Clinical trial NCT04274075
Conditions: Healthy Volunteers
Sponsor: Genentech, Inc.
Start date: 2020-03-06; Completion date: 2020-04-16
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will be an open-label, randomized, three-period, six-sequence crossover study of GDC-9545 administered to healthy females of non-childbearing potential to determine the relative bioavailability of the Phase 3 capsule formulation to the Phase 1 tablet formulation in the fasted state and the effect of food on the Phase 3 capsule formulation.

Detailed description:

Arms: arm 1: Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, B, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days. arm 2: Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, C, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days. arm 3: Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, A, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days. arm 4: Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, C, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days. arm 5: Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, A, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days. arm 6: Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, B, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
Interventions: intervention 1: GDC-9545 Tablet, Fasted: Treatment A intervention 2: GDC-9545 Capsule, Fasted: Treatment B intervention 3: GDC-9545 Capsule, Fed: Treatment C
Intervention descriptions: intervention 1: One dose of the GDC-9545 Phase 1 reference tablet formulation (three 10-mg tablets) administered orally with approximately 240 mL room temperature water after at least an 8-hour fast. intervention 2: One dose of the GDC-9545 Phase 3 capsule formulation (one 30-mg capsule) administered orally with approximately 240 mL room temperature water after at least an 8-hour fast. intervention 3: One dose of the GDC-9545 Phase 3 capsule formulation (one 30-mg capsule) administered orally with approximately 240 mL room temperature water within 30 minutes of eating a high-fat meal.

Protocol documents:
Prot_000.pdf: 
 
Official Title: A Phase 1, Open-Label, Single-Dose, Randomized, Three-Period 
Crossover Study to Evaluate the Relative Bioavailability and Food 
Effect of GDC-9545 in Healthy Female Subjects of Non-Childbearing 
Potential 
NCT Number: NCT04274075 
Document Date: Protocol Version 1: 03 December 2019 
 
 


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A PHASE 1, OPEN-LABEL, SINGLE-DOSE, RANDOMIZED, THREE-PERIOD 
CROSSOVER STUDY TO EVALUATE THE RELATIVE BIOAVAILABILITY AND 
FOOD EFFECT OF GDC-9545 IN HEALTHY FEMALE SUBJECTS OF 
NON-CHILDBEARING POTENTIAL 
 
 
 
 
 
Protocol GP42006 
 
Covance Study 8418446 
 
IND 132673 
 
 
for 
 
Genentech, Inc. 
1 DNA Way 
South San Francisco, California 94080-4990 
 
 
 
 
by 
 
Covance Early Clinical Segment 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
 


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STUDY IDENTIFICATION 
Sponsor 
Genentech, Inc. 
 
1 DNA Way 
 
South San Francisco, California 94080-4990 
 
Sponsor’s Study Contact 
, B.S. 
 
 
 
Genentech, Inc. 
 
1 DNA Way 
 
South San Francisco, California 94080-4990 
 
Sponsor’s Medical Monitor 
, M.D., Ph.D. 
 
 
 
Genentech, Inc. 
 
1 DNA Way 
 
South San Francisco, California 94080-4990 
 
Study Site 
Covance Clinical Research Unit 
 
1900 Mason Avenue, Suite 140 
 
Daytona Beach, Florida 32117 
 
Principal Investigator 
, D.O. 
 
Covance Clinical Research Unit 
 
 
 
Study Institutional 
Review Board 
MidLands Independent Review Board 
8417 Santa Fe Drive, Suite 100 
Overland Park, Kansas 66212 
 
Main Clinical Laboratory 
(Obtain information from Form FDA 1572) 
 
Bioanalytical Laboratory 
Covance Laboratories Inc. 
 
3301 Kinsman Boulevard 
 
Madison, Wisconsin 53704 
 


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Protocol Biostatistician 
, B.Sc., M.Sc. 
 
Covance Clinical Research Unit Limited 
 
 
 
Protocol Pharmacokineticist 
, B.S. 
 
Covance Clinical Pharmacology Services 
 
 
 
Protocol Medical Writer 
, Ph.D. 
 
Covance Global Medical Writing 
 
 


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TABLE OF CONTENTS 
 
1 
SYNOPSIS ........................................................................................................................ 11 
2 
INTRODUCTION ............................................................................................................ 13 
2.1 
BACKGROUND .................................................................................................. 13 
2.2 
PHARMACOLOGY ............................................................................................. 13 
2.3 
PHARMACOKINETICS ...................................................................................... 13 
2.4 
TOXICOLOGY AND SAFETY PHARMACOLOGY ........................................ 14 
2.5 
CLINICAL RESULTS.......................................................................................... 14 
2.6 
STUDY RATIONALE ......................................................................................... 16 
2.7 
DOSE RATIONALE ............................................................................................ 16 
3 
STUDY OBJECTIVES AND CORRESPONDING ENDPOINTS ................................. 17 
3.1 
PRIMARY OBJECTIVES .................................................................................... 17 
3.2 
SECONDARY OBJECTIVES.............................................................................. 17 
3.3 
ENDPOINTS ........................................................................................................ 18 
4 
STUDY DESIGN.............................................................................................................. 18 
4.1 
DESCRIPTION OF THE STUDY ....................................................................... 18 
4.2 
RATIONALE FOR STUDY DESIGN ................................................................. 20 
4.3 
RATIONALE FOR SUBJECT POPULATION ................................................... 20 
4.4 
RATIONALE FOR EXPLORATORY ASSESSMENTS .................................... 21 
4.5 
RATIONALE FOR PHARMACOKINETIC SAMPLING SCHEDULE ............ 21 
5 
SUBJECT SELECTION ................................................................................................... 21 
5.1 
SCREENING PROCEDURES ............................................................................. 21 
5.2 
CHECK-IN PROCEDURES ................................................................................ 21 
5.3 
INCLUSION CRITERIA...................................................................................... 22 
5.4 
EXCLUSION CRITERIA .................................................................................... 23 
5.5 
REMOVAL OF SUBJECTS FROM STUDY PARTICIPATION ....................... 24 
6 
ASSESSMENT OF SAFETY ........................................................................................... 25 


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6.1 
SAFETY PLAN .................................................................................................... 25 
6.1.1 
RISKS ASSOCIATED WITH GDC-9545 ......................................... 25 
6.1.2 
MANAGEMENT OF SUBJECTS WHO EXPERIENCE SPECIFIC 
ADVERSE EVENTS .......................................................................... 28 
7 
STUDY PROCEDURES .................................................................................................. 29 
7.1 
SCHEDULE OF STUDY ACTIVITIES .............................................................. 29 
7.2 
STUDY TREATMENT ........................................................................................ 33 
7.2.1 
DRUG SUPPLIES AND ACCOUNTABILITY ................................ 33 
7.2.2 
DOSE PREPARATION AND ADMINISTRATION ........................ 34 
7.3 
REMOVAL OF STUDY BLIND ......................................................................... 35 
7.4 
ACTIVITY CONTROL ........................................................................................ 35 
7.5 
CONCOMITANT MEDICATIONS .................................................................... 35 
7.5.1 
PERMITTED MEDICATIONS.......................................................... 35 
7.5.2 
PROHIBITED MEDICATIONS ........................................................ 36 
7.5.3 
PROHIBITED FOOD ......................................................................... 36 
7.6 
PHARMACOKINETIC BLOOD SAMPLE COLLECTION AND PROCESSING
............................................................................................................................... 37 
7.7 
ANALYTICAL METHODOLOGY ..................................................................... 37 
7.8 
CLINICAL LABORATORY EVALUATIONS .................................................. 37 
7.9 
SAMPLES FOR THE RESEARCH BIOSAMPLE REPOSITORY .................... 38 
7.9.1 
OVERVIEW OF THE RESEARCH BIOSAMPLE REPOSITORY . 38 
7.9.2 
APPROVAL BY THE INSTITUTIONAL REVIEW BOARD OR 
ETHICS COMMITTEE ...................................................................... 39 
7.9.3 
MANDATORY SAMPLES FOR COLLECTION ............................. 39 
7.9.4 
CONFIDENTIALITY......................................................................... 39 
7.9.5 
CONSENT TO PARTICIPATE IN THE RESEARCH BIOSAMPLE 
REPOSITORY .................................................................................... 40 
7.9.6 
WITHDRAWAL FROM THE RESEARCH BIOSAMPLE 
REPOSITORY .................................................................................... 40 


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7.9.7 
MONITORING AND OVERSIGHT ................................................. 41 
7.10 
12-LEAD ELECTROCARDIOGRAMS .............................................................. 41 
7.11 
VITAL SIGNS ...................................................................................................... 41 
7.12 
HOW DO YOU FEEL? INQUIRY ...................................................................... 41 
7.13 
PHYSICAL EXAMINATIONS ........................................................................... 42 
7.14 
CLINIC DISCHARGE PROCEDURES .............................................................. 42 
7.15 
FOLLOW-UP/EARLY TERMINATION PROCEDURES ................................. 42 
8 
ADVERSE EXPERIENCES ............................................................................................ 42 
8.1 
SAFETY PARAMETERS AND DEFINITIONS ................................................ 42 
8.1.1 
ADVERSE EVENTS .......................................................................... 43 
8.1.2 
SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) .......................................................................... 43 
8.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY 
REPORTABLE TO THE SPONSOR) ............................................... 44 
8.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS .................................................................................................... 45 
8.2.1 
ADVERSE EVENT REPORTING PERIOD ..................................... 45 
8.2.2 
ELICITING ADVERSE EVENT INFORMATION .......................... 46 
8.2.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS ............... 46 
8.2.4 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS ........... 46 
8.3 
PROCEDURES FOR RECORDING ADVERSE EVENTS ................................ 47 
8.3.1 
RECORDING ADVERSE EVENTS ON THE CASE REPORT 
FORM ................................................................................................. 47 
8.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO 
SPONSOR............................................................................................................. 53 
8.4.1 
REPORTING REQUIREMENTS FOR FATAL OR LIFE-
THREATENING SERIOUS ADVERSE EVENTS ........................... 54 
8.4.2 
REPORTING REQUIREMENTS FOR ALL SERIOUS ADVERSE 
EVENTS ............................................................................................. 54 
8.5 
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS ............................ 56 


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8.5.1 
INVESTIGATOR FOLLOW-UP ....................................................... 56 
8.5.2 
SPONSOR FOLLOW-UP .................................................................. 56 
8.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT 
REPORTING PERIOD ......................................................................................... 56 
8.6.1 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES.................................................................... 57 
9 
STATISTICAL ANALYSES ........................................................................................... 57 
9.1 
SAFETY AND TOLERABILITY ANALYSIS ................................................... 58 
9.2 
PHARMACOKINETIC ANALYSIS ................................................................... 58 
9.3 
INTERIM ANALYSIS ......................................................................................... 59 
9.4 
STATISTICAL ANALYSIS OF PHARMACOKINETIC DATA....................... 59 
9.5 
STATISTICAL ANALYSES OF SAFETY DATA ............................................. 60 
9.6 
SAMPLE SIZE ..................................................................................................... 60 
9.7 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 60 
10 
ADMINISTRATIVE ASPECTS ...................................................................................... 60 
10.1 
CHANGE IN PROTOCOL................................................................................... 60 
10.2 
INVESTIGATOR MEETING; SITE INITIATION ............................................. 60 
10.3 
DISCLOSURE ...................................................................................................... 61 
10.4 
MONITORING (CLINICAL RESEARCH ASSOCIATE).................................. 61 
10.5 
INSTITUTIONAL REVIEW BOARD................................................................. 61 
10.6 
INFORMED CONSENT ...................................................................................... 62 
10.7 
RECORDS ............................................................................................................ 62 
10.7.1 
ELECTRONIC CASE REPORT FORMS ......................................... 62 
10.7.2 
SOURCE DATA DOCUMENTATION............................................. 63 
10.7.3 
USE OF COMPUTERIZED SYSTEMS ............................................ 63 
10.7.4 
STUDY MEDICATION ACCOUNTABILITY................................. 64 
10.7.5 
DISCLOSURE OF DATA .................................................................. 64 
10.7.6 
RETENTION OF RECORDS ............................................................ 65 


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10.8 
REFERENCE TO DECLARATION OF HELSINKI/BASIC PRINCIPLES ...... 65 
PRINCIPAL INVESTIGATOR AGREEMENT .......................................................................... 66 
SPONSOR AGREEMENT ........................................................................................................... 67 
REFERENCES ............................................................................................................................. 68 
APPENDIX A – CLINICAL LABORATORY EVALUATIONS ............................................... 69 
APPENDIX B – APPROXIMATE MAXIMUM BLOOD VOLUME COLLECTED ................ 70 
 
TABLE OF TABLES 
 
Table 2-1 
GDC-9545 Single-Dose Pharmacokinetic Parameters ......................................... 15 
Table 4-1 
Three-Period, Six-Sequence Crossover Study Design.......................................... 19 
Table 6-1 
Potential Risks for GDC-9545 .............................................................................. 26 
Table 6-2 
Guidelines for Management of Subjects Who Experience Specific Adverse Events
............................................................................................................................... 29 
Table 7-1 
Schedule of Activities ........................................................................................... 30 
Table 7-2 
Pharmacokinetic Sampling Scheme ...................................................................... 32 
Table 7-3 
Clinical Laboratory and Safety Assessment Windows ......................................... 32 
Table 7-4 
Study Drugs .......................................................................................................... 33 
Table 8-1 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE ................................................................................................................. 46 
Table 8-2 
Causal Attribution Guidance................................................................................. 47 
 
TABLE OF FIGURES 
 
Figure 4-1 
Study Schematic.................................................................................................... 19 
 


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ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from Hour 0 extrapolated to infinity 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours postdose 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last measurable 
concentration 
BMI 
body mass index 
CBC 
complete blood count 
CCOD 
clinical cut-off date 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent total clearance 
Cmax 
maximum observed concentration 
CPET 
Clinical Pharmacology Protocol Execution Team 
CSR 
Clinical Study Report 
Ct 
last measurable concentration 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eMC 
Electronic Medicines Compendium 
ER 
estrogen receptor 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HDYF? 
How do you feel? 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


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ICH 
International Conference on Harmonisation/International Council for 
Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
λz 
apparent terminal elimination rate constant 
LHRH 
luteinizing hormone-releasing hormone 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
PLD 
phospholipidosis 
PPD 
purified protein derivative 
PK 
pharmacokinetic(s) 
PSS 
Patient Safety Solutions 
RBC 
red blood cell 
RBR 
Research Biosample Repository 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SERD 
selective estrogen receptor degrader 
SERM 
selective estrogen receptor modulator 
SOC 
System Organ Class 
SOP 
standard operating procedure 
t1/2 
apparent terminal elimination half-life 
TB 
tuberculosis 
tmax 
time to maximum observed concentration 
UA 
urinalysis 
ULN 
upper limit of normal 
US 
United States 
VZ/F 
apparent volume of distribution during the terminal elimination phase 
WBC 
white blood cell 


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1 SYNOPSIS 
Title of Study: 
A Phase 1, Open-Label, Single-Dose, Randomized, Three-Period Crossover Study to 
Evaluate the Relative Bioavailability and Food Effect of GDC-9545 in Healthy Female 
Subjects of Non-Childbearing Potential 
Objectives: 
The primary objectives of this study are: 
• 
To evaluate the relative bioavailability of GDC-9545 Phase 3 capsule as 
compared to the Phase 1 tablet in the fasted state in healthy adult female 
subjects of non-childbearing potential 
• 
To assess the impact of food on GDC-9545 PK for the Phase 3 capsule in 
healthy adult female subjects of non-childbearing potential. 
The secondary objective of this study is: 
• 
To explore the safety and tolerability of single oral doses of 30 mg GDC-9545 
as a Phase 3 capsule in the fasted and fed states in healthy adult female 
subjects of non-childbearing potential. 
Methodology/Study 
Design: 
This study will be an open-label, randomized, three-period, six-sequence crossover 
study of GDC-9545 administered to healthy females of non-childbearing potential to 
determine the relative bioavailability of the Phase 3 capsule formulation to the Phase 1 
tablet formulation in the fasted state and the effect of food on the Phase 3 capsule 
formulation. Potential subjects will be screened to assess their eligibility to enter the 
study within 34 days (Days -35 to -2) prior to dosing on Period 1 Day 1. Dosing will 
be on Day 1 of each period. 
Number and General 
Description of 
Subjects: 
Eighteen subjects will be enrolled in the study to complete a minimum of 12 subjects. 
Diagnosis and Main 
Criteria for Inclusion: 
Healthy females of non-childbearing potential, between 18 and 65 years of age, 
inclusive, within body mass index range of 8.0 to 30.0 kg/m2, inclusive, who are in 
good health, as determined by no clinically significant findings from medical history, 
12-lead electrocardiogram (ECG), vital signs, and clinical laboratory evaluations. 
Test Product(s), Dose, 
and Mode of 
Administration: 
Subjects will receive the following treatments, according to a randomization schedule 
generated by a Covance Biostatistician: 
Treatment A:  30-mg dose of GDC-9545 (three 10-mg tablets) administered orally 
with approximately 240 mL room temperature water after at least an 8-hour fast. 
Treatment B:  30-mg dose of GDC-9545 (one 30-mg capsule) administered orally 
with approximately 240 mL room temperature water after at least an 8-hour fast. 
Treatment C:  30-mg dose of GDC-9545 (one 30-mg capsule) administered orally 
with approximately 240 mL room temperature water within 30 minutes of eating a 
high-fat meal. 
Duration of Treatment: 
Planned Enrollment/Screening Duration:  approximately 5 weeks. 
Length of Each Confinement:  subjects will be confined at the study site from the time 
of Check-in (Day -1) until Clinic Discharge on Day 8 of each period. The washout 
period between doses will be a minimum of 10 days. All subjects will receive 3 doses 
of GDC-9545. A Follow-up visit will occur 12 to 14 days after the last dose of 
GDC-9545. 
Planned Study Conduct Duration:  approximately 10 weeks. 
Criteria for Evaluation:  
Safety 
Safety and tolerability assessments will include recording of adverse events, clinical 
laboratory evaluations, 12-lead ECGs, vital sign measurements, and physical 
examinations. 
Criteria for Evaluation:  
Pharmacokinetics 
The following pharmacokinetic (PK) parameters will be derived from the plasma 
concentrations of GDC-9545 using the model independent approach:  maximum 
observed concentration (Cmax), time to Cmax (tmax), area under the concentration-time 
curve from Hour 0 to the last measurable concentration (AUC0-t), area under the 
concentration-time curve from Hour 0 extrapolated to infinity (AUC0-∞), apparent 


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terminal elimination rate constant (λz), apparent terminal elimination half-life (t1/2), 
apparent total clearance (CL/F), and apparent volume of distribution during the 
terminal elimination phase (Vz/F). 
Statistical Methods: 
Descriptive statistics (mean, median, minimum, maximum, standard deviation, 
coefficient of variation [CV%], geometric mean, and geometric CV%) will be 
calculated for all PK parameters for GDC-9545. 
The PK parameters Cmax, AUC0-t, and AUC0-∞ for GDC-9545 will be analyzed to 
evaluate the relative bioavailability of GDC-9545 as a Phase 3 capsule formulation 
compared to a Phase 1 tablet formulation under fasted conditions and to assess the 
food effect on GDC-9545 PK for a Phase 3 capsule formulation. The mixed-effect 
analysis of variance model for three-period crossover design will be used for 
formulation comparison and fasted state and fed state comparison of capsule. The 
model will include sequence, formulation, and period as fixed effects and a random 
effect for subject within sequence. Appropriate covariance structure will be used. 
Log transformed Cmax, AUC0-t, and AUC0-∞ values will be evaluated to estimate ratios 
of geometric mean values and the corresponding 90% confidence intervals (CIs). 
(Relative bioavailability-Test:  capsule, Reference:  tablet; food effect-Test:  fed, 
Reference:  fasted.) 
The parameter tmax will be analyzed nonparametrically using the Wilcoxon signed-rank 
test. The median difference between the test and reference investigational products and 
the corresponding 90% CI will be calculated. 
All safety data will be listed and summarized using standard descriptive statistics for 
the Safety Population. No formal statistical analyses are planned. 


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2 INTRODUCTION 
2.1 BACKGROUND 
Breast cancer is the most frequent cancer diagnosed in women, and accounts for approximately 
15% (approximately 522,000 cases) of all cancer deaths (Ferlay et al. 2013). Approximately 80% 
of all breast cancers express estrogen receptor (ER), and the vast majority of these cancers are 
dependent on ER for tumor growth and progression. Modulation of estrogen activity and/or 
synthesis is the mainstay of therapeutic approaches in women with ER+ breast cancer. However, 
despite the effectiveness of available endocrine therapies, many patients ultimately relapse or 
develop resistance. The growth and survival of the majority of tumors are thought to remain 
dependent on ER signaling. Consequently, patients with ER+ breast cancer can still respond to 
second/third line endocrine treatment after progression on prior therapy (Di Leo et al. 2010; 
Baselga et al. 2012). GDC-9545 is a small-molecule therapeutic agent that is being developed for 
the treatment of patients with ER+ breast cancer. GDC-9545 antagonizes the effects of estrogens 
via competitive binding to the ligand-binding domain of both wild-type and mutant ER. In 
addition to its direct antagonist properties, GDC-9545 reduces levels of ERα protein through 
proteasome-mediated degradation. Degradation of ER is hypothesized to enable full suppression 
of ER signaling, which is not achieved by first generation ER therapeutics. 
2.2 PHARMACOLOGY 
GDC-9545 has demonstrated growth inhibition in vitro as a single agent in human breast cancer 
cell lines expressing wild-type or mutant forms of ERα and in vivo in breast cancer xenograft 
models that harbor ERα mutations. In addition, GDC-9545 enhances the in vivo efficacy of the 
CDK4/6 inhibitor palbociclib, a standard-of-care drug for treatment of patients with hormone 
receptor+/HER2- metastatic breast cancer, in the ER+ MCF7 xenograft model. GDC-9545, 
unlike 17α-ethinylestradiol and tamoxifen, did not induce ER agonism when assessed in 
immature rat uteri. Moreover, GDC-9545 is anticipated to have a low risk of adverse 
cardiovascular, neurologic, and respiratory effects at pharmacologically active doses and at doses 
used in the first-in-human Phase 1 clinical trial. 
2.3 PHARMACOKINETICS 
No human-specific metabolites were detected in studies in human, mouse, rat, rabbit, dog, or 
monkey hepatocytes. In vitro data showed that plasma protein binding of GDC-9545 was high 
across all species, ranging from 98% to 99% bound. 
Uridine 5’-diphospho-glucuronosyltransferase 1A4 glucuronidation was the major in vitro 
metabolic pathway of GDC-9545. The contribution from cytochrome P450 (CYP) isoforms was 


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minor and included CYP3A4 and CYP2C9. In vitro studies suggest a low-to-moderate potential 
for drug-drug interaction. 
2.4 TOXICOLOGY AND SAFETY PHARMACOLOGY 
Adverse organ effects identified in pivotal toxicity studies in rat and monkey were 
dose-dependent, largely confined to the kidney and liver, and readily monitorable in the clinic 
using standard laboratory assessments. The findings in reproductive organs in both species are 
consistent with the anti-estrogenic mode of action of GDC-9545 and were partially reversible in 
monkeys but not rats, likely due to the maintenance of pharmacologically active exposures of 
GDC-9545 at the end of the recovery period. In both rats and monkeys, there was 
dose-dependent phospholipidosis (PLD) in numerous organs, including liver and kidney. In rats, 
PLD was not noted at 10 mg/kg, but increased in incidence and severity from 30 to 100 mg/kg. 
In monkeys, PLD was present at all doses, but was limited to minimal changes in the lung at 
20 mg/kg. In general, PLD is of greatest concern when accumulations occur in critical cell types 
such as cardiomyocytes, neurons, and retinal epithelium (Chatman et al. 2009), but PLD was not 
seen in any of these cell types. 
 
No significant inhibition was observed on cloned human sodium or calcium channels in vitro. 
GDC-9545 inhibited human ether à go go related gene potassium current with a 50% inhibitory 
concentration 339-fold higher than the unbound maximum observed concentration of the 100-mg 
dose in humans from the Phase 1 first-in-human trial. There were no GDC-9545-related changes 
in cardiovascular parameters in cynomolgus monkey after single doses up to the maximum dose 
tested. In a four-week study in monkeys, there was a dose-dependent decrease in heart rate that 
was not considered to be toxicologically relevant. GDC-9545 was not mutagenic in the bacterial 
mutagenesis assay, did not induce micronucleus formation in human lymphocytes, and was not 
phototoxic in mammalian cells. 
2.5 CLINICAL RESULTS 
GDC-9545 is currently being evaluated in a Phase 1 study in patients. As of the clinical cut-off 
date (CCOD) of 4 September 2019, safety data is available on 120 patients with ER+/HER2-, 
locally recurrent or metastatic breast cancer that have been treated with GDC-9545 at 10- to 
250-mg doses given once daily, including 74 patients in single-agent dose-escalation or 
expansion cohorts ± luteinizing hormone-releasing hormone (LHRH) agonist and 46 patients in 
palbociclib combination dose-escalation cohorts. Single-dose pharmacokinetic (PK) parameters 
for GDC-9545 as a single agent are shown in Table 2-1. 
 


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Table 2-1 
GDC-9545 Single-Dose Pharmacokinetic Parameters 
Dose 
tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-24 
(hr•ng/mL) 
AUC0-∞ 
(hr•ng/mL) 
t1/2 
(hr) 
10 mg (n = 6) 
2.50 (1.00-4.00) 
53.7 (55.3) 
782 (50.5) 
1910 (66.6) 
38.9 (32.2) 
30 mg (n = 6) 
1.75 (1.00-3.00) 
177 (23.5) 
2110 (25.6) 
5070 (28.3) 
41.4 (8.7) 
90 mg (n = 6) 
3.0 (1.50-4.00) 
382 (31.8) 
5570 (31.8) 
12200 (31.3) 
36.9 (20.9) 
250 mg (n = 3) 
3.0 (3.0-3.0) 
1190 (7.46) 
16600 (6.95) 
32300 (11.8) 
26.2 (17.7) 
AUC0-∞ = area under the concentration-time curve from Hour 0 extrapolated to infinity; AUC0-24 = area under the 
concentration-time curve from Hour 0 to 24 hours postdose; Cmax = maximum observed concentration; 
t1/2 = apparent terminal elimination half-life; tmax = time to maximum observed concentration. 
Geometric mean (geometric coefficient of variation) is presented for all parameters except tmax, for which median 
(range) is reported. 
 
Robust ER target engagement across all doses as evidenced by [18F]-fluoroestradiol-positron 
emission tomography data was demonstrated. Of the 39 patients with post-baseline tumor 
assessments, 2 patients had confirmed partial responses and 28 patients had stable disease or 
non-complete response/non-progressive disease. 
 
There were no withdrawals due to adverse events (AEs), and no dose-limiting toxicities were 
reported. GDC-9545 was well tolerated at all dose levels. As of the CCOD of 4 September 2019, 
74 patients treated with single-agent GDC-9545 (including arms co-administered with LHRH 
agonist) at doses ranging from 10 to 250 mg including 10 patients treated at 30 mg GDC-9545 
(which is the selected dose for this study). 
 
Of the 74 patients treated with single-agent GDC-9545, AEs attributed to GDC-9545 occurring 
in 5% or more of patients included:  fatigue (14 patients [19%]), arthralgia (9 patients [12%]), 
nausea (8 patients [11%]); diarrhea (7 patients [10%]); bradycardia (6 patients [8%]); hot flush, 
alanine aminotransferase (ALT) increased, and aspartate aminotransferase (AST) increased 
(5 patients each [7%]); and constipation and dyspepsia (4 patients each [5%]). Related events 
have been Grade 1 or 2 in severity with the exception of three Grade 3 events of fatigue, 
transaminase increased, and diarrhea (all were in patients treated with 100 mg GDC-9545 and 
confounded by metastatic sites and disease progression). 
 
In the single-agent GDC-9545 30-mg cohort, the AEs attributed to GDC-9545 occurring in 3 or 
more patients with Grade 1 or 2 severity included:  fatigue, nausea, diarrhea, and dyspepsia 
(3 patients each [30%]). 
 


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Of the 74 patients treated with single-agent GDC-9545, five serious AEs (SAEs) occurred in 
4 patients (5%) including:  appendiceal abscess, small intestinal obstruction, fatigue, migraine, 
and paraesthesia. All SAEs except fatigue were considered unrelated to GDC-9545 by the 
Investigators. In the 30-mg single-agent cohort, only a single patient experienced SAEs of 
migraine and paraesthesia; both of which were considered unrelated to GDC-9545. 
 
GDC-9545 treatment resulted in a dose-dependent decrease in heart rate. Of the 74 patients 
treated with single-agent GDC-9545, 7 patients (9.5%) experienced AEs that are mapped into the 
cardiac disorder System Organ Class (SOC). This includes AEs of bradycardia in 7 patients 
(9.5%; 6 patients at 90/100-mg and 1 patient at 250-mg cohorts) and palpitation in 2 patients 
(3%; 1 patient at 90-mg and 1 patient at 250-mg cohorts). All AEs were Grade 1 and 
asymptomatic. No cardiac-related events have been reported at 30 mg. 
 
Refer to the GDC-9545 Investigator’s Brochure (IB) for details on nonclinical and clinical 
studies. 
2.6 STUDY RATIONALE 
The purpose of this study is to evaluate the bioavailability of the GDC-9545 Phase 3 capsule 
relative to the Phase 1 tablet and to assess the effect of food on the GDC-9545 PK of the Phase 3 
capsule. These evaluations will support the use of the Phase 3 capsule in future clinical studies. 
2.7 DOSE RATIONALE 
GDC-9545 is a potent, orally bioavailable, small-molecule therapeutic agent that is being 
developed for the treatment of patients with ER+ breast cancer. GDC-9545 antagonizes the 
effects of estrogens via competitive binding to the ligand-binding domain of both wild-type and 
mutant ER with nanomolar potency. 
 
Based on interim data from safety, PK, and early signs of target modulation/activity in the 
first-in-human study of GDC-9545 in patients, 30 mg was selected as the optimal dose for future 
clinical development. 
 
As of the CCOD, a total of 120 postmenopausal women with locally advanced or metastatic 
ER+/HER2− breast cancer received at least one dose of GDC-9545 in the ongoing Phase Ia/Ib 
Study GO39932. This includes 74 patients who have been treated with single-agent GDC-9545 
(± LHRH agonist) at doses ranging from 10 to 250 mg. The single-agent dose escalation was 
completed in October 2018 after enrolling 29 patients. At the end of the dose-escalation stage, no 


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patients had experienced dose-limiting toxicities, SAEs, or protocol-defined AEs of special 
interest (AESIs) during dose escalation. The maximum tolerated dose was not reached. 
 
As of the CCOD, the most frequent AEs related to GDC-9545 in ≥5% (n=74) patients treated 
with single-agent GDC-9545 (± LHRH agonist) were:  fatigue (14 patients [19%]); arthralgia 
(9 patients [12%]); nausea (8 patients [11%]); diarrhea (7 patients [9.5%]); bradycardia 
(6 patients [8%]); hot flush, ALT increased, and AST increased (5 patients each [7%]); 
constipation and dyspepsia (4 patients each [5%]). All treatment-related events have been 
Grade 1 or 2 severity with the exception of three Grade 3 events of fatigue, transaminase 
increased, and diarrhea (all were in patients treated with 100 mg GDC-9545 and confounded by 
metastatic sites and disease progression). One patient has experienced a treatment-related SAE 
(Grade 3 fatigue) considered related to both GDC-9545 and disease progression. The dose of 
GDC-9545 was reduced in 2 patients (both receiving 100 mg); no patients were withdrawn from 
treatment due to AEs. 
 
Of the 74 patients treated with single-agent GDC-9545, 7 patients (9.5%) experienced AEs that 
are mapped into the cardiac disorder SOC. No cardiac-related events have been reported at 
30 mg. GDC-9545 was well tolerated at all dose levels with no trend for an increase in frequency 
or severity of AEs. 
 
All observations of AEs described above are at higher dose levels with continuous daily dosing. 
Consequently, the single dose of 30 mg represents an acceptable dosage for this study. 
3 STUDY OBJECTIVES AND CORRESPONDING ENDPOINTS 
3.1 PRIMARY OBJECTIVES 
The primary objectives of this study are: 
• To evaluate the relative bioavailability of GDC-9545 Phase 3 capsule as compared to the 
Phase 1 tablet in the fasted state in healthy adult female subjects of non-childbearing 
potential 
• To assess the impact of food on GDC-9545 PK for the Phase 3 capsule in healthy adult 
female subjects of non-childbearing potential. 
3.2 SECONDARY OBJECTIVES 
The secondary objective of this study is: 


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• To explore the safety and tolerability of single oral doses of 30 mg GDC-9545 as a 
Phase 3 capsule in the fasted and fed states in healthy adult female subjects of 
non-childbearing potential. 
3.3 ENDPOINTS 
The primary endpoints are the PK parameters outlined in Section 9.2. The secondary endpoints 
are the incidence and severity of AEs and incidence of abnormalities in laboratory safety 
assessments, 12-lead electrocardiograms (ECGs), vital signs measurements, and physical 
examinations. 
4 STUDY DESIGN 
4.1 DESCRIPTION OF THE STUDY 
This study will be an open-label, randomized, three-period, six-sequence crossover study of 
GDC-9545 administered at 30 mg in healthy females of non-childbearing potential to determine 
the relative bioavailability of the Phase 3 capsule formulation to the Phase 1 tablet formulation in 
the fasted state and the effect of food on the Phase 3 capsule formulation. Eighteen subjects will 
be enrolled in the study at a single study site to complete a minimum of 12 subjects. Study 
treatments are as follows: 
 
 
Treatment A:  30-mg dose of GDC-9545 (three 10-mg tablets) administered orally with 
approximately 240 mL room temperature water after at least an 8-hour 
fast. 
 
 
Treatment B:  30-mg dose of GDC-9545 (one 30-mg capsule) administered orally with 
approximately 240 mL room temperature water after at least an 8-hour 
fast. 
 
 
Treatment C:  30-mg dose of GDC-9545 (one 30-mg capsule) administered orally with 
approximately 240 mL room temperature water within 30 minutes of 
eating a high-fat meal. 
 
A summary of the sequences is presented in Table 4-1. 
 




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Subjects will be confined at the study site from the time of Check-in (Day -1) until Clinic 
Discharge on Day 8 of each period. Subjects will return to the study site for a Follow-up visit 12 
to 14 days after the last dose of GDC-9545. A detailed list of assessments during confinement is 
included in Table 7-1. 
 
In this study design, physical examinations, 12-lead ECGs, vital signs, How do you feel? 
(HDYF?) inquiries, clinical laboratory evaluations (Appendix A), and PK sampling will be 
performed at Screening, at specified times during the study, and/or at Follow-up/Early 
Termination (ET; for specific timepoints and details on each study variable, refer to Section 7). 
After informed consent has been obtained but prior to initiation of study drug administration 
(Period 1 Day 1), only SAEs caused by protocol-mandated interventions will be reported. After 
initiation of study drug administration on Period 1 Day 1, all AEs, whether volunteered, elicited, 
or noted upon physical examination, will be recorded throughout the study (i.e., from Period 1 
Day 1 until Follow-up/ET). The Sponsor should be notified if the Investigator becomes aware of 
any SAE that occurs after the follow-up period (defined as 12 to 14 days after the last dose of 
GDC-9545) if the event is believed to be related to prior study drug treatment. 
 
A schedule of activities is presented in Table 7-1. 
4.2 RATIONALE FOR STUDY DESIGN 
A crossover design will be used to reduce the residual variability as every subject acts as their 
own control. A single-dose, crossover design is the standard design to compare PK. Subjects will 
be randomized to one of six treatment sequences to minimize assignment bias. 
 
This study is an open-label investigation because the PK parameters are believed not to be 
subject to bias. The crossover design further minimizes the effect of inter-subject variability. 
Blood sampling up to 168 hours postdose will allow the PK parameters of GDC-9545 to be 
adequately characterized based on prior data. The 10-day washout between GDC-9545 doses is 
considered sufficient to prevent carryover effects of the treatments based on the GDC-9545 
geometric mean t1/2 of 26.2 to 41.4 hours. 
4.3 RATIONALE FOR SUBJECT POPULATION 
This study will enroll only female subjects since there is no information on safety in males. 
Healthy adult female subjects were chosen for inclusion in this study because they are free of 
health problems that could otherwise make them more susceptible to drug toxicity or confound 
the interpretation of the study results, are not routinely using concomitant medications that could 


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interact with the study drug, and can provide a standard basis for comparison (i.e., control) with 
less variability. 
 
Female subjects will be of non-childbearing potential as no studies assessing the reproductive 
and developmental toxicity of GDC-9545 have been conducted to date. It is not known whether 
GDC-9545 can cross the placenta or cause harm to the fetus when administered to pregnant 
women or whether it affects reproductive capacity. Microscopic evidence of disruption of the 
estrus cycle was present in both rats and cynomolgus monkeys administered GDC-9545 and did 
not reverse during a 4-week recovery period. Additional studies with longer recovery periods are 
required to adequately assess the reversibility of these findings. 
4.4 RATIONALE FOR EXPLORATORY ASSESSMENTS 
Not applicable. 
4.5 RATIONALE FOR PHARMACOKINETIC SAMPLING SCHEDULE 
The frequent sampling schedule is designed to capture data at a sufficient number of timepoints 
to provide a detailed profile of the concentration-time curve, including maximum observed 
concentration (Cmax), time to Cmax (tmax), and t1/2. 
5 SUBJECT SELECTION 
Eighteen healthy female volunteer subjects who meet all the protocol inclusion criteria and none 
of the exclusion criteria will be enrolled into the study. 
5.1 SCREENING PROCEDURES 
Refer to Table 7-1 for procedures performed for all potential subjects at the Screening visit. 
5.2 CHECK-IN PROCEDURES 
Refer to Table 7-1 for procedures performed at Check-in (Day -1) for each period, when subjects 
will report to the study site. 
 
For subjects to continue their participation in the study, the drug screen and the pregnancy test 
must be negative and the clinical laboratory evaluations must be within the normal laboratory 
range (unless deemed not clinically significant by the Investigator). In addition, continued 
compliance with concomitant medication and other restrictions will be verified. 


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5.3 INCLUSION CRITERIA 
Subjects who meet the following criteria may be included in the study: 
1. Females of non-childbearing potential including non-pregnant, non-lactating, and either 
postmenopausal defined as: 
• Age >60 years; 
• Age ≤60 years and amenorrhea ≥12 months in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression and estradiol levels and follicle-
stimulating hormone (FSH) levels in the postmenopausal range; 
or surgically sterile for at least 90 days prior to Screening defined as: 
• Bilateral tubal ligation; 
• Bilateral salpingectomy; 
• Hysterectomy; 
• Bilateral oophorectomy; 
The pregnancy test result must be negative at Screening and Check-in (Day -1) of 
Period 1; 
2. Females between 18 and 65 years of age, inclusive; 
3. Females with body mass index (BMI) range 18.5 to 30.0 kg/m2, inclusive at Screening; 
4. Females in good health, determined by no clinically significant findings from medical 
history, 12-lead ECG, or vital signs; 
5. Clinical laboratory evaluations (including chemistry panel [fasted at least 8 hours], 
complete blood count [CBC], and urinalysis [UA] with complete microscopic analysis at 
Screening) within the reference range for the test laboratory, unless deemed not clinically 
significant by the Investigator. Congenital nonhemolytic hyperbilirubinemia (e.g., 
suspicion of Gilbert’s syndrome based on total and direct bilirubin) is acceptable. In case 
of borderline or questionable results, tests may be repeated to confirm eligibility; 
6. Negative test for selected drugs of abuse at Screening (does not include alcohol) and at 
Check-in (Day -1) for Period 1 (does include alcohol; Appendix A); 
7. Negative hepatitis panel (hepatitis B surface antigen and hepatitis C virus antibody) and 
negative human immunodeficiency virus (HIV) antibody screens (Appendix A); 
8. Subject must receive an explanation of the mandatory Research Biosample Repository 
(RBR) component of the study and be able to comprehend and willing to sign an 
Informed Consent Form (ICF). 


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5.4 EXCLUSION CRITERIA 
The following will exclude potential subjects from the study: 
1. Female subject having a significant history or clinical manifestation of any metabolic, 
allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, 
gastrointestinal (GI), neurological, or psychiatric disorder (as determined by the 
Investigator); 
2. Female subject having a history of significant hypersensitivity, intolerance, or allergy to 
any drug compound, food, or other substance, unless approved by the Investigator; 
3. History of allergy to GDC-9545 or any of its excipients; 
4. Female subject having a history of stomach or intestinal surgery (including 
cholecystectomy) or resection that would potentially alter absorption and/or excretion of 
orally administered drugs except that appendectomy and hernia repair will be allowed; 
5. Female subject having a history or presence of an abnormal ECG that, in the 
Investigator’s opinion, is clinically significant including complete left bundle branch 
block; right bundle branch block; first-, second-, or third-degree heart block; sick sinus 
syndrome; or evidence of prior myocardial infarction; 
6. Having a QTc interval >470 msec, PR interval >210 msec, or QRS complex >120 msec. 
If the ECG parameters are out-of-range, the ECG will be repeated 2 additional times and 
a triplicate average will be used to determine eligibility; 
7. Confirmed (e.g., 2 consecutive measurements) baseline heart rate ≤50 bpm prior to 
enrollment; 
8. Female subject having a history of alcoholism or drug addiction within 1 year prior to 
Check-in (Day -1) of Period 1; 
9. The use of tobacco- or nicotine-containing products (including, but not limited to, 
cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine 
lozenges, or nicotine gum) within 6 months prior to Check-in (Day -1) of Period 1; 
10. History of active or latent tuberculosis (TB), regardless of treatment history; 
11. History of previous use of tamoxifen, aromatase inhibitors, or any other endocrine agent 
for the treatment of breast cancer; 
12. The use of hormone replacement therapy or selective ER modulators (SERMs; e.g., 
raloxifene) within 1 year prior to Check-in (Day -1) of Period 1; 
13. The use of oral antibiotics within 4 weeks or intravenous antibiotics within 8 weeks prior 
to Check-in (Day -1) of Period 1; 
14. The use or intent to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior to 
Check-in (Day -1) of Period 1; 


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15. The participation in any other investigational study drug trial in which receipt of an 
investigational study drug occurred within 5 half-lives or 30 days, whichever is longer, 
prior to Check-in (Day -1) of Period 1; 
16. The use of drugs of abuse (including opioids) within 4 weeks of Screening; 
17. The use of any prescription medications/products within 14 days prior to Check-in 
(Day -1) of Period 1, unless deemed acceptable by the Investigator; 
18. The use of any over-the-counter, non-prescription preparations (including vitamins; 
minerals; and phytotherapeutic-, herbal-, and plant-derived preparations) within 7 days 
prior to Check-in (Day -1) of Period 1, unless deemed acceptable by the Investigator; 
19. The use of poppy seed-containing foods or beverages within 7 days prior to Check-in 
(Day -1) of Period 1, unless deemed acceptable by the Investigator; 
20. The use of alcohol- or caffeine-containing foods or beverages within 72 hours prior to 
Check-in (Day -1) of Period 1, unless deemed acceptable by the Investigator; 
21. Female subjects will refrain from strenuous exercise from 7 days prior to Check-in 
(Day -1) of Period 1; 
22. The need to follow a special diet and unable to consume the high-fat meal; 
23. Poor peripheral venous access; 
24. Female subject having a history of malignancy, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer 
(must be cancer-free for at least 5 years); 
25. The donation of blood from 90 days prior to Screening through Follow-up, inclusive, or 
of plasma from 2 weeks prior to Screening; 
26. Receipt of blood products within 2 months prior to Check-in (Day -1) of Period 1; 
27. Any acute or chronic condition that, in the opinion of the Investigator, would limit the 
subject’s ability to complete and/or participate in this clinical study; 
28. In the opinion of the Investigator or Sponsor, are unsuitable for inclusion in the study. 
5.5 REMOVAL OF SUBJECTS FROM STUDY PARTICIPATION 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator may remove a subject from the study if, in the Investigator’s opinion, it 
is not in the best interest of the subject to continue the study. Subjects may be discontinued due 
to the following:  change in compliance with inclusion/exclusion criterion that is clinically 
relevant and affects subject safety, occurrence of AEs that jeopardize the subject’s safety if she 
continues in the study, occurrence of pregnancy, intake of non-permitted concomitant medication 
that might affect subject safety or study assessments/objectives, etc. Notification of 
discontinuation will immediately be made to the Sponsor’s Study Monitor. In case of premature 
discontinuation of study participation, efforts will be made to perform all final study day 


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assessments (see Section 7.15). The date the subject is withdrawn from the study and the reason 
for discontinuation will be recorded on the subject’s electronic Case Report Form (eCRF). All 
dropouts will be followed until resolution of all their AEs or until the unresolved AEs are judged 
by the Investigator to have stabilized or returned to baseline. 
 
Replacement subjects will not be enrolled in this study. Subjects will be assigned a number by 
study site staff. Assignment of numbers will be in ascending order and no numbers will be 
omitted. Subject numbers will be used on all study documentation. 
 
The entire study may be discontinued at the discretion of the Investigator, Sponsor, or Sponsor’s 
Medical Monitor based on the occurrence of the following: 
• AEs unknown to date with respect to their nature, severity, and duration 
• Increased frequency, and/or severity, and/or duration of known AEs 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of subjects 
• Cancellation of drug development. 
6 ASSESSMENT OF SAFETY 
6.1 SAFETY PLAN 
GDC-9545 is not approved, and clinical development is ongoing. The safety plan for subjects in 
this study is based on clinical experience with GDC-9545 in ongoing studies. The anticipated 
important safety risks for GDC-9545 are outlined below. Please refer to the IB for a complete 
summary of safety information. 
 
Several measures will be taken to ensure the safety of subjects participating in this study. 
Eligibility criteria have been designed to exclude subjects at higher risk for toxicities. Subjects 
will undergo safety monitoring during the study, including assessment of the nature, frequency, 
and severity of AEs. In addition, guidelines for managing AEs are provided below. 
6.1.1 RISKS ASSOCIATED WITH GDC-9545 
6.1.1.1  IDENTIFIED RISKS AND ADVERSE DRUG REACTIONS 
At this time no risks or adverse drug reactions have been identified for GDC-9545. 


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6.1.1.2 POTENTIAL RISKS 
On the basis of the established class effects of estrogen antagonists in patients with breast cancer, 
knowledge of similar molecules, as well as the nonclinical data and clinical experience from 
Phase Ia/Ib Study GO39932, gastrointestinal toxicities (including:  nausea, vomiting, and 
diarrhea), venous thromboembolic events, bradycardia, hepatotoxicity, renal dysfunction, and 
female infertility are the specific safety concerns for GDC-9545. 
Table 6-1 summarizes the key clinical safety data for each of the safety concerns based on the 
cumulative review of clinical data as of CCOD (04 September 2019). Patients received daily 
doses of GDC-9545. 
Table 6-1 
Potential Risks for GDC-9545 
Potential Risks 
Assessment of Risks 
Clinical Data 
Gastrointestinal toxicities 
(nausea, vomiting, and 
diarrhea) 
Gastrointestinal toxicities (e.g., 
nausea, vomiting, and diarrhea) have 
been reported in association with 
some oral SERD molecules currently 
in early development. 
The following treatment-related GI 
toxicities were reported in patients 
who received doses of 10-250 mg of 
GDC-9545 as a single-agent (n=74):  
nausea (11%), diarrhea (9.5%), 
constipation (5%), and vomiting 
(4%). All AEs were Grade 1 or 2, 
except Grade 3 diarrhea in 1 patient 
at 100 mg. 
The following treatment-related GI 
toxicities were reported in patients 
who received 30 mg single-agent 
GDC-9545 (n=10):  nausea and, 
diarrhea (3 patients each [30%]), 
vomiting (2 patients [20%]), and 
constipation (1 patient [10%]); all 
events were Grade 1 or 2.. 
Venous thromboembolic events 
Thromboembolic events occur in 
patients with malignancies. Against 
this background of malignancy, they 
are reported to occur commonly in 
patients receiving fulvestrant (≥1/100 
to <1/10; Falsodex eMC 2016a). The 
SERM tamoxifen is reported to carry 
a 2- to 3-fold increased risk of 
thromboembolic events in the 
adjuvant setting (Tamoxifen eMC 
2016b). 
No patients treated with GDC-9545 
have experienced thromboembolic 
events as defined by MedDRA SMQ 
narrow of “Embolic and thrombotic 
events, venous.” 
Bradycardia 
During the nonclinical 4-week 
toxicity study in cynomolgus 
monkeys, GDC-9545 related 
reductions in heart rate (surface and 
telemetry leads) were observed on 
Seven (9.5%) patients who received 
single-agent GDC-9545 (all treated at 
90 mg or higher dose level), had 
reported Grade 1 asymptomatic 
bradycardia/sinus bradycardia. No 


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Potential Risks 
Assessment of Risks 
Clinical Data 
Day 13 at 20, 60, and 200 mg/kg and 
on Day 23 at 60 mg/kg. These 
changes were considered related to 
GDC-9545 but were within the 
normal range for the cynomolgus 
monkey and not considered adverse. 
At completion of the dose-escalation 
portion of Study GO39932, 3 patients 
(10%) in the 90-mg cohort had 
reported Grade 1 asymptomatic 
bradycardia. Upon further review of 
clinical safety data (e.g., vital 
signs/ECGs) at least 1 patient at all 
dose levels was noted to have 
asymptomatic bradycardia and/or 
asymptomatic heart rate decrease. In 
those patients with a decreased heart 
rate, there were no clinically 
significant ECG changes or evidence 
of exercise intolerance. 
Until there is a clear understanding of 
the clinical profile of decreased heart 
rate with GDC-9545, ECGs will 
continue to be collected. Caution 
should be taken with the 
co-administration of drugs known to 
cause decreases in heart rate. 
clinically significant ECG changes 
(e.g., conduction abnormality), 
exercise intolerance, or changes in 
systolic or diastolic blood pressure 
have been reported as a result of 
bradycardia. 
No cardiac-related events have been 
reported at 30 mg. 
Hepatotoxicity 
Liver enzyme elevation has been 
reported in association with some oral 
SERD molecules currently in early 
development. Changes in liver 
enzymes have been reported with the 
oral SERM tamoxifen (common, 
≥1% to <10%) and the injectable 
SERD fulvestrant (very common, 
≥10%; Falsodex eMC 2016a; 
Tamoxifen eMC 2016b). Hepatitis, 
hepatic failure, and hepatic necrosis 
are reported as rare (≥0.01% and 
<0.1%) in patients receiving 
tamoxifen. Hepatic failure and 
hepatitis are reported as uncommon 
(≥1/1,000 to <1/100) in patients 
receiving fulvestrant. 
Events of ALT or AST increased (all 
Grade 1) were reported in 8% and 
7%, respectively, of patients who 
received doses of 10-250 mg of 
GDC-9545 as a single-agent. 
In addition, 1 patient in Cohort A4 
(GDC-9545 100 mg + LHRH 
agonist) had experienced Grade 3 
transaminase increased that was 
considered related to GDC-9545 by 
the Investigator. The event resolved 
and the patient was able to continue 
GDC-9545 treatment at a reduced 
dose of 60 mg/day with no 
recurrences. 
In the 30 mg single-agent GDC-9545 
cohort, only 1 patient has experienced 
Grade 1 ALT increased. 
Renal dysfunction 
Renal failure or acute kidney injury 
are not listed as unwanted effects of 
fulvestrant (Falsodex eMC 2016a). 
No cases of acute kidney injury as 
defined by MedDRA High Level 
Group Terms of “Renal disorders 
(excluding nephropathies)” or AEs of 
creatinine increase have been 
reported. 


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Potential Risks 
Assessment of Risks 
Clinical Data 
Changes in female reproductive 
organs and menopausal 
symptoms 
Based on the anti-estrogenic 
pharmacological activity of 
GDC-9545, its effects are anticipated 
to be similar to but potentially more 
severe than those of normal 
menopause, such as loss of muscle 
and bone, hot flashes, vaginal dryness 
or discharge, irritation, mood swings, 
and decreased libido. 
Hot flushes and vaginal discharge 
have been reported in association 
with oral SERD molecules currently 
in early development. Unlike 
GDC-9545, the SERM tamoxifen 
promotes the growth of endometrial 
tissue in vitro, acting as an agonist of 
ER in that tissue (Tamoxifen eMC 
2016b). Endometrial changes 
including polyps (≥1% and <10%) 
and endometrial cancer (uncommon, 
≥0.1% and <1%) are listed as 
undesirable effects of tamoxifen. 
GDC-9545 and fulvestrant (both 
SERDs) are not agonistic in 
endometrial cells. The effects of 
GDC-9545 in human endometrial 
tissue are unknown, but endometrial 
agonism is not anticipated. 
The following AEs have been 
reported in the SOC of reproductive 
system and breast disorders in 
patients who received single-agent 
GDC-9545 (n=74):  vulvovaginal 
dryness, vaginal discharge, and 
vulvovaginal pruritus (1 patient each 
[1.4%]). All events were Grade 1. 
In the 30 mg single-agent GDC-9545 
cohort, 2 patients have experienced 
an event mapped to the reproductive 
disorder SOC including Grade 1 
vulvovaginal dryness and Grade 1 
vaginal discharge (1 patient each 
[10%]). 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; 
eMC = Electronic Medicines Compendium; ER = estrogen receptor; GI = gastrointestinal; LHRH = luteinizing 
hormone-releasing hormone; MedDRA = Medical Dictionary for Regulatory Activities; SERD = selective estrogen 
receptor degrader; SERM = selective estrogen receptor modulator; SMQ = Standardised MedDRA Query; 
SOC = System Organ Class. 
Source:  RO7197597 (GDC-9545). Investigator’s Brochure. Genentech, Inc. Version 3. June 2019. 
6.1.2 MANAGEMENT OF SUBJECTS WHO EXPERIENCE SPECIFIC ADVERSE 
EVENTS 
The majority of risks identified for GDC-9545 are following continuous daily dosing over an 
extended period and not likely to occur with single dose administration. Guidelines for 
management of specific AEs are outlined in Table 6-2. 
 


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Table 6-2 
Guidelines for Management of Subjects Who Experience Specific Adverse 
Events 
Event 
Action to be Taken 
Gastrointestinal toxicities (nausea, vomiting, 
diarrhea) 
• 
Infectious or alternate etiology should be excluded. 
• 
Treat and manage per standard-of-care, including 
use of antidiarrheals (e.g., lomotil) and appropriate 
supportive care including hydration if clinically 
indicated. 
• 
Do not administer antidiarrheals until at least 
4 hours postdose. 
• 
Hold GDC-9545 until resolution to Grade ≤1. 
Elevation of hepatic transaminases 
• 
Rule out alternative etiologies (e.g., concomitant 
medications or biliary obstruction). 
• 
Treat and manage per local standard-of-care. 
• 
For Grade ≥3 transaminase increased, withdraw 
the subject from the study. 
Bradycardia 
• 
Monitor patients closely for symptomatic 
bradycardia. 
• 
For Grade ≥2, withdraw the subject from the 
study. 
Venous thromboembolic event 
Any grades: 
• 
Subjects should be advised to seek immediate 
medical attention if they become aware of any 
symptoms of pulmonary embolism or deep vein 
thrombosis, such as acute onset of chest pain, 
shortness of breath, or swelling in extremities. 
• 
Manage and treat subjects according to 
institutional guidelines and local standards of care. 
• 
Withdraw the subject from the study. 
Abnormal vaginal bleeding or uterine hemorrhage 
Any grades: 
• 
Evaluate with a complete gynecological workup 
including consultation with a specialist. 
• 
Consider transvaginal ultrasound. 
• 
Withdraw the subject from the study. 
Creatinine increase 
• 
For Grade ≥2, withdraw the subject from the 
study. 
 
In the unlikely event that any other toxicity is suspected, please contact the Medical Monitor. All 
AEs must be reported according to the procedures documented in Section 8. 
7 STUDY PROCEDURES 
7.1 SCHEDULE OF STUDY ACTIVITIES 
The schedule of activities is presented in Table 7-1. The PK sampling scheme is presented in 
Table 7-2. The clinical laboratory and safety assessment windows are presented in Table 7-3. 


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Table 7-1 
Schedule of Activities 
 
Screening 
Periods 1, 2, and 3a 
Follow-up 
Study Procedures 
Days -35 
to -2 
Day 
12 to 14 days 
after 
last dose 
Check-in 
-1 
1 
2 
3 
4 
5 
6 
7 
Discharge/ET 
8 
Confined to the Study Site 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ambulatory (outpatient) Study Site Visit 
X 
 
 
 
 
 
 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Previous Medication and Compliance with 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
Height, Weight, and BMIc 
X 
X 
 
 
 
 
 
 
 
 
X 
Physical Examinationd 
 
X 
 
 
 
 
 
 
 
 
X 
Single 12-Lead ECG 
X 
X 
Xe 
X 
 
 
 
 
 
X 
X 
Vital Signsf 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel, CBC, and UAg 
X 
X 
 
X 
 
 
 
 
 
X 
X 
Drug and Alcohol Screenh 
X 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, and HIV Screeng 
X 
 
 
 
 
 
 
 
 
 
 
Tuberculosis testingi 
X 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Testj 
X 
X 
 
 
 
 
 
 
 
 
X 
FSHj 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Evaluations (HDYF? Inquiry) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
Xk 
 
 
 
 
 
 
 
 
GDC-9545 Dose 
 
 
X 
 
 
 
 
 
 
 
 
PK Blood Samplesl 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sample for RBRm 
 
 
X 
 
 
 
 
 
 
 
 
AE = adverse event; BMI = body mass index; CBC = complete blood count; ECG = electrocardiogram; ET = Early Termination; FSH = follicle-stimulating 
hormone; HDYF? = how do you feel?; HIV = human immunodeficiency virus; PK = pharmacokinetic; RBR = Research Biosample Repository; 
TB = tuberculosis; UA = urinalysis. 
a There will be a minimum 10-day washout between doses. 
b Interim medical history only. Includes any medical history that occurred between the end of the Screening visit and the Period 1 Check-in. 
c Body weight recorded at Screening, Check-in (Day -1), and Follow-up, and height and BMI recorded at Screening only. 


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d Routine physical examination at Check-in (Day -1) of Period 1, and abbreviated physical examination at Check-in (Day -1) of Periods 2 and 3 and Follow-up. 
(Section 7.13). 
e Predose and 4 hours postdose. 
f Vital signs include:  oral temperature, respiratory rate, and supine blood pressure and pulse. 
g Refer to Appendix A for a list of evaluations. 
h Includes alcohol testing at Check-in (Day -1) only. 
i QuantiFERON® TB Gold test. If positive, subject will be excluded. Indeterminate results may be confirmed by repeat or by a purified protein derivative skin 
test. If a negative tuberculosis test has been documented within 3 months of Screening, no new test is needed. 
j Qualitative serum pregnancy test at Screening and urine pregnancy test at all other times. A positive urine pregnancy test will be confirmed with a serum 
pregnancy test. Follicle-stimulating hormone testing performed on postmenopausal females. 
k Prior to Period 1 dose. 
l For PK blood samples collected during the study, refer to Table 7-2. 
m Sample collected prior to the GDC-9545 dose in Period 1. 


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Table 7-2 
Pharmacokinetic Sampling Scheme 
Study 
Day 
PK Sampling Timepoints 
Window (±) 
Analyte (Matrix) 
Day 1 
Predose (0 Hour) any time prior to study drug 
administration 
NA 
GDC-9545 (Plasma) 
30 minutes 
5 minutes 
GDC-9545 (Plasma) 
1 hour 
10 minutes 
GDC-9545 (Plasma) 
1.5 hours 
10 minutes 
GDC-9545 (Plasma) 
2 hours 
10 minutes 
GDC-9545 (Plasma) 
2.5 hours 
10 minutes 
GDC-9545 (Plasma) 
3 hours 
10 minutes 
GDC-9545 (Plasma) 
4 hours 
10 minutes 
GDC-9545 (Plasma) 
5 hours 
10 minutes 
GDC-9545 (Plasma) 
6 hours 
10 minutes 
GDC-9545 (Plasma) 
8 hours 
10 minutes 
GDC-9545 (Plasma) 
12 hours 
20 minutes 
GDC-9545 (Plasma) 
Day 2 
24 hours 
20 minutes 
GDC-9545 (Plasma) 
Day 3 
48 hours 
20 minutes 
GDC-9545 (Plasma) 
Day 4 
72 hours 
20 minutes 
GDC-9545 (Plasma) 
Day 5 
96 hours 
20 minutes 
GDC-9545 (Plasma) 
Day 6 
120 hours 
20 minutes 
GDC-9545 (Plasma) 
Day 7 
144 hours 
20 minutes 
GDC-9545 (Plasma) 
Day 8 
168 hours 
20 minutes 
GDC-9545 (Plasma) 
NA = not applicable; PK = pharmacokinetic. 
 
Table 7-3 
Clinical Laboratory and Safety Assessment Windows 
Safety Assessment Timepointsa 
Window (±) 
Predose 
45 minutes 
0 to 24 hours postdose 
15 minutes 
Days 2 to 7 
6 hours 
Days 8 to 29 
6 hours 
a Safety assessments may include vital signs, electrocardiograms, physical examinations, and clinical laboratory 
assessments. Not all safety assessments will be performed at each timepoint specified. 


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7.2 STUDY TREATMENT 
The Investigational Medicinal Product for this study is GDC-9545. 
7.2.1 DRUG SUPPLIES AND ACCOUNTABILITY 
The Sponsor or designee will provide the Investigator with adequate quantities of the study drugs 
(see Table 7-4). 
Table 7-4 
Study Drugs 
Study Drug 
GDC-9545 
GDC-9545 
Formulationa 
Tablet (Phase 1 Reference Product) 
Capsule (Phase 3 Test Product) 
Strength 
10 mg 
30 mg 
Supplier 
Genentech 
Roche 
Manufacturer 
Patheon 
Roche 
a Specific ingredients/purity will be identified on the Certificate of Analysis (or equivalent) that is supplied with the 
study drug(s). 
The lot numbers for the study drug(s) will be provided to the study site by the 
supplier/manufacturer as soon as available. 
GDC-9545 tablet will be stored between 2°C and 8°C and GDC-9545 capsule will be stored at 
the recommended condition of “do not store above 25°C” under secure conditions. The study 
drugs will be transferred from the bulk supplies into the subject’s dose container by qualified 
study site employees. Each unit dose container will be appropriately labeled. 
The Investigator or designee will maintain an accurate record of the receipt of the test materials 
as shipped by the Sponsor or designee, including the date received. One copy of this receipt will 
be returned to the Sponsor when the contents of the test material shipment have been verified. In 
addition, an accurate drug disposition record will be kept, specifying the amount dispensed to 
each subject and the date of dispensation. 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. 
If deemed appropriate by the Sponsor, sufficient samples will be randomly selected from the 
supply provided by the Sponsor or designee and retained by the study site to meet the retention 
requirements described in United States (US) Title 21 Code of Federal Regulations (CFR) 
320.38 and 320.63. 


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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. 
 
At the completion of the study, all unused drug supplies (except for retention supplies, if 
appropriate) will be returned to the Sponsor or designee or disposed of by the study site, per the 
Sponsor’s or designee’s written instructions. 
7.2.2 DOSE PREPARATION AND ADMINISTRATION 
Each unit dose will be prepared by qualified clinical staff based on the study randomization that 
will be provided by a Covance Biostatistician. 
 
Appropriate unit doses, as described above, will be administered to consecutively numbered 
subjects. Although the timing of events requires that each subject will be consistently 
administered the appropriate dose at specific times, the exact dose time of consecutive subjects 
may be staggered to obviate the need to have all subjects on precisely the same study schedule. 
For each dose, the subject’s actual time will be recorded in the source documents and transcribed 
into the eCRFs. The approximate amount of the high-fat meal consumed by the subject will also 
be recorded. 
 
Each dose will be administered orally with approximately 240 mL of room temperature water. A 
hand and mouth check will be performed to verify that the dose administered was swallowed. 
Fasted doses will be preceded by an overnight fast (i.e., at least 8 hours) from food (not including 
water) and will be followed by a fast from food (not including water) for at least 4 hours 
postdose. For fed dosing, subjects will be required to fast for at least 8 hours until 30 minutes 
prior to their scheduled GDC-9545 dose on Day 1, when they will be given a high-fat meal that 
must be entirely consumed within 30 minutes. Details regarding the high-fat meal are as follows: 
 
Standardized High-Fat Breakfast 
2 eggs fried in butter 
2 strips of bacon 
2 slices of toast with butter 
4 oz of hash brown potatoes (fried with butter) 
8 oz (240 mL) of whole milk 
 


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Except as part of dose administration, subjects will restrict their consumption of water for 1 hour 
prior to dose and for 2 hours postdose; at all other times during the study, subjects may consume 
water ad libitum. 
7.3 REMOVAL OF STUDY BLIND 
Not applicable; this is an open-label study and will not be blinded. 
7.4 ACTIVITY CONTROL 
Subjects will refrain from use of tobacco- or nicotine-containing products (including, but not 
limited to, cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine 
lozenges, and nicotine gum) within 6 months prior to Check-in (Day -1) of Period 1 and during 
the entire study. 
 
Subjects will refrain from strenuous exercise from 7 days prior to Check-in (Day -1) of Period 1 
and during the entire study and will otherwise maintain their normal level of physical activity 
(i.e., will not begin a new exercise program or participate in any unusually strenuous physical 
exertion). 
 
Subjects will remain seated upright and/or ambulatory for 1 hour following each dose 
administered, except as necessitated by the occurrence of an AE(s) and/or study procedures. 
7.5 CONCOMITANT MEDICATIONS 
Concomitant therapy consists of any prescription medications, herbal preparations, vaccines, 
topical medications, or over-the-counter preparations, including herbal or dietary supplements, 
taken by a subject in addition to protocol-mandated treatment at any time from the first dose in 
Period 1 through Follow-up. 
7.5.1 PERMITTED MEDICATIONS 
Acetaminophen (paracetamol) may be administered as needed up to 1 g every 4 to 6 hours 
(maximum 3 g/day). Prune juice may be given for constipation. 
 
The administration of any other concomitant medications during the study is prohibited without 
prior approval of the Investigator, unless its use is deemed necessary in a medical emergency. 
Any medication taken by a subject during the course of the study and the reason for its use will 
be documented in the source documents and the eCRF. 


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7.5.2 PROHIBITED MEDICATIONS 
Subjects will refrain from use of hormone replacement therapy and SERMs (e.g., raloxifene) 
from 1 year prior to Check-in (Day -1) of Period 1 until Follow-up. Subjects must not have any 
history of previous use of tamoxifen, aromatase inhibitors, or any other endocrine agent for the 
treatment of breast cancer. 
 
Subjects may not take oral antibiotics within 4 weeks or intravenous antibiotics within 8 weeks 
prior to Check-in (Day -1) of Period 1 until Follow-up. 
 
Subjects will not have received any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior to Check-in 
(Day -1) of Period 1 until Follow-up. Subjects will not have received any investigational study 
drug within 5 half-lives or 30 days, whichever is longer, prior to Check-in (Day -1) of Period 1 
until Follow-up. 
 
Subjects will refrain from the use of any other prescription medications during the interval from 
14 days prior to Check-in (Day -1) of Period 1 until Follow-up, unless deemed acceptable by the 
Investigator. In addition, subjects will refrain from the use of any over-the-counter 
non-prescription preparations (including vitamins; minerals; and phytotherapeutic-, herbal-, and 
plant-derived preparations) from 7 days prior to Check-in (Day -1) of Period 1 until Follow-up, 
unless deemed acceptable by the Investigator. 
 
Subjects who have taken drugs of abuse (including opioids) within 4 weeks of Screening or 
during the entire study will be excluded from this study. 
7.5.3 PROHIBITED FOOD 
Subjects will abstain from consuming poppy seed-containing foods and beverages for 7 days 
prior to Check-in (Day -1) of Period 1 and during the entire study, unless deemed acceptable by 
the Investigator. Subjects will abstain from consuming alcohol- or caffeine-containing foods and 
beverages for 72 hours prior to Check-in (Day -1) of Period 1 and during the entire study, unless 
deemed acceptable by the Investigator. 
 
With the exception of dosing, as applicable, while confined at the study site, subjects will receive 
a standardized diet at scheduled times that do not conflict with other study-related activities. 
 
See Section 7.2.2 for diet and fluid restrictions in regards to dose administration. 


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7.6 PHARMACOKINETIC BLOOD SAMPLE COLLECTION AND PROCESSING 
Blood samples for PK analysis of GDC-9545 levels will be collected via an indwelling catheter 
and/or via direct venipuncture using Vacutainer evacuated collection tubes. Blood samples will 
be collected at the timepoints listed in Table 7-2. 
 
Processing, storage, and shipping instructions for these PK blood samples are presented in a 
separate laboratory manual. 
 
After the plasma samples collected in the study are analyzed for GDC-9545 concentrations, any 
residual samples may be used for analysis such as metabolite profiling and identification, 
interacting drug concentration measurements, ex vivo protein binding, or development of PK or 
pharmacodynamic assays. Residual PK samples will be destroyed no later than 5 years after the 
final Clinical Study Report has been completed. When a subject withdraws from the study, 
samples collected prior to the date of withdrawal may still be analyzed, unless the subject 
specifically requests in writing that the samples be destroyed or local laws require destruction of 
the samples. However, if samples have been tested prior to withdrawal, results from those tests 
will remain as part of the overall research data. Sample retention may be detailed in the 
laboratory manual. 
7.7 ANALYTICAL METHODOLOGY 
Plasma concentrations of GDC-9545 will be determined by Covance Laboratories Inc. using a 
validated/qualified analytical procedure. 
7.8 CLINICAL LABORATORY EVALUATIONS 
Clinical laboratory evaluations (including chemistry panel [fasted at least 8 hours], CBC, and 
UA) will be collected at the timepoints listed in Table 7-1. Clinical laboratory evaluations are 
listed in Appendix A. 
 
Screens for a hepatitis panel and HIV antibody will be performed at Screening. A drug screen for 
selected drugs of abuse (not including alcohol) will be performed at Screening and repeated (but 
including an alcohol breath test) at Check-in (Day -1) of each period. A qualitative serum 
pregnancy test will be performed at Screening, and a urine pregnancy test will be performed at 
Check-in (Day -1) of each period and Follow-up. A positive urine pregnancy test will be 
confirmed with a serum pregnancy test. If a qualitative serum pregnancy test is positive, then a 
quantitative serum pregnancy test may be performed for confirmation. An FSH test 
(postmenopausal females) will be performed at Screening. 


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Tuberculosis testing will be performed for all subjects at Screening using the following criteria: 
• QuantiFERON® TB Gold is an acceptable Screening assay for latent mycobacterium 
tuberculosis infection 
• An indeterminate QuantiFERON TB Gold test should be repeated. Indeterminate results 
may also be confirmed by a purified protein derivative (PPD) skin test 
o A positive purified PPD tuberculin skin test reaction is considered ≥10 mm (or 
≥5 mm in subjects receiving the equivalent of >15 mg/day of prednisone) 
• A positive QuantiFERON TB Gold test should be considered a positive diagnostic TB 
test 
• An indeterminate QuantiFERON TB Gold test followed by a negative QuantiFERON TB 
Gold test should be considered a negative diagnostic TB test 
• If a negative TB test has been documented within 3 months of Screening, no new test is 
needed. 
7.9 SAMPLES FOR THE RESEARCH BIOSAMPLE REPOSITORY 
7.9.1 OVERVIEW OF THE RESEARCH BIOSAMPLE REPOSITORY 
The RBR is a centrally administered group of facilities used for the long-term storage of human 
biologic specimens, including body fluids, solid tissues, and derivatives thereof (e.g., DNA, 
RNA, proteins, and/or peptides). The collection, storage, and analysis of RBR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of diagnostic 
tests, which may allow for individualized drug therapy for subjects in the future. 
 
Specimens for the RBR will be collected from subjects who give specific consent to participate 
in this research. The RBR specimen will be analyzed to achieve one or more of the following 
objectives: 
• To study the association of biomarkers with efficacy, AEs, or disease progression 
• To increase knowledge and understanding of disease biology 
• To study drug response, including drug effects and the processes of drug absorption and 
disposition 
• To develop biomarker or diagnostic assays and establish the performance characteristics 
of these assays. 


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7.9.2 APPROVAL BY THE INSTITUTIONAL REVIEW BOARD OR ETHICS 
COMMITTEE 
Collection and submission of biological samples to the RBR is contingent upon the review and 
approval of the exploratory research and the RBR portion of the ICF by each site’s Institutional 
Review Board (IRB)/Ethics Committee (EC) and, if applicable, an appropriate regulatory body. 
If a site has not been granted approval for RBR sampling, Section 7.9 through Section 7.9.7 of 
this protocol will not be applicable at that site. 
7.9.3 MANDATORY SAMPLES FOR COLLECTION 
A mandatory whole blood sample will be collected for DNA extraction for RBR and may be sent 
to one or more laboratories for analysis. 
 
For sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual. 
 
The RBR specimens will be stored until they are no longer needed or until they are exhausted. 
However, the RBR storage period will be in accordance with the IRB/EC-approved ICF and 
applicable laws (e.g., health authority requirements). When a subject withdraws from the study, 
samples collected prior to the date of withdrawal may still be analyzed, unless the subject 
specifically requests in writing that the samples be destroyed or local laws require destruction of 
the samples. However, if samples have been tested prior to withdrawal, results from those tests 
will remain as part of the overall research data. 
7.9.4 CONFIDENTIALITY 
Specimens and associated data will be labeled with a unique subject identification number. 
 
Subject medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the subject, unless permitted or required by 
law. 
 
Given the complexity and exploratory nature of the analyses, data derived from RBR specimens 
will generally not be provided to study Investigators or subjects unless required by law. The 
aggregate results of any conducted research will be available in accordance with the effective 
Sponsor policy on study data publication. 
 


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Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, representatives, 
and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of the RBR data will become and remain the exclusive and unburdened property of the Sponsor, 
except where agreed otherwise. 
7.9.5 CONSENT TO PARTICIPATE IN THE RESEARCH BIOSAMPLE 
REPOSITORY 
The ICF will contain a separate section that addresses participation in the RBR. The Investigator 
or authorized designee will explain to each subject the objectives, methods, and potential hazards 
of participation in the RBR. Subjects will be told that they are free to refuse to participate and 
may withdraw their specimens at any time and for any reason during the storage period (the 
withdrawal of their RBR specimen will coincide with withdrawal from the study; Section 7.9.6). 
A separate, specific signature will be required to document a subject’s agreement to provide an 
RBR specimen. 
The Investigator (or authorized designee) should document whether or not the subject has given 
consent to participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant’s death or loss of competence, the participant’s specimens and 
data will continue to be used as part of the RBR research. 
7.9.6 WITHDRAWAL FROM THE RESEARCH BIOSAMPLE REPOSITORY 
Subjects who give consent to provide RBR specimens have the right to withdraw their specimens 
from the RBR at any time and for any reason. After withdrawal of consent, any remaining 
samples will be destroyed or will no longer be linked to the subject. If a subject wishes to 
withdraw consent to the testing of their specimens, the Investigator must inform the Medical 
Monitor in writing of the subject’s wishes and the Investigator (or authorized designee) must 
complete the RBR Subject Withdrawal Form and, if the trial is ongoing, must enter the date of 
withdrawal on the RBR Research Sample Withdrawal of Informed Consent eCRF. The subject 
will be provided with instructions on how to withdraw consent after the trial is closed. A 
subject’s withdrawal from this study does not, by itself, constitute withdrawal of specimens from 
the RBR. 


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7.9.7 MONITORING AND OVERSIGHT 
The RBR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality as well as adherence to 
authorized use of specimens as specified in this protocol and in the ICF. Sponsor monitors and 
auditors will have direct access to appropriate parts of records relating to subject participation in 
the RBR for the purposes of verifying the data provided to the Sponsor. The site will permit 
monitoring, audits, IRB/EC review, and health authority inspections by providing direct access 
to source data and documents related to the RBR samples. 
7.10 
12-LEAD ELECTROCARDIOGRAMS 
A single 12-lead ECG will be obtained at the timepoints specified in Table 7-1. 
 
To minimize variability in autonomic tone and heart rate, subjects will rest quietly and in a 
supine position for at least 5 minutes prior to recording the ECG. Blood draws, other procedures, 
activity, and environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and between ECG recordings to minimize variability due to 
the effects of activity and stress on cardiac electrophysiology. Whenever possible, ECG tracings 
for each subject should be obtained from the same type of machine throughout the study. 
 
When 12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the 12-lead ECGs will be obtained as close to the 
scheduled blood draw as possible, but prior to the blood draw. 
7.11 
VITAL SIGNS 
Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse) 
will be obtained at the timepoints specified in Table 7-1. 
 
Supine blood pressure and pulse will be obtained after the subject has been supine for at least 
5 minutes. When vital signs are scheduled at the same time as blood draws, the blood draws will 
be obtained at the scheduled timepoint, and the vital signs will be obtained as close to the 
scheduled blood draw as possible, but prior to the blood draw. 
7.12 
HOW DO YOU FEEL? INQUIRY 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified in 


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Table 7-1. Subjects will also be encouraged to voluntarily report AEs occurring at any other time 
during the study. See Section 8.3 and Section 8.4 for reporting requirements for AEs and SAEs, 
respectively. 
7.13 
PHYSICAL EXAMINATIONS 
A routine or abbreviated physical examination will be performed at the timepoints specified in 
Table 7-1. 
 
A routine physical examination will consist of an assessment of general appearance; skin; 
thorax/lungs; abdomen; lymph nodes; head; ears; eyes; nose; throat; neck (including thyroid); 
and cardiovascular, musculoskeletal, and neurological systems. An abbreviated physical 
examination will consist of an assessment of general appearance, skin, thorax/lungs, 
cardiovascular system, and abdomen. 
7.14 
CLINIC DISCHARGE PROCEDURES 
Refer to Table 7-1 for procedures performed on the day of discharge. 
7.15 
FOLLOW-UP/EARLY TERMINATION PROCEDURES 
Refer to Table 7-1 for procedures performed at Follow-up or ET. 
8 ADVERSE EXPERIENCES 
8.1 SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and AESIs, 
performing protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. The Sponsor or its designee is responsible for reporting relevant SAEs to 
the competent authority, other applicable regulatory authorities, and participating Investigators, 
in accordance with International Conference on Harmonisation/International Council for 
Harmonisation (ICH) guidelines, Food and Drug Administration (FDA) regulations, European 
Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory requirements. 
 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 8.4. 


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8.1.1 ADVERSE EVENTS 
According to the ICH Guideline for GCP, an AE is any untoward medical occurrence in a 
clinical investigation subject administered a pharmaceutical product, regardless of causal 
attribution. An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., Screening invasive procedures such as 
biopsies). 
8.1.2 SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO THE 
SPONSOR) 
An SAE is any AE that meets any of the following criteria: 
• Is fatal (i.e., the AE actually causes or leads to death) 
• Is life-threatening (i.e., the AE, in the view of the Investigator, places the subject at 
immediate risk of death); this does not include any AE that had it occurred in a more 
severe form or was allowed to continue might have caused death 
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug 
• Is a significant medical event in the Investigator’s judgment (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes listed 
above). 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 


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The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(e.g., rated as mild, moderate, or severe, according to National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE]); the event itself may be of relatively 
minor medical significance (such as severe headache) without any further findings. An event 
should be considered “serious” only if it meets the regulatory criteria outlined in the 
above-mentioned paragraph outlining seriousness criteria. 
 
Seriousness (not severity) serves as the guide for defining regulatory reporting obligations. 
 
Severity and seriousness need to be independently assessed for each AE recorded on the eCRF. 
 
Serious AEs are required to be reported by the Investigator to the Sponsor via Covance Patient 
Safety Solutions (PSS) immediately (i.e., no more than 24 hours after learning of the event; see 
Section 8.4.2 for reporting instructions). 
8.1.3 ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the Investigator to the Sponsor 
via Covance PSS immediately (i.e., no more than 24 hours after learning of the event; see 
Section 8.4.2 for reporting instructions). Adverse events of special interest for this study are as 
follows: 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s Law 
(see Section 8.3.1.6) 
• Suspected transmission of an infectious agent by the study drug as defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a subject exposed to a medicinal product. The term applies only when a 
contamination of the study drug is suspected 
• Grade ≥3 nausea/vomiting/diarrhea 
• Grade ≥2 thromboembolic events (pulmonary embolism, deep vein thrombosis, and 
embolism) 
• Grade ≥3 renal failure (including acute kidney injury or other similar medical concepts) 
• Grade ≥3 hepatitis or elevation in ALT or AST 
• Grade ≥2 vaginal or uterine hemorrhage 


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• Grade ≥2 bradycardia 
• Any grade of endometrial cancer. 
8.2 METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS 
The Investigator is responsible for ensuring that all AEs (as defined in Section 8.1) are recorded 
on the AE eCRF in accordance with protocol instructions (see Section 8.4.2). 
 
For each AE recorded on the AE eCRF, the Investigator will make an assessment of seriousness 
(see Section 8.1.2 for seriousness criteria), severity (see Section 8.2.3), and causality (see 
Section 8.2.4). 
8.2.1 ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each subject contact. All AEs, whether reported by 
the subject or noted by study personnel, will be recorded in the subject’s medical record and on 
the AE eCRF. 
 
After informed consent has been obtained but prior to initiation of study drug administration, 
only SAEs caused by a protocol-mandated intervention (e.g., discontinuation of medications) 
will be reported (see Section 8.4.2 for instructions for reporting SAEs). After initiation of study 
drug administration, all AEs will be recorded throughout the study until Follow-up (defined as 
12 to 14 days after the last dose of GDC-9545). The Sponsor should be notified if the 
Investigator becomes aware of any SAE that occurs after the follow-up period (defined as 12 to 
14 days after the last dose of GDC-9545) if the event is believed to be related to prior study drug 
treatment. 
 
Instructions for reporting AEs that occur after the AE reporting period are provided in 
Section 8.6. 
 
The Investigator is not required to actively monitor subjects after the study has ended or for AEs 
after the end of the AE reporting period (defined as until Follow-up, 12 to 14 days after the final 
dose of study drug). However, the Sponsor should be notified if the Investigator becomes aware 
of any death, other SAEs, or AESIs occurring after the end of the AE reporting period that are 
believed to be related to prior study drug treatment. The Sponsor should also be notified if the 
Investigator becomes aware of the development of cancer or a congenital anomaly/birth defect in 
a subsequently conceived offspring of a female subject exposed to study drug. 


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8.2.2 ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all subject evaluation timepoints. Examples of non-directive questions include the 
following: 
•
“How have you felt since your last clinic visit?”
•
“Have you had any new or changed health problems since you were last here?”
8.2.3 ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The AE severity grading scale for the NCI CTCAE (version 5.0) will be used for assessing AE 
severity. Table 8-1 will be used for assessing AE severity for AEs that are not specifically listed 
in the NCI CTCAE. 
Table 8-1 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily livinga 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily 
livingb,c 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to adverse eventd 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by subjects who are not bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as an SAE (see Section 8.4.2 for 
reporting instructions), per the definition of SAE in Section 8.1.2. 
d Grade 4 and 5 events must be reported as SAEs (see Section 8.4.2 for reporting instructions), per the definition of 
SAE in Section 8.1.2. 
8.2.4 ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether an AE is considered to 


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be related to the study drug, indicating “yes” or “no” accordingly. The following guidance 
should be taken into consideration (see also Table 8-2): 
•
Temporal relationship of event onset to the initiation of study drug
•
Course of the event, with special consideration of the effects of dose reduction,
discontinuation of study drug, or reintroduction of study drug (as applicable)
•
Known association of the event with the study drug or with similar treatments
•
Known association of the event with the disease under study
•
Presence of risk factors in the subject or use of concomitant medications known to
increase the occurrence of the event
•
Presence of non-treatment-related factors that are known to be associated with the
occurrence of the event.
Table 8-2 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug based on facts, evidence, science-based rationales, 
and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and administration of 
the study drug, and the adverse event cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of 
response to the study drug; and/or the adverse event abates or resolves upon discontinuation of the 
study drug or dose reduction and, if applicable, reappears upon re-challenge. 
Investigators should apply facts, evidence, or rationales based on scientific principles and clinical 
judgment to support a causal/contributory association with a study drug. 
NO 
Adverse events will be considered related, unless they fulfill the criteria as specified below. 
Evidence exists that the adverse event has an etiology other than the study drug (e.g., pre-existing 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the 
adverse event has no plausible temporal relationship to administration of the study drug (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
Note:  The Investigator’s assessment of causality for individual adverse event reports is part of the 
study documentation process. Regardless of the “Yes” or “No” causality assessment for individual 
adverse event reports, the Sponsor will promptly evaluate all reported serious adverse events against 
cumulative product experience to identify and expeditiously communicate possible new safety findings 
to Investigators and applicable regulatory authorities. Attribution of serious adverse events will be 
reviewed on an ongoing basis, and may be changed as additional clinical data emerges (e.g., 
reversibility of adverse event, new clinical findings in subject with adverse event, effects of 
re-treatment, and adverse events in other subjects). 
8.3 PROCEDURES FOR RECORDING ADVERSE EVENTS 
8.3.1 RECORDING ADVERSE EVENTS ON THE CASE REPORT FORM 
Investigators should use correct medical terminology/concepts when recording AEs on the AE 
eCRF. Colloquialisms and abbreviations should be avoided. 


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All AEs should be recorded on the AE eCRF page. If the AE qualifies as an SAE or non-serious 
AESI, the Investigator should record all case details that can be gathered immediately (i.e., 
within 24 hours after learning of the event) on a paper Clinical Trial SAE/AESI Reporting Form 
to Covance PSS within 24 hours of learning of the event (see Section 8.4.2). The AE and SAE 
eCRF should also be completed within this timeframe. It is important that the information on the 
SAE Reporting Form and AE and SAE eCRF is consistent and identical. 
 
Only one AE term should be recorded in the event field on the AE eCRF. 
8.3.1.1 DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
If known, a diagnosis should be recorded on the AE eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded on the AE eCRF. If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by one AE report 
based on the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
8.3.1.2 ADVERSE EVENTS THAT ARE SECONDARY TO OTHER EVENTS 
In general, AEs that are secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events. A medically significant secondary AE that is separated in time from the initiating event 
should be recorded as an independent event on the AE eCRF. For example: 
• If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF. 
• If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• If dizziness leads to a fall and subsequent fracture, all three events should be reported 
separately on the eCRF. 
• If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF. 
 
All AEs should be recorded separately on the AE eCRF if it is unclear as to whether the events 
are associated. 


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8.3.1.3 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
timepoints. Such events should only be recorded once in the AE eCRF. The initial severity 
(intensity or grade) of the event will be recorded at the time the event is first reported. If a 
persistent AE becomes more severe, the most extreme severity should also be recorded on the 
AE eCRF. If the event becomes serious, it should be reported to Covance PSS immediately (i.e., 
no more than 24 hours after learning that the event became serious; see Section 8.4.2 for 
reporting instructions). The AE eCRF should be updated by changing the event from 
“non-serious” to “serious,” providing the date that the event became serious, and completing all 
data fields related to SAEs. 
 
A recurrent AE is one that resolves between subject evaluation timepoints and subsequently 
recurs. Each recurrence of an AE should be recorded as a separate event on the AE eCRF. 
8.3.1.4 ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be reported 
as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• Is clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 times the upper limit of normal [ULN] associated with cholestasis), 
only the diagnosis (i.e., cholestasis) should be recorded on the AE eCRF. 
 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the AE eCRF, along with a descriptor indicating 
whether the test result is above or below the normal range (e.g., “elevated potassium,” as 
opposed to “abnormal potassium”). If the laboratory abnormality can be characterized by a 


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precise clinical term per standard definitions, the clinical term should be recorded as the AE. For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the AE eCRF (see Section 8.3.1.3 for details on recording persistent 
AEs). 
8.3.1.5 ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as an 
AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Is clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the AE eCRF. 
 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the AE eCRF (see Section 8.3.1.3 for details on recording persistent 
AEs). 
8.3.1.6 ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST (>3 × ULN) in combination with either an elevated total 
bilirubin (>2 × ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by Hy’s 
Law). Therefore, Investigators must report the occurrence of either of the following as an AE: 
• Treatment-emergent ALT or AST >3 × ULN in combination with total bilirubin 
>2 × ULN 
• Treatment-emergent ALT or AST >3 × ULN in combination with clinical jaundice. 
 


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the AE eCRF (see Section 8.3.1) and reported to Covance PSS 
immediately (i.e., no more than 24 hours after learning of the event), either as an SAE or an 
AESI (see Section 8.4.2). 
8.3.1.7 ACCIDENTAL OVERDOSE OR MEDICATION ERROR 
Accidental overdose and medication error (hereafter collectively referred to as “special 
situations”) are defined as follows: 
• Accidental overdose:  accidental administration of a drug in a quantity that is higher than 
the assigned dose 
• Medication error:  accidental deviation in the administration of a drug. 
 
In some cases, a medication error may be intercepted prior to administration of the drug. 
 
Special situations are not in themselves AEs, but may result in AEs. Each AE associated with a 
special situation should be recorded separately on the AE eCRF. If the associated AE fulfills 
seriousness criteria, the event should be reported to Covance PSS immediately (i.e., no more than 
24 hours after learning of the event; see Section 8.4.2). For GDC-9545, AEs associated with 
special situations should be recorded as described below for each situation: 
• Accidental overdose:  Enter the AE term. Check the “Accidental overdose” and 
“Medication error” boxes. 
• Medication error that does not qualify as an overdose:  Enter the AE term. Check the 
“Medication error” box. 
• Medication error that qualifies as an overdose:  Enter the AE term. Check the “Accidental 
overdose” and “Medication error” boxes. 
 
In addition, all special situations associated with GDC-9545, regardless of whether they result in 
an AE, should be recorded on the AE eCRF and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event). Special situations should be recorded as 
described below: 
• Accidental overdose:  Enter the drug name and “accidental overdose” as the event term. 
Check the “Accidental overdose” and “Medication error” boxes. 
• Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong dosing 
schedule, incorrect route of administration, wrong drug, expired drug administered) as the 
event term. Check the “Medication error” box. 


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• Medication error that qualifies as an overdose:  Enter the drug name and “accidental 
overdose” as the event term. Check the “Accidental overdose” and “Medication error” 
boxes. Enter a description of the error in the additional case details. 
• Intercepted medication error:  Enter the drug name and “intercepted medication error” as 
the event term. Check the “Medication error” box. Enter a description of the error in the 
additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require the completion 
of two AE eCRF pages, one to report the accidental overdose and one to report the headache. 
The “Accidental overdose” and “Medication error” boxes would need to be checked on both 
eCRF pages. 
8.3.1.8 DEATHS 
All deaths that occur during the protocol-specified AE reporting period (see Section 8.2.1), 
regardless of relationship to study drug, will be recorded on the AE eCRF as well as on the paper 
Clinical Trial SAE Reporting Form and immediately reported to the Sponsor via Covance PSS 
(see Section 8.4.2 for reporting instructions). 
 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the AE eCRF. Generally, only one such event should be reported. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, “unexplained death” should be 
recorded on the AE eCRF. If the cause of death later becomes available (e.g., after autopsy), 
“unexplained death” should be replaced by the established cause of death. The term “sudden 
death” should not be used unless combined with the presumed cause of death (e.g. “sudden 
cardiac death”). 
 
Deaths that occur after the AE reporting period should be reported as described in Section 8.6. 
8.3.1.9 PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing medical condition is one that is present at the Screening visit for this study. Such 
conditions should be recorded on the General Medical History and Baseline Conditions eCRF 
page. 
 
A pre-existing medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on an AE 


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eCRF, it is important to convey the concept that the pre-existing condition has changed by 
including applicable descriptors (e.g., “accelerated worsening of headaches”). 
8.3.1.10 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE in 
Section 8.1.2) except as outlined below. 
 
An event that leads to hospitalization under the following circumstances should not be reported 
as an AE or SAE: 
• Hospitalization for respite care 
• Hospitalization for a pre-existing condition, provided that all of the following criteria are 
met: 
o The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease. 
o The subject has not experienced an AE. 
 
An event that leads to hospitalization under the following circumstances is not considered to be 
an SAE but should be reported as an AE instead: 
• Hospitalization that was necessary because of the subject’s requirement for outpatient 
care outside of normal outpatient clinic operation hours. 
8.4 IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO 
SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial. The Investigator must report such events to the 
Sponsor immediately via Covance PSS; under no circumstances should reporting take place 
more than 24 hours after the Investigator learns of the event. The following is a list of events that 
the Investigator must report to the Sponsor within 24 hours (see Section 8.4.2) after learning of 
the event, regardless of relationship to study drug: 
• SAEs (see Section 8.4.2 for further details) 
• AESIs (see Section 8.1.3 for further details) 
• Pregnancies (see Section 8.4.2.3 for further details). 
 


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For SAEs and AESIs, the Investigator must report new significant follow-up information for 
these events to the Sponsor immediately via Covance PSS (i.e., no more than 24 hours after 
becoming aware of the information). New significant information includes the following: 
•
New signs or symptoms or a change in the diagnosis
•
Significant new diagnostic test results
•
Change in causality based on new information
•
Change in the event’s outcome, including recovery
•
Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
8.4.1 REPORTING REQUIREMENTS FOR FATAL OR LIFE-THREATENING 
SERIOUS ADVERSE EVENTS 
Any life-threatening (e.g., imminent risk of death) or fatal AE that is attributed by the 
Investigator to study drug will be telephoned to the Medical Monitor immediately, followed by 
completion of the paper Clinical Trial SAE Reporting Form within 24 hours of learning of the 
event as described in Section 8.4.2. 
Medical Monitor: 
, M.D., Ph.D. 
Genentech, Inc. 
 (Office Telephone No.)
 (Mobile Telephone No.)
8.4.2 REPORTING REQUIREMENTS FOR ALL SERIOUS ADVERSE EVENTS 
8.4.2.1 EVENTS THAT OCCUR PRIOR TO STUDY DRUG INITIATION 
After informed consent has been obtained but prior to initiation of study drug, only SAEs caused 
by protocol-mandated intervention should be reported. The completed paper Clinical Trial 
SAE/AESI Reporting Form provided to the Investigator should be completed and submitted to 
the Sponsor via Covance PSS immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or email 
address provided below. 
Covance PSS to receive the Investigator-generated SAE reports: 
Email:  saeintake@covance.com 
Fax:  1-888-887-8097 


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8.4.2.2 EVENTS THAT OCCUR AFTER STUDY DRUG INITIATION 
After initiation of study drug, SAEs and AESIs will be reported after Follow-up (12 to 14 days 
after the final dose of study drug). Investigators should record all case details that can be 
gathered immediately on a paper Clinical Trial SAE/AESI Reporting Form. The completed paper 
Clinical Trial SAE/AESI Reporting Form should be completed and submitted to the Sponsor (via 
Covance PSS) immediately (i.e., no more than 24 hours after learning of the event), either by 
faxing or by scanning and emailing the form using the fax number or email address provided in 
Section 8.4.2.1. All information will also need to be entered into the AE eCRF. 
 
Relevant follow-up information should be submitted to Covance PSS on an updated paper 
Clinical Trial SAE/AESI Reporting Form as soon as it becomes available and/or upon request. 
Any updates to the paper Clinical Trial SAE/AESI Reporting Form must also be updated in 
electronic data capture (EDC) on the AE eCRF. 
8.4.2.3 REPORTING REQUIREMENTS FOR PREGNANCIES 
8.4.2.3.1 
PREGNANCIES IN FEMALE SUBJECTS 
Female subjects will be instructed to immediately inform the Investigator if they become 
pregnant during the study or within 90 days after the final dose of study drug. A paper Clinical 
Trial Pregnancy Reporting Form should be completed by the Investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and emailed to Covance PSS (see 
Section 8.4.2 for reporting instructions). Pregnancy should not be recorded on the AE eCRF. The 
Investigator should discontinue study drug and counsel the subject, discussing the risks of the 
pregnancy and the possible effects on the fetus. Monitoring of the subject should continue until 
conclusion of the pregnancy. Any SAEs associated with the pregnancy (e.g., an event in the 
fetus, an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect 
in the child) should be reported on the AE eCRF. In addition, the Investigator will submit a paper 
Clinical Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available. 
8.4.2.3.2 
CONGENITAL ANOMALIES/BIRTH DEFECTS AND ABORTIONS 
Any congenital anomaly/birth defect in a child born to a female subject exposed to the study 
drug should be classified as an SAE, recorded on the AE eCRF, and reported to the Sponsor 
immediately via Covance PSS (i.e., no more than 24 hours after learning of the event; see 
Section 8.4.2). Any abortion should be reported in the same fashion (as the Sponsor considers 
abortions to be medically significant events). All abortions should be reported as pregnancy 
outcomes on the paper Clinical Trial Pregnancy Reporting Form. 


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8.5 FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
8.5.1 INVESTIGATOR FOLLOW-UP 
The Investigator should follow each AE until the event has resolved to baseline grade or better, 
the event is assessed as stable by the Investigator, the subject is lost to follow-up, or the subject 
withdraws consent. Every effort should be made to follow all SAEs considered to be related to 
study drug or trial-related procedures until a final outcome can be reported. During the study 
period, resolution of AEs (with dates) should be documented on the AE eCRF and in the 
subject’s medical record to facilitate source data verification. 
 
All pregnancies reported during the study should be followed until pregnancy outcome. 
8.5.2 SPONSOR FOLLOW-UP 
For SAEs, AESIs, and pregnancies, the Sponsor or a designee may follow-up by telephone, fax, 
email, and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
8.6 ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT REPORTING 
PERIOD 
At the Follow-up/ET visit, the Investigator should instruct each subject to report to the 
Investigator any subsequent AEs that the subject’s personal physician believes could be related 
to prior study drug treatment or study procedures. The Sponsor should be notified if the 
Investigator becomes aware of any SAE that occurs after the end of the AE reporting period 
(defined as until Follow-up, 12 to 14 days after the final dose of study drug) if the event is 
believed to be related to prior study drug treatment. 
 
These events should be reported through the use of the AE eCRF. However, if the EDC system is 
not available, the Investigator should report these events directly to the Sponsor or its designee, 
by faxing or by scanning and emailing the paper Clinical Trial SAE/AESI Reporting Form using 
the below fax number or email address provided to Investigators. 
 
Genentech United Kingdom Drug Safety 
Email Address: 
welwyn.uk_dsc@roche.com 
Fax No.: 
 
44 1707 367 582 


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8.6.1 EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, 
INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and AESIs against cumulative product experience 
to identify and expeditiously communicate possible new safety findings to Investigators, IRBs, 
ECs, and applicable health authorities based on applicable legislation. 
 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference document(s): 
 
• GDC-9545 IB 
 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
 
Reporting requirements will also be based on the Investigator’s assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
 
The IRB will be notified by the investigative site in writing (e.g., email) within the timeframe 
required per local IRB regulations when a reportable AE is first recognized or reported. In 
addition, a copy of the written confirmation or summary of the AE, as submitted to the Sponsor, 
will also be submitted to the IRB within that same timeframe from when the AE is first 
recognized or reported. The IRB Serious and Unexpected AE Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
9 STATISTICAL ANALYSES 
The Safety Population will consist of all subjects who received at least one dose of study drug. 
 
The PK Population will consist of all subjects who received at least one dose of study drug and 
have at least one evaluable postdose PK sample. 
 
Baseline is defined as the last result prior to the first dose of study drug on Period 1 Day 1. As 
necessary, baseline will be further defined in the Statistical Analysis Plan (SAP). 


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9.1 SAFETY AND TOLERABILITY ANALYSIS 
Safety will be assessed by a review of AEs, clinical laboratory assessments, vital signs, and 
ECGs. Clinical laboratory assessments, vital signs (including oral temperature, respiratory rate, 
and supine blood pressure and pulse), and ECGs will be listed by subject number and scheduled 
time, and changes from baseline will be summarized. 
 
Verbatim descriptions of AEs will be coded according to current Medical Dictionary for 
Regulatory Activities version 22.0 (or higher) guidelines. Adverse events will be summarized. 
Enrollment and discontinuations from the study will be summarized overall. Demographics and 
baseline characteristics such as age, sex, and BMI will be summarized overall. 
9.2 PHARMACOKINETIC ANALYSIS 
The following PK parameters will be derived from the plasma concentrations of GDC-9545 
using the model independent approach (Gibaldi and Perrier 1982): 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal 
rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations 
AUC0-∞ 
area under the concentration-time curve from Hour 0 extrapolated 
to infinity, calculated using the formula: 
AUC0-∞ = AUC0-t + 
z
t
λ
C  
where Ct is the last measurable concentration and λz is the apparent 
terminal elimination rate constant 
λz 
apparent terminal elimination rate constant, where λz is the 
magnitude of the slope of the linear regression of the log 
concentration versus time profile during the terminal phase 
t1/2 
apparent terminal elimination half-life (whenever possible), where 
t1/2 = (ln2)/λz 
CL/F 
apparent total clearance 
VZ/F 
apparent volume of distribution during the terminal elimination 
phase 
 


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Pharmacokinetic calculations will be performed, if appropriate, using commercial software such 
as Phoenix WinNonlin (Certara Inc., version 8.1 or higher). 
 
Other parameters may be added as appropriate. Final PK parameters reported will be detailed in 
the SAP. 
 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. Other data handling 
procedures will be detailed in the SAP. 
9.3 INTERIM ANALYSIS 
No interim analyses are planned 
9.4 STATISTICAL ANALYSIS OF PHARMACOKINETIC DATA 
Descriptive statistics (mean, median, minimum, maximum, standard deviation, coefficient of 
variation [CV%], geometric mean, and geometric CV%) will be calculated for all PK parameters 
for GDC-9545. 
 
The PK parameters Cmax, AUC0-t, and AUC0-∞ for GDC-9545 will be analyzed to evaluate the 
relative bioavailability of GDC-9545 as a Phase 3 capsule formulation compared to a Phase 1 
tablet formulation under fasted conditions and to assess the food effect on GDC-9545 PK for a 
Phase 3 capsule formulation. The mixed-effect analysis of variance model for three-period 
crossover design will be used for formulation comparison and fasted state and fed state 
comparison of capsule. The model will include sequence, formulation, and period as fixed effects 
and a random effect for subject within sequence. Appropriate covariance structure will be used. 
 
Log transformed Cmax, AUC0-t, and AUC0-∞ values will be evaluated to estimate ratios of 
geometric mean values and the corresponding 90% confidence intervals (CIs). (Relative 
bioavailability-Test:  capsule, Reference:  tablet; food effect-Test:  fed, Reference:  fasted.) 
 
The parameter tmax will be analyzed nonparametrically using the Wilcoxon signed-rank test. The 
median difference between the test and reference investigational products and the corresponding 
90% CI will be calculated. 
 
Caution should be used when interpreting results since this study was not based on power 
calculations. 
 
All calculations will be performed using SAS version 9.4 or greater. 


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Specification of PK parameters for analysis; statistical level of significance to be used; criteria 
for study termination; procedures for accounting for missing, unused, or spurious data; 
procedures for reporting deviations from the original statistical plan; and selection of subjects to 
be included in the analyses population(s) will be presented in the Clinical Study Report (CSR) 
and/or SAP as appropriate. 
9.5 STATISTICAL ANALYSES OF SAFETY DATA 
All safety data will be listed and summarized using standard descriptive statistics for the Safety 
Population. No formal statistical analyses are planned. 
9.6 SAMPLE SIZE 
The sample size chosen for this study was based upon precedent set by other PK studies of 
similar nature and was not based on power calculations. Eighteen subjects will be enrolled so 
that a minimum of 12 subjects will complete the study without the need for replacement subjects. 
9.7 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control and quality assurance will be performed in Data Management according to 
Covance standard operating procedures (SOPs) or per client request and as applicable according 
to the contract between Covance and the Sponsor, including but not limited to Covance’s 
validated EDC system, specifications, and quality checks. 
10 ADMINISTRATIVE ASPECTS 
10.1 
CHANGE IN PROTOCOL 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator. 
 
There will be no alterations in the protocol affecting subject safety without the express written 
approval of the Sponsor, Investigator, and the IRB (see Form FDA 1572). 
10.2 
INVESTIGATOR MEETING; SITE INITIATION 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator(s) and appropriate clinical staff to familiarize the Investigator and clinical staff with 
the materials necessary for conducting the clinical study. 


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10.3 
DISCLOSURE 
All information provided regarding the study, as well as all information collected and 
documented during the course of the study, will be regarded as confidential. The Investigator 
agrees not to disclose such information in any way without prior written permission from the 
Sponsor. 
 
Any publication of the results, either in part or in total (e.g., articles in journals or newspapers, 
oral presentations, abstracts) by the Investigator(s) or their representative(s), shall require prior 
notification and review, within a reasonable timeframe, by the Sponsor, and cannot be made in 
violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property rights. 
10.4 
MONITORING (CLINICAL RESEARCH ASSOCIATE) 
The Sponsor will designate a Sponsor’s Study Monitor who will be responsible for monitoring 
this clinical trial. The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF and 
source documentation completion and retention, and accurate study drug accountability. To this 
end, the Sponsor’s Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. It is essential that the Sponsor’s Study 
Monitor have access to all documents, including study data, subject medical records, and eCRFs, 
at any time these are requested. In turn, the Sponsor’s Study Monitor will adhere to all 
requirements for subject confidentiality as outlined in the ICF. The Investigator and 
Investigator’s staff will be expected to cooperate with the Sponsor’s Study Monitor, to be 
available during a portion of the monitoring visit to answer questions, and to provide any missing 
information. 
10.5 
INSTITUTIONAL REVIEW BOARD 
In accordance with 21 CFR 56, the protocol, advertisement, and ICF will be reviewed and 
approved by the IRB. The Sponsor will supply relevant material for the Investigator to submit to 
the IRB for the protocol’s review and approval. Verification of the IRB unconditional approval 
of the protocol and the written ICF statement will be transmitted to the Investigator. 
 
The IRB will be informed by the Investigator of subsequent protocol amendments and of serious 
and unexpected AEs. Approval for protocol amendments will be transmitted in writing to the 
Investigator. If requested, the Investigator will permit audits by the IRB and regulatory 
inspections by providing direct access to source data and documents. 
 


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The Investigator will provide the IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a Study Progress Report following the completion, termination, or 
discontinuation of the Investigator’s participation in the study. 
10.6 
INFORMED CONSENT 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the protocol) 
by the IRB and will be acceptable to the Sponsor. 
 
The Investigator or designee will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can withdraw 
from the study at any time. In accordance with 21 CFR 50, the informed consent process shall be 
documented by the use of a written ICF approved by the IRB and signed by the subject prior to 
protocol-specific procedures being performed. 
 
The subject will sign two copies of the ICF. One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 
10.7 
RECORDS 
The results from Screening and data collected during the study will be recorded in the subject’s 
eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
 
The completed eCRFs will be transferred to the Sponsor or designee. Copies of each eCRF will 
be retained by the Investigator. All source documents, records, and reports will be retained by the 
study site in accordance with 21 CFR 312.62(c). 
 
All primary data, or copies thereof (e.g., laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report, will be 
retained in the study site archives. 
10.7.1 ELECTRONIC CASE REPORT FORMS 
Electronic Case Report Forms are to be completed using the Medidata RAVE EDC system. The 
site will receive training and have access to a manual for appropriate eCRF completion. 
Electronic Case Report Forms will be submitted electronically to Covance and should be handled 
in accordance with instructions from Genentech/Covance. All eCRFs should be completed by 
designated, trained examining personnel as appropriate. 


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The results from Screening and data collected during the study will be recorded in the subject’s 
eCRF. To maintain confidentiality, the subjects will be identified only by numbers. The 
Investigator will ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the eCRF by providing an electronic signature. The completed eCRFs will be 
transferred to the Sponsor or designee. 
 
In addition, at the end of the study, the Investigator will receive subject data for the site in a 
readable format (e.g., a compact disc) that must be kept with the study records. 
10.7.2 SOURCE DATA DOCUMENTATION 
Study Monitors will perform ongoing source data verification and review to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents. 
 
Source documents (paper or electronic) are those in which subject data are recorded and 
documented for the first time. They include, but are not limited to, hospital records; clinical and 
office charts; laboratory notes; memoranda; subject diaries or evaluation checklists; pharmacy 
dispensing records; recorded data from automated instruments; copies of transcriptions that are 
certified after verification as being accurate and complete; microfiche; photographic negatives; 
microfilm or magnetic media; X-rays; subject files; and records kept at the pharmacy, 
laboratories, and medico-technical departments involved in a clinical trial. Source documents 
that are required to verify the validity and completeness of data entered into the eCRFs must 
never be obliterated or destroyed. To facilitate source data verification and review, the 
Investigator and institution(s) must provide the Sponsor direct access to applicable source 
documents and reports for trial-related monitoring, Sponsor audits, and IRB/EC review. The 
study site must also allow inspection by applicable health authorities. 
10.7.3 USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical record 
system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with FDA requirements pertaining to 
computerized systems used in clinical research. An acceptable computerized data collection 
system (for clinical research purposes) would be one that (1) allows data entry only by 
authorized individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the database 
from tampering; and (4) ensures data preservation. 


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In collaboration with the Study Monitor, Genentech’s or Covance’s Quality Assurance group 
may assist in assessing whether electronic records generated from computerized medical record 
systems used at study sites can serve as source documents for the purposes of this protocol. If a 
site’s computerized medical record system is not adequately validated for the purposes of clinical 
research (as opposed to general clinical practice), applicable hardcopy source documents must be 
maintained to ensure that critical protocol data entered into the eCRFs can be verified. 
10.7.4 STUDY MEDICATION ACCOUNTABILITY 
The recipient of study medication will acknowledge receipt by returning the appropriate 
documentation form indicating shipment content and condition. Damaged supplies will be 
replaced. Accurate records of all study drug received at, dispensed from, returned to, and 
disposed of by the study site should be recorded by using the Drug Inventory Log. 
 
Study drug will either be disposed of at the study site according to the study site’s institutional 
SOP or returned to Genentech with the appropriate documentation, as determined by the 
Sponsor. If the study site is able to destroy study drug, the method of destruction must be 
documented. Genentech must evaluate and approve the study site’s drug destruction SOP prior to 
the initiation of drug destruction by the study site. 
10.7.5 DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the ICF (or separate authorization to use and disclose personal 
health information) signed by the subject or unless permitted or required by law. Medical 
information may be given to a subject’s personal physician or other appropriate medical 
personnel responsible for the subject’s welfare for treatment purposes. 
 
Given the complexity and exploratory nature of the analyses, data derived from exploratory 
biomarker specimens will generally not be provided to study Investigators or subjects unless 
required by law. The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on study data publication. 
 
Data generated by this study must be available for inspection upon request by representatives of 
the US FDA and other regulatory agencies, national and local health authorities, Genentech 
monitors/representatives and collaborators, and the IRB/EC for the study site, if appropriate. 
 


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Study data may be submitted to government or other health research databases or shared with 
researchers, government agencies, companies, or other groups that are not participating in this 
study. These data may be combined with or linked to other data and used for research purposes; 
to advance science and public health; or for analysis, development, and commercialization of 
products to treat and diagnose disease. In addition, redacted CSRs and other summary reports 
will be provided upon request. 
10.7.6 RETENTION OF RECORDS 
United States FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP require that 
records and documents pertaining to the conduct of this study and the distribution of 
investigational drug, including eCRFs, ICFs, laboratory test results, and medication inventory 
records, must be retained by the Investigator for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of the study drug. All state and local laws for retention of records also 
apply. No records should be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to another party 
or moving them to another location. For studies conducted outside the US under a US 
Investigational New Drug (IND), the Investigator must comply with the record retention 
requirements set forth in the US FDA IND regulations and the relevant national and local health 
authorities, whichever is longer. 
 
All primary data, or copies thereof (e.g., laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report will be 
retained in the study site archives. 
10.8 
REFERENCE TO DECLARATION OF HELSINKI/BASIC PRINCIPLES 
The study procedures outlined in this protocol will be conducted in accordance with the US CFR 
governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), IND Application (21 CFR 312), and Applications 
for FDA Approval to Market a New Drug (21 CFR 314), as appropriate. As such, these sections 
of US Title 21 CFR, along with the applicable ICH Guidelines, are commonly known as GCP, 
which are consistent with the Declaration of Helsinki. 






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REFERENCES 
Baselga J, Campone M, Martine P, et al. Everolimus in postmenopausal hormone receptor 
positive advanced breast cancer. N Engl J Med 2012;366:520-9. 
Chatman LA, Morton D, Johnson TO, et al. A strategy for risk management of drug-induced 
phospholipidosis. Toxicol Pathol 2009:37(7);997-1005. 
Di Leo A, Jerusalem G, Petruzeldka L, et al. Results of the CONFIRM Phase III trial comparing 
fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen 
receptor-positive advanced breast cancer. J Clin Oncol 2010;28:4594-600. 
Electronic Medicines Compendium. Faslodex 250 mg solution for injection [resource on the 
Internet]. 2016a [updated 2016 Sep 23; cited 2017 March]. Available from: 
https://www.medicines.org.uk/emc/medicine/14381 
Electronic Medicines Compendium. Tamoxifen 20 mg Tablets [resource on the Internet]. 2016b 
[updated 2016 July 8; cited 2017 March]. Available from: 
https://www.medicines.org.uk/emc/medicine/30769 
Ferlay J., Soerjomataram I, Ervik M. "GLOBOCON 2012 v1. 0, Cancer Incidence and Mortality 
Worldwide: IARC Cancer Base No. 11. Lyon, France: International Agency for Research on 
Cancer." (2013). Accessed on 16 August 2016. Available from: http://globocan.iarc.fr. 
Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY: Marcel Dekker, Inc.; 1982. 
 


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APPENDIX A – CLINICAL LABORATORY EVALUATIONS 
Clinical Chemistry Panel (Fasted at 
least 8 hours): 
Complete Blood Count: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatine kinase/creatine phosphokinase 
Glucose 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Triglycerides 
Uric acid 
 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity 
Protein 
Urobilinogen 
Microscopic exam including 
bacteria, casts, crystals, epithelial 
cells, RBCs, and WBCs (if 
protein, leukocyte esterase, 
nitrite, or blood is positive)a 
Drug Screen: 
Other Tests: 
 
Including but not limited to the 
following: 
Alcohol (ethanol)c 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids (THC) 
Cocaine (metabolite) 
Cotinineb 
Methadone 
Opiates 
Phencyclidine 
Hepatitis B virus core antibodyb 
Hepatitis B surface antigenb 
Hepatitis C virus antibodyb 
Human immunodeficiency virus antibodyb 
Pregnancy testd 
Follicle-stimulating hormone (postmenopausal females)b 
QuantiFERON® TB Gold tuberculosis testb 
a A microscopic examination will be performed at Screening. During other scheduled urinalysis assessments, a 
microscopic examination will only be performed if protein, leukocyte esterase, nitrite, or blood is positive. 
b Measured at the Screening visit only. 
c Alcohol breath testing will be performed at Check-in (Day -1) of each period. 
d Serum qualitative pregnancy test at Screening and urine pregnancy test at all other times. A positive urine 
pregnancy test will be confirmed with a serum pregnancy test. If a qualitative serum pregnancy test is positive, then 
a quantitative serum pregnancy test may be performed for confirmation. 


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CPET Protocol Template, Version 12.0:  31 January 2019 
APPENDIX B – APPROXIMATE MAXIMUM BLOOD VOLUME COLLECTED 
Note:  Additional samples may be drawn for safety purposes. 
 
 
Sample Volume 
(mL) 
Number of 
Samples 
Total Volume 
(mL) 
Serology 
7.0 
1 
7.0 
Tuberculosis (Quantiferon® TB Gold) 
3.0 
1 
3.0 
Chemistry panel (includes serum pregnancy, 
estradiol, and follicle-stimulating hormone) 
8.5 
11 
93.5 
Complete blood count 
4.0 
11 
44.0 
PK samples 
4.0 
57 
228.0 
RBR sample 
6.0 
1 
6.0 
Total 
381.5 
PK = pharmacokinetic; TB = tuberculosis; RBR = Research Biosample Repository. 

SAP_001.pdf: 
 
Official Title: A Phase 1, Open-Label, Single-Dose, Randomized, Three-Period 
Crossover Study to Evaluate the Relative Bioavailability and Food 
Effect of GDC-9545 in Healthy Female Subjects of Non-Childbearing 
Potential 
NCT Number: NCT04274075 
Document Date: SAP Version 1: 04 February 2020 
 
 


 
 
 
Statistical Analysis Plan 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, RANDOMIZED, THREE-PERIOD 
CROSSOVER STUDY TO EVALUATE THE RELATIVE BIOAVAILABILITY AND 
FOOD EFFECT OF GDC-9545 IN HEALTHY FEMALE SUBJECTS OF              
NON-CHILDBEARING POTENTIAL 
 
SAP Status: Sponsor Final  
SAP Version: 1 
SAP Date: 03 February 2020 
Investigational Product: GDC-9545 
Protocol Reference: GP42006 
Covance Study: 8418446 
 
 
Sponsor: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, California 94080-4990 
USA 
Study Site: 
Covance Clinical Research Unit  
1900 Mason Avenue, Suite 140 
Daytona Beach, Florida 32117 
USA 
 
 
 
Principal Investigator: 
, D.O. 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
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Covance Study: 8418446 
Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
Page 2 of 20 
 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 5 
2. STUDY OBJECTIVES .......................................................................................................... 5 
2.1. Primary Objectives .......................................................................................................... 5 
2.2. Secondary Objective ....................................................................................................... 5 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondary Endpoints ....................................................................................................... 6 
4. STUDY DESIGN................................................................................................................... 6 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 7 
6. STUDY TREATMENTS ....................................................................................................... 8 
7. DEFINITIONS OF POPULATIONS .................................................................................... 9 
7.1. All Subjects Population ................................................................................................... 9 
7.2. Safety Population ............................................................................................................ 9 
7.3. Pharmacokinetic Population ........................................................................................... 9 
8. STATISTICAL METHODOLOGY ...................................................................................... 9 
8.1. General ............................................................................................................................ 9 
8.1.1. Calculation of the Summary Statistics ................................................................... 10 
8.1.2. Triplicate Readings................................................................................................. 10 
8.1.3. Repeat and Unscheduled Readings ........................................................................ 10 
8.1.4. Definitions of Baseline and Change from Baseline ............................................... 11 
8.2. Subject Disposition and Population Assignment .......................................................... 11 
8.3. Screening Demographics .............................................................................................. 11 
8.4. Prior and Concomitant Medication ............................................................................... 11 
8.5. Pharmacokinetic Assessments ...................................................................................... 11 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 11 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 14 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 15 
8.6. Safety and Tolerability Assessments ............................................................................ 16 
8.6.1. Adverse Events ....................................................................................................... 16 
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8.6.2. Clinical Laboratory Parameters .............................................................................. 18 
8.6.3. Vital Signs Parameters ........................................................................................... 18 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 18 
8.6.5. Other Assessments ................................................................................................. 19 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 19 
9. INTERIM ANALYSES ....................................................................................................... 19 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 19 
11. REFERENCES .................................................................................................................. 19 
12. APPENDICES ................................................................................................................... 20 
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Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
Page 4 of 20 
 
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 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the concentration-time curve calculated from Hour 0 to the 
last measurable concentration 
AUC0- 
area under the concentration-time curve from Hour 0 extrapolated to 
infinity 
%AUCextrap 
percentage of area under the concentration-time curve that is due to 
extrapolation from the last measurable concentration to infinity 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent total clearance 
Cmax 
maximum observed concentration  
CSR 
clinical study report 
CV 
coefficient of variation 
ECG 
electrocardiogram 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
λz  
apparent terminal elimination rate constant 
NC 
not calculated 
NR 
no result 
PK 
pharmacokinetic(s) 
R2 adjusted 
adjusted coefficient for determination of exponential fit  
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlast 
time of last quantifiable concentration 
tlag 
time to first quantifiable concentration 
tmax 
time to maximum observed concentration 
t1/2 
apparent terminal elimination half-life 
VZ/F 
apparent volume of distribution during the terminal elimination phase 
 
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Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
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1. INTRODUCTION
This SAP has been developed after review of the clinical study protocol (Final Version 1 
dated 26 November 2019) and electronic case report form. 
This SAP describes the planned analysis of the pharmacokinetic (PK) and 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 Genentech, 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 for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR. 
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 Genentech, Inc. and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES
2.1. Primary Objectives 
The primary objectives of this study are: 
●To evaluate the relative bioavailability of GDC-9545 Phase 3 capsule as compared to
the Phase 1 tablet in the fasted state in healthy adult female subjects of
non-childbearing potential
●To assess the impact of food on GDC-9545 PK for the Phase 3 capsule in healthy adult
female subjects of non-childbearing potential.
2.2. Secondary Objective 
The secondary objective of this study is: 
●To explore the safety and tolerability of single oral doses of 30 mg GDC-9545 as a
Phase 3 capsule in the fasted and fed states in healthy adult female subjects of
non-childbearing potential.
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Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
Page 6 of 20 
 
3. STUDY ENDPOINTS 
3.1. Primary Endpoints 
The following PK parameters will be derived from the plasma concentrations of GDC-9545: 
● maximum observed concentration (Cmax) 
● time to Cmax (tmax) 
● area under the concentration-time curve (AUC) calculated from Hour 0 to the last 
measurable concentration (AUC0-t) 
● area under the concentration-time curve from Hour 0 extrapolated to infinity (AUC0-∞) 
● apparent terminal elimination rate constant (λz) 
● apparent terminal elimination half-life (t1/2) 
● apparent total clearance (CL/F) 
● apparent volume of distribution during the terminal elimination phase (VZ/F). 
3.2. Secondary Endpoints 
The secondary endpoints are: 
● Incidence and severity of adverse events (AEs) and incidence of abnormalities in 
laboratory safety assessments, 12-lead electrocardiograms (ECGs), vital signs 
measurements, and physical examinations. 
4. STUDY DESIGN 
This study will be an open-label, randomized, three-period, six-sequence crossover study of 
GDC-9545 administered at 30 mg in healthy females of non-childbearing potential to 
determine the relative bioavailability of the Phase 3 capsule formulation to the Phase 1 tablet 
formulation in the fasted state and the effect of food on the Phase 3 capsule formulation. 
Eighteen subjects will be enrolled in the study at a single study site to complete a minimum 
of 12 subjects. Study treatments are as follows: 
Treatment A: 30-mg dose of GDC-9545 (three 10-mg tablets) administered orally with 
                         approximately 240 mL room temperature water after at least an 8-hour fast. 
Treatment B: 30-mg dose of GDC-9545 (one 30-mg capsule) administered orally with 
                        approximately 240 mL room temperature water after at least an 8-hour fast. 
Treatment C: 30-mg dose of GDC-9545 (one 30-mg capsule) administered orally with 
approximately 240 mL room temperature water within 30 minutes of eating a 
high-fat meal. 
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Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
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A summary of the sequences is presented in Table 1. 
Table 1: 
 Three-Period, Six-Sequence Crossover Study Design 
A schematic of the study design is presented in Figure 1. 
Figure 1: Study Design 
 
Potential subjects will be screened to assess their eligibility to enter the study within 34 days 
(Days -35 to -2) prior to dosing on Period 1 Day 1. Replacement subjects will not be enrolled. 
For all subjects, routine Screening procedures will be performed. 
Eligible subjects will be admitted to the study site on the day prior to GDC-9545 dosing 
(Check-in [Day -1]) of Period 1 to collect baseline data and familiarize the subjects with 
study procedures that will be used during the rest of the study. On Period 1 Day 1, subjects 
will be randomly assigned to one of six possible treatment sequences and the first dose of 
GDC-9545 in the assigned sequence will be administered in the morning. The washout period 
between doses will be a minimum of 10 days based on the GDC-9545 geometric mean t1/2 of 
approximately 40 hours. 
5. SAMPLE SIZE JUSTIFICATION 
The sample size chosen for this study was based upon precedent set by other PK studies of 
similar nature and was not based on power calculations. Eighteen subjects will be enrolled so 
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Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
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that a minimum of 12 subjects will complete the study without the need for replacement 
subjects. 
6. STUDY TREATMENTS 
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 2. 
Table 2: 
Presentation of Study Treatments in TFLs 
Study Treatment 
Abbreviation 
Order in TFLs 
30-mg dose of GDC-9545 (three 10-mg tablets) fasted 
A 
1 
30-mg dose of GDC-9545 (one 30-mg capsule) fasted 
B 
2 
30-mg dose of GDC-9545 (one 30-mg capsule) fed 
C 
3 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
treatments received, and dose levels will be displayed in increasing order. 
The study treatment sequence names, abbreviations, and ordering to be used in the TFLs are 
presented in Table 3.  
Table 3: 
Presentation of Study Treatment Sequences in TFLs 
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
30-mg dose of GDC-9545 (three 10-mg tablets) fasted/  
30-mg dose of GDC-9545 (one 30-mg capsule) fasted/  
30-mg dose of GDC-9545 (one 30-mg capsule) fed 
A/B/C 
1 
30-mg dose of GDC-9545 (one 30-mg capsule) fasted/  
30-mg dose of GDC-9545 (one 30-mg capsule) fed/  
30-mg dose of GDC-9545 (three 10-mg tablets) fasted  
B/C/A 
2 
30-mg dose of GDC-9545 (one 30-mg capsule) fed/ 
30-mg dose of GDC-9545 (three 10-mg tablets) fasted/  
30-mg dose of GDC-9545 (one 30-mg capsule) fasted 
C/A/B 
3 
30-mg dose of GDC-9545 (three 10-mg tablets) fasted/  
30-mg dose of GDC-9545 (one 30-mg capsule) fed/ 
30-mg dose of GDC-9545 (one 30-mg capsule) fasted 
A/C/B 
4 
30-mg dose of GDC-9545 (one 30-mg capsule) fasted/  
30-mg dose of GDC-9545 (three 10-mg tablets) fasted/ 
30-mg dose of GDC-9545 (one 30-mg capsule) fed 
B/A/C 
5 
30-mg dose of GDC-9545 (one 30-mg capsule) fed/ 
30-mg dose of GDC-9545 (one 30-mg capsule) fasted/ 
30-mg dose of GDC-9545 (three 10-mg tablets) fasted 
C/B/A 
6 
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Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
Page 9 of 20 
 
7. DEFINITIONS OF POPULATIONS 
Any protocol deviations 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 informed consent form 
and had any study assessment recorded in the database per the protocol. 
7.2. Safety Population 
The safety population will consist of all subjects who received at least 1 dose of study drug. 
7.3. Pharmacokinetic Population 
The PK population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 evaluable postdose PK sample. A subject may be excluded from the PK 
summary statistics and statistical analysis if the subject has an AE of vomiting that occurs 
within 2 times median tmax. 
8. STATISTICAL METHODOLOGY 
8.1. General 
Listings will be provided for all data captured in the database. 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 completed all protocol-specified procedures and assessments for the Follow-up visit. 
Any subject who discontinued 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 upversioned 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 upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
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 ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivations, changes from baseline, and any parameter 
derivations. 
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Protocol Reference: GP42006 
Sponsor Final, Version 1, 03 February 2020 
Page 10 of 20 
 
8.1.1. 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.  
● As Early Termination data is not associated with any scheduled timepoint, it will be 
excluded from all calculations of summary statistics. 
For categorical data the following rules will be applied: 
● If the categories of a parameter are ordered (eg, AE severity), all categories between the 
possible minimum and maximum categories will be included, even if n = 0 for a given 
category. If the categories are not ordered (eg, race), only those categories for which 
there is at least 1 subject represented will be included. 
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or 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. 
8.1.2. Triplicate Readings  
For ECG data only, where triplicate readings are taken, the mean of triplicate readings will 
replace the original 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 based on the number of readings available.  
8.1.3. Repeat and Unscheduled Readings 
For vital signs and 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.  
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of baseline derivations (see Section 8.1.4). 
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8.1.4. Definitions of Baseline and Change from Baseline 
The period specific baseline will be defined as the last value recorded prior to the first dose of 
study drug in each period. If the date/time of the value is incomplete or missing, it will be 
excluded from the baseline calculation, unless the incomplete date/time indicates the value 
was recorded prior to the first dose.  
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from period specific 
baseline will be defined as the mean of the individual changes from period specific baseline 
for all subjects.  
See Section 8.1.3 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 8.1.2 for more detail on handling of triplicate readings in the 
calculations. 
8.2. Subject Disposition and Population Assignment 
Subject disposition and population assignment will be listed. 
A summary table by treatment sequence will be provided, based on the all subjects 
population.  
8.3. Screening Demographics 
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed. 
A summary table by treatment sequence 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 the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary Global, Format B3, Version September 2019 (or later if upversioned during the 
study). Prior and concomitant medications will be listed.  
8.5. Pharmacokinetic Assessments  
8.5.1. Pharmacokinetic Analysis 
The following PK parameters will be determined where possible from the plasma 
concentrations of GDC-9545 using non-compartmental methods performed using Phoenix 
WinNonlin (Certara USA, Inc., Version 8.1 or higher): 
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Protocol Reference: GP42006 
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Parameter 
Definition 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
tlast 
time of last quantifiable concentration 
tlag 
time to first quantifiable concentration 
AUC0-t 
area under the concentration-time curve calculated from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal rule for 
increasing concentrations and the logarithmic rule for decreasing 
concentrations 
AUC0-∞ 
area under the concentration-time curve from Hour 0 extrapolated to infinity, 
calculated using the formula: 
AUC0-∞ = AUC0-t + (Ct/λz) 
where Ct is the last measurable concentration and λz is the apparent terminal 
elimination rate constant  
%AUCextrap 
percentage of area under the concentration-time curve that is due to 
extrapolation from the last measurable concentration to infinity 
λz 
apparent terminal elimination rate constant, where λz is the magnitude of the 
slope of the linear regression of the log concentration versus time profile 
during the terminal phase 
t1/2 
apparent terminal elimination half-life (wherever possible), where 
t1/2 = natural log(ln)2/λz 
CL/F 
apparent total clearance, calculated as dose/AUC0-∞  
VZ/F 
apparent volume of distribution during the terminal elimination phase, 
calculated as CL/F/λz  
Additional PK parameters may be determined where appropriate. 
The PK analysis will, where possible, be carried out using actual postdose times recorded in 
the raw data. If actual times are missing, nominal times may be used with sponsor approval.  
Concentrations will be used as supplied by the analytical laboratory for PK analysis. The 
units of concentration and resulting PK parameters, with amount or concentration in the unit, 
will be presented as they are received from the analytical laboratory.  
The dose level of GDC-9545 will be converted to its free base equivalent for PK analysis if 
the analytical laboratory reports the free base concentration. 
The Cmax and tmax will be obtained directly from the plasma 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. 
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8.5.1.1. Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis 
Concentration values that are below the limit of quantification (BLQ) will be set to zero, with 
defined exceptions as follows; 
● Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
● If there are late positive concentration values following 2 BLQ concentration values in 
the apparent terminal phase, these values will be evaluated. If these values are 
considered to be anomalous, they will be set to missing. 
● If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. 
● If a predose concentration is missing, these values may be set to zero. 
8.5.1.2. Criteria for the Calculation of an Apparent Terminal Elimination Half-life 
8.5.1.2.1. Number of Data Points 
At least 3 data points will be included in the regression analysis which preferably should not 
include Cmax. 
8.5.1.2.2. Goodness of Fit 
When assessing terminal elimination phases, the adjusted coefficient for determination of 
exponential fit (R2 adjusted) will be used as a measure of the goodness of fit of the data 
points to the determined line.  
Regression-based parameters (ie, λz, t1/2, AUC0-∞, CL/F, VZ/F) will only be calculated if the 
R2 adjusted value of the regression line is ≥0.7. 
8.5.1.2.3. Period of Estimation 
The time period used for the estimation of t1/2 will be over at least 2 half-lives, where 
possible.  
Where elimination half-life is estimated over a time period of less than 2 half-lives, it will be 
flagged in the data listings at the discretion of the Pharmacokineticist, and the robustness of 
the value should be discussed in the CSR. 
8.5.1.3. Calculation of Area Under the Concentration-time Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive plasma concentrations above the lower limit of quantification, with at least one 
of these concentrations following Cmax. 
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For any partial AUC determination (where applicable), nominal time will generally be used 
for the end of the interval. Actual times for partial AUC intervals may be used at the 
discretion of the Pharmacokineticist.  
The AUC0-∞ values (and related parameters [CL/F and Vz/F]) where the percentage 
extrapolation is <30% will be reported. Any AUC0-∞ values (and related parameters) where 
the percentage extrapolation is ≥30% will be reported and flagged but excluded from 
statistics.  
8.5.1.4. Anomalous Values 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data and 
CSR. 
Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
Positive predose values >5% of Cmax may be excluded from the summary statistics and 
statistical analysis at the discretion of the Pharmacokineticist. 
8.5.2. Presentation of Pharmacokinetic Data 
8.5.2.1. Presentation of Pharmacokinetic Concentration Data 
The following rules will be applied if there are values that are BLQ or if there are missing 
values (eg, no result [NR]) in a plasma concentration data series to be summarized. 
● For the calculation of summary statistics, BLQ values will be set to zero. 
● If an 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 fewer than 3 values in the data series, only the minimum, maximum, and n 
will be presented. The other summary statistics will be denoted as not calculated (NC). 
A BLQ is considered a value. 
● If all the values are BLQ, then the arithmetic mean, arithmetic standard deviation (SD), 
median, minimum, and maximum will be presented as zero, and the geometric mean 
and geometric coefficient of variation (CV) will be denoted as NC. 
● If the value of the arithmetic mean or median is BLQ, it will be presented as zero and 
the geometric mean and geometric CV will be denoted as NC. 
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8.5.2.2. Presentation of Pharmacokinetic Parameters 
For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing. 
The AUC values will be set to NC if they have been calculated using fewer than 
3 concentrations, and/or 3 concentrations if the last is Cmax. 
8.5.3. Pharmacokinetic Statistical Methodology 
All PK concentrations and parameters will be listed.  
Descriptive statistics (mean, median, minimum, maximum, SD, geometric mean, and 
geometric CV) will be calculated for all PK parameters for GDC-9545. 
Summary tables, mean (+ 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. The +SD bars will only be 
displayed on the linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
regression diagnostic PK parameters.  
The PK parameters Cmax, AUC0-t, and AUC0-∞ for GDC-9545 will be analyzed to evaluate the 
relative bioavailability of GDC-9545 as a Phase 3 capsule formulation compared to a Phase 1 
tablet formulation under fasted conditions and to assess the food effect on GDC-9545 PK for 
a Phase 3 capsule formulation. The mixed-effect analysis of variance model for three-period 
crossover design will be used for formulation comparison and fasted state and fed state 
comparison of capsule. The model will include sequence, formulation, and period as fixed 
effects and a random effect for subject within sequence. An unstructured covariance structure 
will be used; however, if this fails to converge, an alternative covariance structure may be 
applied. 
Log transformed Cmax, AUC0-t, and AUC0-∞ values will be evaluated to estimate ratios of 
geometric mean values and the corresponding 90% confidence intervals (CIs).  
The comparisons of interest are: 
Relative bioavailability: Treatment B, capsule (Test) vs Treatment A, tablet (Reference) 
Food effect on capsule: Treatment C, fed (Test) vs Treatment B, fasted (Reference) 
An example of the SAS code that will be used (assuming formulation coding is 
1 = Treatment A, 2 = Treatment B and 3 = Treatment C) is as follows: 
proc mixed data=pk; 
   by parcat1n parcat1 pkday paramn param; 
   class trtan aperiod trtseqp usubjid; 
model log_pk = trtan aperiod trtseqp / residual ddfm=kr;  
   random intercept / subject=usubjid(trtseqp) type=un; 
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   estimate ‘Capsule - tablet’ trtan -1 1 0/ cl alpha=0.1; 
   estimate ‘fed - fasted’ trtan 0 -1 1/ cl alpha=0.1; 
run; 
The parameter tmax will be analyzed nonparametrically using the Wilcoxon signed-rank test. 
The median difference between the test and reference investigational products and the 
corresponding 90% CI will be calculated. 
8.6. Safety and Tolerability Assessments 
8.6.1. Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities Version 22.1 
(or higher if upversioned during the study). All AEs will be assigned severity grade using 
Nationcal Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (or 
higher if upversioned during the study).  
A treatment-emergent AE (TEAE) will be defined as an AE that starts during or after the first 
dose, or starts prior to the first dose and increases in severity after the first dose.  
A treatment-related TEAE will be defined as a TEAE with a relationship of related to the 
study treatment, as determined by the investigator.  
The AEs of special interest for this study are defined as follows: 
● Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy’s Law 
● Suspected transmission of an infectious agent by the study drug as defined below: 
o o Any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a subject exposed to a medicinal product. The term applies only when a 
contamination of the study drug is suspected 
● Grade ≥3 nausea/vomiting/diarrhea 
● Grade ≥2 thromboembolic events (pulmonary embolism, deep vein thrombosis, and 
embolism) 
● Grade ≥3 renal failure (including acute kidney injury or other similar medical concepts) 
● Grade ≥3 hepatitis or elevation in ALT or AST 
● Grade ≥2 vaginal or uterine hemorrhage 
● Grade ≥2 bradycardia 
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● Any grade of endometrial cancer. 
All AEs, serious AEs and AEs of special interest 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 the last dose for TEAEs only. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories: 
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment 
● TEAEs by severity and treatment 
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment 
● Treatment-related TEAEs by severity and treatment 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following: 
● System organ class, preferred term, and treatment 
● Preferred term and treatment 
The frequency of subjects will be summarized separately for clustered TEAEs, presenting the 
TEAEs by the combined preferred term and treatment by the following: 
● (1) combining the preferred terms “sinus bradycardia” and “bradycardia”  
● (2) combining the preferred terms “neutropenia” and “neutrophil count decreased”  
● (3) combining the preferred terms “thrombocytopenia” and “platelet count decreased”  
● (4) combining the preferred terms “thrombocytosis” and “platelet count increased” 
● (5) combining the preferred terms “leukopenia” and “leukocyte count decreased” 
● (6) combining the preferred terms “leukocytosis” and “leukocyte count increased” 
For the AE data the following rules will apply: 
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates an AE started prior to the first dose. 
● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE. 
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● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE 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 the last dose is 01MAY2019/08:00 and recorded start 
date/time of an AE is 03MAY2019, then the minimum possible onset time will be 
calculated by assuming the AE 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). 
● For the derivation of duration: 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 the 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). 
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted under the maximum severity possible. 
● For the calculation of 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, with changes from period specific baseline, will be listed; 
any value outside the clinical reference range will be flagged. Separate listings will be 
provided for any parameter for which there is any individual subject value outside the 
respective clinical reference range.  
Summary tables and boxplots by treatment and timepoint will be provided for clinical 
chemistry and complete blood count parameters, with changes from period specific baseline.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to half of x, whereas >x and ≥x values will be set to x. 
8.6.3. Vital Signs Parameters 
All vital signs parameters, with changes from period specific baseline, will be listed; any 
value outside the clinical reference range will be flagged.  
Summary tables and boxplots by treatment and timepoint will be provided for all vital signs 
parameters, with changes from period specific baseline.  
8.6.4. 12-lead Electrocardiogram Parameters 
All 12-lead ECG parameters, with changes from period specific baseline, will be listed; any 
value outside the clinical reference range will be flagged.  
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Summary tables and boxplots by treatment and timepoint will be provided for all 12-lead 
ECG parameters, with changes from period specific baseline.  
8.6.5. Other Assessments 
Medical history and surgical and procedure history will be listed.  
All other safety and tolerability assessments not detailed in the above sections will be listed 
only. 
8.6.6. Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned.  
9. INTERIM ANALYSES 
No interim analyses are planned. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
There were no significant changes from the protocol-specified analyses. 
11. REFERENCES 
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998. 
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
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12. APPENDICES 
Appendix 1: 
Document History 
Version, Status 
Date of Change 
Summary/Reason for Changes 
Version 1, Final 
NA 
NA; the first version 
NA = not applicable 
 
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