-mediated metabolism 
alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, 
lomitapide, lovastatin, lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, ticagrelor, tipranavir, tolvaptan, 
triazolam, vardenafil 
Examples of strong clinical inhibitors for CYP3A-mediated metabolisms 
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, 
elvitegravir and ritonavir, grapefruit juice, idelalisib, indinavir and ritonavir, itraconazole, 
ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, troleandomycin, voriconazole 
Examples of strong clinical inducers for CYP3A-mediated metabolisms 
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
Source:  https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers 
 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 1 of 21 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Phase 1, Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 510 in Subjects of Chinese Descent With 
Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation (CodeBreaK 105)  
 
Amgen Protocol Number AMG 510 20190147 
 
Amendment Date: 
05 January 2022 
 
Rationale: 
This protocol has been amended mainly to:    
 
Update dosage modification guidelines for hematologic and non-hematologic toxicities 
(Section 6.2.3.1, Table 6-3) and dosing instructions for AMG 510 (Section 6.1.1, 
Table 6-1) as the Amgen investigational product in the study.   
 
Update key safety information to be monitored in the clinical study, newly added 
information pertaining to thyroid abnormalities, and interstitial lung disease/pneumonitis 
(Section 2.3). 
 
Clarify definition of AMG 510 overdose and instructions for the physician/investigator to 
manage such event (Section 6.6).   
 
Add information regarding the treatments that must be avoided prior to enrollment and 
during the study period (Sections 6.1.7 and 6.7.2) and instructions on how to administer 
such medications (concomitant medications) in case they are considered a medical 
necessity (ie, antacid therapy). 
 
Update instructions for reporting serious adverse events observed by the investigator or 
reported by the subject during the study and after end of study (Sections 1.3 and 8.2.4) 
as well as language related to definitions and procedures for recording, evaluating, 
follow-up and reporting safety events (Section 11.4).   

Product:  AMG 510 
Protocol Number:  20190147 
Date:  05 January 2022 
Page 2 of 21 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Clarify that standard of care treatment (eg, procedures, laboratory studies) can be used 
during the screening process if they were conducted within the 28-day screening window 
prior to cycle 1 day 1 (Sections 1.1, 5, 8.1.1).  
 
Clarify nature of laboratory assessments in the schedule of activities (ie, lipid panel) and 
inform that local urinalysis and coagulation assessments are at the discretion of the 
investigator (Section 1.3, 11.2). 
 
Add background information regarding AMG 510 as a new approved treatment for adult 
patients with KRAS pG12C-mutated locally advanced or metastatic non-small cell lung 
cancer (Section 2.2.1).   
 
Clarify that individuals who experience a screen failure may be rescreened up to 2 times 
(Section 5.3). 
 
Update study assessments and procedures to describe alternative methods to continue 
safety assessments and study medication in patients unable to visit the study sites 
(Section 8) and to describe requirement for completion of physical measurements 
(Sections 1.3 and 8.2.1.5). 
 
Add language pertaining to Coronavirus disease 2019 (COVID-19) related benefit/risk 
assessment (Section 2.3). 
 
Add strategies to increase data quality assurance including implementation of the 
remote Source Data Review and Verification and read-only access for the clinical 
monitor to the electronic medical record system (Section 11.3).   
 
Provide general clarifications about the use of investigational medical devices in this 
study (Section 6.1.3) and about product complaints (Section 6.1.6).    
 
Multiple changes for clarification, administrative, typographical, and formatting were 
made throughout the protocol.   
 
 
 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  16 December 2020 
Page 1 of 26 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Phase 1, Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 510 in Subjects of Chinese Descent With 
Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation (CodeBreaK 105)  
 
Amgen Protocol Number AMG 510 20190147 
 
Amendment Date: 
16 December 2020 
 
Rationale: 
This protocol is being amended to: 
 
To add additional subjects at a dose level considered safe and tolerable by the dose 
level review team (DLRT) to collect additional pharmacokinetic (PK), safety, and 
preliminary efficacy data. 
 
To clarify allowable time windows for visits and study-required assessments.  
 
To add additional concomitant medication use information regarding gastric acid 
controllers based on developing pharmacokinetic data.  
 
Updates to statistical sections to align with the addition of more subjects to the study.  
 
Corrections and clarifications to the analyte Table 11-1.  

Product:  AMG 510 
Protocol Number:  20190147 
Date:  18 September 2020 
Page 1 of 29 
Amgen Proprietary - Confidential 
Amendment 2 
Protocol Title:  A Phase 1, Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 510 in Subjects of Chinese Descent With 
Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation (CodeBreaK 105) 
Amgen Protocol Number AMG 510 20190147 
 
Amendment Date: 
18 September 2020 
 
Rationale: 
This amendment is being updated to: 
 
Remove the timing requirement for predose safety lab assessments 
 
Changes to eligibility to have received an anti-PD(L)1 and/or platinum as well as received 
2 prior systemic therapies rather than 3  
 
Clarification of a second DLRM for the second cohort 
 
Remove thyroid panel assessment at cycle 1 day 1 
 
Added key safety information (increases in AST and ALT) 
 
Other administrative changes (typographical, formatting) 
 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  04 February 2020 
Page 1 of 29 
CONFIDENTIAL 
 
 
Amendment 1.0 
Protocol Title:  A Phase 1, Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AMG 510 in Subjects of Chinese Descent With 
Advanced/Metastatic Solid Tumors with KRAS p.G12C Mutation (CodeBreak 105) 
 
Amgen Protocol Number:  AMG 510 20190147 
 
Amendment Date: 
04 February 2020 
 
Rationale: 
The below AMG 510 program-wide changes were incorporated into the study:   
 
Thyroid function, cholesterol, and triglyceride tests were added to the Schedule of 
Activities in this study to make it consistent with Study 20170543 that was amended 
to address regulatory agency feedback (US Food & Drug Administration) 
 
Removed food restriction for AMG 510 at cycle 2 day 2 and beyond (after intensive 
pharmacokinetics assessments) as the studies evaluating the effect of food (high fat 
meal) on pharmacokinetic characteristics of AMG 510 demonstrated that high-fat 
meal does not appear to result in clinically meaningful alteration of AMG 510 
exposure 
 
Removed reference to “30 tablets/bottle” to allow flexibility in AMG 510 supply 
 
Updated language for AMG 510 dose modification to allow additional dose 
reductions of AMG 510 in the case of indicated toxicities 
 
Added AMG 510 Hepatotoxicity Guidelines for management and monitoring of 
subjects with increased AST, ALT, or ALP while on trial  
 
Revised the Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information based on data from recently completed nonclinical studies (absence of 
genotoxic risk for AMG 510 based on recently completed GLP-compliant in vitro 
bacterial mutagenicity Ames assay and in vivo genotoxicity study including the 
erythrocyte micronucleus test and the alkaline comet assay). 
 
Modified hepatotoxicity stopping rules (Appendix 7) to align with guidelines for the 
management of AMG 510 hepatotoxicity 
Other Changes:  
 
Added CodeBreak 105 study name 
 
Removed exploratory objective/endpoint to identify metabolites of AMG 510 in 
plasma and urine 
 
Modified header rows in Schedule of Activities to clarify that assessments on  
cycle 2 day 8, cycles 3,5;4,6; QC and Q2C will be completed prior to dosing 
 
Clarified timepoints for electrocardiogram and vital signs assessments in Schedule of 
Assessments footnote e 

Product:  AMG 510 
Protocol Number:  20190147 
Date:  04 February 2020 
Page 2 of 29 
CONFIDENTIAL 
 
 
 
Changed language to allow MRI brain scans to be performed in all subjects at 
screening, and in subjects with brain metastases or history of brain metastases at 
other indicated timepoints  
 
Added language to update AMG 510 nonclinical toxicology information with 3-month 
dog and rat results. 
 
Added language to clarify the definition of predose and timepoint window for predose 
laboratory assessments 
 
Added language to clarify the minimum time interval for determination of stable 
disease 
 
Modified table of analyte listings in Appendix 2 to include new laboratory tests 
 
Corrected the number of target lesions for RECIST v1.1 in Appendix 8 
 
Added language to clarify that an assessment of PR and CR must be confirmed  
≥ 4 weeks after the initial assessment 
 
Added a new appendix to present examples of excluded treatments  
 
Administrative and editorial updates