Clinical trial NCT05048784
Conditions: Healthy Participants
Keywords: Sotorasib AMG 510 Bioequivalence
Sponsor: Amgen
Start date: 2021-08-16; Completion date: 2022-02-18
Enrollment: 145 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this study is to compare the pharmacokinetics (PK) of sotorasib dose A administered orally as 3 tablets (test) to sotorasib dose A administered orally as 8 tablets (reference).

Detailed description:

Arms: arm 1: Participants will be administered sotorasib dose A orally in the following order:

* Treatment A - as 3 tablets (test 1)
* Treatment B - as 8 tablets (reference)
* Treatment C - as 3 tablets (test 2) arm 2: Participants will be administered sotorasib dose A orally in the following order:

* Treatment B - as 8 tablets (reference)
* Treatment A - as 3 tablets (test 1)
* Treatment C - as 3 tablets (test 2)
Interventions: intervention 1: Sotorasib
Intervention descriptions: intervention 1: Oral tablet

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 2 
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Labcorp Drug Development Study: 8471128 
Amgen Protocol: 20210093 
Protocol Version 3.0, 09 September 2021 
Page 1 of 70 
TITLE PAGE 
Protocol 
An Open-label, Randomized, Two-way Crossover, Bioequivalence Study in 
Healthy Volunteers to Compare the Pharmacokinetics of Two Different 
Tablets of Sotorasib 
Protocol Amendment 2 Status: Final 
Protocol Amendment 2 Date: 09 September 2021 
Protocol Amendment 1 Date: 02 September 2021 
Original Protocol Date: 04 June 2021 
Protocol Version: 3.0 
Amgen Investigational Product: Sotorasib (AMG 510) 
Amgen Protocol Reference Number: 20210093 
Labcorp Drug Development Study Number: 8471128 
IND Number: 139023 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
This protocol was developed, reviewed, and approved in accordance with Labcorp’s 
standard operating procedures. This format and content of this protocol is aligned with 
Good Clinical Practice: Consolidated Guidance (ICH E6). 
NCT Number: NCT05048784
This NCT number has been applied to the document for purposes of 
posting on Clinicaltrials.gov


Protocol Amendment 2 
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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 staffs 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, Randomized, Two-way Crossover, 
Bioequivalence Study in Healthy Volunteers to Compare the Pharmacokinetics of Two Different 
Tablets of Sotorasib” 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) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 
                                  


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Protocol Amendment 2 
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Labcorp Drug Development Study: 8471128 
Amgen Protocol: 20210093 
Protocol Version 3.0, 09 September 2021  
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SYNOPSIS 
Title of study: An Open-label, Randomized, Two-way Crossover, Bioequivalence Study in 
Healthy Volunteers to Compare the Pharmacokinetics of Two Different Tablets of Sotorasib 
Objectives:  
The primary objective of the study is: 
 
to compare the pharmacokinetics (PK) of 960 mg sotorasib administered orally as 3 x 
320 mg tablets (test 1) under fasted conditions to 960 mg sotorasib administered orally 
as 8 x 120 mg tablets (reference) under fasted conditions. 
The secondary objectives of the study are: 
 
in 14 subjects, to evaluate the PK of 960 mg sotorasib administered orally as 3 x 320 
mg tablets with a high-fat meal (test 2). 
 
to assess the safety and tolerability of 960 mg sotorasib administered orally as 3 x 
320 mg tablets and 960 mg sotorasib administered orally as 8 x 120 mg tablets. 
Study design: 
This will be an open-label, multi-center (United States), crossover, 3-period bioequivalence 
study. Period 1 and 2 will enroll approximately 146 subjects and compare the PK of a single 
oral dose of 960 mg sotorasib administered as 3 x 320 mg tablets (test 1) to a single oral dose 
of 960 mg sotorasib administered as 8 x 120 mg tablets (reference) under fasted conditions in 
healthy male and healthy female subjects. Fourteen out of the 146 subjects will enter Period 3 
and receive an additional 960 mg sotorasib administered as 3 x 320 mg tablets with a high-fat 
meal (test 2). After informed consent is obtained, potential subjects will be screened to assess 
their eligibility to enter the study within 28 days prior to the first dose administration. Subjects 
will be admitted into the Clinical Research Unit (CRU) on Day -1 and be confined to the CRU 
until discharge on Day 6 or Day 9. 
On Day 1, subjects will be randomized to Group 1 or Group 2. Each subject will receive one 
administration of 960 mg sotorasib administered orally under fasted condition as 3 x 320 mg 
tablets (Treatment A: test 1) and one administration of 960 mg sotorasib administered orally 
under fasted condition as 8 x 120 mg tablets (Treatment B: reference) in either Period 1 or 
Period 2 according to the treatment sequence below. On Day 7, fourteen subjects in either 
Group 1 or Group 2 will proceed to Period 3 and receive one additional administration of 960 
mg sotorasib administered orally as 3x 320 mg tablets with a high-fat meal (Treatment C: 
test 2). 
Group 
Period 1 (Day 1) 
Period 2 (Day 4) 
Period 3 (Day 7) 
1 
Treatment A 
Treatment B 
Treatment C 
2 
Treatment B 
Treatment A 
Number of subjects: 
Approximately 146 subjects will be enrolled to ensure that at least 132 subjects complete the 
study. 
Diagnosis and main criteria for inclusion: 
Healthy male subjects or female subjects of nonchildbearing potential, 18 to 60 years of age 
(inclusive), and body mass index of 18 to 30 kg/m2 (inclusive). 


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Investigational products, dose, and mode of administration: 
Investigational medicinal products: 
 
120 mg tablet of sotorasib 
 
320 mg tablet of sotorasib 
Treatment A: 960 mg sotorasib administered orally as 3 x 320 mg tablets, after an overnight 
fast of at least 10 hours 
Treatment B: 960 mg sotorasib administered orally as 8 x 120 mg tablets, after an overnight 
fast of at least 10 hours 
Treatment C: following an overnight fast of at least 10 hours, subjects will consume the 
entirety of a standard high‑fat breakfast within 20 minutes. A 960 mg oral dose of sotorasib 
(3 xx 320‑mg tablets) will be given orally 30 minutes after start of the meal. 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned Study duration (Screening to end of study): approximately 5 weeks. 
Primary endpoints: 
The primary endpoints of the study are sotorasib PK parameters in Period 1 and Period 2: 
maximum observed plasma concentration (Cmax), area under the plasma concentration‑time 
curve (AUC) from time zero to the last quantifiable concentration (AUClast), and AUC from 
time zero to infinity (AUCinf).  
Secondary endpoints: 
The secondary endpoints for this study are: adverse events, clinical laboratory tests, 12-lead 
electrocardiograms (ECGs), vital signs, and sotorasib PK parameters in Period 3: Cmax, 
AUClast, AUCinf. 
Statistical methods: 
The primary PK parameters are Cmax, AUClast, and AUCinf for sotorasib on Days 1 and 4. All 
other PK parameters will be regarded as secondary. A linear mixed-effects model will be used 
to analyze log-transformed primary PK parameters. The model assumes fixed effect for 
treatment, period, and sequence and a random effect for subject. Geometric mean ratios 
(test/reference) for Cmax and AUC values and associated 90 confidence intervals 
(test/reference) will be estimated. The “reference” treatment for PK analysis will be 
Treatment B while the “test 1” treatment will be Treatment A for the bioequivalence analysis. 
For the food-effect analysis, the model will use 14 subjects’ data and assumes fixed effects for 
treatment and random effect for subject while test treatment would be fed (test 2; Treatment C) 
and reference would be fasted (test 1; Treatment A).  
The final safety analysis for the study will be performed at the end of the study. Adverse 
events will be summarized using descriptive methodology. Each adverse event will be coded 
using the Medical Dictionary for Regulatory Activities. Endpoints for clinical laboratory tests, 
ECGs, and vital signs will be summarized. 
Additional details will be included in the Statistical Analysis Plan. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................11 
LIST OF ABBREVIATIONS ..................................................................................................12 
1. 
INTRODUCTION ...........................................................................................................14 
1.1. 
Background ............................................................................................................14 
1.2. 
Pharmacokinetics ...................................................................................................15 
1.3. 
Study Rationale ......................................................................................................16 
1.4. 
Benefit-risk Assessment.........................................................................................16 
1.4.1. 
Therapeutic Context .....................................................................................16 
1.4.1.1. 
Key Benefits.......................................................................................16 
1.4.1.2. 
Risks ...................................................................................................16 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................17 
2.1. 
Objectives ..............................................................................................................17 
2.2. 
Endpoints ...............................................................................................................17 
2.2.1. 
Primary Endpoints .......................................................................................17 
2.2.2. 
Secondary Endpoints ...................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................18 
3.1. 
Overall Study Design and Plan ..............................................................................18 
3.2. 
Discussion of Study Design ...................................................................................19 
3.3. 
Selection of Doses in the Study .............................................................................20 
4. 
SELECTION OF STUDY POPULATION .....................................................................20 
4.1. 
Inclusion Criteria ...................................................................................................20 
4.2. 
Exclusion Criteria ..................................................................................................20 
4.3. 
Screen Failures and Rescreening ...........................................................................23 
4.4. 
Subject Number and Identification ........................................................................23 
4.5. 
Subject Withdrawal and Replacement ...................................................................23 
4.6. 
Study Termination .................................................................................................24 
4.7. 
Discontinuation of Study Treatment ......................................................................24 
5. 
STUDY TREATMENTS .................................................................................................25 
5.1. 
Investigational Product ..........................................................................................25 
5.2. 
Investigational Product Administration .................................................................27 


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5.2.1. 
Standard High-fat Meal................................................................................29 
5.3. 
Treatment of Overdose ..........................................................................................30 
5.4. 
Medical Devices.....................................................................................................30 
5.5. 
Product Complaints ................................................................................................30 
5.6. 
Randomization .......................................................................................................30 
5.7. 
Blinding..................................................................................................................30 
5.8. 
Treatment Compliance ...........................................................................................30 
5.9. 
Drug Accountability...............................................................................................31 
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 ...............................................................................32 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................32 
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 .........................................................................36 
7.2.5. 
Physical Examination...................................................................................37 
7.3. 
Subject Questionnaire ............................................................................................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 
8.5. 
Interim Analysis .....................................................................................................38 
9. 
REFERENCES ................................................................................................................38 
10. APPENDICES .................................................................................................................40 


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Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Adverse Events and Serious Adverse Events ..........41 
Appendix 2: Clinical Laboratory Evaluations ...................................................................49 
Appendix 3: Total Blood Volume......................................................................................50 
Appendix 4: Contraception Requirements .........................................................................51 
Appendix 5: Collection of Pregnancy and Lactation Information .....................................53 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations ............................57 
Appendix 7: Hepatotoxicity Stopping Rules: Suggested Actions and Follow-up 
Assessments ...........................................................................................................62 
Appendix 8: Sample Subject Questionnaire ......................................................................66 
Appendix 9: Schedule of Assessments ..............................................................................68 
 


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LIST OF TABLES AND FIGURES 
Table 1: 
Treatment Sequence ...................................................................................18 
Table 2: 
Investigational Product ..............................................................................27 
Table 3: 
Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity ..............................................................................................................63 
  
Figure 1: 
Study Schematic.........................................................................................19 
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 
ALP 
alkaline phosphatase 
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 
AUClast 
area under the plasma concentration-time curve from time zero to the 
last quantifiable concentration 
AV 
atrioventricular 
BIL 
bilirubin 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum observed plasma concentration 
COVID-19 
Coronavirus Disease 2019 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug-induced liver injury 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOS 
end of study 
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 (protein) 
KRAS 
Kirsten rat sarcoma viral oncogene homolog (gene) 
KRASG12C 
KRAS protein with a glycine to cysteine amino acid substitution at 
position 12 


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KRAS p.G12C 
KRAS gene with a mutation resulting in a glycine to cysteine amino 
acid substitution at position 12  
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cell 
TBL 
total bilirubin 
tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
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 
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 
M24 was low ( 10) in the study, consistent with extensive metabolism of sotorasib. 
Metabolite profiling by liquid chromatography high-resolution mass spectrometry methods 
identified low amounts of sotorasib and M24 excreted into bile 
, feces 
 and urine 
 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, including assessments 
of mass-balance, food effect, and various 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 
pembrolizumab. As of 01 June 2020, 199 subjects were enrolled in the Phase 1 monotherapy 


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treatment cohorts; of these, 197 subjects received at least 1 dose of sotorasib (dose range: 180 to 
960 mg). 
A summary of completed and ongoing clinical studies for sotorasib is provided in the IB 
(Table 6-1 and Table 6-2).1 
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; however, the 
increase in exposure was less than dose-proportional. There was no accumulation with multiple 
oral QD dosing for 8 days. The 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 observed 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 plasma 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 sotorasib 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 or strong inducers of 
cytochrome P450 3A4. Following coadministration with digoxin, systemic exposure of digoxin 
increased and caution should be used when sotorasib is administered with substrates of 
P-glycoprotein. 


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1.3. 
Study Rationale 
The purpose of this study is to compare the PK of 960 mg sotorasib administered as 3 x 320 mg 
oral tablets (test) under fasted condition to 960 mg sotorasib administered as 8 x 120 mg oral 
tablets (reference) under fasted condition and to compare the PK of 960 mg sotorasib 
administered as 3 x 320 mg oral tablets following a high-fat meal (test 2) to 960 mg sotorasib 
administered as 3 x 320 mg oral tablets under fasted condition (test 1) in healthy male subjects 
and healthy female subjects of nonchildbearing potential. Oral dosing is the intended route of 
administration for sotorasib. The 320 mg tablet formulation of sotorasib would help reduce pill 
burden for patients requiring sotorasib treatment. 
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 
Healthy 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  
To limit the risk of excessive exposure to healthy subjects in the current study, each subject will 
receive a single oral dose of 960 mg sotorasib administered as 3 x 320 mg tablets (test 1, 
treatment A) and a single oral dose of 960 mg sotorasib administered as 8 x 120 mg tablets 
(reference, treatment B) in either Period 1 or Period 2 according to their assigned group, with 
sufficient washout in between periods (details provided in Section 3.3). Fourteen healthy subjects 
in either Groups 1 or 2 will receive a single oral dose of 960 mg sotorasib administered as 
3 x 320 mg tablets (test 2, treatment C) following a high-fat meal (detailed provided in 
Section 5.2.1) in Period 3 with sufficient washout in between periods. 
Safety monitoring: During the study, subjects will receive all IMP doses by site staff and will be 
instructed not to crush, chew, or split the sotorasib tablets when taking the dose under the 
supervision of the site staff. Safety assessments throughout the study include adverse event 
monitoring, electrocardiograms (ECGs), physical examination, vital signs, and clinical 
laboratory evaluations. 
Risks of Sotorasib 
Based on sotorasib clinical trials experience, adverse drug reactions with sotorasib include 
diarrhea, nausea, fatigue, vomiting, abdominal pain, and increased liver enzymes. Based on 
nonclinical toxicity studies of sotorasib, potential safety concerns to be monitored in clinical 


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studies of sotorasib include renal toxicity, anemia, leukocytosis, thyroid dysfunction, 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 sotorasib therapy. 
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. Specific 
eligibility for sotorasib are provided in Section 4. 
As of January 13th 2021, no clinically meaningful sotorasib-related renal toxicity, anemia, 
leukocytosis, thyroid dysfunction or splenomegaly have been observed. More detailed 
information about the key safety information of sotorasib, including a list of adverse drug 
reactions, may be found in the sotorasib IB and USPI.1,12   
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
 to compare the PK of 960 mg sotorasib administered orally as 3 x 320 mg tablets (test 1) 
under fasted condition to 960 mg sotorasib administered orally as 8 x 120 mg tablets 
(reference) under fasted condition. 
The secondary objectives of the study are: 
 in 14 subjects, to evaluate the PK of 960 mg sotorasib administered orally as 3 x 320 mg 
tablets with a high-fat meal (test 2). 
 to assess the safety and tolerability of 960 mg sotorasib administered orally as 3 x 320 mg 
tablets and 960 mg sotorasib administered orally as 8 x 120 mg tablets. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints of the study are sotorasib PK parameters in Period 1 and Period 2: 
 Cmax 
 AUC from time zero to the last quantifiable concentration (AUClast) 


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 AUCinf. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
 adverse events 
 clinical laboratory tests 
 12-lead ECGs 
 vital signs 
 sotorasib PK parameters in Period 3: Cmax, AUClast, AUCinf. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be an open-label, multi-center (United States), crossover, 3-period bioequivalence 
study to compare the PK of a single oral dose of 960 mg sotorasib administered as 3 x 320 mg 
tablets (test 1) under fasted condition to a single oral dose of 960 mg sotorasib administered as 
8 x 120 mg tablets (reference) under fasted condition and the PK of 960 mg sotorasib 
administered as 3 x 320 mg oral tablets following a high-fat meal (test 2) to 960 mg sotorasib 
administered as 3 x 320 mg oral tablets under fasted condition (test 1) in healthy male subjects 
and healthy female subjects. Approximately 146 subjects will be enrolled to ensure that at least 
132 subjects complete the study.  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the Clinical Research Unit 
(CRU) on Day -1 and be confined to the CRU until discharge on Day 6 or Day 9. On Day 1, 
subjects will be randomized to Group 1 or Group 2. Each subject will receive one administration 
of 960 mg sotorasib administered orally as 3 x 320 mg tablets (Treatment A: test 1) and one 
administration of 960 mg sotorasib administered orally as 8 x 120 mg tablets (Treatment B: 
reference) in either Period 1 or Period 2 according to their assigned group. Each subject will 
receive both treatments following an overnight fast according to the treatment sequence in Table 
1. On Day 7, 14 subjects in either Group 1 or Group 2 will proceed to Period 3 and receive one 
additional administration of 960 mg sotorasib administered orally as 3x 320 mg tablets with a 
high-fat meal (Treatment C: test 2). 
Table 1: 
Treatment Sequence 
Group 
Period 1 (Day 1) 
Period 2 (Day 4) 
Period 3 (Day 7) 
1 
Treatment A 
Treatment B 
Treatment C 
2 
Treatment B 
Treatment A 


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An overview of the study design is shown in Figure 1. 
Figure 1: 
Study Schematic 
 
Abbreviations: EOS  End of Study; ET  Early Termination; N  number of subjects 
*Subjects will receive a single dose in each treatment period, on Days 1, 4, and 7.  
** Subjects will be discharged on Day 6 or Day 9 according to their treatment assignment. 
The total duration of study participation for each subject (from Screening through end of study 
[EOS]) is anticipated to be approximately 5 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 Schedule of Assessments is presented in Appendix 9. 
3.2. 
Discussion of Study Design 
This is a 3-period crossover study in healthy subjects where all subjects receive at least two 
treatments. The randomized, crossover design in Period 1 and Period 2 used in this study is 
typical to evaluate the relative bioavailability of the different treatments. The number of subjects 
is adequate since the design selected for this study allows intra-subject comparisons and thereby 
reduces variability. This study will be open-label because the primary endpoints of the study are 
considered objective.  


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Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
3.3. 
Selection of Doses in the Study 
The 960 mg dose was selected for the present study because this is the approved dose.12 There 
have been 6 clinical studies in healthy subjects where sotorasib has been administered on 2 to 3 
occasions at the 960 mg dose, and was well tolerated across all studies. 
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: 
1. Subject has provided informed consent before initiation of any study-specific 
activities/procedures. 
2. Healthy male subjects or female subjects, between 18 and 60 years of age (inclusive) at 
the time of Screening. 
3. 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 [e.g., suspicion of Gilbert’s 
syndrome based on total and direct bilirubin] is not acceptable) as assessed by the 
Investigator (or designee). 
4. Body mass index between 18 and 30 kg/m2 (inclusive) at the time of Screening. 
5. Females of nonchildbearing potential defined as permanently sterile (ie, due to 
hysterectomy, bilateral salpingectomy, and/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). 
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: 
1. History or evidence, at Screening or Check-in, of clinically significant disorder, 
condition, or disease not otherwise excluded that, in the opinion of the Investigator (or 


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designee), would pose a risk to subject safety or interfere with the study evaluation, 
procedures, or completion. 
2. History or evidence of clinically significant arrhythmia at Screening, including any 
clinically significant findings on the ECG taken at Check-in. 
3. A QT interval corrected for heart rate (HR) based on the Fridericia method (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. 
4. PR interval 200 msec, 2nd degree atrioventricular (AV) block or 3rd degree AV block, 
at Screening or Check-in. An average of the triplicate measurements of the PR interval 
will be used to evaluate subject’s eligibility at Screening and at Check-in. 
5. Systolic blood pressure (BP) 140 mmHg or 90 mmHg, or diastolic BP 90 mmHg, or 
HR 100 bpm, at Screening or Check-in. Subjects with out-of-range values that are not 
clinically significant (as determined by the Investigator) may have the test repeated once 
during Screening or Check-in (within 1 hour of original assessment) and the subject may 
be enrolled if a repeated value is within normal range. 
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. 
7. Inability to swallow oral medication or history of malabsorption syndrome. 
8. History of 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 less than 70 mL/min/1.73 m2 as calculated by the 
Modification of Diet in Renal Disease equation, at Screening or Check-in. A subject with 
out-of-range value may have the test repeated once at the discretion of the Investigator. 
11. ALT or AST  upper limit of normal (ULN), at Screening or Check-in. ALT and AST 
should be below ULN at Screening (for these parameters, a subject with out-of-range 
values may have the tests repeated once and the subject may be enrolled if the repeated 
values are ULN or if the repeated values above ULN are deemed not clinically 
significant by the Investigator [eg, 1.5 ULN]). 
12. Positive hepatitis B or hepatitis C panel and/or positive human immunodeficiency virus 
test, at Screening. Subjects whose results are compatible with prior immunity may be 
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13. Use of any over-the-counter or prescription medications within 30 days or 5 half-lives 
(whichever is longer) before enrollment. 
a. Acetaminophen (paracetamol; up to 2 g per day) for analgesia will be allowed. 
14. All herbal medicines (e.g., 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. Administration of a Coronavirus Disease 2019 (COVID-19) vaccine in the past 30 days 
prior to dosing.  
16. Consumption of foods and beverages containing poppy seeds, grapefruit, or Seville 
oranges within 7 days prior to Check-in. 
17. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 
18. Alcohol consumption from 48 hours prior to Check-in. 
19. 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. 
20. Use of tobacco- or nicotine-containing products within 6 months prior to Check-in. 
21. Positive test for illicit drugs, cotinine (tobacco or nicotine use), and/or alcohol use at 
Screening or Check-in. 
22. Consumption of caffeine-containing foods and beverages within 48 hours prior to 
Check-in. 
23. Female subjects with a positive pregnancy test at Screening or Check-in.  
24. Female subjects lactating/breastfeeding or who plan to breastfeed during the study 
through 7 days after the EOS. 
25. Unwilling to adhere to contraceptive requirements through 7 days after the EOS (see 
Appendix 4).  
26. Unwilling to abstain from sperm donation and ovum donation through 7 days after the 
EOS (see Appendix 4). 
27. Male subjects with a female partner of childbearing potential and not willing to inform 
his partner of his participation in this clinical study. 
28. Male subjects with a pregnant partner or partner planning to become pregnant who are 
unwilling to practice abstinence (refrain from heterosexual intercourse) or use 
contraception while the subject is on study through 7 days after the EOS. 
29. Subject has received a dose of an investigational drug within the past 30 days or 
5 half-lives, whichever is longer, prior to Check-in. 
30. Have previously completed or withdrawn from this study or any other study investigating 
sotorasib or have previously received the investigational product.  


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31. Donation of blood from 90 days prior to Check-in, plasma from 2 weeks prior to 
Check-in, or platelets from 6 weeks prior to Check-in. 
32. Receipt of blood products within 2 months prior to Check-in.  
33. Unwilling to abide with study restrictions. 
34. Subjects who, in the opinion of the Investigator (or designee), should not participate in 
this study. 
35. Performed strenuous exercise, began a new exercise program, or participated in any 
unusually strenuous physical exertion within 7 days prior to Check-in. 
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 because they do not meet eligibility requirements. A minimal 
set of screen failure information will be collected that includes demography, screen failure 
details, eligibility criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only once.  
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 (e.g., Subjects 0101, 0102, 0103). Replacement 
subjects will be assigned a subject number corresponding to the number of the subject he/she is 
replacing plus 1000 (e.g., 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) 
 occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) v5 
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 occurrence of Grade 2 AE considered by the Investigator (or designee) to be at least 
possibly related to sotorasib and, in the opinion of the Investigator (or designee), warrants 
subject withdrawal (e.g., neuropathy, chronic diarrhea, etc.) 
 any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
If two or more subjects are withdrawn from the study due to AEs that are considered by the 
Investigator to be at least possibly related to sotorasib or if there is one Grade 3 event, dosing 
would be paused, and the Investigator and Sponsor will convene to review the data and 
determine the next step. 
If a subject is withdrawn from dosing, the Sponsor (or designee) 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 9). Other procedures may be performed at the Investigator’s (or designee’s) 
and/or Sponsor’s discretion. If the subject is inhouse-, 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 and serious adverse events, or until the unresolved 
adverse events and serious 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/serious 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 
Good Clinical Practice. 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. 
4.7. 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving investigational 
product and/or other protocol-required therapies or study procedures at any time during the study 


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but continue participation in the study. If this occurs, the Investigator is to discuss with the 
subject the appropriate processes for discontinuation from investigational product or other 
protocol-required therapies and must discuss with the subject the possibilities for continuation of 
the Schedule of Assessments (Appendix 9) including different options of follow-up (e.g., in 
person, by phone/mail, through family/friends, in correspondence/communication with other 
treating physicians, from the review of medical records) and collection of data, including 
endpoints, adverse events, serious adverse events and must document this decision in the 
subject’s medical records. Subjects who have discontinued investigational product and/or other 
protocol-required therapies or study procedures should not be automatically removed from the 
study. Whenever safe and feasible, it is imperative that subjects remain on study to ensure safety 
surveillance and/or collection of outcome data. 
Reasons for removal from protocol-required investigational product(s) or procedural assessments 
include any of the following: 
 Decision by the Sponsor 
 Lost to Follow-up 
 Death 
 Protocol deviation 
 Noncompliance  
 Adverse events  
 Subject request 
 Pregnancy.  
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 products will be stored at the study site in a location that is locked 
with restricted access. 


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5.2. 
Investigational Product Administration 
Table 2: 
Investigational Product 


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Study Treatment 
Name 
(Treatment A, C) 
Investigational Medicinal 
Product: 
Sotorasib 
(Treatment B)  
Investigational Medicinal Product: 
Sotorasib 
Unit Strength and 
Formulation 
320 mg tablet 
120 mg tablet 
Dosage Level 
960 mg (3 x 320 mg tablets) 
960 mg (8 x 120 mg tablets) 
Route of 
Administration 
Oral 
Oral 
Accountability 
The quantity administered, date 
administered, and lot number of 
investigational product are to be 
recorded on each subject's Case 
Report Form.  
The quantity administered, date 
administered, and lot number of 
investigational product are to be 
recorded on each subject's Case 
Report Form. 


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Dosing Instructions 
Treatment A: The 
Investigator/designee will 
administer the treatment after the 
completion of all predose 
procedures and after a fast of at 
least 10 hours. Three tablets should 
be taken (the first tablet by itself 
immediately followed by two 
tablets) with 8 ounces (240 mL) of 
water. Additional water may be 
used during dosing, as required. 
Tablets should not be broken or 
chewed.  
No food will be given for at least 
4 hours post administration. 
Treatment C: The 
Investigator/designee will 
administer the treatment after the 
completion of all predose 
procedures and after a fast of at 
least 10 hours. Subjects will 
consume the entirety of a standard 
high‑fat breakfast within 20 
minutes. A 960-mg dose of 
sotorasib will be given orally 30 
minutes after start of the meal. 
Three tablets should be taken (the 
first tablet by itself immediately 
followed by two tablets) with 
8 ounces (240 mL) of water. 
Additional water may be used 
during dosing, as required. Tablets 
should not be broken or chewed.  
No food will be given for at least 
4 hours post administration. 
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 should be taken (the first 
tablet by itself immediately followed 
by seven tablets) with 8 ounces (240 
mL) of water.  Additional water may 
be used during dosing, as required. 
Tablets should not be broken or 
chewed. 
No food will be given for at least 
4 hours post 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. 
5.2.1. 
Standard High-fat Meal 
The standardized high-fat meal breakfast should consist of approximately 800 to 1000 calories 
(including approximately 150 protein calories, 250 carbohydrate calories, and 500 to 600 fat 
calories). A typical meal is equivalent to 2 eggs fried in butter, 2 strips of bacon, 2 slices of 


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buttered toast or bread, 4 ounces of hash brown potatoes (fried with butter), and 8 ounces (240 
mL) of whole milk.13 Substitutions can be made as long as the meal provides a similar amount of 
calories from protein, carbohydrate, and fat and has similar meal volume and consistency. 
Substitutions will apply to all subjects and all subjects will receive an identical meal. 
5.3. 
Treatment of Overdose 
The effects of overdose of sotorasib are not known. In case of overdose, consultation with the 
medical monitor is recommended for prompt reporting of clinically apparent or laboratory 
adverse events possible related to over dosage, and to discuss further management of the subject. 
5.4. 
Medical Devices  
Other non-investigational medical devices may be used in the conduct of this study as part of 
standard care. Non-Amgen non-investigational medical devices (e.g., 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.  
5.5. 
Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
drug(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 are to be reported according to the instructions provided in the Amgen IPIM. 
5.6. 
Randomization 
In Period 1 and Period 2, subjects will be randomized 1:1 into 1 of 2 treatment groups based on 
the study randomization scheme that will be provided by a biostatistician. Subjects in Period 3 
will not be randomized. 
5.7. 
Blinding 
This is an open-label study. 
5.8. 
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. 


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 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 IMP will be performed.  
5.9. 
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. 
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.  
Acetaminophen (paracetamol; up to 2 g/day) is an acceptable concomitant medication. 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/serious 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 
Subjects will be fasted overnight (at least 8 hours) before collection of blood samples for clinical 
laboratory evaluations. While confined at the study site, subjects will receive a standardized diet 
at scheduled times that do not conflict with other study-related activities.  
Refer to Section 5 and Table 2 for diet requirements/restrictions on applicable days of study 
treatment and/or PK assessments. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 7 days prior to check-in until EOS.  
Caffeine-containing foods and beverages will not be allowed from 48 hours before Check-in 
until EOS.  


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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 6 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 
(i.e., 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 90 days 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 laboratory assessments. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples (approximately 1 x 4 mL for sotorasib) will be collected by venipuncture or 
cannulation at the times indicated in the Schedule of Assessments in Appendix 9. Procedures for 


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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 9) 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 will be determined using a validated analytical procedure. 
Specifics of the analytical method 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 
Adverse Events and 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. 
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 and Serious Adverse Events occurring at any other time 
during the study. 
Adverse Events 
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 the 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 visit (whichever is later) are reported using the 


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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. 
The criteria for grade 4 in the Common Terminology Criteria for Adverse Events grading scale 
differs from the regulatory criteria for serious adverse events. It is left to the Investigator’s 
judgment to report these grade 4 abnormalities as serious adverse events. 
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 should 
be reported to Amgen (regardless of causality) if the Investigator becomes aware of them. 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/awareness 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 
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. 


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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 (e.g., 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 EOS. Details of all pregnancies in female partners of male 
subjects will be collected after the start of study treatment until 7 days after EOS. 
If a pregnancy is reported, the Investigator is to inform Amgen within 24 hours of learning of the 
pregnancy and/or lactation and is to follow the procedures outlined in Appendix 5. Amgen 
Global Patient Safety will follow-up with the Investigator regarding additional information that 
may be requested. 
Abnormal pregnancy outcomes (e.g., 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. 


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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 9. 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 CRF/eCRF. The Investigator must determine 
whether an abnormal value in an individual study subject represents a clinically significant 
change from the subject’s baseline values. In general, abnormal laboratory findings without 
clinical significance (based on the Investigator’s judgment) are not to be recorded as adverse 
events. However, laboratory value changes that require treatment or adjustment in current 
therapy are considered adverse events. Where applicable, clinical sequelae (not the laboratory 
abnormality) are to be recorded as the adverse event. Subjects who develop any lab 
abnormalities outside the reference range that are deemed clinically meaningful during the study 
period will have follow-up labs once a week, or more frequently if deemed necessary, until the 
abnormalities have resolved or returned to within the reference range or to the subject’s baseline 
values. 
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 9. 
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 9.  
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
7.2.3. 
Vital Signs 
Supine blood pressure, supine heart rate, respiratory rate, and oral body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 9. 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 heart rate 
measurements. When vital signs are scheduled at the same time as blood draws, the blood draws 
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 9. Single 12-lead 


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ECGs will be repeated twice, and an average taken of the 3 readings, if either of the following 
criteria apply: 
 QTcF is 500 ms 
 QTcF change from the baseline (predose) is 60 ms. 
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 9.  
7.3. 
Subject Questionnaire 
Subjects will be asked to provide feedback on the tablets after each dose. Site staff will 
administer a brief questionnaire to subjects after dosing has occurred in Periods 1 and 2 only 
(Appendix 8). 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
The study will require at least 132 subjects completing the study to establish equivalence 
between the 2 groups with 90 power. This test is based on a 2-sided ratio of means test for a 2 
x 2 crossover design for continuous data with significance level 5. The ratio of means between 
treatment and control groups under the alternative hypothesis is 0.95. This test assumes lower 
and upper equivalence limits of 0.8 and 1.25, respectively, and root mean squared error of the log 
ratio equal to 0.472. Assuming approximately 10 drop out rate, approximately 146 subjects (73 
subjects per treatment) will be enrolled in this study. 
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 events 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 at least 1 dose of sotorasib and have 
at least 1 postdose safety assessment. 
8.3. 
Pharmacokinetic Analyses 
The plasma PK parameters of sotorasib on Days 1 and 4 will be calculated using standard 
noncompartmental methods. 
The primary PK parameters are Cmax, AUClast, and AUCinf for sotorasib on Days 1 and 4. All 
other PK parameters will be regarded as secondary. A linear mixed-effects model will be used to 
analyze log-transformed primary PK parameters. The model assumes fixed effect for treatment, 
period, and sequence and a random effect for subject. Geometric mean ratios for Cmax and AUC 
values and associated 90 confidence intervals (test/reference) will be estimated. The 
“reference” treatment for PK analysis will be Treatment B while the “test 1” treatment will be 
Treatment A for the bioequivalence analysis. For the food-effect analysis, the model will use 
14 subjects’ data and assumes fixed effects for treatment and random effect for subject while test 
treatment would be fed (test 2; Treatment C) and reference would be fasted (test 1; 
Treatment A).   
Additional parameters may be calculated. 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 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.  
Endpoints for clinical laboratory tests, ECG, and vital signs will be summarized. 
8.5. 
Interim Analysis 
No interim analyses are planned for this study.  
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. 


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3. Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS; from structural insights 
to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771-785. 
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 LUMAKRASTM (sotorasib) tablets prescribing information. 
Revised May 2021. Amgen. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214665s000lbl.pdf.  
13. Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. 
Rockville (MD): Department of Health and Human Services (US), Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER); Dec 2002. 
 


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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 Events and Serious Adverse Events 
Definition of Adverse Event 
Adverse Event Definition 
 An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.  
 Note: An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device, or procedure. 
 Note: Treatment-emergent adverse events will be defined in the Statistical Analysis 
Plan (SAP). 
Events Meeting the Adverse Event Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the Investigator (i.e., 
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. 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an adverse event or serious adverse event. Such instances will be 
captured in the efficacy assessments. However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as adverse event or serious 
adverse event if they fulfill the definition of an adverse event or serious adverse 
event.  


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


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Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These 
events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 When an adverse event or serious adverse event occurs, it is the responsibility of 
the Investigator to review all documentation (e.g., 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 Did the event start prior to first dose of investigational product, other protocol-
required therapies; 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to the investigational product(s) and/or study-
mandated procedures;  
o Action taken; and  
o Outcome of event. 
 If the severity of an adverse event changes from the date of onset to the date of 
resolution, record 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. 


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 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 (CTCAE) grading 
scale. For the CTCAE grading scale version 5.0 or higher, refer to: 
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 judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 The Investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 For each adverse event/serious adverse event, the Investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and 
has provided an assessment of causality. 
 There may be situations in which a serious adverse event has occurred and the 
Investigator has minimal information to include in the initial report. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 


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 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. 
 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. 
 Once the study has ended, serious event(s) should be reported to Sponsor 
(regardless of causality) if the Investigator becomes aware of a serious adverse 
event. The Investigator should use the paper-based Serious Adverse Event Report 
Form to report the event.  


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Figure 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 CO2 (measured as 
bicarbonate) 
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 
Microscopic examination (if 
protein, leukocyte esterase, 
nitrite, or blood is positive) 
Serologyb: 
Drug screenc: 
Hormone panel - females 
only: 
Anti-hepatitis B surface antibody 
Anti-hepatitis B core antibody  
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies 
and p24 antigen 
Including but not limited to:  
Alcohol test 
Amphetamines/methamphetamin
es 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Cotinine 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
 
 
Follicle-stimulating hormoneb 
(postmenopausal females only) 
Serum pregnancy test (human 
chorionic gonadotropin)d 
Urine pregnancy testd 
Other tests: 
Thyroid-stimulating hormonee 
International normalized ratio 
(INR)f 
Estimated glomerular filtration 
rate (eGFR)c,g 
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.  
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 Only analyzed at Screening, Check-in and at EOS. 
f International normalized ratio will be tested if hepatotoxicity is suspected, per guidelines presented in Appendix 7. 
g Estimated glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease equation. 
 


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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations 
12.5 
5 
62.5 
Serology 
7 
1 
7 
Sotorasib 
pharmacokinetics 
4 
34-51 
136-204 
Total: 
205.5-273.5 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject will 
not exceed 500 mL. 


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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 the end of study (EOS). 
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 
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 must be of nonchildbearing potential and will not be required to use 
contraception.  
Female subjects should refrain from donation of ova from Check-in (Day -1) until 7 days after 
the EOS. 
Male Subjects:  
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (i.e., male condom with spermicide) in addition to a 
second method of acceptable contraception by female partner from Check-in until 7 days after 
the EOS. 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 (i.e., the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
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 the EOS.  
Same-sex Relationships 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. 
A subject in a same-sex relationships 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 the 
EOS. 


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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 end of study 
(EOS). 
 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 signed 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 EOS. 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 (e.g., female subject experiences a spontaneous abortion, stillbirth, or 
neonatal death or there is a fetal or neonatal congenital anomaly) the Investigator will 
report the event as a serious adverse event. 
 Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the Investigator will be reported 
to Amgen Global Patient Safety as described in 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 4.7 for details). 


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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 EOS, 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 any information on 
the Pregnancy Notification Form that violates the country or regions local privacy laws). 
 The Investigator will attempt to obtain a signed consent for release of pregnancy and 
infant health information directly from the pregnant female partner to obtain additional 
pregnancy information. 
 After obtaining the female partner’s signed consent for release of pregnancy and infant 
health information, the Investigator will collect pregnancy outcome and infant health 
information on the pregnant partner and her baby and complete the pregnancy 
questionnaires. This information will be forwarded to Amgen Global Patient Safety. 
 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 EOS. 
 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 signed consent for release of mother and infant health 
information, the Investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while taking 
protocol-required therapies through 7 days after EOS. 


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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 Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
 Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator’s Brochure, and 
other relevant documents (e.g., 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.) 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 
28 days from the previous ICF signature date and the same version of the ICF is in use at the 
time of rescreening. 
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 (or designee). Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  


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On the electronic Case Report Form (eCRF) demographics page, in addition to the unique 
subject identification number (Section 4.4), include the age at time of enrollment. 
For serious adverse events reported to the Sponsor (or designee), subjects are to be identified by 
their unique subject identification number (Section 4.4) (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 (e.g., 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. 
Subjects will be assigned a unique identifier by the Sponsor (or designee). 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 eCRF demographics page, in addition to the unique subject identification number 
(Section 4.4), 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 (Section 4.4), 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 (e.g., signed ICFs) are to be kept in confidence by 
the Investigator, except as described below. 


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Data Quality Assurance 
The following data quality steps will be implemented: 
 All relevant subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (e.g., 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 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (e.g., 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, 
will review the supporting source documentation against the data entered into the eCRFs to 


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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. 
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 Stopping Rules: Suggested Actions and Follow-up Assessments  
Subjects with abnormal hepatic laboratory values (i.e., alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) and/or 
international normalized ratio (INR) and/or signs/symptoms of hepatitis (as described below) 
may meet the criteria for withholding or permanent discontinuation of Amgen investigational 
product or other protocol-required therapies, as specified in the Guidance for Industry 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another cause of 
their changes in liver biomarkers (TBL, INR, and transaminases) has not been identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are not 
limited to: 
 Hepatobiliary tract disease 
 Viral hepatitis (e.g., 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 (e.g., Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, 
atazanavir) 
 Alpha-one antitrypsin deficiency 
 Alcoholic hepatitis 
 Autoimmune hepatitis 
 Wilson’s disease and hemochromatosis 
 Nonalcoholic fatty liver disease including steatohepatitis 
 Non-hepatic causes (e.g., rhabdomylosis, hemolysis). 
If investigational product(s) is/are withheld, the subject is to be followed for possible 
drug-induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) 
and/or elevated TBL is discovered and the laboratory abnormalities resolve to normal or baseline 
(see next section in this appendix). 


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Table 3: 
Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity  
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
3x ULN at any time 
2x ULN 
INR 
-- 
 
OR 
1.5x (for subjects not on 
anticoagulation therapy) 
AND 
AST/ALT 
8x ULN at any time 
5x ULN but 8x ULN for 2 weeks 
5x ULN but 8x ULN and unable to 
adhere to enhanced monitoring schedule 
3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, fever, 
nausea, vomiting, and jaundice) 
OR 
In the presence of no 
important alternative 
causes for elevated 
AST/ALT and/or TBL 
values 
3x ULN (when baseline 
was  ULN) 
ALP 
8x ULN at any time 
-- 
Abbreviations: ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
INR  international normalized ratio; TBL  total bilirubin; ULN  upper limit of normal. 
 
Criteria for Rechallenge of Amgen Investigational Product and Other Protocol-required 
Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon unanimously by the 
subject, Investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then OM is to be permanently discontinued.   
Subjects who clearly meet the criteria for permanent discontinuation (as described in Table 3) are 
never to be rechallenged. 
 


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


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o Prior and/or concurrent disease 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 
 Appropriate blood sampling for pharmacokinetic analysis, if this has not already been 
collected 
 Hepatology consult (liver biopsy may be considered in consultation with a hepatologist). 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the Investigator. The “close 
observation period” is to continue for a minimum of 4 weeks after discontinuation of all 
investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications, and laboratory results must be captured in the corresponding eCRFs.  
 
 
 
 
 


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Appendix 8: Sample Subject Questionnaire 
 


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Appendix 9: Schedule of Assessment


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Schedule of Assessments 
Study Procedures 
Screening 
Check-in 
Period 1 
Period 2 
Period 3 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 6 or 
Day 9 
(EOS/ 
ET) 
Confined to the CRU 
  
X 
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 
  
  
  
  
  
  
 
 
 Xl 
Drug Screen 
X 
X 
  
  
  
  
  
   
 
 
 
Alcohol Test 
X 
X 
  
  
  
  
  
  
 
 
 
Pregnancy Test (females only)b 
X 
X 
  
  
  
  
  
 
 
 
 Xl 
FSH (postmenopausal females 
only) 
X 
  
  
  
  
  
  
   
 
 
 
12-lead Electrocardiogramc 
X 
X 
X 
 
  
X 
 
 
X 
 
 Xl 
Vital Signsd 
X 
X 
X 
X 
  
X 
X 
 
X 
X 
 Xl 
Clinical Laboratory Evaluationse 
X 
X 
  
  
X  
  
  
X 
 
 
 Xl 
eGFRf 
X 
X 
  
  
  
  
  
  
 
 
 
Physical Examinationg 
  
X 
  
  
  
  
  
 
 
 
 Xl 
Sotorasib Doseh 
  
  
X 
  
  
X 
  
  
X 
 
 
Subject Questionnaire 
 
 
X 
 
 
X 
 
 
 
 
 
Sotorasib PK Blood Samplesi 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Adverse Event Monitoringj 
  
  
X 
Serious Adverse Event 
Monitoringj 
X 
X 
Prior/Concomitant Medicationsk 
X 
X 
Abbreviations: BMI  body mass index; CRU  Clinical Research Unit; eGFR  estimated glomerular filtration rate; EOS  end of study; ET  early termination; 
FSH  follicle-stimulating hormone; PK  pharmacokinetic. 
a Interim medical history only. 
b 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. 


Protocol Amendment 2 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
Protocol Version 3.0, 09 September 2021  
Page 70 of 70 
c 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 following sotorasib administration on Days 1, 4 and 7; and EOS or ET. The 30-minute postdose ECG measurement will 
have a collection window of  2 minutes, the 2-hour postdose ECG measurement will have a collection window of  5 minutes, and the 4-hour postdose ECG measurement will 
have a collection window of  10 minutes.  
d Vital signs measurements (supine blood pressure [BP], supine heart rate, respiratory rate, and oral body temperature) should be carried out prior to having blood drawn. 
Screening; Check-in; prior to sotorasib administration on Days 1, 4 and 7; 1 and 24 hours following sotorasib administration on Days 1, 4 and 7; and EOS/ET. Heart 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. 
e Clinical chemistry (fasted at least 8 hours), hematology, and urinalysis. 
f eGFR will be calculated using the Modification of Diet in Renal Disease equation. 
g A full physical examination at Check-in and a symptom-directed physical examination at EOS/ET. 
h Dose administration of sotorasib is to occur during the mornings of Days 1, 4 and 7 in accordance with the formulation of sotorasib administration specific to their treatment 
(Treatment A, Treatment B or Treatment C). 
i Blood samples for determination of sotorasib plasma concentrations will be collected: Predose (Hour 0), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours postdose 
following administration of sotorasib on Days 1, 4 and 7. The PK 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 48 hours postdose will have a sampling window of  20 minutes. Times of all PK samples will be recorded to the nearest minute. 
j 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 through 30 days after the last dose of study treatment or the EOS (whichever is later). 
k 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 enrollment administration for over-the-counter or prescription medications, and 30 days prior to enrollment for herbal 
medicines (eg, St. John’s wort), vitamins, and supplements, will be recorded on the subject’s electronic Case Report Form. 
l Assessment to be performed at the EOS or if a subject is withdrawn early from the study. 
 


Protocol Amendment 2 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
Sponsor Reference: 20210093 
 
Draft Protocol Amendment 3.0, 10 September 2021 
Page 1 of 4 
Summary of Amended Protocol Changes 
An Open-label, Randomized, Two-way Crossover, Bioequivalence Study in 
Healthy Volunteers to Compare the Pharmacokinetics of Two Different 
Tablets of Sotorasib  
Protocol Amendment 2 Status: Draft 
Protocol Amendment 2 Date: 10 September 2021 
Protocol Amendment 1 Date: 02 September 2021 
Original Protocol Date: 04 June 2021 
Protocol Version 3.0 
Amgen Investigational Product: Sotorasib (AMG 510) 
Amgen Protocol Reference Number: 20210093 
Labcorp Drug Development Study Number: 8471128 
IND Number: 139023 
 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
 
 
 
Sponsor Signatory: 
, PhD 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
________________________________________ 


Protocol Amendment 2 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
Sponsor Reference: 20210093 
 
Draft Protocol Amendment 3.0, 10 September 2021 
Page 2 of 4 
The primary changes in this amendment, along with the rationale for the/each change as 
appropriate, are: 
1. Based on recommendations from the regulatory agency, the protocol was modified to add 
additional criteria for subject withdrawal from the study and criteria for pausing dosing. 
2. Based on recommendations from the regulatory agency, the protocol was modified to add 
additional follow-up laboratory evaluations for subjects who develop clinically 
meaningful abnormalities outside the reference range during the study period. 
Minor changes: 
1. The synopsis was updated according to the changes in the protocol body, as applicable. 
2. The amendment/version number and date were updated throughout the protocol. 
3. Typographical errors and formatting errors were corrected, as necessary. 
4. Abbreviations were added and/or removed, as appropriate. 
A detailed summary of changes is presented below: 
Section 4.5 Subject Withdrawal and Replacement 
Previously read: 
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. 
 
If a subject is withdrawn from dosing, the Sponsor (or designee) 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 9). 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 and serious adverse events, or until the unresolved 
adverse events and serious adverse events are judged by the Investigator (or designee) to have 
stabilized. 
 


Protocol Amendment 2 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
Sponsor Reference: 20210093 
 
Draft Protocol Amendment 3.0, 10 September 2021 
Page 3 of 4 
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/serious adverse events thought to be related to the study drug will generally not be 
replaced. 
Now reads: 
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) 
• occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) v5 
Grade ≥3 AE 
• occurrence of Grade 2 AE considered by the Investigator (or designee) to be at least 
possibly related to sotorasib and, in the opinion of the Investigator (or designee), warrants 
subject withdrawal (e.g., neuropathy, chronic diarrhea, etc.) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
If two or more subjects are withdrawn from the study due to AEs that are considered by the 
Investigator to be at least possibly related to sotorasib or if there is one Grade 3 event, dosing 
would be paused, and the Investigator and Sponsor will convene to review the data and 
determine the next step. 
If a subject is withdrawn from dosing, the Sponsor (or designee) 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 9). 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 and serious adverse events, or until the unresolved 
adverse events and serious 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/serious adverse events thought to be related to the study drug will generally not be 
replaced. 


Protocol Amendment 2 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
Sponsor Reference: 20210093 
 
Draft Protocol Amendment 3.0, 10 September 2021 
Page 4 of 4 
Section 7.2.2. Clinical Laboratory Evaluations, Paragraph 2 
Previously read: 
The Investigator is responsible for reviewing laboratory test results and recording any clinically 
relevant changes occurring during the study in CRF/eCRF. The Investigator must determine 
whether an abnormal value in an individual study subject represents a clinically significant 
change from the subject’s baseline values. In general, abnormal laboratory findings without 
clinical significance (based on the Investigator’s judgment) are not to be recorded as adverse 
events. However, laboratory value changes that require treatment or adjustment in current 
therapy are considered adverse events. Where applicable, clinical sequelae (not the laboratory 
abnormality) are to be recorded as the adverse event. 
Now reads: 
The Investigator is responsible for reviewing laboratory test results and recording any clinically 
relevant changes occurring during the study in CRF/eCRF. The Investigator must determine 
whether an abnormal value in an individual study subject represents a clinically significant 
change from the subject’s baseline values. In general, abnormal laboratory findings without 
clinical significance (based on the Investigator’s judgment) are not to be recorded as adverse 
events. However, laboratory value changes that require treatment or adjustment in current 
therapy are considered adverse events. Where applicable, clinical sequelae (not the laboratory 
abnormality) are to be recorded as the adverse event. Subjects who develop any lab 
abnormalities outside the reference range that are deemed clinically meaningful during the study 
period will have follow-up labs once a week, or more frequently if deemed necessary, until the 
abnormalities have resolved or returned to within the reference range or to the subject’s baseline 
values. 
 
 


Protocol Amendment 1 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 1 of 17 
Summary of Amended Protocol Changes 
An Open-label, Randomized, Two-way Crossover, Bioequivalence Study in 
Healthy Volunteers to Compare the Pharmacokinetics of Two Different 
Tablets of Sotorasib 
Protocol Amendment 1 Status: Final 
Protocol Amendment 1 Date: 02 September 2021  
Original Protocol Date: 04 June 2021 
 
Protocol Version 2.0 
Amgen Investigational Product: Sotorasib (AMG 510) 
Amgen Protocol Reference Number: 20210093 
Labcorp Drug Development Study Number: 8471128 
IND Number: 139023 
 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
 
 
 
Sponsor Signatory: 
, PhD 
 
 
 
Information described herein is confidential and may be disclosed only with the 
express written permission of the Sponsor. 
________________________________________ 
Page 148 of 233


Protocol Amendment 1 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 2 of 17 
The primary changes in this amendment are:  
1. Based on recommendations from the regulatory agency, the protocol was modified to add 
a food-effect arm to the study design:  
• Updated applicable sections of the protocol including the objectives, endpoints, 
study design, investigational product information, randomization, and statistical 
methods.  
• Updated the study design schema. 
• Added details on the standard high-fat meal for the food-effect arm. 
• Updated the details for the subject questionnaire to clarify that the questionnaire 
will be administered to subjects in Periods 1 and 2 only. 
• Updated the estimates for the total blood volume collected from each subject. 
• Updated the schedule of assessments. 
2. Updated the protocol to clarify that for Exclusion Criterion #4 an average of the triplicate 
measurement of the PR interval will be used to evaluate subject’s eligibility at Screening 
and at Check-in (previously described in Letter of Administrative Change No. 1). 
Minor changes: 
1. To update the company name from "Covance" to "Labcorp" as Covance is re-branding 
into the parent company Labcorp (applicable only for business units transitioned on or 
after 25 Jun 2021).  
2. The synopsis was updated according to the changes in the protocol body, as applicable. 
3. The version number and date were updated throughout the protocol. 
4. Typographical errors and formatting errors were corrected, as necessary. 
A detailed summary of changes is presented below: 
Page 149 of 233


Protocol Amendment 1 
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 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 3 of 17 
Title page, Study Identification page, and all headers 
Previously read: 
Covance 
Now reads: 
Labcorp Drug Development 
Section 1.3 Study Rationale 
Previously read: 
The purpose of this study is to compare the PK of 960 mg sotorasib administered as 3 x 320 mg 
oral tablets (test) to 960 mg sotorasib administered as 8 x 120 mg oral tablets (reference) in 
healthy male subjects and healthy female subjects of nonchildbearing potential. Oral dosing is 
the intended route of administration for sotorasib. The 320 mg tablet formulation of sotorasib 
would help reduce pill burden for patients requiring sotorasib treatment. 
Now reads: 
The purpose of this study is to compare the PK of 960 mg sotorasib administered as 3 x 320 mg 
oral tablets (test) under fasted condition to 960 mg sotorasib administered as 8 x 120 mg oral 
tablets (reference) under fasted condition and to compare the PK of 960 mg sotorasib 
administered as 3 x 320 mg oral tablets following a high-fat meal (test 2) to 960 mg sotorasib 
administered as 3 x 320 mg oral tablets under fasted condition (test 1) in healthy male subjects 
and healthy female subjects of nonchildbearing potential. Oral dosing is the intended route of 
administration for sotorasib. The 320 mg tablet formulation of sotorasib would help reduce pill 
burden for patients requiring sotorasib treatment. 
Section 1.4.1.2 Risks, paragraph 1 
Previously read: 
To limit the risk of excessive exposure to healthy subjects in the current study, each subject will 
receive a single oral dose of 960 mg sotorasib administered as 3 x 320 mg tablets (test 1, 
treatment A) and a single oral dose of 960 mg sotorasib administered as 8 x 120 mg tablets 
(reference, treatment B) in either Period 1 or Period 2 according to their assigned group, with 
sufficient washout in between periods (details provided in Section 3.3).  
Now reads: 
To limit the risk of excessive exposure to healthy subjects in the current study, each subject will 
receive a single oral dose of 960 mg sotorasib administered as 3 x 320 mg tablets (test) and a 
single oral dose of 960 mg sotorasib administered as 8 x 120 mg tablets (reference) in either 
Period 1 or Period 2 according to their assigned group, with sufficient washout in between 
periods (details provided in Section 3.3). Fourteen healthy subjects in either Groups 1 or 2 will 
Page 150 of 233


Protocol Amendment 1 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 4 of 17 
receive a single oral dose of 960 mg sotorasib administered as 3 x 320 mg tablets (test 2, 
treatment C) following a high-fat meal (detailed provided in Section 5.2.1) in Period 3 with 
sufficient washout in between periods. 
Section 2.1 Objectives 
Previously read: 
The primary objective of the study is: 
• to compare the PK of 960 mg sotorasib administered orally as 3 x 320 mg tablets (test) to 
960 mg sotorasib administered orally as 8 x 120 mg tablets (reference). 
The secondary objective of the study is: 
• to assess the safety and tolerability of 960 mg sotorasib administered orally as 3 x 320 mg 
tablets and 960 mg sotorasib administered orally as 8 x 120 mg tablets. 
Now reads: 
The primary objective of the study is: 
• to compare the PK of 960 mg sotorasib administered orally as 3 x 320 mg tablets (test 1) 
under fasted condition to 960 mg sotorasib administered orally as 8 x 120 mg tablets 
(reference) under fasted condition. 
The secondary objectives of the study are: 
• in 14 subjects, to evaluate the PK of 960 mg sotorasib administered orally as 3 x 320 mg 
tablets with a high-fat meal (test 2). 
• to assess the safety and tolerability of 960 mg sotorasib administered orally as 3 x 320 mg 
tablets and 960 mg sotorasib administered orally as 8 x 120 mg tablets. 
Section 2.2.1 Primary Endpoints 
Previously read: 
The primary endpoints of the study are: 
• Cmax 
• AUC from time zero to the last quantifiable concentration (AUClast) 
• AUCinf. 
Now reads: 
The primary endpoints of the study are sotorasib PK parameters in Period 1 and Period 2: 
Page 151 of 233


Protocol Amendment 1 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 5 of 17 
• Cmax 
• AUC from time zero to the last quantifiable concentration (AUClast) 
• AUCinf. 
Section 2.2.2 Secondary Endpoints 
Previously read: 
The secondary endpoints of the study are: 
• adverse events 
• clinical laboratory tests 
• 12-lead ECGs 
• vital signs 
Now reads: 
The secondary endpoints of the study are: 
• adverse events 
• clinical laboratory tests 
• 12-lead ECGs 
• vital signs 
• sotorasib PK parameters in Period 3: Cmax, AUClast, AUCinf. 
Section 3.1 Overall Study Design and Plan 
Previously read: 
This will be an openlabel, multi-center (United States), randomized two-way crossover, 
bioequivalence study to compare the PK of a single oral dose of 960 mg sotorasib administered 
as 3 x 320 mg tablets (test 1) to a single oral dose of 960 mg sotorasib administered as 8 x 120 
mg tablets (reference) in healthy male subjects and healthy female subjects. Approximately 
146 subjects will be enrolled to ensure that at least 132 subjects complete the study.  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the Clinical Research Unit 
(CRU) on Day 1 and be confined to the CRU until discharge on Day 6. On Day 1, subjects will 
be randomized to Group 1 or Group 2. Each subject will receive one administration of 960 mg 
sotorasib administered orally as 3 x 320 mg tablets (Treatment A: test 1-) and one administration 
of 960 mg sotorasib administered orally as 8 x 120 mg tablets (Treatment B: reference) in either 
Period 1 or Period 2 according to their assigned group. Each subject will receive both treatments 
following an overnight fast according to the treatment sequence in Table 1.  
Page 152 of 233


Protocol Amendment 1 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 6 of 17 
Table 1: 
Treatment Sequence 
Group 
Period 1 (Day 1) 
Period 2 (Day 4) 
1 
Treatment A 
Treatment B 
2 
Treatment B 
Treatment A 
An overview of the study design is shown in Figure 1. 
Figure 1: 
Study Schematic 
 
Abbreviations: EOS = End of Study; ET = Early Termination; N = number of subjects 
*Subjects will receive a single dose in each treatment period, on Day 1 and 4.  
The total duration of study participation for each subject (from Screening through end of study 
[EOS]) is anticipated to be approximately 5 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 Schedule of Assessments is presented in Appendix 9. 
Now reads: 
This will be an open-label, multi-center (United States), crossover, 3-period bioequivalence 
study to compare the PK of a single oral dose of 960 mg sotorasib administered as 3 x 320 mg 
tablets (test 1) under fasted condition to a single oral dose of 960 mg sotorasib administered as 8 
x 120 mg tablets (reference) under fasted condition and the PK of 960 mg sotorasib administered 
as 3 x 320 mg oral tablets following a high-fat meal (test 2) to 960 mg sotorasib administered as 
3 x 320 mg oral tablets under fasted condition (test 1) in healthy male subjects and healthy 
female subjects. Approximately 146 subjects will be enrolled to ensure that at least 132 subjects 
complete the study.  
Page 153 of 233


Protocol Amendment 1 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 7 of 17 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the Clinical Research Unit 
(CRU) on Day 1 and be confined to the CRU until discharge on Day 6. On Day 1, subjects will 
be randomized to Group 1 or Group 2. Each subject will receive one administration of 960 mg 
sotorasib administered orally as 3 x 320 mg tablets (Treatment A: test 1) and one administration 
of 960 mg sotorasib administered orally as 8 x 120 mg tablets (Treatment B: reference) in either 
Period 1 or Period 2 according to their assigned group. Each subject will receive both treatments 
following an overnight fast according to the treatment sequence in Table 1. On Day 7, 14 
subjects in either Group 1 or Group 2 will proceed to Period 3 and receive one additional 
administration of 960 mg sotorasib administered orally as 3 x 320 mg tablets with a high-fat 
meal (Treatment C: test 2). 
Table 1: 
Treatment Sequence 
Group 
Period 1 (Day 1) 
Period 2 (Day 4) 
Period 3 (Day 7) 
1 
Treatment A 
Treatment B 
Treatment C 
2 
Treatment B 
Treatment A 
An overview of the study design is shown in Figure 1. 
Figure 1: 
Study Schematic 
 
Abbreviations: EOS = End of Study; ET = Early Termination; N = number of subjects 
*Subjects will receive a single dose in each treatment period, on Days 1, 4, and 7. 
** Subjects will be discharged on Day 6 or Day 9 according to their treatment assignment. 
 
Page 154 of 233


Protocol Amendment 1 
CONFIDENTIAL 
Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 8 of 17 
The total duration of study participation for each subject (from Screening through end of study 
[EOS]) is anticipated to be approximately 5 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 Schedule of Assessments is presented in Appendix 9. 
Section 3.2 Discussion of Study Design, paragraph 1 
Previously read: 
This is a 2-treatment, 2-period crossover study in healthy subjects where all subjects receive both 
treatments. The randomized, crossover design used in this study is typical to evaluate the relative 
bioavailability of the different treatments. The number of subjects is adequate since the design 
selected for this study allows intra-subject comparisons and thereby reduces variability. This 
study will be open-label because the primary endpoints of the study are considered objective.  
Now reads: 
This is a 3-period crossover study in healthy subjects where all subjects receive at least two 
treatments. The randomized, crossover design in Period 1 and Period 2 used in this study is 
typical to evaluate the relative bioavailability of the different treatments. The number of subjects 
is adequate since the design selected for this study allows intra-subject comparisons and thereby 
reduces variability. This study will be open-label because the primary endpoints of the study are 
considered objective.  
Section 4.2 Exclusion Criteria #4 
Previously read: 
PR interval >200 msec, 2nd degree atrioventricular (AV) block or 3rd degree AV block, at 
Screening or Check-in. 
Now reads: 
PR interval >200 msec, 2nd degree atrioventricular (AV) block or 3rd degree AV block, at 
Screening or Check-in. An average of the triplicate measurement of the PR interval will be used 
to evaluate subject’s eligibility at Screening and at Check-in. 
Page 155 of 233


Protocol Amendment 1 
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Labcorp Drug Development Study: 8471128 
 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 9 of 17 
Section 5.2 Investigational Product Administration, Table 2 
Previously read: 
Study Treatment 
Name 
(Treatment A) 
Investigational Medicinal 
Product: 
Sotorasib 
(Treatment B)  
Investigational Medicinal Product: 
Sotorasib 
Unit Strength and 
Formulation 
320 mg tablet 
120 mg tablet 
Dosage Level 
960 mg (3 x 320 mg tablets) 
960 mg (8 x 120 mg tablets) 
Route of 
Administration 
Oral 
Oral 
Accountability 
The quantity administered, date 
administered, and lot number of 
investigational product are to be 
recorded on each subject's Case 
Report Form.  
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. Three tablets should 
be taken (the first tablet by itself 
immediately followed by two 
tablets) with 8 ounces (240 mL) of 
water. Additional water may be 
used during dosing, as required. 
Tablets should not be broken or 
chewed.  
No food will be given for at least 
4 hours post administration. 
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 should be taken (the first 
tablet by itself immediately followed 
by seven tablets) with 8 ounces (240 
mL) of water.  Additional water may 
be used during dosing, as required. 
Tablets should not be broken or 
chewed. 
No food will be given for at least 
4 hours post administration. 
 
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 Amgen Protocol: 20210093 
 
Protocol Version 2.0, 02 September 2021  
Page 10 of 17 
Now reads: 
Study Treatment 
Name 
(Treatment A, C) 
Investigational Medicinal 
Product: 
Sotorasib 
(Treatment B)  
Investigational Medicinal Product: 
Sotorasib 
Unit Strength and 
Formulation 
320 mg tablet 
120 mg tablet 
Dosage Level 
960 mg (3 x 320 mg tablets) 
960 mg (8 x 120 mg tablets) 
Route of 
Administration 
Oral 
Oral 
Accountability 
The quantity administered, date 
administered, and lot number of 
investigational product are to be 
recorded on each subject's Case 
Report Form.  
The quantity administered, date 
administered, and lot number of 
investigational product are to be 
recorded on each subject's Case 
Report Form. 
Dosing Instructions 
Treatment A: The 
Investigator/designee will 
administer the treatment after the 
completion of all predose 
procedures and after a fast of at 
least 10 hours. Three tablets should 
be taken (the first tablet by itself 
immediately followed by two 
tablets) with 8 ounces (240 mL) of 
water. Additional water may be 
used during dosing, as required. 
Tablets should not be broken or 
chewed.  
No food will be given for at least 
4 hours post administration. 
Treatment C: The 
Investigator/designee will 
administer the treatment after the 
completion of all predose 
procedures and after a fast of at 
least 10 hours. Subjects will 
consume the entirety of a standard 
high‑fat breakfast within 20 
minutes. A 960-mg dose of 
sotorasib will be given orally 30 
minutes after start of the meal. 
Three tablets should be taken (the 
first tablet by itself immediately 
followed by two tablets) with 
8 ounces (240 mL) of water. 
Additional water may be used 
during dosing, as required. Tablets 
should not be broken or chewed.  
No food will be given for at least 
4 hours post administration. 
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 should be taken (the first 
tablet by itself immediately followed 
by seven tablets) with 8 ounces (240 
mL) of water.  Additional water may 
be used during dosing, as required. 
Tablets should not be broken or 
chewed. 
No food will be given for at least 
4 hours post administration. 
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Protocol Version 2.0, 02 September 2021  
Page 11 of 17 
Section 5.2.1 Standard High-fat Meal 
Previously read: 
Not applicable. 
Now reads: 
The standardized high-fat meal breakfast should consist of approximately 800 to 1000 calories 
(including approximately 150 protein calories, 250 carbohydrate calories, and 500 to 600 fat 
calories). A typical meal is equivalent to 2 eggs fried in butter, 2 strips of bacon, 2 slices of 
buttered toast or bread, 4 ounces of hash brown potatoes (fried with butter), and 8 ounces (240 
mL) of whole milk.13 Substitutions can be made as long as the meal provides a similar amount of 
calories from protein, carbohydrate, and fat and has similar meal volume and consistency. 
Substitutions will apply to all subjects and all subjects will receive an identical meal. 
Section 5.6 Randomization 
Previously read: 
This is a randomized, two-way crossover study. Subjects will be randomized 1:1 into 1 of 
2 treatment groups based on the study randomization scheme that will be provided by a 
biostatistician.  
Now reads: 
In Period 1 and Period 2, subjects will be randomized 1:1 into 1 of 2 treatment groups based on 
the study randomization scheme that will be provided by a biostatistician. Subjects in Period 3 
will not be randomized. 
Section 7.3 Subject Questionnaire 
Previously read: 
Subjects will be asked to provide feedback on the tablets after each dose. Site staff will 
administer a brief questionnaire to subjects after dosing has occurred (Appendix 8). 
Now reads: 
Subjects will be asked to provide feedback on the tablets after each dose. Site staff will 
administer a brief questionnaire to subjects after dosing has occurred in Periods 1 and 2 only 
(Appendix 8). 
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Protocol Version 2.0, 02 September 2021  
Page 12 of 17 
Section 8.3 Pharmacokinetic Analyses, paragraph 2 
Previously read: 
The primary PK parameters are Cmax, AUClast, and AUCinf for sotorasib on Days 1 and 4. All 
other PK parameters will be regarded as secondary and will not be subject to inferential 
statistical analysis. A linear mixed-effects model will be used to analyze log-transformed 
primary PK parameters. The model assumes fixed effect for treatment, period, and sequence and 
a random effect for subject. Geometric mean ratios for Cmax and AUC values and associated 90% 
confidence intervals (test/reference) will be estimated. The “reference” treatment for PK analysis 
will be Treatment B while the “test” treatment will be Treatment A.  
Now reads: 
The primary PK parameters are Cmax, AUClast, and AUCinf for sotorasib on Days 1 and 4. All 
other PK parameters will be regarded as secondary and will not be subject to inferential 
statistical analysis. A linear mixed-effects model will be used to analyze log-transformed 
primary PK parameters. The model assumes fixed effect for treatment, period, and sequence and 
a random effect for subject. Geometric mean ratios for Cmax and AUC values and associated 90% 
confidence intervals (test/reference) will be estimated. The “reference” treatment for PK analysis 
will be Treatment B while the “test 1” treatment will be Treatment A for the bioequivalence 
analysis. For the food-effect analysis, the model will use 14 subjects’ data and assumes fixed 
effects for treatment and random effect for subject while test treatment would be fed (test 2; 
treatment C) and reference would be fasted (test 1; Treatment A).  
Section 9 References, Added Reference #13 
Previously read: 
Not applicable. 
Now reads: 
13 
Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. 
Rockville (MD): Department of Health and Human Services (US), Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER); Dec 2002. 
Appendix 3 Total Blood Volume 
Previously read: 
The following blood volumes will be withdrawn for each subject. 
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Protocol Version 2.0, 02 September 2021  
Page 13 of 17 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations 
12.5 
4 
50 
Serology 
7 
1 
7 
Sotorasib 
pharmacokinetics 
4 
34 
136 
Total: 
193 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject will 
not exceed 500 mL. 
Now reads: 
The following blood volumes will be withdrawn for each subject. 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations 
12.5 
5 
62.5 
Serology 
7 
1 
7 
Sotorasib 
pharmacokinetics 
4 
34-51 
136-204 
Total: 
205.5-273.5 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject will 
not exceed 500 mL. 
 
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Protocol Version 2.0, 02 September 2021  
Page 14 of 17 
Appendix 9 Schedule of Assessments 
Previously read: 
Schedule of Assessments 
Study Procedures 
Screening 
Check-in 
Period 1 
Period 2 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
(EOS/ET) 
Confined to the CRU 
  
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 
  
  
  
  
  
 Xl 
Drug Screen 
X 
X 
  
  
  
  
  
   
Alcohol Test 
X 
X 
  
  
  
  
  
  
Pregnancy Test (females only)b 
X 
X 
  
  
  
  
  
Xl 
FSH (postmenopausal females only) 
X 
  
  
  
  
  
  
   
12-lead Electrocardiogramc 
X 
X 
X 
 
  
X 
 
Xl 
Vital Signsd 
X 
X 
X 
X 
  
X 
X 
Xl 
Clinical Laboratory Evaluationse 
X 
X 
  
  
X  
  
  
Xl 
eGFRf 
X 
X 
  
  
  
  
  
  
Physical Examinationg 
  
X 
  
  
  
  
  
Xl 
Sotorasib Doseh 
  
  
X 
  
  
X 
  
  
Subject Questionnaire 
 
 
X 
 
 
X 
 
 
Sotorasib PK Blood Samplesi 
  
  
X 
X 
X 
X 
X 
X 
Adverse Event Monitoringj 
  
  
X 
Serious Adverse Event Monitoringj 
X 
X 
Prior/Concomitant Medicationsk 
X 
X 
Abbreviations: BMI = body mass index; CRU = Clinical Research Unit; eGFR = estimated glomerular filtration rate; EOS = end of study; ET = early termination; 
FSH = follicle-stimulating hormone; PK = pharmacokinetic. 
a Interim medical history only. 
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Protocol Version 2.0, 02 September 2021  
Page 15 of 17 
b 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. 
c 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 following sotorasib administration on Days 1 and 4; and EOS or ET. The 30-minute postdose ECG measurement will have 
a collection window of ± 2 minutes, the 2-hour postdose ECG measurement will have a collection window of ± 5 minutes, and the 4-hour postdose ECG measurement will have 
a collection window of ± 10 minutes.  
d Vital signs measurements (supine blood pressure [BP], supine heart rate, respiratory rate, and oral body temperature) should be carried out prior to having blood drawn. 
Screening; Check-in; prior to sotorasib administration on Days 1 and 4; 1 and 24 hours following sotorasib administration on Days 1 and 4; and EOS/ET. Heart 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. 
e Clinical chemistry (fasted at least 8 hours), hematology, and urinalysis. 
f eGFR will be calculated using the Modification of Diet in Renal Disease equation. 
g A full physical examination at Check-in and a symptom-directed physical examination at EOS/ET. 
h Dose administration of sotorasib is to occur during the mornings of Days 1 and 4 in accordance with the formulation of sotorasib administration specific to their treatment 
(Treatment A or Treatment B). 
i Blood samples for determination of sotorasib plasma concentrations will be collected: Predose (Hour 0), 0.5, 1, 1.5, 2, 2.5, 3, 3.5 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours postdose 
following administration of sotorasib on Days 1 and 4. The PK 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 48 hours postdose will have a sampling window of ± 20 minutes. Times of all PK samples will be recorded to the nearest minute. 
j 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 through 30 days after the last dose of study treatment or the EOS (whichever is later). 
k 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 enrollment administration for over-the-counter or prescription medications, and 30 days prior to enrollment for herbal 
medicines (eg, St. John’s wort), vitamins, and supplements, will be recorded on the subject’s electronic Case Report Form. 
l Assessment to be performed at the EOS or if a subject is withdrawn early from the study. 
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Protocol Version 2.0, 02 September 2021  
Page 16 of 17 
Now reads: 
Schedule of Assessments 
Study Procedures 
Screening 
Check-in 
Period 1 
Period 2 
Period 3 
Day -28 to 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 6 or 
Day 9 
(EOS/ 
ET) 
Confined to the CRU 
  
X 
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 
  
  
  
  
  
  
 
 
 Xl 
Drug Screen 
X 
X 
  
  
  
  
  
   
 
 
 
Alcohol Test 
X 
X 
  
  
  
  
  
  
 
 
 
Pregnancy Test (females only)b 
X 
X 
  
  
  
  
  
 
 
 
 Xl 
FSH (postmenopausal females 
only) 
X 
  
  
  
  
  
  
   
 
 
 
12-lead Electrocardiogramc 
X 
X 
X 
 
  
X 
 
 
X 
 
 Xl 
Vital Signsd 
X 
X 
X 
X 
  
X 
X 
 
X 
X 
 Xl 
Clinical Laboratory Evaluationse 
X 
X 
  
  
X  
  
  
X 
 
 
 Xl 
eGFRf 
X 
X 
  
  
  
  
  
  
 
 
 
Physical Examinationg 
  
X 
  
  
  
  
  
 
 
 
 Xl 
Sotorasib Doseh 
  
  
X 
  
  
X 
  
  
X 
 
 
Subject Questionnaire 
 
 
X 
 
 
X 
 
 
 
 
 
Sotorasib PK Blood Samplesi 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Adverse Event Monitoringj 
  
  
X 
Serious Adverse Event 
Monitoringj 
X 
X 
Prior/Concomitant Medicationsk 
X 
X 
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Protocol Version 2.0, 02 September 2021  
Page 17 of 17 
Abbreviations: BMI = body mass index; CRU = Clinical Research Unit; eGFR = estimated glomerular filtration rate; EOS = end of study; ET = early termination; 
FSH = follicle-stimulating hormone; PK = pharmacokinetic. 
a Interim medical history only. 
b 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. 
c 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 following sotorasib administration on Days 1, 4 and 7; and EOS or ET. The 30-minute postdose ECG measurement will 
have a collection window of ± 2 minutes, the 2-hour postdose ECG measurement will have a collection window of ± 5 minutes, and the 4-hour postdose ECG measurement will 
have a collection window of ± 10 minutes.  
d Vital signs measurements (supine blood pressure [BP], supine heart rate, respiratory rate, and oral body temperature) should be carried out prior to having blood drawn. 
Screening; Check-in; prior to sotorasib administration on Days 1, 4 and 7; 1 and 24 hours following sotorasib administration on Days 1, 4 and 7; and EOS/ET. Heart 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. 
e Clinical chemistry (fasted at least 8 hours), hematology, and urinalysis. 
f eGFR will be calculated using the Modification of Diet in Renal Disease equation. 
g A full physical examination at Check-in and a symptom-directed physical examination at EOS/ET. 
h Dose administration of sotorasib is to occur during the mornings of Days 1, 4 and 7 in accordance with the formulation of sotorasib administration specific to their treatment 
(Treatment A, Treatment B or Treatment C). 
i Blood samples for determination of sotorasib plasma concentrations will be collected: Predose (Hour 0), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours postdose 
following administration of sotorasib on Days 1, 4 and 7. The PK 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 48 hours postdose will have a sampling window of ± 20 minutes. Times of all PK samples will be recorded to the nearest minute. 
j 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 through 30 days after the last dose of study treatment or the EOS (whichever is later). 
k 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 enrollment administration for over-the-counter or prescription medications, and 30 days prior to enrollment for herbal 
medicines (eg, St. John’s wort), vitamins, and supplements, will be recorded on the subject’s electronic Case Report Form. 
l Assessment to be performed at the EOS or if a subject is withdrawn early from the study. 
 
Page 164 of 233

SAP_001.pdf: 
TITLE PAGE 
Statistical Analysis Plan 
 An Open-label, Randomized, Two-way Crossover, Bioequivalence Study in 
Healthy Volunteers to Compare the Pharmacokinetics of Two Different 
Tablets of Sotorasib 
SAP Status: Final 
SAP Version: 1.0 
SAP Date: 15Oct2021 
Investigational Medicinal Product: Sotorasib (AMG 510) 
Protocol Reference: 20210093 
Labcorp Study: 8471128 
Sponsor: 
Amgen, Inc.  
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Study Sites: 
Covance Clinical Research Unit 
1900 Mason Avenue,  Suite 140 
Daytona Beach, Florida 32117 
USA 
Covance Dallas Clinical Research Unit 
1341 W. Mockingbird Lane, Suite 400E, 
Dallas, TX 75247 
USA 
Principal Investigators: 
, DO 
, MD 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
Page 2 of 47
NCT Number: NCT05048784
This NCT number has been applied to the document for purposes of
posting on Clinicaltrials.gov
PPD
PPD


SAP 
CONFIDENTIAL 
Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 2 of 22 
 
 
ST-AD-031 Version 02 
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 ....................................................................................................... 8 
7. DEFINITIONS OF POPULATIONS .................................................................................. 10 
7.1. All Subjects Population ................................................................................................. 10 
7.2. Safety Population .......................................................................................................... 10 
7.3. Pharmacokinetic Population ......................................................................................... 10 
8. STATISTICAL METHODOLOGY .................................................................................... 10 
8.1. General .......................................................................................................................... 10 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 11 
8.1.2. Calculation of the Summary Statistics ................................................................... 12 
8.1.3. Triplicate Readings................................................................................................. 12 
8.1.4. Repeat and Unscheduled Readings ........................................................................ 12 
8.2. Subject Disposition and Population Assignment .......................................................... 13 
8.3. Screening Demographics and Baseline Characteristics ................................................ 13 
8.4. Prior and Concomitant Medication ............................................................................... 13 
8.5. Pharmacokinetic Assessments ...................................................................................... 13 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 13 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 16 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 16 
8.6. Safety and Tolerability Assessments ............................................................................ 18 
8.6.1. Adverse Events ....................................................................................................... 18 
8.6.2. Clinical Laboratory Parameters .............................................................................. 20 
8.6.3. Vital Signs Parameters ........................................................................................... 20 
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Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 3 of 22 
 
 
ST-AD-031 Version 02 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 20 
8.6.5. Other Assessments ................................................................................................. 20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
9. INTERIM ANALYSES ....................................................................................................... 20 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 20 
11. REFERENCES .................................................................................................................. 21 
12. APPENDICES ................................................................................................................... 22 
Appendix 1: 
Document History ................................................................................ 22 
 
LIST OF IN-TEXT TABLES AND FIGURES 
  
Figure 1: 
Study Design ........................................................................................................... 8 
 
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SAP 
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Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 4 of 22 
 
 
ST-AD-031 Version 02 
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 
AUC 
area under the concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero 
extrapolated to infinity 
AUClast 
area under the plasma concentration-time curve from time zero to the 
last quantifiable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CDER 
Center for Drug Evaluation and Research 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CL/F 
apparent total clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CRU 
clinical research unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
EOS 
end of study 
eCRF 
electronic case report form 
GLSM 
geometric least square means 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation 
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio 
time period over which lambda z was determined as a ratio of apparent 
terminal elimination half-life 
λz Upper 
end of exponential fit 
LLOQ 
lower limit of quantification 
ln 
natural log 
LSM 
least squares mean 
Page 5 of 47


SAP 
CONFIDENTIAL 
Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 5 of 22 
 
 
ST-AD-031 Version 02 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
not applicable 
PK 
pharmacokinetic(s) 
R2-adj 
adjusted coefficient for determination of exponential fit 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable plasma concentration 
tmax 
time of the maximum observed plasma concentration 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  
 
Page 6 of 47


SAP 
CONFIDENTIAL 
Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 6 of 22 
ST-AD-031 Version 02 
1. INTRODUCTION
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 04 June 2021, Amendment 1 dated 02 September 2021 and Amendment 2 dated 09 
September 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 compare the PK of 960 mg sotorasib administered orally as 3 x 320 mg tablets
(test 1) under fasted condition to 960 mg sotorasib administered orally as 8 x 120 mg
tablets (reference) under fasted condition.
The secondary objectives of the study are: 
●
in 14 subjects, to evaluate the PK of 960 mg sotorasib administered orally as 3 x 320
mg tablets with a high-fat meal (test 2).
●
to assess the safety and tolerability of 960 mg sotorasib administered orally as 3 x 320
mg tablets and 960 mg sotorasib administered orally as 8 x 120 mg tablets.
3. STUDY ENDPOINTS
The primary endpoints of the study are sotorasib PK parameters in Period 1 and Period 2: 
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SAP 
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Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 7 of 22 
ST-AD-031 Version 02 
●
maximum observed plasma concentration (Cmax)
●
area under the plasma concentration-time curve (AUC) from time zero to the last
quantifiable concentration (AUClast)
●
area under the plasma concentration-time curve from time zero extrapolated to
infinity (AUCinf).
The secondary endpoints of the study are: 
●
adverse events (AE)
●
clinical laboratory tests
●
12-lead electrocardiograms (ECGs)
●
vital signs
●
sotorasib PK parameters in Period 3: Cmax, AUClast, AUCinf.
4. STUDY DESIGN
This will be an open-label, multi-center (United States), crossover, 3-period bioequivalence 
study to compare the PK of a single oral dose of 960 mg sotorasib administered as 3 x 320 
mg tablets (test 1) under fasted condition to a single oral dose of 960 mg sotorasib 
administered as 8 x 120 mg tablets (reference) under fasted condition and the PK of 960 mg 
sotorasib administered as 3 x 320 mg oral tablets following a high-fat meal (test 2) to 960 mg 
sotorasib administered as 3 x 320 mg oral tablets under fasted condition (test 1) in healthy 
male subjects and healthy female subjects. Approximately 146 subjects will be enrolled to 
ensure that at least 132 subjects complete the study.  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the Clinical Research 
Unit (CRU) on Day -1 and be confined to the CRU until discharge on Day 6 or Day 9. On 
Day 1, subjects will be randomized to Group 1 or Group 2. Each subject will receive one 
administration of 960 mg sotorasib administered orally as 3 x 320 mg tablets (Treatment A: 
test 1) and one administration of 960 mg sotorasib administered orally as 8 x 120 mg tablets 
(Treatment B: reference) in either Period 1 or Period 2 according to their assigned group. 
Each subject will receive both treatments following an overnight fast according to the 
treatment sequence in Table below. On Day 7, 14 subjects in either Group 1 or Group 2 will 
proceed to Period 3 and receive one additional administration of 960 mg sotorasib 
administered orally as 3x 320 mg tablets with a high-fat meal (Treatment C: test 2). 
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SAP 
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Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 8 of 22 
ST-AD-031 Version 02 
An overview of the study design is shown in Figure 1. 
Figure 1: Study Design  
Abbreviations: EOS = End of Study; ET = Early Termination; N = number of subjects 
*Subjects will receive a single dose in each treatment period, on Days 1, 4, and 7.
** Subjects will be discharged on Day 6 or Day 9 according to their treatment assignment.
The total duration of study participation for each subject (from Screening through end of 
study [EOS]) is anticipated to be approximately 5 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). 
5. SAMPLE SIZE JUSTIFICATION
The study will require at least 132 subjects completing the study to establish equivalence 
between the 2 groups with 90% power. This test is based on a 2-sided ratio of means test for a 
2 x 2 crossover design for continuous data with significance level 5%. The ratio of means 
between treatment and control groups under the alternative hypothesis is 0.95. This test 
assumes lower and upper equivalence limits of 0.8 and 1.25, respectively, and root mean 
squared error of the log ratio equal to 0.472. Assuming approximately 10% drop out rate, 
approximately 146 subjects (73 subjects per treatment) will be enrolled in this study.  
6. STUDY TREATMENTS
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table . 
Table 1: Presentation of Study Treatments in TFLs 
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Treatments 
Abbreviation 
Order in TFLs 
one administration of 960 mg sotorasib administered 
orally as 3 x 320 mg tablets (Test 1) 
Treatment A 
1 
one administration of 960 mg sotorasib administered 
orally as 8 x 120 mg tablets (Reference) 
Treatment B 
2 
one administration of 960 mg sotorasib administered 
orally as 3x 320 mg tablets with a high-fat meal 
(Test 2) 
Treatment C 
3 
The study treatment sequence names, abbreviations, and ordering to be used in the TFLs are 
presented in Table 1.  
Table 1: 
Presentation of Study Treatment Sequences in TFLs 
For all subjects: 
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
one administration of 960 mg sotorasib administered 
orally as 3 x 320 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 8 x 120 mg tablets on Period 2 (Day 4)  
Sequence AB 
1 
one administration of 960 mg sotorasib administered 
orally as 8 x 120 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 3 x 320 mg tablets on Period 2 (Day 4)  
Sequence BA 
2 
 
For the 14 subjects attending all 3 periods: 
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
one administration of 960 mg sotorasib administered 
orally as 3 x 320 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 8 x 120 mg tablets on Period 2 (Day 4) and one 
administration of 960 mg sotorasib administered orally 
as 3x 320 mg tablets with a high-fat meal (Day 7) 
Sequence 
ABC 
1 
one administration of 960 mg sotorasib administered 
orally as 8 x 120 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 3 x 320 mg tablets on Period 2 (Day 4) and one 
administration of 960 mg sotorasib administered orally 
as 3x 320 mg tablets with a high-fat meal (Day 7) 
Sequence 
BAC 
2 
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The summaries will be based on planned treatment sequences and listings will be based on 
actual treatment sequences (eg, if subject was assigned to receive placebo in Period 1 and 
active treatment in Period 2 (sequence [A/B]) but was wrongfully dosed with active treatment 
in Period 1 and discontinued before start of Period 2, they would be summarized under ‘A/B’ 
treatment sequence and listed under ‘B’ treatment sequence).  
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 at least 1 dose of 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 adverse events of vomiting that occurs at or before 2 times 
median time to maximum concentration or diarrhea within 24 hours of dosing.  
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database, with the exception of 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 end of study 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.  
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 4.2.0 (or higher if a new 
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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 COVID19 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 
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.  
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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 electrocardiogram (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 
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.   
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As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment will be provided, based on the safety population.  
8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including sex, age, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by treatment 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.  
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 on Day 1, Day 4, and Day 7, data 
permitting, from plasma concentrations of sotorasib using noncompartmental methods in a 
validated installation of Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUClast 
h*ng/mL 
area under the plasma concentration-time curve from time zero 
to the last quantifiable concentrationb 
AUCinf 
h*ng/mL 
area under the plasma concentration-time curve from time zero 
extrapolated to infinityc 
Cmax 
ng/mL 
maximum observed plasma concentration 
tmax 
h 
time of the maximum observed plasma concentration 
tlast 
h 
time of the last quantifiable plasma concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance  
Vz/F 
L 
apparent volume of distribution during the terminal phase  
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. 
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b The AUC will be calculated using the linear trapezoidal rule.  
c Based on the last observed quantifiable concentration 
 
Additional PK parameters may be determined where appropriate. 
Pharmacokinetic analysis will be carried out where possible using actual dose administered 
(mg) and actual postdose blood sampling times. If an actual time is missing, nominal times 
may be used with sponsor’s approval. 
The parameters Cmax, tlast, and tmax will be obtained directly from the concentration-time 
profiles.  
For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest tmax will be reported. 
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 area under the concentration-time curve 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. 
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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.  
If the extrapolated area is >20%, AUCinf (and derived parameters) will be flagged and may be 
excluded from the summary statistics and statistical analysis at the discretion of the sponsor 
or pharmacokineticist.  
If AUCinf cannot be determined reliably for all subjects and/or treatments, an alternative AUC 
measure, such as AUC to a fixed timepoint or AUClast, may be used in the statistical analysis 
upon sponsor approval. 
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 BLQ concentrations will be treated as 
missing. The following rules apply to the specific 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 will be set to 0 by default within 
Phoenix WinNonlin. 
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 in the first treatment period will be considered 
anomalous and set to missing for the PK analysis. This will be set to 0 by default in Phoenix 
WinNonlin. 
If the predose concentration is >5% of Cmax in the second or third treatment periods, all PK 
concentration and parameter data will be flagged and reported but excluded from the 
summary statistics and statistical analysis for that period. 
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8.5.2. Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the plasma concentration will be flagged and excluded from the summary statistics.  
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For plasma concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● If the embedded BLQ value is considered anomalous within the concentration-time 
profile, this value will be excluded from the summary statistics.  
● Where there is NR, these will be set to missing.  
● If there are less than three values in the data series, only the min, max and N will be 
presented. The other summary statistics will be denoted as not calculated (NC). BLQ 
is considered a value.  
● If the values are BLQ, then the arithmetic mean, arithmetic SD, median, min and max 
will be presented as zero, 0 and the geometric mean and geometric coefficient of 
variation (CV%) will be denoted as NC.  
● Arithmetic mean or median values that are BLQ will be presented as 0, and the 
geometric mean and geometric CV% will be denoted as NC.  
For PK parameters the following rule will apply: 
● For the calculation of summary statistics of PK parameters, all non-reportable and NC 
values in a data series will be set to missing.  
● AUCinf and AUClast will be set to NC if they were calculated using fewer than three 
concentrations, and/or three concentrations if the last is Cmax.  
● Geometric mean and coefficient of variation will not be calculated for tlast or tmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed. 
Summary tables, 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 and semi-logarithmic scales. 
Summary tables by treatment will be provided for all PK parameters, with the exception of 
regression-related PK parameters.  
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Bioequivalence: 
A statistical analysis will be conducted to investigate the bioequivalence of 960 mg sotorasib 
administered orally as 3 x 320 mg tablets (test 1) to 960 mg sotorasib administered orally as 8 
x 120 mg tablets (reference treatment) for AUClast, AUCinf, and Cmax. Data from the entire 
study population will be used for this analysis. 
The natural log (ln)-transformed4 PK parameters will be analyzed using a mixed model.5 The 
model will include treatment, period, and sequence as fixed effect and subject nested within 
sequence as a random effect. 
For AUClast, AUCinf, and Cmax separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test 1 and reference treatments, and corresponding 90% 
confidence interval (CI) will be calculated; these values will then be backtransformed to give 
the geometric least square mean (GLSM), ratio of GLSMs, and corresponding 90% CI. 
Additionally, the pooled estimate (across all treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted. 
It will be concluded that the test treatment is bioequivalent to the reference treatment if, for 
Cmax and AUCs, the 90% CI for the ratio of GLSMs is completely contained within the 
predefined interval of (0.8000, 1.2500).6 This procedure is equivalent to Schuirmann’s7 two 
one-sided tests at the 0.05 level of significance. 
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
  by parcat1n parcat1 pkday paramn param; 
  class trtan aperiod trtseqp usubjid; 
  model lpk = trtan aperiod trtseqp / cl residual ddfm = kr; 
  lsmeans trtan / cl pdiff = control('2') alpha = 0.1; 
  random intercept / subject = usubjid(trtseqp); 
  ods output lsmeans = <data out>;  
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
Food Effect: 
A statistical analysis will be conducted to investigate the food effect for 960 mg sotorasib 
administered orally as 3 x 320 mg tablets under fed condition (test 2) to 960 mg sotorasib 
administered orally as 3 x 320 mg tablets under fasted condition (test 1) for AUClast, AUCinf, 
and Cmax. Data from 14 subjects who are enrolled in Period 3 will be used for this analysis. 
The natural log (ln)-transformed4 PK parameters will be analyzed using a mixed model.5 The 
model will include treatment as fixed effect and subject nested within sequence as a random 
effect. 
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For AUClast, AUCinf, and Cmax separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test 1 and test 2, and corresponding 90% confidence interval 
(CI) will be calculated; these values will then be backtransformed to give the geometric least 
square mean (GLSM), ratio of GLSMs, and corresponding 90% CI. 
Additionally, the pooled estimate (across all treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted. 
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
  by parcat1n parcat1 pkday paramn param; 
  class trtan usubjid; 
  model lpk = trtan / cl residual ddfm = kr; 
  lsmeans trtan / cl pdiff = control('2') alpha = 0.1; 
  random intercept / subject = usubjid(trtseqp);  
  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
 
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 within each period. 
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  
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● 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.  
● 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. 
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● 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, 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 by treatment and timepoint will be provided for clinical chemistry and 
hematology parameters. 
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, will be listed, as applicable; any value outside the clinical 
reference range will be flagged.  
Summary tables by treatment and timepoint will be provided by treatment group for all vital 
signs parameters as applicable.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters will be listed; any value outside the clinical reference range will 
be flagged. 
Summary tables by treatment and timepoint will be provided for all 12-lead ECG parameters. 
8.6.5. Other Assessments  
Medical history will not 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.  
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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. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
5. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
6. Statistical Approaches to Establishing Bioequivalence. Rockville, MD: US Dept of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER); January 2001. 
7. Schuirmann DJ. A comparison of the two one sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm. 1987;15(6):657-680. 
 
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Protocol Reference: 20210093 
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ST-AD-031 Version 02 
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:
20210093
Covance 
Study 
ID:
8471128
SAP text 
filename:
Amgen510_20210093_SAP_Final_15
Oct2021.pdf
TFL 
shells 
filename:
Amgen510_20210093_TFL_Final_15
Oct2021.pdf
Version:
1
Date:
15Oct2021
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
Biostatist
20Oct2021
Please scan/email completed form(s) to the Lead Statistician listed below:
Printed Name/Title:
, Biostatistician
Email:
t
Page 24 of 47
PPD
PPD
PPD
PPD
PPD
PPD


 
 
TITLE PAGE 
Statistical Analysis Plan 
 An Open-label, Randomized, Two-way Crossover, Bioequivalence Study in 
Healthy Volunteers to Compare the Pharmacokinetics of Two Different 
Tablets of Sotorasib 
SAP Status: Final 
SAP Version: 1.0 
SAP Date: 15Oct2021 
Investigational Medicinal Product: Sotorasib (AMG 510) 
Protocol Reference: 20210093 
Labcorp Study: 8471128 
Sponsor: 
Amgen, Inc.  
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Study Sites: 
Covance Clinical Research Unit 
1900 Mason Avenue,  Suite 140 
Daytona Beach, Florida 32117 
USA 
 
Covance Dallas Clinical Research Unit 
1341 W. Mockingbird Lane, Suite 400E,  
Dallas, TX 75247 
USA 
 
Principal Investigators: 
, DO 
 MD 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 
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SAP 
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Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
Page 2 of 22 
 
 
ST-AD-031 Version 02 
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 ................................................................................................ 8 
7. DEFINITIONS OF POPULATIONS..............................................................................10 
7.1. All Subjects Population ...........................................................................................10 
7.2. Safety Population ....................................................................................................10 
7.3. Pharmacokinetic Population.....................................................................................10 
8. STATISTICAL METHODOLOGY................................................................................10 
8.1. General ...................................................................................................................10 
8.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ................................................................................................................11 
8.1.2. Calculation of the Summary Statistics ................................................................12 
8.1.3. Triplicate Readings ...........................................................................................12 
8.1.4. Repeat and Unscheduled Readings.....................................................................12 
8.2. Subject Disposition and Population Assignment .......................................................13 
8.3. Screening Demographics and Baseline Characteristics ..............................................13 
8.4. Prior and Concomitant Medication ...........................................................................13 
8.5. Pharmacokinetic Assessments ..................................................................................13 
8.5.1. Pharmacokinetic Analysis .................................................................................13 
8.5.2. Presentation of Pharmacokinetic Data ................................................................16 
8.5.3. Pharmacokinetic Statistical Methodology...........................................................16 
8.6. Safety and Tolerability Assessments ........................................................................18 
8.6.1. Adverse Events .................................................................................................18 
8.6.2. Clinical Laboratory Parameters..........................................................................20 
8.6.3. Vital Signs Parameters ......................................................................................20 
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ST-AD-031 Version 02 
8.6.4. 12-lead Electrocardiogram Parameters ...............................................................20 
8.6.5. Other Assessments ............................................................................................20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................20 
9. INTERIM ANALYSES .................................................................................................20 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........20 
11. REFERENCES ............................................................................................................21 
12. APPENDICES .............................................................................................................22 
Appendix 1: 
Document History............................................................................22 
 
LIST OF IN-TEXT TABLES AND FIGURES 
  
Figure 1: 
Study Design .................................................................................................... 8 
 
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ST-AD-031 Version 02 
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 
AUC 
area under the concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero 
extrapolated to infinity 
AUClast 
area under the plasma concentration-time curve from time zero to the 
last quantifiable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CDER 
Center for Drug Evaluation and Research 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CL/F 
apparent total clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CRU 
clinical research unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
EOS 
end of study 
eCRF 
electronic case report form 
GLSM 
geometric least square means 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation 
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio 
time period over which lambda z was determined as a ratio of apparent 
terminal elimination half-life 
λz Upper 
end of exponential fit 
LLOQ 
lower limit of quantification 
ln 
natural log 
LSM 
least squares mean 
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Protocol Reference: 20210093 
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ST-AD-031 Version 02 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
not applicable 
PK 
pharmacokinetic(s) 
R2-adj 
adjusted coefficient for determination of exponential fit 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable plasma concentration 
tmax 
time of the maximum observed plasma concentration 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  
 
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SAP 
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Covance Study: 8471128 
Protocol Reference: 20210093 
Final Version 1.0, 15Oct2021 
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ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 
dated 04 June 2021, Amendment 1 dated 02 September 2021 and Amendment 2 dated 09 
September 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 compare the PK of 960 mg sotorasib administered orally as 3 x 320 mg tablets 
(test 1) under fasted condition to 960 mg sotorasib administered orally as 8 x 120 mg 
tablets (reference) under fasted condition.  
The secondary objectives of the study are:  
● in 14 subjects, to evaluate the PK of 960 mg sotorasib administered orally as 3 x 320 
mg tablets with a high-fat meal (test 2).  
● to assess the safety and tolerability of 960 mg sotorasib administered orally as 3 x 320 
mg tablets and 960 mg sotorasib administered orally as 8 x 120 mg tablets.   
3. STUDY ENDPOINTS  
The primary endpoints of the study are sotorasib PK parameters in Period 1 and Period 2:  
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ST-AD-031 Version 02 
● maximum observed plasma concentration (Cmax)  
● area under the plasma concentration-time curve (AUC) from time zero to the last 
quantifiable concentration (AUClast)  
● area under the plasma concentration-time curve from time zero extrapolated to 
infinity (AUCinf).  
The secondary endpoints of the study are:  
● adverse events (AE) 
● clinical laboratory tests  
● 12-lead electrocardiograms (ECGs) 
● vital signs  
● sotorasib PK parameters in Period 3: Cmax, AUClast, AUCinf.  
4. STUDY DESIGN  
This will be an open-label, multi-center (United States), crossover, 3-period bioequivalence 
study to compare the PK of a single oral dose of 960 mg sotorasib administered as 3 x 320 
mg tablets (test 1) under fasted condition to a single oral dose of 960 mg sotorasib 
administered as 8 x 120 mg tablets (reference) under fasted condition and the PK of 960 mg 
sotorasib administered as 3 x 320 mg oral tablets following a high-fat meal (test 2) to 960 mg 
sotorasib administered as 3 x 320 mg oral tablets under fasted condition (test 1) in healthy 
male subjects and healthy female subjects. Approximately 146 subjects will be enrolled to 
ensure that at least 132 subjects complete the study.  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the Clinical Research 
Unit (CRU) on Day -1 and be confined to the CRU until discharge on Day 6 or Day 9. On 
Day 1, subjects will be randomized to Group 1 or Group 2. Each subject will receive one 
administration of 960 mg sotorasib administered orally as 3 x 320 mg tablets (Treatment A: 
test 1) and one administration of 960 mg sotorasib administered orally as 8 x 120 mg tablets 
(Treatment B: reference) in either Period 1 or Period 2 according to their assigned group. 
Each subject will receive both treatments following an overnight fast according to the 
treatment sequence in Table below. On Day 7, 14 subjects in either Group 1 or Group 2 will 
proceed to Period 3 and receive one additional administration of 960 mg sotorasib 
administered orally as 3x 320 mg tablets with a high-fat meal (Treatment C: test 2). 
 
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ST-AD-031 Version 02 
An overview of the study design is shown in Figure 1.  
Figure 1: Study Design  
  
 
Abbreviations: EOS = End of Study; ET = Early Termination; N = number of subjects  
*Subjects will receive a single dose in each treatment period, on Days 1, 4, and 7.  
** Subjects will be discharged on Day 6 or Day 9 according to their treatment assignment.   
The total duration of study participation for each subject (from Screening through end of 
study [EOS]) is anticipated to be approximately 5 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). 
5. SAMPLE SIZE JUSTIFICATION  
The study will require at least 132 subjects completing the study to establish equivalence 
between the 2 groups with 90% power. This test is based on a 2-sided ratio of means test for a 
2 x 2 crossover design for continuous data with significance level 5%. The ratio of means 
between treatment and control groups under the alternative hypothesis is 0.95. This test 
assumes lower and upper equivalence limits of 0.8 and 1.25, respectively, and root mean 
squared error of the log ratio equal to 0.472. Assuming approximately 10% drop out rate, 
approximately 146 subjects (73 subjects per treatment) will be enrolled in this study.  
6. STUDY TREATMENTS  
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table . 
Table 1: Presentation of Study Treatments in TFLs  
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ST-AD-031 Version 02 
Treatments 
Abbreviation 
Order in TFLs 
one administration of 960 mg sotorasib administered 
orally as 3 x 320 mg tablets (Test 1) 
Treatment A 
1 
one administration of 960 mg sotorasib administered 
orally as 8 x 120 mg tablets (Reference) 
Treatment B 
2 
one administration of 960 mg sotorasib administered 
orally as 3x 320 mg tablets with a high-fat meal 
(Test 2) 
Treatment C 
3 
The study treatment sequence names, abbreviations, and ordering to be used in the TFLs are 
presented in Table 1.  
Table 1: 
Presentation of Study Treatment Sequences in TFLs 
For all subjects: 
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
one administration of 960 mg sotorasib administered 
orally as 3 x 320 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 8 x 120 mg tablets on Period 2 (Day 4)  
Sequence AB 
1 
one administration of 960 mg sotorasib administered 
orally as 8 x 120 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 3 x 320 mg tablets on Period 2 (Day 4)  
Sequence BA 
2 
 
For the 14 subjects attending all 3 periods: 
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
one administration of 960 mg sotorasib administered 
orally as 3 x 320 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 8 x 120 mg tablets on Period 2 (Day 4) and one 
administration of 960 mg sotorasib administered orally 
as 3x 320 mg tablets with a high-fat meal (Day 7) 
Sequence 
ABC 
1 
one administration of 960 mg sotorasib administered 
orally as 8 x 120 mg tablets on Period 1 (Day 1) and one 
administration of 960 mg sotorasib administered orally 
as 3 x 320 mg tablets on Period 2 (Day 4) and one 
administration of 960 mg sotorasib administered orally 
as 3x 320 mg tablets with a high-fat meal (Day 7) 
Sequence 
BAC 
2 
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Protocol Reference: 20210093 
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ST-AD-031 Version 02 
The summaries will be based on planned treatment sequences and listings will be based on 
actual treatment sequences (eg, if subject was assigned to receive placebo in Period 1 and 
active treatment in Period 2 (sequence [A/B]) but was wrongfully dosed with active treatment 
in Period 1 and discontinued before start of Period 2, they would be summarized under ‘A/B’ 
treatment sequence and listed under ‘B’ treatment sequence).  
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 at least 1 dose of 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 adverse events of vomiting that occurs at or before 2 times 
median time to maximum concentration or diarrhea within 24 hours of dosing.  
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database, with the exception of 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 end of study 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.  
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 4.2.0 (or higher if a new 
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Protocol Reference: 20210093 
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ST-AD-031 Version 02 
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 COVID19 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 
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.  
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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 electrocardiogram (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 
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.   
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As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment will be provided, based on the safety population.  
8.3. Screening Demographics and Baseline Characteristics  
The screening demographics and baseline characteristics including sex, age, race, ethnicity, 
height, body weight, and body mass index will be listed.  
A summary table by treatment 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.  
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 on Day 1, Day 4, and Day 7, data 
permitting, from plasma concentrations of sotorasib using noncompartmental methods in a 
validated installation of Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUClast 
h*ng/mL 
area under the plasma concentration-time curve from time zero 
to the last quantifiable concentrationb 
AUCinf 
h*ng/mL 
area under the plasma concentration-time curve from time zero 
extrapolated to infinityc 
Cmax 
ng/mL 
maximum observed plasma concentration 
tmax 
h 
time of the maximum observed plasma concentration 
tlast 
h 
time of the last quantifiable plasma concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance  
Vz/F 
L 
apparent volume of distribution during the terminal phase  
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. 
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b The AUC will be calculated using the linear trapezoidal rule.  
c Based on the last observed quantifiable concentration 
 
Additional PK parameters may be determined where appropriate. 
Pharmacokinetic analysis will be carried out where possible using actual dose administered 
(mg) and actual postdose blood sampling times. If an actual time is missing, nominal times 
may be used with sponsor’s approval. 
The parameters Cmax, tlast, and tmax will be obtained directly from the concentration-time 
profiles.  
For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest tmax will be reported. 
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 area under the concentration-time curve 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. 
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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.  
If the extrapolated area is >20%, AUCinf (and derived parameters) will be flagged and may be 
excluded from the summary statistics and statistical analysis at the discretion of the sponsor 
or pharmacokineticist.  
If AUCinf cannot be determined reliably for all subjects and/or treatments, an alternative AUC 
measure, such as AUC to a fixed timepoint or AUClast, may be used in the statistical analysis 
upon sponsor approval. 
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 BLQ concentrations will be treated as 
missing. The following rules apply to the specific 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 will be set to 0 by default within 
Phoenix WinNonlin. 
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 in the first treatment period will be considered 
anomalous and set to missing for the PK analysis. This will be set to 0 by default in Phoenix 
WinNonlin. 
If the predose concentration is >5% of Cmax in the second or third treatment periods, all PK 
concentration and parameter data will be flagged and reported but excluded from the 
summary statistics and statistical analysis for that period. 
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8.5.2. Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the plasma concentration will be flagged and excluded from the summary statistics.  
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For plasma concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● If the embedded BLQ value is considered anomalous within the concentration-time 
profile, this value will be excluded from the summary statistics.  
● Where there is NR, these will be set to missing.  
● If there are less than three values in the data series, only the min, max and N will be 
presented. The other summary statistics will be denoted as not calculated (NC). BLQ 
is considered a value.  
● If the values are BLQ, then the arithmetic mean, arithmetic SD, median, min and max 
will be presented as zero, 0 and the geometric mean and geometric coefficient of 
variation (CV%) will be denoted as NC.  
● Arithmetic mean or median values that are BLQ will be presented as 0, and the 
geometric mean and geometric CV% will be denoted as NC.  
For PK parameters the following rule will apply: 
● For the calculation of summary statistics of PK parameters, all non-reportable and NC 
values in a data series will be set to missing.  
● AUCinf and AUClast will be set to NC if they were calculated using fewer than three 
concentrations, and/or three concentrations if the last is Cmax.  
● Geometric mean and coefficient of variation will not be calculated for tlast or tmax. 
8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed. 
Summary tables, 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 and semi-logarithmic scales. 
Summary tables by treatment will be provided for all PK parameters, with the exception of 
regression-related PK parameters.  
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Bioequivalence: 
A statistical analysis will be conducted to investigate the bioequivalence of 960 mg sotorasib 
administered orally as 3 x 320 mg tablets (test 1) to 960 mg sotorasib administered orally as 8 
x 120 mg tablets (reference treatment) for AUClast, AUCinf, and Cmax. Data from the entire 
study population will be used for this analysis. 
The natural log (ln)-transformed4 PK parameters will be analyzed using a mixed model.5 The 
model will include treatment, period, and sequence as fixed effect and subject nested within 
sequence as a random effect. 
For AUClast, AUCinf, and Cmax separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test 1 and reference treatments, and corresponding 90% 
confidence interval (CI) will be calculated; these values will then be backtransformed to give 
the geometric least square mean (GLSM), ratio of GLSMs, and corresponding 90% CI. 
Additionally, the pooled estimate (across all treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted. 
It will be concluded that the test treatment is bioequivalent to the reference treatment if, for 
Cmax and AUCs, the 90% CI for the ratio of GLSMs is completely contained within the 
predefined interval of (0.8000, 1.2500).6 This procedure is equivalent to Schuirmann’s7 two 
one-sided tests at the 0.05 level of significance. 
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
  by parcat1n parcat1 pkday paramn param; 
  class trtan aperiod trtseqp usubjid; 
  model lpk = trtan aperiod trtseqp / cl residual ddfm = kr; 
  lsmeans trtan / cl pdiff = control('2') alpha = 0.1; 
  random intercept / subject = usubjid(trtseqp);  
  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
 
Food Effect: 
A statistical analysis will be conducted to investigate the food effect for 960 mg sotorasib 
administered orally as 3 x 320 mg tablets under fed condition (test 2) to 960 mg sotorasib 
administered orally as 3 x 320 mg tablets under fasted condition (test 1) for AUClast, AUCinf, 
and Cmax. Data from 14 subjects who are enrolled in Period 3 will be used for this analysis. 
The natural log (ln)-transformed4 PK parameters will be analyzed using a mixed model.5 The 
model will include treatment as fixed effect and subject nested within sequence as a random 
effect. 
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For AUClast, AUCinf, and Cmax separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test 1 and test 2, and corresponding 90% confidence interval 
(CI) will be calculated; these values will then be backtransformed to give the geometric least 
square mean (GLSM), ratio of GLSMs, and corresponding 90% CI. 
Additionally, the pooled estimate (across all treatments) of the within-subject CV will be 
calculated, and residual plots will be produced to assess the adequacy of the model(s) fitted. 
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
  by parcat1n parcat1 pkday paramn param; 
  class trtan usubjid; 
  model lpk = trtan / cl residual ddfm = kr; 
  lsmeans trtan / cl pdiff = control('2') alpha = 0.1; 
  random intercept / subject = usubjid(trtseqp);  
  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
run; 
 
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 within each period. 
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  
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● 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.  
● 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. 
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● 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, 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 by treatment and timepoint will be provided for clinical chemistry and 
hematology parameters. 
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, will be listed, as applicable; any value outside the clinical 
reference range will be flagged.  
Summary tables by treatment and timepoint will be provided by treatment group for all vital 
signs parameters as applicable.  
8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters will be listed; any value outside the clinical reference range will 
be flagged. 
Summary tables by treatment and timepoint will be provided for all 12-lead ECG parameters. 
8.6.5. Other Assessments  
Medical history will not 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.  
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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. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
5. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
6. Statistical Approaches to Establishing Bioequivalence. Rockville, MD: US Dept of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER); January 2001. 
7. Schuirmann DJ. A comparison of the two one sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm. 1987;15(6):657-680. 
 
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ST-AD-031 Version 02 
12. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change Summary/Reason for Changes 
Final Version 1.0 
10Jan2022 
Corrected Pinnacle 21 version: 
Change from: 
Pinnacle 21 Enterprise Version 4.2.1 
To: 
Pinnacle21 Community Validator 3.1.2 
Final Version 1.0 
03May2022 
SAP page 17 Section Food Effect. Updated wording typo as there’s only 1 
sequence for Food Effect analysis, there’re no subject nested within 
sequence for the analysis model. 
Change: 
The model will include treatment as fixed effect and subject nested within 
sequence as a random effect. 
To: 
The model will include treatment as fixed effect and subject nested within 
sequence as a random effect. 
 
 
 
 
 
 
 
 
 
 
 
 
NA = not applicable 
 
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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 a significant 
impact on interpretation of the 
primary endpoint because of 
limited/insufficient exposure. 
N: 146 
(enrolled to complete 132) 
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Final