Conditions: Hepatic Impairment
Keywords: Hepatic Impairment Sotorasib
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: yes

Brief summary:
The main purpose of the study is to evaluate the pharmacokinetics (PK) of a single oral dose of sotorasib administered in participants with moderate or severe hepatic impairment compared to participants with normal hepatic function.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Sotorasib
Intervention descriptions: intervention 1: Sotorasib will be administered as an oral tablet.

Protocol document:
Prot_000.pdf: 
Protocol 
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Amgen Protocol Number: 20200362 
Protocol Version 1.0, 09 February 2021 
Page 1 of 67 
TITLE PAGE 
Protocol 
An Open-label Single-dose Study to Evaluate the Pharmacokinetics of 
Sotorasib in Healthy Subjects and Subjects with Moderate or Severe Hepatic 
Impairment  
Protocol Status: Final 
Protocol Date: 09 February 2021 
Protocol Version: 1.0 
Investigational Product: Sotorasib (AMG 510) 
Amgen Protocol Reference Number: 20200362 
Covance Study Number: 8454975 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
NCT Number: NCT04887064
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


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Protocol Version 1.0, 09 February 2021  
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Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the Institutional Review Board/Independent Ethics Committee/Institutional 
Scientific Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


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INVESTIGATOR AGREEMENT 
I have read the protocol entitled “An Open-label Single-dose Study to Evaluate the 
Pharmacokinetics of Sotorasib in Subjects with Moderate and Severe Hepatic Impairment 
Compared to Healthy Subjects” and agree to conduct the study as described herein. 
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 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) 


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STUDY IDENTIFICATION 
Sponsor 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Sponsor’s Study Contact 
, PhD 
Clinical Pharmacologist 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Tel: 
Email: 
 
Medical Monitor 
 
, MD, PhD 
Medical Director 
Covance Clinical Pharmacology Services 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA  
Tel (Office)
Email: 
 
Covance Project Manager 
 
Project Manager 
Covance Clinical Pharmacology Services 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Tel:
Email: 
 
Sponsor’s Study Manager 
 
Global Early Clinical Development Manager 
Amgen Inc. 
One Amgen Center Drive,  
Thousand Oaks, California 91320 
USA 
Tel:
Email: 
 
Statistician 
, MS 
Senior Biostatistician 
Covance, Inc. 


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3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Tel:
Email: 
 


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SYNOPSIS 
Title of study: An Open-label Single-dose Study to Evaluate the Pharmacokinetics of 
Sotorasib in Subjects with Moderate or Severe Hepatic Impairment Compared to Healthy 
Subjects 
Objectives:  
The primary objective of the study is: 
 
to evaluate the pharmacokinetics (PK) of a single oral dose of sotorasib administered 
in subjects with moderate or severe hepatic impairment compared to subjects with 
normal hepatic function. 
The secondary objective of the study is:  
 
to evaluate the safety and tolerability of sotorasib administered in subjects with 
moderate or severe hepatic impairment compared to subjects with normal hepatic 
function. 
Study design: 
This will be a Phase 1, parallel-arm, multi-center (US), open-label, non-randomized study to 
evaluate the PK of a single oral dose of sotorasib administered in subjects with normal hepatic 
function (control) and in subjects with moderate or severe hepatic impairment (according to 
Child-Pugh classification) under fasted conditions. Subjects who meet eligibility requirements 
will be assigned to 1 of 3 groups as shown below: 
Group 
Degree of Hepatic Impairment 
Number of Subjects 
1 
Normal function (no impairment) 
6 to 8 
2 
Moderate impairment (Child-Pugh Class B) 
6 to 8 
3 
Severe impairment (Child-Pugh Class C) 
6 to 8 
The classification is based on Child-Pugh scores as per Figg and Dukes.  
 Attempts will be made to match for age (mean  10 years), sex, and body mass index (mean  
20) of the healthy subjects to the combined moderate and severe impairment subjects.  
Up to 8 subjects can be enrolled in Group 1 to satisfy matching criteria. Up to 8 subjects will 
be enrolled in Groups 2 and 3 to ensure 6 evaluable subjects. Subjects will maintain the same 
group assignment throughout the study. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the dose administration. Subjects will be admitted into the study site on Day 1 and be 
confined until discharge on Day 8. On Day 1, after at least a 10-hour fast, all subjects will 
receive a single oral dose of 960 mg sotorasib (8 x 120-mg tablets). 
Number of subjects: 
Approximately up to 24 subjects will be enrolled, with a minimum of 6 evaluable subjects and 
a maximum of up to 8 subjects in Group 1, and a maximum of 16 subjects enrolled in Groups 2 
and 3 (8 subjects in each hepatic impairment group to ensure 6 evaluable subjects). 


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Diagnosis and main criteria for inclusion: 
Male subjects or female subjects, aged between 18 and 70 years (inclusive); with a body mass 
index between 18.0 and 38.0 kg/m2 (inclusive); with normal hepatic function, moderate hepatic 
impairment, or severe hepatic impairment. Female subjects will be of nonchildbearing 
potential.  
Investigational products, dose, and mode of administration: 
960 mg sotorasib, given orally as 8 x 120-mg tablets, on Day 1 following at least a 10-hour 
fast.  
Duration of subject participation in the study: 
The total duration of study participation for each subject (from Screening through end of 
study) is anticipated to be approximately 4 weeks.  
Primary Endpoints: 
The primary endpoints of the study are PK parameters for sotorasib: 
 
maximum observed plasma concentration (Cmax) 
 
area under the plasma concentration‑time curve (AUC) from time zero to the last 
quantifiable concentration (AUClast) 
 
AUC from time zero to infinity (AUCinf). 
 
Additional PK parameters may be calculated. 
 
Secondary Endpoints: 
The secondary endpoints of the study are: 
 
adverse events 
 
clinical laboratory evaluations 
 
12-lead electrocardiograms 
 
vital signs 
 
unbound Cmax (Cmax,u) 
 
unbound AUClast (AUClast,u) 
 
unbound AUCinf (AUCinf,u) 
 
unbound apparent total plasma clearance (CLu/F) 
 
unbound apparent volume of distribution during the terminal phase (Vz,u/F). 


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Statistical methods: 
The primary PK parameters are Cmax, AUClast, and AUCinf for sotorasib. Other PK parameters 
for sotorasib may include time of maximum observed concentration (tmax), apparent plasma 
terminal elimination half-life (t1/2,z), apparent total plasma clearance (CL/F), apparent volume 
of distribution during the terminal elimination phase (Vz/F), unbound fraction (fu), Cmax,u, 
AUClast,u, AUCinf,u, CLu/F, and Vz,u/F. A linear model will be used to analyze log-transformed 
primary PK parameters. The data from hepatically impaired subjects (Group 2 and 3; tests) and 
control subjects (normal hepatic function [Group 1]; reference) will be included in the analysis. 
Geometric mean ratios (Test/Reference) for Cmax and AUC values and associated 90 
confidence intervals will be estimated. 
Additional parameters may be calculated, and sotorasib metabolites may be analyzed.  Specific 
details will be presented in the Statistical Analysis Plan for this study. 
Safety analysis: 
The number and percentage of subjects reporting any treatment-emergent adverse events will 
be tabulated by Medical Dictionary for Regulatory Activities system organ class and preferred 
term. Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product or other protocol-required therapies, and significant 
treatment-emergent adverse events will also be provided. Subject-level data may be provided 
instead of tables if the subject incidence is low.  
Observed values for clinical laboratory data, 12-lead electrocardiograms, and vital signs will 
be summarized. There will be no formal statistical analysis for safety. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF TABLES AND FIGURES........................................................................................12 
LIST OF ABBREVIATIONS ..................................................................................................13 
1. 
INTRODUCTION ...........................................................................................................15 
1.1. 
Background ............................................................................................................15 
1.2. 
Pharmacokinetics ...................................................................................................16 
1.3. 
Study Rationale ......................................................................................................17 
1.4. 
Benefit-risk Assessment.........................................................................................17 
1.4.1. 
Therapeutic Context .....................................................................................17 
1.4.1.1. 
Key Benefits.......................................................................................17 
1.4.1.2. 
Risks ...................................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................19 
2.1. 
Objectives ..............................................................................................................19 
2.2. 
Endpoints ...............................................................................................................20 
2.2.1. 
Primary Endpoints .......................................................................................20 
2.2.2. 
Secondary Endpoints ...................................................................................20 
3. 
INVESTIGATIONAL PLAN ..........................................................................................20 
3.1. 
Overall Study Design and Plan ..............................................................................20 
3.2. 
Discussion of Study Design ...................................................................................22 
3.3. 
Selection of Doses in the Study .............................................................................22 
4. 
SELECTION OF STUDY POPULATION .....................................................................23 
4.1. 
Inclusion Criteria ...................................................................................................23 
4.2. 
Exclusion Criteria ..................................................................................................24 
4.3. 
Screen Failures and Rescreening ...........................................................................27 
4.4. 
Subject Number and Identification ........................................................................27 
4.5. 
Subject Withdrawal and Replacement ...................................................................27 
4.6. 
Study Termination .................................................................................................28 
5. 
STUDY TREATMENTS .................................................................................................28 
5.1. 
Investigational Product ..........................................................................................28 
5.2. 
Treatment of Overdose ..........................................................................................29 
5.2.1. 
Medical Devices...........................................................................................29 


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5.2.2. 
Product Complaints ......................................................................................30 
5.3. 
Randomization .......................................................................................................30 
5.4. 
Blinding..................................................................................................................30 
5.5. 
Treatment Compliance ...........................................................................................30 
5.6. 
Drug Accountability...............................................................................................30 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................31 
6.1. 
Concomitant Therapies ..........................................................................................31 
6.2. 
Diet .........................................................................................................................31 
6.3. 
Smoking .................................................................................................................32 
6.4. 
Exercise ..................................................................................................................32 
6.5. 
Blood Donation ......................................................................................................32 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................32 
7.1. 
Pharmacokinetic Assessments ...............................................................................33 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................33 
7.1.2. 
Analytical Methodology ..............................................................................33 
7.2. 
Safety and Tolerability Assessments .....................................................................33 
7.2.1. 
Adverse Events and Serious Adverse Events: Time Period and Frequency 
for Collecting and Reporting Safety Event Information ..............................33 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................36 
7.2.3. 
Vital Signs ....................................................................................................36 
7.2.4. 
12-lead Electrocardiogram ...........................................................................37 
7.2.5. 
Physical Examination...................................................................................37 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................37 
8.1. 
Determination of Sample Size ...............................................................................37 
8.2. 
Analysis Populations ..............................................................................................37 
8.2.1. 
Pharmacokinetic Population ........................................................................37 
8.2.2. 
Safety Population .........................................................................................38 
8.3. 
Pharmacokinetic Analyses .....................................................................................38 
8.4. 
Safety Analysis ......................................................................................................38 
9. 
REFERENCES ................................................................................................................38 
10. APPENDICES .................................................................................................................40 
Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Adverse Event .........................................................41 
Appendix 2: Clinical Laboratory Evaluations ...................................................................49 
Appendix 3: Child-Pugh Classification of Severity of Cirrhosis.......................................50 
Appendix 4: Contraception Requirements .........................................................................51 


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Appendix 5: Collection of Pregnancy and Lactation Information .....................................53 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations ............................57 
Appendix 7: Hepatotoxicity: Suggested Actions and Follow-up Assessments .................62 
Appendix 8: Schedule of Assessments ..............................................................................65 


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LIST OF TABLES AND FIGURES 
Table 1: 
Classification of Hepatic Impairment Groups ...........................................21 
Table 2: 
Investigational Product(s) ..........................................................................29 
 
Figure 1: 
Study Schematic.........................................................................................22 
Figure 2:  
Sample Serious Adverse Event Report Form ............................................46 
Figure 3:  
Pregnancy Notification Form .....................................................................55 
Figure 4:  
Lactation Notification Form ......................................................................56 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero to 
infinity 
AUCinf,u 
unbound area under the plasma concentration-time curve from time 
zero to infinity 
AUClast 
area under the plasma concentration-time curve from time zero to time 
of last quantifiable concentration 
CFR 
Code of Federal Regulations 
CLu/F 
unbound apparent total plasma clearance 
Cmax 
maximum observed plasma concentration 
Cmax,u 
unbound maximum observed plasma concentration 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOS 
end of study 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PPI 
proton-pump inhibitor 
QD 
once daily 


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QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell 
t1/2,z 
apparent plasma terminal elimination half-life 
TBL 
total bilirubin 
tmax 
time of the maximum observed plasma concentration 
ULN 
upper limit of normal 
Vz,u/F 
unbound apparent volume of distribution during the terminal phase 
WBC 
white blood cell 
 


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1. INTRODUCTION 
Refer to the Investigator’s Brochure (IB)1 for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational medicinal product (IMP). 
1.1. 
Background 
Investigational Medicinal Product 
The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutations in human 
cancers has been known for decades;2 however, no anticancer therapies targeting KRAS 
mutations have been successfully developed. Thus, an unmet need exists for therapies that can 
specifically target cancers driven by KRAS mutations. Sotorasib is one such small molecule that 
specifically and irreversibly inhibits the protein product of a mutant KRAS gene, which results in 
a G12C mutation at the protein level (KRAS p.G12C). One mutant version of KRAS, KRAS 
p.G12C, which encodes the KRASG12C protein, might be tractable for small molecule inhibition 
through a covalent interaction with the mutant cysteine3,4,5 found in approximately 13 of lung 
adenocarcinoma (nonsquamous, non-small---cell lung carcinoma), 3 of colorectal cancer, and 
1 to 2 of numerous other solid tumors.6,7,8 Sotorasib forms a specific covalent bond with the 
mutant cysteine of KRASG12C, irreversibly locking the protein in an inactive conformation that 
cripples oncogenic signaling.5 As inactivation of KRAS has been demonstrated to inhibit cell 
growth and/or promote apoptosis selectively in tumor cells harboring KRAS mutations,3,4,9,10,11 
sotorasib may provide a therapeutic benefit for patients with KRAS p.G12C-driven cancers. 
The metabolism and excretion of sotorasib were evaluated in bile duct-cannulated male rats after 
a single intravenous (1 mg/kg) or oral (10 mg/kg) dose of sotorasib. Recovery of sotorasib and 
metabolites was low ( 10) in the study, consistent with extensive metabolism of sotorasib. 
Metabolite profiling by liquid chromatography high-resolution mass spectrometry (LC-HRMS) 
methods identified low amounts of sotorasib and  metabolites excreted into bile (approximately 
0.4 to 3.4 of dose), feces (approximately 1.0 to 2.2 of dose), and urine (0.4 to 1.7 of 
dose) following both intravenous and oral administration, with metabolites that included 
products of oxidative metabolism and glucuronidation (M3, M4, M16), cysteine and N-acetyl 
cysteine conjugation (M10, M15, M20), reduction (M21), and dealkylation (M24). Refer to the 
IB1 for more information.  
Four sotorasib clinical studies (20170543, 20190009, 20190135, and 20190147) are currently 
ongoing in subjects with KRAS p.G12C-mutated tumors. In addition, a number of studies in 
healthy volunteers have explored the pharmacokinetics (PK) of sotorasib in a mass-balance 
study, the PK of sotorasib in the fasted versus fed conditions, and the drug-drug interactions.  
Preliminary data are available for phase 1 of the phase 1/2 Study 20170543 that evaluates the 
safety, tolerability, PK, pharmacodynamics, and efficacy of sotorasib in subjects with KRAS 
p.G12C-mutated advanced solid tumors as monotherapy and in combination with 


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pembrolizumab. As of 01 June 2020, 199 subjects were enrolled in the phase 1 monotherapy 
treatment cohorts; of these, 197 subjects received at least 1 dose of sotorasib (dose range: 180 to 
960 mg).  
1.2. 
Pharmacokinetics 
Preliminary sotorasib PK data were available as of 20 May 2020 for subjects with a specific 
KRAS mutation with advanced solid tumors in the dose-exploration part of the first-in-human 
study, with once daily (QD) oral doses ranging from 180 to 960 mg. Dose-related increases in 
exposure on Day 1 were observed in oral QD doses from 180 through 960 mg. Increase in 
exposure was less than dose-proportional on Day 1. There was no accumulation with multiple 
oral QD dosing for 8 days. Increase in exposure from 180 through 960 mg following oral QD 
dosing was less than dose-proportional on Day 8. Rapid absorption was observed, with time to 
maximum plasma concentration (tmax) between 1 to 2 hours after oral administration. 
A mass-balance study was conducted to characterize the PK and primary route(s) of elimination 
of 14C-sotorasib and drug-related material, and to estimate the overall recovery of radiolabeled 
material in healthy male subjects after a single oral suspension dose of 720 mg 14C-sotorasib. 
Based upon preliminary analysis of interim data, the mean PK parameter estimates are similar to 
those observed in subjects with advanced solid tumors. The mean cumulative recovery over the 
collection period (0 to 312 hours) was 80.8, with 74.6 being excreted in the feces and 6.18 
excreted in the urine.  
A food-effect study was conducted to evaluate the PK of sotorasib administered in the fasted and 
fed conditions in healthy subjects. When 360 mg of sotorasib was administered with a high-fat 
meal, area under the plasma concentration-time- curve (AUC) from time zero to infinity (AUCinf-
) increased 1.38-fold compared with administration in the fasted condition. The maximum 
observed drug concentration (Cmax) was comparable in fasted and fed conditions. Time to peak 
was delayed by 1.25 hours under the fed condition. These results support the administration of 
sotorasib in either the fed or fasted condition.  
Multiple drug-drug interaction studies have been conducted with sotorasib. Coadministration of 
sotorasib with single doses of metformin, rifampin, and multiple doses of itraconazole resulted in 
no clinically meaningful changes in exposure. Results from coadministration of sotorasib with 
multiple doses of rifampin or omeprazole indicated that exposure of sotorasib may fall to 
suboptimal levels when administered with a proton-pump inhibitor (PPI) or strong inducers of 
cytochrome P450 (CYP)3A4. Following coadministration with digoxin, systemic exposure of 
digoxin increased and caution should be used when sotorasib is administered with substrates of 
P-glycoprotein (P-gp). 
More details of these studies are available in the IB.1 


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1.3. 
Study Rationale 
The liver plays a significant role in the clearance of many drugs through a variety of oxidative 
and conjugative metabolic pathways and/or through biliary excretions. Alterations of these 
excretory and metabolic activities by hepatic impairment can lead to increased drug exposure 
and toxicity. As outlined in the Food and Drug Administration (FDA) Guidance for Industry,12 
PK studies are recommended in patients with impaired hepatic function if hepatic metabolism 
and/or excretion accounts for 20 of the elimination of a parent drug or active metabolite.  
Results from this study will provide information on the safety, tolerability, and PK of sotorasib 
and guide dosing in subjects with normal hepatic function and in subjects with moderate hepatic 
impairment (Child-Pugh B) and severe hepatic impairment (Child-Pugh C).  
1.4. 
Benefit-risk Assessment 
The following benefit-risk assessment supports the conduct of this clinical study. Refer to the IB1 
for more information. 
1.4.1. 
Therapeutic Context 
1.4.1.1. 
Key Benefits 
Subjects in the current study will not receive any health benefit (beyond that of an assessment of 
their medical status) from participating in the study.  
1.4.1.2. 
Risks  
Risks of Sotorasib 
Based on clinical and nonclinical toxicity studies of sotorasib, the key safety information to be 
monitored in clinical studies of sotorasib include abnormal liver function tests, renal toxicity, 
anemia, leukocytosis, thyroid abnormalities, and splenomegaly. Clinical signs and symptoms of 
these toxicities observed in clinical and nonclinical studies, along with relevant laboratory 
parameters, will be monitored during the study to ensure subjects’ safety. 
Abnormal Liver Function Tests  
Abnormal liver function tests (increased aspartate aminotransferase [AST] and increased alanine 
aminotransferase [ALT]) have been observed in oncology subjects receiving both sotorasib 
monotherapy and combination therapy with sotorasib and anti-programmed cell death protein 1 
(PD-1) antibody. The events of abnormal liver function blood tests generally resolved in subjects 
upon interruption of treatment. The risk mitigation plan consists of monitoring liver enzymes, 
with regular measurement of AST, ALT, alkaline phosphatase, and bilirubin to be performed. 


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Specific eligibility criteria and dose-modification guidelines for sotorasib are provided in 
Section 4. 
Renal Toxicity 
Sotorasib-related degeneration/necrosis of renal tubule epithelium was observed in the rat 
repeated-dose toxicology studies. The incidence and severity of tubular degeneration/necrosis 
was dependent on dose/exposure levels and treatment duration. In the 28-day study, 2 of 20 
animals at 200 mg/kg (the highest dose tested) had minimal to mild change. In the 3-month 
study, the same renal change progressed to a chronic change that involved more of the renal 
tubule, which was attributed to higher exposures and longer study duration (60 mg/kg: 7/20 [6 
minimal and 1 mild], 180 mg/kg: 12/19 [5 minimal, 6 mild, and 1 moderate], and 750 mg/kg: 
20/20 [4 minimal, 13 mild, 1 moderate, and 2 marked]). Partial recovery was confirmed at the 
end of the recovery phase; however, marked tubular degeneration/necrosis was also accompanied 
with interstitial fibrosis and glomerulosclerosis, which are considered irreversible changes. The 
changes in renal tubular injury biomarkers in urine were observed as early as Day 8, with the 
largest magnitude of increase for kidney injury molecule (KIM)-1 and clusterin generally 
occurring at this timepoint, and were observed predominantly in animals at 750 mg/kg. 
The risk mitigation plan consists of monitoring of renal function with measurement of the serum 
creatinine and/or estimated creatinine clearance along with urinalysis examinations. Specific 
eligibility criteria to only include subjects with adequate renal function are included, as described 
in Section 4. 
Anemia 
Sotorasib-related decrease in red blood cell (RBC) mass (hemoglobin, RBC count, and 
hematocrit) was observed in both rat and dog toxicology studies. In the rat studies, decreased 
RBC cell mass was observed inconsistently associated with secondary physiologically 
appropriate increases in reticulocyte counts, and increases in RBC indices and platelets. 
Increased reticulocytes correlated with minimally increased hematopoiesis in the spleen were 
seen only in the 28-day rat study. In the dog studies, minimal to mild decreases in RBC mass 
were seen associated with decreased reticulocytes. Due to the small magnitudes of change, the 
sotorasib-related effects on hematology parameters were considered non-adverse and were 
reversible after a 28-day recovery in rats; reversibility was expected based on the normal 
regenerative capacity of the hematopoietic system and the absence of overt bone-marrow toxicity 
(eg, hypocellularity). 
The risk mitigation plan consists of monitoring hemoglobin, hematocrit, and associated adverse 
events. Specific eligibility criteria and dose-modification guidelines pertaining to hematology 
parameters are provided in Section 4. 


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Leukocytosis 
Sotorasib-related increased leukocytes were observed in the rat repeated-dose toxicology studies, 
including increases in white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and large unstained cells with no light microscopic correlates. Due to the 
small magnitudes of change, the sotorasib-related effects on hematology parameters were 
considered non-adverse and were not observed after recovery period. The risk mitigation plan 
consists of monitoring WBC count and differential and associated adverse events. 
Thyroid Dysfunction  
In the 3-month dog toxicology study (0, 200, and 1000 mg/kg/day administered as 0, 100 and 
500 mg/kg twice daily), there was abnormal content in the gall bladder and microscopic changes 
in the liver, pituitary, or thyroid that were considered to be either non-severely toxic and/or 
adaptive or secondary responses to hepatocellular enzyme induction.  In the thyroid, mild to 
moderate follicular cell hypertrophy and moderate to marked colloid depletion were observed 
accompanied with decreased thyroid weights. A few animals at 1000 mg/kg/day also had marked 
atrophy of the thyroid. The risk mitigation plan consists of monitoring thyroid function with 
regular measurement of serum triiodothyronine (T3), free thyroxine (T4), and thyroid-
stimulating hormone (TSH), and for any clinical signs or symptoms concerning for thyroid 
dysfunction.  
Splenomegaly 
Sotorasib-related increase in spleen weights was observed in males at  100 mg/kg in a Good 
Laboratory Practice 28-day rat toxicology study. At 100 and 200 mg/kg, spleen weights were 
increased up to 21 and these increases were not observed at the end of the 28-day recovery 
period. Although minimal increased hematopoiesis was observed in the spleen at 200 mg/kg, the 
degree of increased hematopoiesis was interpreted to be insufficient to account for increased 
spleen weights. There was no sotorasib-related change in spleen weight in the rat 3-month study. 
The risk mitigation plan consists of monitoring the size of the spleen (with physical examination) 
and hematology parameters. 
More detailed information about the key safety information of sotorasib, including a list of 
adverse drug reactions, may be found in the sotorasib IB.1  
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
 to evaluate the PK of a single oral dose of sotorasib administered in subjects with 
moderate or severe hepatic impairment compared to subjects with normal hepatic 
function. 


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The secondary objective of the study is: 
 to evaluate the safety and tolerability of sotorasib administered in subjects with moderate 
or severe hepatic impairment compared to subjects with normal hepatic function. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints of the study are PK parameters for sotorasib: 
 Cmax 
 AUC from time zero to the last quantifiable concentration (AUClast) 
 AUCinf. 
Additional PK parameters may be calculated. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
 adverse events 
 clinical laboratory evaluations 
 12-lead electrocardiograms (ECGs) 
 vital signs 
 unbound Cmax (Cmax,u) 
 unbound AUClast (AUClast,u) 
 unbound AUCinf (AUCinf,u) 
 unbound apparent total plasma clearance (CLu/F) 
 unbound apparent volume of distribution during the terminal phase (Vz,u/F).  
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a Phase 1, parallel-arm, multi-center (US), open-label, non-randomized study to 
evaluate the PK of a single oral dose of sotorasib administered in subjects with normal hepatic 
function (control) and in subjects with moderate or severe hepatic impairment (according to 
Child-Pugh classification) under fasted conditions. Subjects who meet eligibility requirements 
will be assigned to 1 of 3 groups as shown in Table 1. The Child-Pugh classification will be 


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based on the Child-Pugh score at Screening. The Child-Pugh scores classification is described in 
Appendix 3.  
Attempts will be made to match for age (mean  10 years), sex, and body mass index (mean  
20) between normal and hepatically impaired groups. Up to 8 subjects can be enrolled in 
Group 1 to satisfy matching criteria. Up to 8 subjects will be enrolled in Groups 2 and 3 to 
ensure 6 evaluable subjects. Subjects will maintain the same group assignment throughout the 
study.  
Table 1: 
Classification of Hepatic Impairment Groups 
Group 
Degree of Hepatic Impairment 
Number of Subjects 
1 
Normal function (no impairment) 
6 to 12 
2 
Moderate impairment (Child-Pugh Class B) 
6 to 8 
3 
Severe impairment (Child-Pugh Class C) 
6 to 8 
The classification is based on Child-Pugh- scores as per Figg and Dukes.13 Child-Pugh scores classification is described in 
Appendix 3. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the dose administration. Subjects will be admitted into the study site on Day 1 and be 
confined until discharge on Day 8. On Day 1, after at least a 10-hour fast, all subjects will 
receive a single oral dose of 960 mg sotorasib (8 x 120-mg tablets). 
The total duration of study participation for each subject (from Screening through end of study 
[EOS]) is anticipated to be approximately 4 weeks. 
The start of the study is defined as the date the first enrolled subject signs an Informed Consent 
Form (ICF). The point of enrollment occurs at the time of subject number allocation. The end of 
the study is defined as the date of the last subject’s last assessment (scheduled or unscheduled).  
An overview of the study design is shown in Figure 1. 


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Figure 1: 
Study Schematic 
A Schedule of Assessments is presented in Appendix 8. 
3.2. 
Discussion of Study Design 
This study has been designed in accordance with the FDA regulatory guidance for the study of 
PK in subjects with impaired hepatic function.12  
A single-dose, parallel design is the standard design to investigate the PK of a drug in subjects 
with hepatic impairment. A parallel design is required to include subjects with hepatic 
impairment and control subjects with normal hepatic function.  Control healthy subjects with 
normal hepatic function will be enrolled in this study to serve as a reference group for 
interpretation of the results. The safety and PK assessments are standard parameters for clinical 
studies in drug development. 
This study will be open label because the study endpoints are not considered subjective. 
3.3. 
Selection of Doses in the Study 
The 960-mg dose was selected for the present study because this is the recommended dose in the 
Phase 2 portion of an ongoing clinical study (Study 20170543). Sotorasib is primarily 
metabolized by CYP3A4. Study 20190318 evaluated the impact of itraconazole (a strong 
CYP3A4 inhibitor) on the PK of 360 mg sotorasib in healthy subjects. Geometric least squares 
mean ratio (test/reference) of sotorasib AUCinf and Cmax were 1.261 and 1.040, respectively, 
when comparing sotorasib coadministered with itraconazole (test) and sotorasib administered 
alone (reference). Doses of 360 mg sotorasib were safe and well tolerated when coadministered 
with 200 mg itraconazole to healthy subjects.  The mean magnitude of the relative effect in this 
hepatic impairment study is anticipated to be similar to the past DDI study with a potent 
CYP3A4 inhibitor. A substudy in Study 20170543 evaluated the food effect on 960 mg sotorasib 
PK in patients with advanced solid tumors. Coadministration with high-fat meals resulted in a 
geometric least squares mean ratio (test/reference) of 1.25 and 0.66 for AUC from time zero to 
Study day 
-28 
-1 
1 
2 
3 
8 
Resident in the Clinical Research Unit 
Check-in 
960 mg sotorasib 
Discharge/ End 
of Study 
PK sample collection 


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24 hours postdose (AUC0-24) and Cmax, respectively. Exposure in this hepatically impaired 
population is anticipated to be similar to those exposures observed in Study 20190318 and food-
effect substudy in Study 20170543. 
There have been no dose-limiting toxicities observed with sotorasib monotherapy at 960 mg in 
subjects with advanced solid tumors with the KRAS p.G12C mutation. Please refer to the IB1 for 
more information. 
4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria prior to enrollment unless otherwise stated: 
All subjects: 
1. Subject has provided informed consent before initiation of any study-specific 
activities/procedures. 
2. Male subjects or female subjects, between 18 and 70 years of age (inclusive) at the time 
of Screening. 
3. Body mass index between 18.0 and 38.0 kg/m2 (inclusive) at the time of Screening. 
4. Females of nonchildbearing potential defined as permanently sterile (ie, due to 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal 
(defined as at least 45 years of age with amenorrhea for 12 months without an alternative 
medical cause and follicle-stimulating hormone [FSH] level  40 mIU/mL). 
Subjects with Normal Hepatic Function Only (Group 1) 
5. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory 
evaluations (congenital nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s 
syndrome based on total and direct bilirubin] is not acceptable) as assessed by the 
Investigator (or designee). 
Subjects with Hepatic Impairment Only (Groups 2 and 3) 
6. Child-Pugh B (Group 2) or C (Group 3) classification (Appendix 3) defined by both 
Screening and Check-in clinical laboratory values and clinical examination findings. 
7. Clinically stable hepatic disease in the opinion of the Investigator (eg, not including 
rapidly progressive primary or secondary hepatic malignancy). Documented medical 
history of chronic liver disease including, but not limited to, liver cirrhosis, hepatitis B 
infection, alcoholic liver disease, or previous hepatitis C virus (HCV) infection (HCV 
RNA to be undetectable in all enrolled subjects at Screening) or as assessed by the 
Investigator (or designee). 


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8. Subjects with moderate or severe hepatic impairment may have medical findings 
consistent with their hepatic dysfunction, as determined by medical history, physical 
examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations 
at Screening and Check-in.  Subjects with abnormal findings considered not clinically 
significant by the Investigator will be eligible. 
4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria prior to 
enrollment unless otherwise stated: 
All subjects: 
1. Any unstable medical condition, defined as having been hospitalized within 21 days 
before Check-in, major surgery within 6 months before Check-in, or otherwise unstable 
in the judgment of the Investigator and/or Medical Monitor (eg, risk of complications or 
adverse events unrelated to study participation). 
2. History or evidence, at Screening or Checkin-, of clinically significant disorder, 
condition, or disease not otherwise excluded that, in the opinion of the Investigator (or 
designee), would pose a risk to subject safety or interfere with the study evaluation, 
procedures, or completion. 
3. Venous thromboembolic disease in the last 6 months. 
4. History of malignancy of any type, with the exception of the following: in situ cervical 
cancer or surgical excised nonmelanomatous skin cancers more than 5 years before 
receiving sotorasib. 
5. History or evidence of clinically significant arrhythmia at Screening, including any 
clinically significant findings on the ECG taken at Check-in.  
6. History suggestive of esophageal (including esophageal spasm, esophagitis), gastric, or 
duodenal ulceration or bowel disease (including but not limited to peptic ulceration, 
gastrointestinal bleeding, ulcerative colitis, Crohn’s disease, or irritable bowel 
syndrome); or a history of gastrointestinal surgery other than uncomplicated 
appendectomy cholecystectomy, and hernia repair. 
7. Inability to swallow oral medication or history of malabsorption syndrome. 
8. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee) and in 
consultation with the Sponsor. 
9. Poor peripheral venous access. 
10. Estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m2 as calculated by 
the Modification of Diet in Renal Disease (MDRD) equation, at Screening or Checkin. 
11. Positive human immunodeficiency virus test at Screening.  


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12. Use of any over-the-counter or prescription medications within 30 days or 5 half-lives 
(whichever is longer) prior to study Day 1 that was not reviewed and approved by the 
Investigator (or designee) and the Sponsor, which include known CYP3A4 and P-gp-
sensitive substrates (with a narrow therapeutic window) and strong inducers of CYP3A4 
(including herbal supplements such as St. John’s wort), with below exceptions. 
a. Ibuprofen and hormone-replacement therapy (eg, estrogen, thyroid) will be 
allowed. 
b. Therapies for hepatic disease and treatments of associated disorders that have 
been stable for at least 30 days prior to study drug administration and deemed 
acceptable, by the Investigator (or designee) and the Sponsor, to be given 
concurrently with sotorasib during the study period. 
13. Administration of an approved (authorized) Coronavirus Disease 2019 (COVID-19) 
vaccine in the past 28 days prior to dosing or a COVID-19 vaccine given Emergency Use 
Approvals (US) in the past 30 days prior to dosing.  
14. All herbal medicines (eg, St. John’s wort), vitamins, and supplements consumed by the 
subject within the 30 days prior to enrollment, unless deemed acceptable by the 
Investigator (or designee) and in consultation with the Sponsor. 
15. Consumption of foods and beverages containing poppy seeds, grapefruit, or Seville 
oranges within 7 days prior to Check-in. 
16. History of alcoholism or drug/chemical abuse within the last 3 months prior to Check-in. 
17. Alcohol consumption from 48 hours prior to Check-in. 
18. Regular alcohol consumption of  14 units per week for males and  7 units for females. 
One unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL) 
wine. 
19. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in. 
20. Positive test for illicit drugs, cotinine (tobacco or nicotine use), and/or alcohol use at 
Check-in. 
21. Consumption of caffeine-containing foods and beverages within 48 hours prior to Check-
in. 
22. Female subjects with a positive pregnancy test at Screening or Check-in.  
23. Male subjects (with a female partner of childbearing potential) who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or unwilling to adhere 
to contraceptive requirements through 7 days after sotorasib dosing (see Appendix 4).  
24. Unwilling to abstain from sperm donation and ovum donation through 7 days after 
sotorasib dosing (see Appendix 4). 
25. Male subjects with a female partner of childbearing potential and not willing to inform 
his partner of his participation in this clinical study. 


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26. Male subjects with a pregnant partner or partner planning to become pregnant who are 
unwilling to practice abstinence or use a condom for 7 days after sotorasib dosing. 
27. Subject has received a dose of an investigational drug (new chemical entity) within the 
past 30 days or 5 half-lives, whichever is longer, prior to Check-in. 
28. Have previously completed or withdrawn from this study or any other study investigating 
sotorasib or have previously received the investigational product.  
29. Donation of blood from 3 months prior to Check-in, plasma from 2 weeks prior to Check-
in, or platelets from 6 weeks prior to Check-in. 
30. Receipt of blood products within 2 months prior to Check-in. 
31. Unwilling to abide with study restrictions. 
32. Subjects who, in the opinion of the Investigator (or designee), should not participate in 
this study. 
Subjects with Normal Hepatic Function Only (Group 1) 
33. Positive hepatitis B or hepatitis C panel at Screening. Subjects whose results are 
compatible with prior immunity (vaccination or prior infection) may be included. 
34. ALT or AST  upper limit of normal (ULN) at Screening or Check-in. 
35. Total bilirubin levels  ULN at Screening or Check-in. 
36. A QT interval corrected for heart rate based on the Fridericia correction (QTcF) interval 
 450 msec in male subjects or  470 msec in female subjects or history/evidence of long 
QT syndrome at Screening or Check-in, confirmed by calculating the mean of the 
original value and 2 repeats. 
Subjects with Hepatic Impairment Only (Groups 2 and 3) 
37. Values outside the normal range for liver function tests that are not consistent with their 
hepatic condition, as determined by the Investigator (or designee). 
38. A QTcF interval  470 msec in male subjects or  480 msec in female subjects at 
Screening or Check-in, confirmed by calculating the mean of the original value and 
2 repeats. 
39. Use of a new medication, or a change in dose, for the treatment, or worsening of, hepatic 
encephalopathy within 30 days prior to Check-in. 
40. Recent history of, or the treatment of, gastrointestinal bleeding (within the past 6 
months). 
41. Presence of a portosystemic shunt. 
42. Recent history of paracentesis within 30 days prior to Check-in. 
43. Current functioning organ transplant or are waiting for an organ transplant. 
44. Evidence of severe ascites. 


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45. History within 60 days prior to the Screening visit or current symptoms of hepatic 
encephalopathy Grade 2 or above. 
4.3. 
Screen Failures and Rescreening 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently enrolled in the study. A minimal set of screen failure information will be collected 
that includes demography, screen failure details, eligibility criteria, medical history, prior 
therapies, and any serious adverse events. 
If a subject has not met all eligibility criteria the subject will be registered as a screen fail. Screen 
fail subjects may be eligible for rescreening one time, at the discretion of the Investigator in 
consultation with the Sponsor. 
Rescreened subjects must first be documented as screen failures, and subsequently registered as 
rescreens. Once the subject is registered as rescreened, a new 20-day Screening window will 
begin. Subjects will retain the same subject identification number assigned at the original 
Screening. If the rescreening period begins more than 30 days after the original signing of the 
ICF, all Screening procedures including informed consent must be repeated.  
4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be assigned a 
subject number prior to the first dosing occasion. Assignment of subject numbers will be in 
ascending order and no numbers will be omitted (eg, Subjects 0101, 0102, 0103). Replacement 
subjects (Section 4.5) will be assigned a subject number corresponding to the number of the 
subject he/she is replacing plus 1000 (eg, Subject 1101 replaces Subject 0101). 
Subjects will be identified by subject number only on all study documentation. A list identifying 
the subjects by subject number will be kept in the Site Master File. 
4.5. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be withdrawn 
from dosing if any of the following criteria are met: 
 change in compliance with any inclusion/exclusion criterion that is clinically relevant and 
affects subject safety as determined by the Investigator (or designee) 
 noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
 any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 


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If a subject is withdrawn from the study, the Sponsor will be notified and the date and reason(s) 
for the withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all EOS assessments, if possible 
(Appendix 8). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before the 
subject is discharged from the clinic. The Investigator (or designee) may also request that the 
subject return for an additional follow-up visit. All withdrawn subjects will be followed until 
resolution of all their adverse events or until the unresolved adverse events are judged by the 
Investigator (or designee) to have stabilized. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of adverse 
events thought to be related to the study drug will generally not be replaced. 
4.6. 
Study Termination 
The Sponsor 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 the Sponsor 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 Institutional Review Board (IRB) in writing of the study's completion or early termination 
and send a copy of the notification to the Sponsor. The Sponsor reserves the unilateral right, at 
its sole discretion, to determine whether to supply investigational product and by what 
mechanism, after termination of the study. 
In addition, the study may be terminated by the Sponsor at any time and for any reason. If the 
Sponsor decides to terminate the study, they will inform the Investigator as soon as possible. 
5. STUDY TREATMENTS 
Study treatment is defined as any investigational product, non-investigational product, placebo, 
or medical device 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. 
5.1. 
Investigational Product 
The IMP will be supplied by the Sponsor. The Investigational Product Instruction Manual, a 
document external to this protocol, contains detailed information regarding the storage, 
preparation, destruction, and administration of the IMP shown in Table 2. 
All supplies of investigational product, both bulk and subject-specific, will be stored in 
accordance with the manufacturer’s instructions or pharmacy instructions. Until dispensed to the 


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subjects, the investigational and non-investigational products will be stored at the study site in a 
location that is locked with restricted access. 
Table 2: 
Investigational Product(s) 
Study Treatment Name 
Investigational Medicinal Product: 
 Sotorasib 
Unit Strength and Formulation 
120-mg tablet 
Dosage Level 
960 mg (8 x 120 mg) 
Route of Administration 
Oral 
Accountability 
The quantity administered, date administered, and lot 
number of investigational product are to be recorded on 
each subject's Case Report Form.  
Dosing Instructions 
The Investigator/designee will administer the treatment after 
the completion of all predose procedures and after a fast of 
at least 10 hours. Eight tablets of sotorasib should be taken 
with up to 16 ounces (480 mL) of water. Tablets should not 
be broken or chewed. No food will be given for at least 4 
hours post sotorasib administration.  
Except as part of the dose administration, subjects will restrict their consumption of water for 1 
hour prior to dosing and for 2 hours after dosing; at all other times during the study, subjects may 
consume water as desired. Subjects will continue fasting for at least 4 hours postdose. 
Subjects will be dosed while standing and will not be permitted to lie supine for 2 hours after 
administration of IMP, except as necessitated by the occurrence of an adverse event(s) and/or 
study procedures. 
5.2. 
Treatment of Overdose 
Neither the effects of overdose of sotorasib nor an antidote to overdose are known. 
5.2.1. 
Medical Devices  
No investigational medical device(s) will be used in this study. 
Other non-investigational medical devices may be used in the conduct of this study as part of 
standard care. Non-investigational medical devices (eg, syringes, sterile needles) that are 
commercially available are not usually provided or reimbursed by the Sponsor (except, for 
example, if required by local regulation). The Investigator will be responsible for obtaining 
supplies of these devices.   


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5.2.2. 
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 the Sponsor or 
by distributors and partners for whom the Sponsor manufactures the material. This includes any 
investigational product (sotorasib) provisioned and/or repackaged/modified by the Sponsor. 
Any product complaint(s) associated with an investigational product (sotorasib) supplied by the 
Sponsor is to be reported according to the instructions provided in the Amgen IPIM. 
5.3. 
Randomization 
This is a non-randomized study. Subjects will receive their first dose of sotorasib in a gated 
fashion, with at least 3 moderately impaired subjects being dosed first followed by a period of at 
least 2 days before the remaining moderate or severely impaired subjects are dosed.  
5.4. 
Blinding 
This is an open-label study. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
 All doses will be administered under the supervision of suitably qualified study site staff. 
 Immediately after dose administration, visual inspection of the mouth and hands will be 
performed for each subject. 
 At each dosing occasion, a predose and postdose inventory of sotorasib will be 
performed.  
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of sotorasib tablets 
received. In addition, an accurate drug disposition record will be kept, specifying the amount 
dispensed to each subject and the date of dispensing. This drug accountability record will be 
available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused assembled 
unit doses will be retained until completion of the study. 


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At the completion of the study, all unused sotorasib tablets will be returned to the Sponsor, 
retained at the study site, or disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or nonprescription medications/products during 
the study until the EOS, unless the Investigator (or designee) and/or Sponsor have given their 
prior consent.  
Subjects will refrain from use of any PPIs within 5 days or H2-receptor antagonists within 1 day 
prior to study Day 1 until at least 4 hours after IMP administration.  
For hepatically impaired subjects, treatment for the underlying liver disease and comorbid 
conditions (including prescribed analgesia) will be permitted if prescribed by the subject’s 
personal physician and approved by the Medical Monitor and Investigator, in consultation with 
the Sponsor as needed. Administration of medications should be withheld for at least 4 hours 
after study drug administration as clinically appropriate, unless needed for treatment of an 
adverse event, at the discretion of the Investigator. Throughout the study, the Investigator may 
prescribe any concomitant medications or treatments deemed necessary to provide adequate 
supportive care except for those listed in the exclusion criteria. 
Foods and medicines that are known strong CYP3A4 inducers (eg, rifampin, corticosteroids, 
anticonvulsants, and St. John’s wort) or CYP3A4 or P-gp substrates with narrow therapeutic 
index are prohibited prior to IMP administration as specified in the exclusion criteria 
(Section 4.2) and during the study until the EOS. 
Ibuprofen and hormone-replacement therapy are acceptable concomitant medications. The 
administration of any other concomitant medications during the study is prohibited without prior 
approval of the Investigator (or designee), unless its use is deemed necessary for treatment of an 
adverse event. Any medication taken by a subject during the course of the study and the reason 
for its use will be documented in the source data.   
6.2. 
Diet 
While confined at the study site, subjects will receive a standardized diet at scheduled times that 
do not conflict with other study-related activities. Subjects will be fasted overnight (at least 
8 hours) before collection of blood samples for clinical laboratory evaluations. 
Refer to Section 5.1 and Table 2 for diet requirements/restrictions on Day 1. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 7 days prior to Check-in until EOS.  


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Caffeine-containing foods and beverages will not be allowed from 48 hours before Check-in 
until EOS.  
Consumption of alcohol will not be permitted from 48 hours prior to Check-in until EOS. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco or nicotine-containing products within 3 months 
prior to Check-in until the EOS.  
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check--in until the 
EOS. Subjects will otherwise maintain their normal level of physical activity during this time (ie, 
will not begin a new exercise program nor participate in any unusually strenuous physical 
exertion).  
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to Check-in, plasma 
from 2 weeks prior to Check-in, and platelets from 6 weeks prior to Check-in until 3 months 
after the EOS.  
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
 dosing 
 PK blood samples 
 safety assessments (ECGs will be scheduled before vital signs measurements) 
 any other procedures. 
Where activities at a given timepoint coincide, consideration must be given to ensure that the 
following order of activities is maintained: ECGs, vital signs, and safety labs. 


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7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples (approximately 1 x 4 mL for sotorasib, approximately 1 x 4 mL for metabolites, 
and approximately 1 x 4 mL for unbound sotorasib) will be collected by venipuncture or 
cannulation at the times indicated in the Schedule of Assessments in Appendix 8. Procedures for 
collection, processing, and shipping of PK blood samples will be detailed in a separate 
document.  
Any blood sample collected according to the Schedule of Assessments (Appendix 8) 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.  
7.1.2. 
Analytical Methodology 
Plasma concentrations of sotorasib and metabolites will be determined using validated analytical 
procedures. Specifics of the analytical method will be provided in a separate document. 
Unbound fraction of sotorasib will be determined using an established plasma protein binding 
assay and analytical procedure. Specifics of the methods will be provided in a separate 
document.   
7.2. 
Safety and Tolerability Assessments 
7.2.1. 
Adverse Events and Serious Adverse Events: Time Period and Frequency for 
Collecting and Reporting Safety Event Information 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
serious adverse events are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to EOS. If an 
event is reported as beginning prior to signing of the ICF or occurs prior to initiation of study 
treatment on Day 1 and is assessed as not related to study procedures by the Investigator (or 
designee), the event will be recorded as subject medical history. Any events occurring after study 
drug administration on Day 1 through EOS will be reported as adverse events. Subjects will be 
observed for any signs or symptoms and asked about their condition by open questioning, such 
as “How have you been feeling since you were last asked?”, at least once each day while resident 
at the study site and at each study visit. Subjects will also be encouraged to spontaneously report 
adverse events occurring at any other time during the study. 
Adverse Events 


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The adverse event grading scale to be used in this study is described in Appendix 1. 
The Investigator is responsible for ensuring that all non-serious adverse events observed by the 
Investigator or reported by the subject (whether reported by the subject voluntarily or upon 
questioning, or noted on physical examination) from enrollment through EOS are 
recorded/reported using the appropriate eCRF. 
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 30 days after 
the last dose of study treatment or the EOS (whichever is later) are reported using the appropriate 
eCRF and reported on the paper-based- Serious Adverse Event Report Form (described in 
Appendix 1). 
All serious adverse events will be collected, recorded, and reported to the Sponsor within 
24 hours of the Investigator’s knowledge of the event. The Investigator will submit any updated 
serious adverse event data to the Sponsor within 24 hours of it being available. 
Serious Adverse Events After the Protocol-required Reporting Period  
There is no requirement to monitor study subjects for serious adverse events following the 
protocol-required reporting period or after EOS. However, these serious adverse events can be 
reported to Amgen. Per local requirements in some countries, Investigators are required to report 
serious adverse events that they become aware of after EOS. If serious adverse events are 
reported, the Investigator is to report them to the Sponsor within 24 hours following the 
Investigator’s knowledge of the event using the paper-based Serious Adverse Event Report 
Form.  
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the Sponsor’s safety database as clinical trial cases and handled accordingly 
based on relationship to investigational product.  
Method of Detecting Adverse Events and Serious Adverse Events  
Care will be taken not to introduce bias when detecting adverse events and/or serious adverse 
events. Open-ended and non-leading verbal questioning of the subject is the preferred method to 
inquire about adverse event occurrence. 
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, where possible, until resolution, stabilization, until the event is 


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otherwise explained, or the subject is lost to follow-up. This will be completed at the 
Investigator’s (or designee’s) discretion. 
All new information for previously reported serious adverse events must be sent to Amgen 
within 24 hours following knowledge of the new information. If specifically requested, the 
Investigator may need to provide additional follow-up information, such as discharge summaries, 
medical records, or extracts from the medical records. Information provided about the serious 
adverse event must be consistent with that recorded on the eCRF. 
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 the Sponsor. 
Prompt notification by the Investigator to the Sponsor of serious adverse events is essential so 
that legal obligations and ethical responsibilities toward 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/Independent Ethics Committees, and Investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an individual safety report describing a serious adverse event or 
other specific safety information (eg, summary or listing of serious adverse events) from the 
Sponsor will file it along with the IB and will notify the IRB, if appropriate according to local 
requirements. 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Sponsor’s safety surveillance and 
signal management processes. 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects will be collected after the start of 
study treatment and until 7 days after sotorasib dosing. Details of all pregnancies in female 
partners of male subjects will be collected after the start of study treatment until 7 days after 
sotorasib dosing. 


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If a pregnancy and/or lactation 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 
Appendix 5. Amgen Global Patient Safety will follow-up with the Investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
7.2.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including clinical 
chemistry, hematology, urinalysis, and serology) at the times indicated in the Schedule of 
Assessments in Appendix 8. Clinical laboratory evaluations are listed in Appendix 2. 
The Investigator is responsible for reviewing laboratory test results and recording any clinically 
relevant changes occurring during the study in the 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 judgement) 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. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, and 
will undergo an alcohol test at the times indicated in the Schedule of Assessments in Appendix 8. 
For all female subjects, a pregnancy test and FSH screen for postmenopausal women will be 
performed at the times indicated in the Schedule of Assessments in Appendix 8.  
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
7.2.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and oral body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 8. Vital signs may 
also be performed at other times if judged to be clinically appropriate or if the ongoing review of 
the data suggests a more detailed assessment of vital signs is required. 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. When vital signs are scheduled at the same time as blood draws, the blood draws 


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will be obtained at the scheduled timepoint, and the vitals will be obtained as close to the 
scheduled blood draw as possible, but prior to the blood draw. 
7.2.4. 
12-lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at least 
5 minutes at the times indicated in the Schedule of Assessments in Appendix 8. Single 12-lead 
ECGs will be repeated twice, and an average taken of the 3 readings, if either of the following 
criteria apply: 
 QTcF  500 msec 
 QTcF change from the baseline (predose) is  60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a more detailed assessment of ECGs is required. 
The Investigator (or designee) will perform a clinical assessment of each 12-lead ECG. 
7.2.5. 
Physical Examination 
A full physical examination or symptom-directed- physical examination will be performed at the 
timepoints specified in the Schedule of Assessments in Appendix 8.  
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
Approximately up to 24 subjects will be enrolled, with a minimum of 6 evaluable subjects and a 
maximum of up to 8 subjects in Group 1, and a maximum of 16 subjects enrolled in Groups 2 
and 3 (8 subjects in each hepatic impairment group to ensure 6 evaluable subjects). The sample 
size of 6 subjects per hepatic impairment group is based on practical considerations and 
consistent with regulatory guidance for studies evaluating the effect of hepatic impairment on the 
PK of an IMP. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of sotorasib and have 
evaluable PK data. A subject may be excluded from the PK summary statistics and statistical 
analysis if the subject has an adverse event of vomiting that occurs at or before 2 times median 
time to maximum concentration or diarrhea within 24 hours of dosing.  


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8.2.2. 
Safety Population 
The safety population will include all subjects who received sotorasib and have at least 1 
postdose safety assessment. 
8.3. 
Pharmacokinetic Analyses 
The plasma PK parameters of sotorasib will be calculated using standard noncompartmental 
methods. 
The primary PK parameters are Cmax, AUClast, and AUCinf for sotorasib. Other PK parameters for 
sotorasib  may include time of tmax, apparent plasma terminal elimination half-life (t1/2,z), 
apparent total plasma clearance (CL/F), apparent volume distribution during the terminal 
elimination phase (Vz/F), unbound fraction (fu), Cmax,u, AUClast,u, AUCinf,u, CLu/F, and Vz,u/F. A 
linear model will be used to analyze log-transformed primary PK parameters. The data from 
hepatically impaired subjects (Group 2 and 3; tests) and control subjects (normal hepatic 
function [Group 1]; reference) will be included in the analysis. Geometric mean ratios 
(Test/Reference) for Cmax and AUC values and associated 90 confidence intervals will be 
estimated. 
Additional parameters may be calculated, and sotorasib metabolites may be analyzed.  Specific 
details will be presented in the Statistical Analysis Plan for this study. 
8.4. 
Safety Analysis 
The number and percentage of subjects reporting any treatment-emergent adverse events will be 
tabulated by Medical Dictionary for Regulatory Activities system organ class and preferred term. 
Tables of fatal adverse events, serious adverse events, adverse events leading to withdrawal from 
investigational product or other protocol-required therapies, and significant treatment-emergent 
adverse events will also be provided. Subject-level data may be provided instead of tables if the 
subject incidence is low.  
Observed values for clinical laboratory data, 12-lead ECGs, and vital signs will be summarized. 
There will be no formal statistical analysis for safety. 
9. REFERENCES 
1. Amgen. AMG 510 – Investigator’s Brochure. (Version 5.1). 13 January 2021. 
2. Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell 
Sci. 2016;129(7):1287-1292. 
3. Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS; from structural insights 
to mechanism-based design. Nature Rev Drug Discov. 2016;15(11):771-785. 


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4. Patricelli MP, Janes MR, Li LS, et al. Selective inhibition of oncogenic KRAS output with 
small molecules targeting the inactive state. Cancer Discov. 2016;6:316-329. 
5. Canon J, Rex K, Saiki AY, et al. The clinical KRAS (G12C) inhibitor AMG 510 drives anti-
tumour immunity. Nature. 2019;575:217-223.  
6. The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision 
Medicine Through an International Consortium. Cancer Discov. 2017;7(8):818-831. 
7. Biernacka A, Tsongalis PD, Peterson JD, et al. The potential utility of re-mining results of 
somatic mutation testing: KRAS status in lung adenocarcinoma. Cancer Genet. 
2016;209(5):195-198. 
8. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations 
in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 
2009;205(12):858-862. 
9. Janes MR, Zhang J, Li LS, et al. Targeting KRAS mutant cancers with a covalent 
G12C-specific inhibitor. Cell. 2018;172(3):578-589. 
10. McDonald ER, de Weck A, Schlabach MR, et al. Project DRIVE: A compendium of cancer 
dependencies and synthetic lethal relationships uncovered by large-scale deep RNAi 
screening. Cell. 2017;170(3):577-592. 
11. Xie C, Li Y, Li LL, et al. Identification of a new potent inhibitor targeting KRAS in non-
small cell lung cancer cells. Front Pharmacol. 2017;8:823. 
12. Food and Drug Administration. Guidance for Industry Pharmacokinetics in Patients with 
Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling. May 2003. 
13. Figg WD, Dukes GE, Lesesne HR et al. Comparison of quantitative methods to assess 
hepatic function: Pugh’s classification, indocyanine green, antipyrine, and dextromethorphan. 
Pharmacotherapy 1995; 15:693-700. 
 


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10. APPENDICES 


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Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting of Adverse Event 
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 judgement 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. 
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. For instance, 
drug-induced hepatitis that resolved without evidence of hepatic failure would not 
be considered life-threatening- even though drug-induced hepatitis can be fatal. 
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 adverse events. 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 judgement 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 


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convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 When an adverse event or serious adverse event occurs, it is the responsibility of 
the Investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 The Investigator will then record all relevant adverse event/serious adverse event 
information in the Event electronic Case Report Form (eCRF). 
 The Investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to the investigational product(s) and/or study-
mandated procedures; and 
o Action taken. 
 If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the appropriate eCRF.  
 It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to Sponsor in lieu of completion of the appropriate eCRF 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 the Sponsor. 
 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 or higher, 


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which is available at the following location: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Assessment of Causality 
 The Investigator is obligated to assess the relationship between investigational 
product(s), protocol-required therapy and/or study-mandated procedure, and each 
occurrence of each adverse event/serious adverse event. 
 Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
 The Investigator will use clinical judgement 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 the 
Sponsor 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 the Sponsor. 
 If a subject dies during participation in the study the Investigator will provide the 
Sponsor with a copy of any post-mortem findings including histopathology.  
 New or updated information will be recorded in the originally completed eCRF. 


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 The Investigator will submit any updated serious adverse event data to the Sponsor 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Paper Serious Adverse Event Report Form 
 Facsimile transmission of the Serious Adverse Event Report Form (see Figure 2) is 
the preferred method to transmit this information. 
 In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the Serious Adverse Event Report Form sent 
by overnight mail or courier service. 
 Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting time frames.  


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Figure 2:  
Sample Serious Adverse Event Report Form  
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubina 
Gamma-glutamyl transferase 
Glucose 
Indirect bilirubina 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubina 
Total protein 
Uric acid 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
Bilirubin 
Blood 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Serologyb: 
Drug screenc: 
Hormone panel - females 
only: 
Hepatitis B surface antibody 
Hepatitis B core antibody  
Hepatitis B surface antigen 
Hepatitis C antibody 
Hepatitis C virus RNA 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies 
and p24 antigen 
Including but not limited to:  
Alcohol (breath, urine, or serum) 
Amphetamines/methamphetamin
es 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
 
Follicle-stimulating hormoneb  
(postmenopausal females only) 
Serum pregnancy test (human 
chorionic gonadotropin)d 
Urine pregnancy testd 
Other Tests: 
Thyroid-stimulating hormoneb 
Total cholesterolb 
Low-density lipoprotein 
cholesterol (indirect)b 
Triglyceridesb 
International normalized ratio 
(INR)e 
Estimated glomerular filtration 
rate (eGFR)f 
 
a Direct and indirect bilirubin will be analyzed if total bilirubin is elevated.  
b Only analyzed at Screening. 
c Only analyzed at Screening and Check-in. Alcohol testing is not included at Screening. 
d Performed in serum at Screening and in urine at all other times for all females. A positive urine pregnancy test will be 
confirmed with a serum pregnancy test. 
e INR will be tested if hepatotoxicity is suspected guidelines presented in Appendix 7. 
f Estimated glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease (MDRD) equation. 


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Appendix 3: Child-Pugh Classification of Severity of Cirrhosis 
Finding 
Points Scored for Each Observed Finding 
1 
2 
3 
Encephalopathy1 
None 
1 or 2 (or 
suppressed with 
medication) 
3 or 4 (refractory) 
Ascites2 
Absent 
Slight or Subject on 
1 medication to 
control ascites 
Moderate or Severe 
or Subject on 2 
medications to 
control ascites 
Bilirubin (mg/dL) 
 2 
2 to 3 
 3 
Albumin (g/dL) 
 3.5 
2.8 to 3.5 
 2.8 
INR 
 1.7 
1.7 to 2.2 
 2.2 
Abbreviation: INR  international normalized ratio 
1 Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2 to 3 cycles per second delta activity 
2 Ascites is graded according to the following criteria: 
Absent: No ascites detectable by manual investigation 
 Slight: Ascites palpitation doubtful 
 Moderate: Ascites detectable by palpation 
Severe: Necessity of paracentesis, does not respond to medication treatment. 


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Appendix 4: Contraception Requirements 
All subjects must receive pregnancy prevention counseling and be advised of the risk to the fetus 
if they conceive a child during treatment and for 7 days after sotorasib dosing. 
Additional medications given during the study may alter the contraceptive requirements. The 
Investigator must discuss these contraceptive changes with the subject. 
Definitions  
 
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche.  
 
Women of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or medical 
records. Surgical sterilization to have occurred a minimum of 6 weeks, or at the 
Investigator’s discretion, prior to Screening.  
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating hormone 
(FSH) levels of  40 mIU/mL. The amenorrhea should not be induced by a medical 
condition such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, or 
by extreme exercise. It should not be due to concomitant medications that may have 
induced the amenorrhea such as oral contraceptives, hormones, gonadotropin-releasing 
hormones, anti-estrogens, or selective estrogen receptor modulators.  
 
Fertile male: a male that is considered fertile after puberty.  
 
Infertile male: permanently sterile male via bilateral orchiectomy.  
 
Contraception Requirements 
 
Female Subjects  
 
Female subjects who are of nonchildbearing potential will not be required to use contraception. 
Female subjects are required to refrain from donation of ovum from Check-in until 7 days after 
sotorasib dosing.  
 
Male Subjects:  
 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to a 
second method of acceptable contraception by female partner from Check-in until 7 days after 
sotorasib dosing. Acceptable methods of contraception for female partners include:  
 


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 hormonal injection  
 combined oral contraceptive pill or progestin/progestogen-only pill  
 combined hormonal patch  
 combined hormonal vaginal ring  
 surgical method (bilateral tubal ligation or regulatory approved method of hysteroscopic 
bilateral tubal occlusion)  
 hormonal implant  
 hormonal or non-hormonal intrauterine device  
 over-the-counter sponge with spermicide  
 cervical cap with spermicide  
 diaphragm with spermicide.  
 
Male subjects are required to refrain from donation of sperm from Check-in until 7 days after the 
EOS.  
 
Sexual Abstinence  
 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, sympto-thermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months prior 
to Screening and must agree to remain abstinent from the time of signing the Informed Consent 
Form (ICF) until 7 days after sotorasib dosing.  
 
Same-sex Relationships 
 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 7 days after 
sotorasib dosing. 
 
 


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Appendix 5: Collection of Pregnancy and Lactation Information 
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 7 days after sotorasib dosing. 
 Information will be recorded on the Pregnancy Notification Form (see Figure 3). The 
form must be submitted to Amgen Global Patient Safety within 24 hours of learning of a 
subject’s pregnancy. (Note: Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
 After obtaining the female subject’s informed consent for release of pregnancy and infant 
health information, the Investigator will collect pregnancy and infant health information 
and complete the pregnancy questionnaire for any female subject who becomes pregnant 
while taking protocol-required therapies through 7 days after sotorasib dosing. This 
information will be forwarded to Amgen Global Patient Safety. Generally, infant follow-
up will be conducted up to 12 months after the birth of the child (if applicable). 
 Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for procedure.  
 While pregnancy itself is not considered to be an adverse event or serious adverse event, 
any pregnancy complication or report of a congenital anomaly or developmental delay, 
fetal death, or suspected adverse reactions in the neonate will be reported as an adverse 
event or serious adverse event. Note that an elective termination with no information on a 
fetal congenital malformation or maternal complication is generally not considered an 
adverse event, but still must be reported to the Sponsor as a pregnancy exposure case. 
 If the outcome of the pregnancy meets a criterion for immediate classification as a serious 
adverse event (eg, female subject experiences a spontaneous abortion, stillbirth, or 
neonatal death or there is a fetal or neonatal congenital anomaly), the Investigator will 
report the event as a serious adverse event. 
 Any serious adverse event occurring as a result of a post-study pregnancy that is 
considered reasonably related to the study treatment by the Investigator will be reported 
to Amgen Global Patient Safety as described in Appendix 1. 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 4.5 for details). 
Male Subjects with Partners Who Become Pregnant or Were Pregnant at the Time of Enrollment 
 In the event a male subject fathers a child during treatment, and for an additional 7 days 
after sotorasib dosing, the information will be recorded on the Pregnancy Notification 
Form. The form (see Figure 3) 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 


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any information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws.) 
 The Investigator will attempt to obtain informed 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 informed consent for release of pregnancy and infant 
health information, the Investigator will collect pregnancy outcome and infant health 
information on the pregnant partner and her baby and complete the pregnancy 
questionnaires. This information will be forwarded to Amgen Global Patient Safety. 
 Generally, infant follow-up will be conducted up to 12 months after the birth of the child 
(if applicable).  
 Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for procedure. 
Collection of Lactation Information 
 Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 7 days after sotorasib dosing. 
 Information will be recorded on the Lactation Notification Form (Figure 4) and submitted 
to Amgen Global Patient Safety within 24 hours of the Investigator’s knowledge of event. 
 Study treatment will be discontinued if the female subject breastfeeds during the study. 
 With the female subject’s informed 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 7 days after sotorasib dosing. 


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Figure 3:  
Pregnancy Notification Form 
 


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Figure 4:  
Lactation Notification Form 
 


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Appendix 6: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines. 
 Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines. 
 Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and 
other relevant documents (eg, advertisements) must be submitted to an Institutional Review 
Board (IRB) by the Investigator and reviewed and approved by the IRB before the study is 
initiated.  
Any amendments to the protocol will require IRB and regulatory authority (as locally required) 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.  
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB. 
 Notifying the IRB of serious adverse events or other significant safety findings as 
required by IRB procedures. 
 Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
An initial sample ICF will be provided for the Investigator (or designee) 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 Study Manager to the Investigator. The written ICF 
is to be prepared in the language(s) of the potential study participant population. 


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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, and the IRB 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 acquisition of informed consent and the subject’s agreement or refusal of his/her notification 
of the primary-care physician is to be documented in the subject’s medical records, and the ICF 
is to be signed and personally dated by the subject or a legally acceptable representative and by 
the person who conducted the informed consent discussion. Subject withdrawal of consent or 
discontinuation from study treatment and/or procedures must also be documented in the subject’s 
medical records. 
Subjects must be re-consented to the most current version of the ICF 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 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.) 
Subject Data Protection 
The Investigator must ensure that the subject’s confidentiality is maintained for documents 
submitted to the Sponsor. 
Subjects 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 electronic Case Report Form (eCRF) demographics page, in addition to the unique 
subject identification number, include the age at time of enrollment. 


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For serious adverse events reported to the Sponsor, subjects are to be identified by their unique 
subject identification number (for faxed reports, in accordance with local laws and regulations) 
and age (in accordance with local laws and regulations). 
Documents that are not submitted to the Sponsor (eg, signed ICFs) are to be kept in confidence 
by the Investigator, except as described below. 
In compliance with 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 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. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential information of the 
Sponsor, Amgen Inc. The Investigator (or designee) agrees not to disclose such information in 
any way without prior written permission from the Sponsor. 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 permission from the Sponsor. 
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 
that would make the subject identifiable will not be transferred.  
On the eCRF demographics page, in addition to the unique subject identification number, include 
the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their unique 
subject identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in confidence by the 
Investigator, except as described below. 
Data Quality Assurance 
The following data quality steps will be implemented: 


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 All relevant subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
 The Investigator must permit study-related monitoring, audits, IRB 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. Predefined agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the data 
may be included in a Data Management Plan.  
 A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c) unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR Part 11compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and transmitted 
to the Sponsor or designee electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled subject who undergoes any Screening procedures, 
according to the eCRF completion instructions. The Sponsor, or Contract Research Organization 
(CRO), will review the supporting source documentation against the data entered into the eCRFs 
to verify the accuracy of the electronic data. The Investigator will ensure that corrections are 
made to the eCRFs and that data queries are resolved in a timely fashion by the study staff. 


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The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the data on 
the eCRF, data queries, and site notifications. 
Publications 
The policy for publication of data obtained during this study will be documented in the Clinical 
Study Agreement. 
 


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Appendix 7: Hepatotoxicity: Suggested Actions and Follow-up Assessments  
Subjects with normal hepatic function at Screening who experience aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) elevations  3 x upper limit of normal (ULN) or 
subjects with elevated values before drug exposure who have a 2-fold increase above baseline 
values (as specified in the Guidance for Industry Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation, July 2009) are to undergo clinical assessments and a period of “close 
observation” until abnormalities return to normal or to the subject’s baseline level as described 
below. 
 
Clinical Assessments and Observation 
Assessments that are to be performed during this period include:  
 Repeat AST, ALT, alkaline phosphatase, bilirubin (total and direct), and international 
normalized ratio (INR) within 24 hours  
 In cases of total bilirubin (TBL)  2 x ULN or INR  1.5, retesting of liver tests, bilirubin 
(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.  
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 G, anti-nuclear antibody, anti-smooth muscle antibody, and 
liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 Serum acetaminophen (paracetamol) levels 
 A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-
type reactions, fatigue, nausea, vomiting, and fever 
o Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
o Concomitant use of medications (including nonprescription 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 


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 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 are 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 drug-induced liver injury (DILI) event and additional information such as medical 
history, concomitant medications, and laboratory results must be captured in the corresponding 
electronic Case Report Form (eCRF). 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are not 
limited to: 
 Hepatobiliary tract disease 
 Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 Right-sided heart failure, hypotension, or any cause of hypoxia to the liver causing 
ischemia 
 Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms 
 Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, Crigler-
Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg-, indinavir, 
atazanavir) 
 Alpha-one antitrypsin deficiency 
 Alcoholic hepatitis 
 Autoimmune hepatitis 
 Wilson’s disease and hemochromatosis 
 Nonalcoholic fatty liver disease including steatohepatitis 
 Non-hepatic causes (eg, rhabdomylosis, hemolysis). 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, ie, cases of AST or ALT  3 x ULN and 
concurrent TBL  2 x ULN or INR  1.5 (for subjects not on anticoagulation therapy) without 
evidence of alternative cause of the elevations, require the following: 


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 The event is to be reported to the Sponsor 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 eCRF captures information necessary to facilitate the evaluation of 
treatment-emergent liver abnormalities is to be completed and sent to the Sponsor. 
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 Appendix 1. 
 


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Appendix 8: Schedule of Assessments 


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Schedule of Assessments 
Study Procedures 
Screening 
Check-
in 
Drug Administration 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
(EOS) 
Confined to the CRU 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Outpatient Visit 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xa 
 
 
 
 
 
 
 
 
Height and BMI 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
Xb 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
Alcohol Test 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test (females only)c 
X 
X 
 
 
 
 
 
 
 
Xb 
FSH (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
12-lead Electrocardiogramd 
X 
X 
X 
 
 
 
 
 
 
Xb 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Clinical Laboratory Evaluationsf 
X 
X 
 
X 
 
 
 
X 
 
Xb 
eGFRg 
X 
X 
 
 
 
 
 
 
 
 
Physical Examinationh 
X 
X 
 
 
 
 
 
 
 
Xb 
Sotorasib Dosei 
 
 
X 
 
 
 
 
 
 
 
Sotorasib PK Blood Samplesj 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Sotorasib Metabolite PK Blood 
Samplesk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Protein Bindingl 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Monitoringm 
 
 
X 
Serious Adverse Event Monitoringm 
X 
X 
Prior/Concomitant Medicationsn 
X 
X 
Abbreviations: BMI  body mass index; CRU  Clinical Research Unit; D  day; eGFR  estimated glomerular filtration rate; EOS  end of study; ET  early termination; 
FSH  follicle-stimulating hormone; PK  pharmacokinetic. 


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a  Interim medical history only. 
b  Assessment to be performed at the End of Study (EOS) visit or early termination (ET). 
c  Performed in serum at Screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
d  12-lead electrocardiograms will be collected after the subject has rested in the supine position for at least 5 minutes, and will be obtained prior to the scheduled blood draws at: 
Screening; Check-in; prior to and 0.5, 2, and 4 hours postdose following administration of sotorasib on Day 1; and EOS or ET. ECG should be collected prior to any PK 
corresponding timepoints. Three sets of triplicate ECGs to be collected at baseline and 1 set of triplicate ECGs to be collected at any other timepoints. 
e  Vital signs measurements (supine blood pressure [BP], supine pulse rate, respiratory rate, and oral body temperature) should be carried out prior to having blood drawn. 
Screening; Check-in; prior to sotorasib administration and 1, 2, and 24 hours following sotorasib administration on Day 1; and daily thereafter. Pulse rate and BP will be 
measured using the same arm for each reading after the subject has been resting in the supine position for at least 5 minutes. 
f  Clinical chemistry (fasted at least 10 hours), hematology, and urinalysis. 
g  eGFR will be calculated using the Modification of Diet in Renal Disease equation. 
h  A full physical examination at Screening and Check-in, and an abbreviated physical examination at EOS/ET. 
i  Dose administration of sotorasib will be given in the morning on Day 1 after a 10-hour fast.  
j  Blood samples for determination of sotorasib plasma concentrations will be collected: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 
168 hours postdose following administration of sotorasib on Day 1. The blood sample collected at 30 minutes postdose will have a sampling window of  2 minutes, samples 
collected from 1 through 3 hours postdose will have a sampling window of  5 minutes, samples collected from 4 through 10 hours postdose will have a sampling window of 
 10 minutes, and samples collected from 12 through 168 hours postdose will have a sampling window of  20 minutes. Times of all blood samples will be recorded to the 
nearest minute. 
k  Blood samples for determination of sotorasib metabolite plasma concentrations will be collected: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 
and 168 hours postdose following administration of sotorasib on Day 1. The blood sample collected at 30 minutes postdose will have a sampling window of  2 minutes, samples 
collected from 1 through 3 hours postdose will have a sampling window of  5 minutes, samples collected from 4 through 10 hours postdose will have a sampling window of  
10 minutes, and samples collected from 12 through 168 hours postdose will have a sampling window of  20 minutes. Times of all blood samples will be recorded to the nearest 
minute. 
l  Blood samples for determination of unbound fraction will be collected: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose 
following administration of sotorasib on Day 1. The blood sample collected at 30 minutes postdose will have a sampling window of  2 minutes, samples collected from 1 
through 3 hours postdose will have a sampling window of  5 minutes, samples collected from 4 through 10 hours postdose will have a sampling window of  10 minutes, and 
samples collected from 12 through 168 hours postdose will have a sampling window of  20 minutes. Times of all blood samples will be recorded to the nearest minute.  
m Adverse events will be recorded from initiation of study treatment on Day 1 until EOS completion. Serious adverse events will be recorded from the time the subject signs the 
ICF until 30 days after the last dose of study treatment or the EOS (whichever is later). 
n Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved medications taken by a subject within 
30 days or 5 half-lives (whichever is longer) prior to Check-in for over-the-counter or prescription medications, and 30 days prior to Check-in for herbal medicines (eg, St. 
John’s wort), vitamins, and supplements, will be recorded on the subject’s electronic Case Report Form. 

SAP_001.pdf: 
TITLE PAGE 
Statistical Analysis Plan 
An Open-label Single-dose Study to Evaluate the Pharmacokinetics of 
Sotorasib in Healthy Subjects and Subjects with Moderate or Severe 
Hepatic Impairment 
SAP Status: Final 
SAP Version: 1 
SAP Date: 02June2021 
Investigational Medicinal Product: Sotorasib (AMG 510) 
Protocol Reference: 20200362 
Covance Study: 8454975 
Sponsor: 
Amgen, Inc.  
One Amgen Center Drive 
Thousand Oaks, California 91320 USA 
Study Sites: 
Orlando Clinical Research Center 
5055 S. Orange Ave.,  
Orlando, FL 32809 
Texas Liver Institute 
607 Camden Street, Suite 101 
San Antonio, TX 78215 
Clinical Pharmacology of Miami, LLC. 
550 West 84th Street,  
Miami, FL 33014 
Orange County Research Center 
14351 Myford Road, Suite B, 
Tustin, CA 92780 
Pinnacle Clinical Research 
5109 Medical Drive, Suite 200, 
San Antonio, TX 78229 
Principal Investigators: 
, MD 
, MD 
, MD 
, MD 
, MD 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
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NCT Number: NCT04887064
This NCT number has been applied to the document for
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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
4. STUDY DESIGN................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 8 
6. STUDY TREATMENTS ....................................................................................................... 9 
7. DEFINITIONS OF POPULATIONS .................................................................................... 9 
7.1. All Subjects Population ................................................................................................... 9 
7.2. Safety Population ............................................................................................................ 9 
7.3. Pharmacokinetic Population ........................................................................................... 9 
8. STATISTICAL METHODOLOGY ...................................................................................... 9 
8.1. General ............................................................................................................................ 9 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 10 
8.1.2. Calculation of the Summary Statistics ................................................................... 11 
8.1.3. Triplicate Readings................................................................................................. 11 
8.1.4. Repeat and Unscheduled Readings ........................................................................ 11 
8.1.5. Definitions of Baseline, Change from Baseline, and Percentage Change from 
Baseline ............................................................................................................................ 12 
8.2. Subject Disposition and Population Assignment .......................................................... 12 
8.3. Screening Demographics and Baseline Characteristics ................................................ 12 
8.4. Prior and Concomitant Medication ............................................................................... 12 
8.5. Pharmacokinetic Assessments ...................................................................................... 13 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 13 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 15 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 16 
8.6. Safety and Tolerability Assessments ............................................................................ 16 
8.6.1. Adverse Events ....................................................................................................... 16 
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8.6.2. Clinical Laboratory Parameters .............................................................................. 18 
8.6.3. Vital Signs Parameters ........................................................................................... 18 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 18 
8.6.5. Other Assessments ................................................................................................. 19 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 19 
9. INTERIM ANALYSES ....................................................................................................... 19 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 19 
11. REFERENCES .................................................................................................................. 19 
12. APPENDICES ................................................................................................................... 20 
Appendix 1: 
Document History ................................................................................ 20 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1: 
Classification of Hepatic Impairment Groups ........................................................ 7 
Figure 1: 
Study Design ........................................................................................................... 8 
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LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
ADaM 
Analysis Data Model 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the plasma concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero to 
infinity 
AUCinf,u 
unbound AUCinf 
AUClast 
AUC from time zero to the last quantifiable concentration 
AUClast,u 
unbound AUClast 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CLu/F 
unbound apparent total plasma clearance 
Cmax 
maximum observed plasma concentration 
Cmax,u 
unbound Cmax 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
ICF 
informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
LLOQ 
lower limit of quantification 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAP 
statistical analysis plan 
SD 
standard deviation 
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SDV 
source document verification 
TEAE 
treatment-emergent adverse event 
tmax 
time of the maximum observed concentration 
TFL 
table, figure, and listing 
Vz,u/F 
unbound apparent volume of distribution during the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  
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1. INTRODUCTION
This SAP has been developed after review of the clinical study protocol (Final Version dated 
09 February 2021) and electronic case report form (eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), safety, and tolerability 
data from this study. A detailed description of the planned TFLs to be presented in the 
clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Amgen Inc. A limited amount of information about this study 
(eg, objectives, study design) is given to help the reader’s interpretation.  
This SAP must be finalized prior to the lock of the clinical database. Additionally, the SAP 
and TFL shells should be finalized prior to any programming activities commencing.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Amgen Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, ICH E9 guideline 
Statistical Principles for Clinical Trials.1,2,3 
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES
The primary objective of the study is: 
•
to evaluate the PK of a single oral dose of sotorasib administered in subjects with
moderate or severe hepatic impairment compared to subjects with normal hepatic function.
The secondary objective of the study is: 
•
to evaluate the safety and tolerability of sotorasib administered in subjects with moderate
or severe hepatic impairment compared to subjects with normal hepatic function.
3. STUDY ENDPOINTS
The primary endpoints of the study are PK parameters for sotorasib: 
•
maximum observed plasma concentration (Cmax)
•
area under the plasma concentration-time curve (AUC) from time zero to the last
quantifiable concentration (AUClast)
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•
area under the plasma concentration-time curve from time zero to infinity (AUCinf).
Additional PK parameters may be calculated. 
The secondary endpoints of the study are:  
•
adverse events (AE)
•
clinical laboratory evaluations
•
12-lead electrocardiograms (ECGs)
•
vital signs
•
unbound Cmax (Cmax,u)
•
unbound AUClast (AUClast,u)
•
unbound AUCinf (AUCinf,u)
•
unbound apparent total plasma clearance (CLu/F)
•
unbound apparent volume of distribution during the terminal phase (Vz,u/F).
4. STUDY DESIGN
This will be a Phase 1, parallel-arm, multi-center (US), open-label, non-randomized study to 
evaluate the PK of a single oral dose of sotorasib administered in subjects with normal 
hepatic function (control) and in subjects with moderate or severe hepatic impairment 
(according to Child-Pugh classification) under fasted conditions. Subjects who meet 
eligibility requirements will be assigned to 1 of 3 groups as shown in Table 1. The Child-
Pugh classification will be based on the Child-Pugh score at Screening. 
Attempts will be made to match for age (mean ± 10 years), sex, and body mass index (mean 
± 20%) between normal and hepatically impaired groups. Up to 8 subjects can be enrolled in 
Group 1 to satisfy matching criteria. Up to 8 subjects will be enrolled in Groups 2 and 3 to 
ensure 6 evaluable subjects. Subjects will maintain the same group assignment throughout the 
study.  
Table 1: 
Classification of Hepatic Impairment Groups 
Group 
Degree of Hepatic Impairment 
Number of Subjects 
1 
Normal function (no impairment) 
6 to 8 
2 
Moderate impairment (Child-Pugh Class B) 
6 to 8 
3 
Severe impairment (Child-Pugh Class C) 
6 to 8 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the dose administration. Subjects will be admitted into the study site on Day -1 and 
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be confined until discharge on Day 8. On Day 1, after at least a 8-hour fast, all subjects will 
receive a single oral dose of 960 mg sotorasib (8 × 120-mg tablets). 
The total duration of study participation for each subject (from Screening through end of 
study [EOS]) is anticipated to be approximately 4 weeks. 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
A schematic of the study design is presented in Figure 1. 
Figure 1: Study Design  
5. SAMPLE SIZE JUSTIFICATION
Approximately up to 24 subjects will be enrolled, with a minimum of 6 evaluable subjects 
and a maximum of up to 8 subjects in Group 1, and a maximum of 16 subjects enrolled in 
Groups 2 and 3 (8 subjects in each hepatic impairment group to ensure 6 evaluable subjects). 
The sample size of 6 subjects per hepatic impairment group is based on practical 
considerations and consistent with regulatory guidance for studies evaluating the effect of 
hepatic impairment on the PK of an investigational medicinal product (IMP).  
Study day 
-28 
-1 
1 
2 
3 
8 
Resident in the Clinical Research Unit 
Check-in 
960 mg sotorasib 
Discharge/ End 
of Study 
PK sample collection 
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6. STUDY TREATMENTS
The treatment will be a single oral dose of 960 mg sotorasib (8 × 120-mg tablets). 
The hepatic function groups and ordering to be used in the TFLs are presented in Table 2. 
Table 2: 
Presentation of Hepatic Function Groups in TFLs  
Hepatic Function Group 
Order in TFLs 
Normal Hepatic Function 
1 
Moderate Hepatic Impairment 
2 
Severe Hepatic Impairment 
3 
7. DEFINITIONS OF POPULATIONS
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 8.1.1), will be considered prior to database lock for their 
importance and taken into consideration when assigning subjects to populations.  
7.1. All Subjects Population 
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
7.2. Safety Population 
The safety population will include all subjects who received sotorasib and have at least 1 
postdose safety assessment.  
7.3. Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of sotorasib and have 
evaluable PK data. A subject may be excluded from the PK summary statistics and statistical 
analysis if the subject has an AE of vomiting that occurs at or before 2 times median time to 
maximum concentration (tmax) or diarrhea within 24 hours of dosing.  
8. STATISTICAL METHODOLOGY
8.1. General 
Listings will be provided for all data captured in the database, including medical history. 
Listings will include all subjects assigned to the all subjects population and include data up to 
the point of study completion or discontinuation. Subjects are generally considered to have 
completed the study if they complete the scheduled follow-up visit (rather than early 
termination visit). Any subject who discontinues the study will be identified accordingly in 
the listings. Summaries and statistical analyses will include the subjects assigned to the 
relevant population based on data type.  
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Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if a new version is issued during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if a new 
version is issued during the study). Pinnacle 21 Enterprise Version X.X.X (or higher if a new 
version is issued during the study) will be utilized to ensure compliance with CDISC 
standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.   
Where reference is made to ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, percentage changes 
from baseline, and any parameter derivations.  
All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognized potential for: 
●Missed visits, caused by, for example:
o Subject unable to travel to site due to restrictions, the need to quarantine, or
COVID-19 infection
o Subject unwilling to go to site due to fear of COVID-19 infection
o Site postponing subject’s visit due to investigator not being available (eg, if they
have been dispatched to hospital handling COVID-19 infections)
●Site unable to replenish supply of investigational product
●Incomplete data entry by sites due to limited resources to support study or no access to
source documents or to eCRF
●Outstanding source document verification (SDV) due to sponsor or country restrictions
on remote SDV, or no or limited access to site(s) for on-site visits
●Unanswered queries
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At the time of the reporting of the study results, all protocol deviations due to COVID-19 or 
related restriction will be assessed for their severity and impact on the analyses. If needed, 
appropriate statistical methods will be applied as a mitigating action (eg, data might be 
categorized into 2 analysis groups, with and without COVID-19 and related restrictions 
impact); however, this will exclude any imputations of the missing values. Any mitigating 
actions will be agreed with Amgen Inc. in advance and identified in the CSR.  
8.1.2. Calculation of the Summary Statistics  
For continuous data the following rules will be applied: 
●Missing values will not be imputed, unless specifically stated otherwise.
●Unrounded data will be used in the calculation of summary statistics.
●If the number of subjects with valid observations (n) <3, summary statistics will not be
calculated, with the exception of n, minimum, and maximum.
●In general, as early termination data are not associated with any scheduled timepoint,
they will be excluded from all calculations of summary statistics and statistical
analyses. Exceptions may be made where justified.
For categorical data the following rules will be applied: 
●For ordered categorical data (eg, AE severity), all categories between the possible
minimum and maximum categories will be included, even if n = 0 for a given category.
●For non-ordered categorical data (eg, race), only those categories for which there is at
least 1 subject represented will be included; unless specifically stated otherwise.
●Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’
category will be included for any parameter for which information is missing. This will
ensure that the population size totals are consistent across different parameters.
8.1.3. Triplicate Readings 
For 12-lead ECG data only, where triplicate readings are taken, the mean of triplicate 
readings will replace the separate individual triplicate readings in all calculations.  
In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean and/or medians will be calculated, as appropriate, based on the number of readings 
available.  
8.1.4. Repeat and Unscheduled Readings 
For vital signs and 12-lead ECG data only, any predose value recorded in addition to the 
original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 
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parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations, with 
the exception of the 12-lead ECG outlier analysis (see Section 8.6.4).   
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.5) and 12-lead ECG outlier analysis (see Section 8.6.4).  
8.1.5. Definitions of Baseline, Change from Baseline, and Percentage Change from 
Baseline  
The baseline will be defined as the last value recorded prior to dosing. If the date/time of the 
value is incomplete or missing, it will be excluded from the baseline calculation, unless the 
incomplete date/time indicates the value was recorded prior to dosing. 
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint.   
The summary statistics for change from baseline will be derived from individual subjects’ 
values (eg, mean change from baseline will be the mean of the individual changes from 
baseline for all subjects, rather than difference between the mean value at the postdose 
timepoint and mean value at baseline).  
See Section 8.1.4 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 8.1.3 for more detail on handling of triplicate readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed. 
A summary table by hepatic function groups will be provided, based on the safety population. 
8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including age, sex, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by hepatic function groups will be provided, based on the safety population. 
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to dosing. Concomitant 
medication will be defined as medication that starts during or after dosing or starts but does 
not end prior to dosing.  
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Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version September 2020 (or later if a new 
version is issued during the study; see the data management plan [DMP] for more details). 
Prior and concomitant medications will be listed.  
8.5. Pharmacokinetic Assessments 
8.5.1. Pharmacokinetic Analysis 
The following PK parameters will be determined where possible from the plasma 
concentrations of sotorasib (total and unbound, unbound parameters to be distinguished with 
a subscripted “u”) and metabolites using noncompartmental methods in validated software 
program Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUClastd 
h*ng/mL 
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration (tlast)b 
AUCinf d 
h*ng/mL 
area under the concentration-time curve from time 0 extrapolated 
to infinityc 
Cmax d 
ng/mL 
maximum observed concentration 
tmax d 
h 
time of the maximum observed concentration 
tlast d 
h 
time of the last quantifiable concentration 
t1/2 d
h 
apparent terminal elimination half-life 
CL/F d 
L/h 
apparent total clearance (parent analyte only) 
Vz/F d 
L 
apparent volume of distribution during the terminal phase (parent 
analyte only) 
fu 
NA 
fraction of unbound drug in plasma, calculated as the mean from 
available time points for each individual subject (sotorasib only) 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b Area under the concentration-time curve will be calculated using the linear trapezoidal linear interpolation rule. 
c Based on the last observed quantifiable concentration 
d PK parameters for unbound sotorosib will be distinguished with a subscripted “u” (i.e., AUClast,u; AUCinf,u; Cmax,u; Tmax,u; 
etc.) 
Additional PK parameters may be determined where appropriate. 
Pharmacokinetic analysis will be carried out where possible using actual blood sampling 
times postdose. If an actual time is missing, the sample concentration result will be treated as 
missing unless there is scientific justification to include the result using the nominal time.  
The parameters Cmax, tlast, and tmax will be obtained directly from the concentration-time 
profiles. If Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence 
of Cmax. 
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8.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.8. 
Parameters requiring λz for their calculation (eg, AUCinf, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.8. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
%AUCextrap 
% 
percentage of AUC due to extrapolation from the last quantifiable 
concentration to infinity 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie, the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR. 
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification (LLOQ). If there are only 
3 consecutive concentrations, at least 1 should follow Cmax. An exception may be made for 
metabolites, where Cmax may be the last timepoint.  
If the extrapolated area is >20%, AUCinf (and derived parameters) will be listed but flagged 
and excluded from statistics. 
If AUCinf cannot be determined reliably for all subjects, an alternative AUC measure, such as 
AUC to a fixed timepoint or AUC0-tlast, may be used in the statistical analysis of hepatic 
impairment. 
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8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQs will be treated as missing. The 
following rules apply with special situations defined below: 
●If an entire concentration-time profile is BLQ, it will be excluded from PK analysis.
●Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile
will be deemed to have terminated and any further quantifiable concentrations will be
set to missing for the calculation of the PK parameters, unless they are considered to be
a true characteristic of the profile of the drug.
●If a predose plasma concentration is missing, it may be set to zero by default.
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value will be considered anomalous and set to 
missing for the PK analysis. 
8.5.2. Presentation of Pharmacokinetic Data 
All PK concentrations and parameters will be listed. 
Summary tables, arithmetic mean (+ standard deviation [SD]) figures, overlaying individual 
figures, and individual figures by treatment and time postdose will be provided for plasma 
PK concentrations. All figures will be produced on both linear-linear and linear-logarithmic 
scales, with the exception of figures across all days, which will be produced on the 
linear-linear scale only. The +SD bars will only be displayed on the linear-linear scale.  
Summary tables by hepatic function groups will be provided for all PK parameters, with the 
exception of diagnostic regression-related PK parameters. Separate summary tables by 
treatment and time interval will be provided for excretion parameters and cumulative 
excretion parameters.  
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times the median tmax.   
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the concentration will be flagged, but included in the summary statistics. Individual 
concentrations deemed to be anomalous will be flagged in the listings and excluded from the 
summary statistics. 
For PK concentration data the following rules will apply: 
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●
Values that are BLQ will be set to 0 for the calculation of summary statistics.
●
Arithmetic mean or median values that are BLQ will be presented as 0.
●
If any BLQ results (treated as 0) are in a series of summarized data, geometric mean
and CV% of geometric mean will be reported as not calculated (NC).
For PK parameters the following rule will apply: 
Geometric mean and coefficient of variation (CV) will not be calculated for tlast or tmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
A statistical analysis will be conducted to investigate the PK of sotorasib (total and unbound) 
following a single dose in subjects with moderate hepatic impairment or severe hepatic 
impairment compared to subjects with normal hepatic function. The natural log 
(ln)-transformed4 PK parameters will be analyzed using an analysis of variance (ANOVA) 
model.5 The model will include the factor “hepatic impairment” (ie, moderate, severe, or 
none) as a fixed effect. Geometric mean ratios (test/reference) and the corresponding 90% 
confidence intervals (CIs) of AUClast, AUCinf, and Cmax of sotorasib between the groups of 
hepatically impaired subjects (test) and subjects with normal hepatic function (reference) will 
be calculated. 
8.6. Safety and Tolerability Assessments 
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.0 (or higher if a new version is issued during the study; see the DMP for more 
details). All AEs will be assigned a severity grade using Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 (or higher if a new version is issued during the study; 
see the protocol for more details). 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after dosing, or starts prior to dosing and increases in severity after dosing. 
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A treatment-related TEAE will be defined as a TEAE with a relationship related to the study 
treatment, as determined by the investigator.  
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of 
dosing for TEAEs only.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
●TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment
●TEAEs by severity and treatment
●Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to
death) by treatment
●Treatment-related TEAEs by severity and treatment
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
●System organ class, preferred term, and treatment
●Preferred term and treatment
For the AE data the following rules will apply: 
●For the derivation of treatment-emergent status (applicable to all AEs): If the start
date/time of an AE is incomplete or missing, an AE will be assumed to not be a TEAE,
unless the incomplete start date/time or the end date/time indicates an AE started after
dosing.
●For the derivation of treatment-related status (applicable to TEAEs only): If the study
treatment relationship for a TEAE is missing, a TEAE will be assumed to not be a
treatment-related TEAE.
●For the derivation of onset time (applicable to TEAEs only): If the start date/time of a
TEAE is missing, onset time will not be calculated. If the start date/time of a TEAE is
incomplete, where possible, the minimum possible onset time will be calculated and
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of dosing is
01MAY2019/08:00 and recorded start date/time of a TEAE is 03MAY2019, then the
minimum possible onset time will be calculated by assuming a TEAE started at the first
hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as onset
time ≥01:16:00 in the listing). If the start date of a TEAE is the same as the date of
dosing but the start time of a TEAE is missing, an onset time will be presented as
‘≥00:00:01’. Any clock changes will be accounted for in the derivation.
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●For the derivation of duration (applicable to all AEs): If the end date/time of an AE is
missing, duration will not be calculated. If the start or end date/time of an AE is
incomplete, where possible, the maximum possible duration will be calculated and
presented in ‘≤DD:HH:MM’ format (eg, if the start of an AE date/time is
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the maximum
possible duration will be calculated by assuming an AE ended at the last hour and
minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as
duration ≤02:15:59 in the listing). Any clock changes will be accounted for in the
derivation.
●For the calculation of TEAE summary statistics: If the severity of a TEAE is missing,
that TEAE will be counted under the ‘missing’ category.
●For the calculation of TEAE summary statistics: If a subject experienced multiple
TEAEs with the same preferred term for the same treatment, this will be counted as 1
TEAE for that treatment under the maximum severity recorded.
8.6.2. Clinical Laboratory Parameters 
All clinical laboratory parameters, their changes from baseline, will be listed, as applicable; 
any value outside the clinical reference range will be flagged. Separate listings will be 
provided for any parameter for which there is any individual subject value outside the 
respective clinical reference range  
Summary tables and boxplots by treatment and timepoint will be provided by hepatic 
function group for clinical chemistry, hematology, and coagulation parameters, their changes 
from baseline, as applicable.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, and presentation in the figures, <x and ≤x values 
will be set to 0, whereas >x and ≥x values will be set to x.  
8.6.3. Vital Signs Parameters 
All vital signs parameters, their changes from baseline, will be listed, as applicable; any value 
outside the clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided by hepatic 
function group for all vital signs parameters, their changes from baseline, as applicable. 
8.6.4. 12-lead Electrocardiogram Parameters 
All 12-lead ECG parameters, their changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided by hepatic 
function group for all 12-lead ECG parameters, their changes from baseline.
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8.6.5. Other Assessments  
Medical history will be listed. 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned.  
9. INTERIM ANALYSES
No interim analyses are planned. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES
There were no significant changes from the protocol-specified analyses. 
11. REFERENCES
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports
(E3). 30 November 1995.
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8).
17 July 1997.
3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9).
5 February 1998.
4. Figg WD, Dukes GE, Lesesne HR et al. Comparison of quantitative methods to assess
hepatic 
function: 
Pugh’s 
classification, 
indocyanine 
green, 
antipyrine, 
and
dextromethorphan. Pharmacotherapy 1995; 15:693-700.
5. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819.
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12. APPENDICES
Appendix 1: 
Document History 
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable 
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Statistical Analysis Plan (SAP) Approval Form
COVANCE INC. CONFIDENTIAL
Page 1 of 1
ST-AD-030 version 01
Type of Approval (select one) : 
SAP  
Sponsor
Name:
Amgen, Inc.
Sponsor
Protocol/CIP
ID:
20200362
Covance 
Study 
ID:
8454975
SAP text 
filename:
Amgen510_20200362_SAP_Final.pdf
TFL 
shells 
filename:
Amgen510_20200362_TFL_Final.pdf
Version:
1
Date:
02June2021
Covance Approval(s):
Lead Statistician
Approval Signature
Print Name
Job Title
Date
Sponsor Approval(s):
By signing below when the statistical analysis plan (SAP) is considered final, the 
signatories agree to the analyses to be performed for this study and to the format of 
the associated tables, figures, and listings (TFLs). Once the SAP has been signed, 
programming of the Analysis Dataset Model (ADaM) datasets and TFLs based on these
documents can proceed. Any modifications to the SAP text and TFL shells made after 
signing may result in a work-scope change.
Approval Signature
Print Name
Job Title
Date
Biostatistics Senior Manager
09June2021
Please scan/email completed form(s) to the Lead Statistician listed below:
Printed Name/Title:
 Biostatistician
Email:
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Clinical Study Report 
CONFIDENTIAL 
Labcorp Drug Development Study: 8454975 
Protocol Reference: 20200362 
16.1.9.2. 
Quality Tolerance Limit Definitions
Parameter 
Justification for Parameter 
Unit Tolerance 
Minimum number of 
evaluable subjects needed. 
A shortfall in the overall number of 
subjects could have had a 
significant impact on interpretation 
of the primary endpoint because of 
limited/insufficient exposure. 
Healthy Matches 
(n = 6 to 8)
Moderate
(n = 6 to 8)
Severe
(n = 6 to 8)
Page 23 of 23
Final


Approval Signatures
Document Name:
161-09-csr-20200362-statistical-met
Document Number: CLIN-000300020
Document Version: 1
Document Approvals
Reason for Signing: Management
Name: 
Date of Signature: 05-Oct-2022 21:10:18 GMT+0000