A Phase I, Multicenter, Open-Label Preoperative, Short-Term Window Study of GDC-9545 in Postmenopausal Women With Stage I-III Operable, Estrogen Receptor-Positive Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: Genentech, Inc.

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
GDC-9545—Genentech, Inc.
Protocol GO40987, Version 4
PROTOCOL
TITLE:
A PHASE I, MULTICENTER, OPEN-LABEL
PREOPERATIVE, SHORT-TERM WINDOW STUDY 
OF GDC-9545 IN POSTMENOPAUSAL WOMEN 
WITH STAGE IIII OPERABLE, ESTROGEN 
RECEPTOR-POSITIVE BREAST CANCER
PROTOCOL NUMBER:
GO40987
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003798-85
IND NUMBER:
132673
NCT NUMBER:
NCT03916744
TEST PRODUCT:
GDC-9545 (RO7197597)
MEDICAL MONITOR:
 M.D., M.P.H.
SPONSOR:
Genentech, Inc.
APPROVAL FINAL:
See electronic date stamp below.
 
07-Apr-2020 03:05:35
Title
Approver's Name
Company Signatory
Date and Time (UTC)
Protocol Number: 
 Report Number: 
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PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
4
See electronic date 
stamp on title page
France
5
See electronic date 
stamp on title page
Belgium
4
See electronic date 
stamp on title page
3
12 September 2019
France
4
22 November 2019
Belgium
3
15 November 2019
United Kingdom
2
10 April 2019
1
21 December 2018



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PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol GO40987, Version 3 has been amended primarily to reflect the increase of 
30 patients in the GDC-9545 30 mg treatment cohort to provide additional 
pharmacodynamic data 
.  These changes 
are as follows:

The total number of patients in the GDC-9545 30 mg treatment cohort has been 
increased to 45 patients to enable a better evaluation of Ki67 expression change at 
that dose level.  A corresponding increase has been made to the total number of 
patients enrolled in the study (now 75 patients) (Sections 3.1, 4.1, 6.1, and 9.4; 
Figure 1 and Table 4).

The projected length of study has been amended to approximately 30 months 
(Section 3.2).
The following sections have been amended for consistency with institutional practice:

Language has been modified to clarify that confirmation of available tissue sample is 
required prior to Day 1 of treatment, rather than confirmation of tissue shipment to 
the central laboratory (Sections 4.1.1 and 4.5.9; Appendix 1).

Language related to vital sign measurement has been amended to clarify that 
temperature may be measured according to institutional practice (Section 4.5.4). 
Other changes made to the protocol are as follows:

Language has been added to clarify that the post-surgery visit should be performed 
on Day 43 (1 week) or prior to the initiation of another anti-cancer therapy, 
whichever occurs first (Figure 1 and Appendix 1).

The number of tissue slides requested at screening has been revised to 
approximately 15 slides for consistency with the preferred number of slides for 
analysis (Sections 4.1.1 and 4.5.9).

A reference to next-generation sequencing performed by Foundation Medicine, 
which had inadvertently been retained in protocol amendment Version 3, has been 
removed (Section 4.5.9).

A global change has been made throughout the protocol to update the Medical 
Monitor, including emergency contact information (Section 5.4.1). 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 18
1.1
Background on Breast Cancer............................................... 18
1.2
Background on GDC-9545 .................................................... 19
1.2.1
Nonclinical ............................................................................. 19
1.2.1.1
Pharmacokinetics and Metabolism........................................ 19
1.2.1.2
Toxicology ............................................................................. 20
1.2.2
Clinical Summary................................................................... 22
1.3
Study Rationale and BenefitRisk Assessment..................... 22
2.
OBJECTIVES AND ENDPOINTS ............................................................... 24
2.1
Safety Objective .................................................................... 24
2.2
Pharmacokinetic Objectives .................................................. 24
2.3
Activity Objective ................................................................... 24
2.4
Biomarker Objective .............................................................. 24
3.
STUDY DESIGN......................................................................................... 25
3.1
Description of the Study......................................................... 25
3.2
End of Study and Length of Study......................................... 26
3.3
Rationale for Study Design.................................................... 26
3.3.1
Rationale for Patient Population ............................................ 26
3.3.2
Rationale for GDC-9545 Dose and Schedule........................ 27
3.3.3
Rationale for PK Sampling Schedule..................................... 27
3.3.4
Rationale for Biomarker Assessments................................... 27
3.3.4.1
Ki67 ....................................................................................... 28
3.3.4.2
Pharmacodynamic Pathway Modulation................................ 29
3.3.4.3
Plasma Samples for Somatic Tumor Mutation 
Analysis ................................................................................. 29
3.3.4.4
Tumor Samples for Somatic Mutation Analysis ..................... 30
3.3.4.5
Blood Sample for Next-Generation Sequencing.................... 30
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4.
MATERIALS AND METHODS .................................................................... 30
4.1
Patients.................................................................................. 30
4.1.1
Inclusion Criteria.................................................................... 30
4.1.2
Exclusion Criteria................................................................... 31
4.2
Method of Treatment Assignment.......................................... 32
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 33
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 33
4.3.1.1
GDC-9545 ............................................................................. 33
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 33
4.3.3
Investigational Medicinal Product Accountability ................... 34
4.3.4
Continued Access to GDC-9545............................................ 34
4.4
Concomitant Therapy and Additional Restrictions................. 35
4.4.1
Permitted Therapy................................................................. 35
4.4.2
Cautionary Therapy ............................................................... 35
4.4.2.1
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 35
4.4.2.2
Medications Given with Precaution due to Effects 
Related to Decreases in Heart Rate...................................... 35
4.4.2.3
Herbal Therapies................................................................... 35
4.4.3
Prohibited Therapy ................................................................ 35
4.5
Study Assessments............................................................... 36
4.5.1
Informed Consent Forms and Screening Log........................ 36
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 36
4.5.3
Physical Examinations........................................................... 36
4.5.4
Vital Signs.............................................................................. 37
4.5.5
Eastern Cooperative Oncology Group 
Performance Status............................................................... 37
4.5.6
Tumor Evaluations................................................................. 37
4.5.7
Biological Response Assessment.......................................... 37
4.5.8
Surgical Treatment Plan ........................................................ 37
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4.5.9
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 38
4.5.10
Electrocardiograms................................................................ 40
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 41
4.5.11.1
Overview of the Research Biosample Repository.................. 41
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 41
4.5.11.3
Sample Collection.................................................................. 41
4.5.11.4
Confidentiality........................................................................ 42
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 42
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 43
4.5.11.7
Monitoring and Oversight....................................................... 43
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 44
4.6.1
Study Treatment Discontinuation........................................... 44
4.6.2
Patient Discontinuation from the Study.................................. 44
4.6.3
Study Discontinuation............................................................ 45
4.6.4
Site Discontinuation............................................................... 45
5.
ASSESSMENT OF SAFETY....................................................................... 45
5.1
Safety Plan ............................................................................ 45
5.1.1
Potential Risks Associated with GDC-9545........................... 46
5.1.1.1
Hepatotoxicity........................................................................ 46
5.1.1.2
Gastrointestinal Toxicities (Nausea, Vomiting, 
Diarrhea)................................................................................ 46
5.1.1.3
Thromboembolic Events........................................................ 46
5.1.1.4
Renal Dysfunction ................................................................. 47
5.1.1.5
Changes in Female Reproductive Organs and 
Menopausal Symptoms ......................................................... 47
5.1.1.6
Female Infertility .................................................................... 48
5.1.1.7
Bradycardia ........................................................................... 48
5.1.1.8
DrugDrug Interactions.......................................................... 49
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5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 49
5.1.2.1
Dose Modifications ................................................................ 49
5.1.2.2
Treatment Interruption ........................................................... 49
5.1.2.3
Management Guidelines........................................................ 49
5.1.2.4
Management of Increases in QT Interval............................... 51
5.2
Safety Parameters and Definitions ........................................ 52
5.2.1
Adverse Events ..................................................................... 52
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 52
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 53
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 54
5.3.1
Adverse Event Reporting Period ........................................... 54
5.3.2
Eliciting Adverse Event Information....................................... 54
5.3.3
Assessment of Severity of Adverse Events ........................... 55
5.3.4
Assessment of Causality of Adverse Events ......................... 55
5.3.5
Procedures for Recording Adverse Events............................ 56
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 56
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 57
5.3.5.3
Persistent or Recurrent Adverse Events................................ 57
5.3.5.4
Abnormal Laboratory Values ................................................. 58
5.3.5.5
Abnormal Vital Sign Values ................................................... 58
5.3.5.6
Abnormal Liver Function Tests.............................................. 59
5.3.5.7
Deaths ................................................................................... 59
5.3.5.8
Preexisting Medical Conditions.............................................. 60
5.3.5.9
Lack of Efficacy or Worsening of Breast Cancer ................... 60
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 60
5.3.5.11
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse .......................................................... 61
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 63
5.4.1
Emergency Medical Contacts................................................ 64
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5.4.2
Reporting Requirements for Serious Adverse 
Events and  Adverse Events of Special Interest.................... 64
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 64
5.4.2.2
Events That Occur after Study Drug Initiation........................ 64
5.5
Follow-Up of Patients after Adverse Events .......................... 65
5.5.1
Investigator Follow-Up........................................................... 65
5.5.2
Sponsor Follow-Up ................................................................ 65
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 65
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 66
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 66
6.1
Determination of Sample Size ............................................... 66
6.2
Summaries of Conduct of Study............................................ 67
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 67
6.4
Safety Analyses..................................................................... 67
6.5
Pharmacokinetic Analyses..................................................... 68
6.6
Activity Analyses.................................................................... 68
6.7
Biomarker Analyses............................................................... 68
7.
DATA COLLECTION AND MANAGEMENT ............................................... 68
7.1
Data Quality Assurance......................................................... 68
7.2
Electronic Case Report Forms............................................... 69
7.3
Source Data Documentation.................................................. 69
7.4
Use of Computerized Systems .............................................. 70
7.5
Retention of Records............................................................. 70
8.
ETHICAL CONSIDERATIONS.................................................................... 70
8.1
Compliance with Laws and Regulations ................................ 70
8.2
Informed Consent.................................................................. 71
8.3
Institutional Review Board or Ethics Committee.................... 72
8.4
Confidentiality........................................................................ 72
8.5
Financial Disclosure .............................................................. 73
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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 73
9.1
Study Documentation ............................................................ 73
9.2
Protocol Deviations................................................................ 73
9.3
Site Inspections ..................................................................... 74
9.4
Administrative Structure......................................................... 74
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 74
9.6
Protocol Amendments ........................................................... 75
10. REFERENCES ........................................................................................... 76
LIST OF TABLES
Table 1
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 50
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 55
Table 3
Causal Attribution Guidance ....................................................... 56
Table 4
Two-Sided 80% Confidence Intervals for Ki67 Expression 
Change ....................................................................................... 67
LIST OF FIGURES
Figure 1
Sample Study Schema ............................................................... 26
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 80
Appendix 2
Drugs with Known Torsades de Pointes Risk ............................. 83
Appendix 3
Drugs Known to Increase QT Interval......................................... 84
Appendix 4
Eastern Cooperative Oncology Group Performance Status........ 85
Appendix 5
American Joint Committee on Cancer TNM Classification of 
Malignant Tumors ....................................................................... 86
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE I, MULTICENTER, OPEN-LABEL 
PREOPERATIVE, SHORT-TERM WINDOW STUDY 
OF GDC-9545 IN POSTMENOPAUSAL WOMEN 
WITH STAGE IIII OPERABLE, ESTROGEN 
RECEPTOR-POSITIVE BREAST CANCER
PROTOCOL NUMBER:
GO40987
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003798-85
IND NUMBER:
132673
NCT NUMBER:
NCT03916744
TEST PRODUCT:
GDC-9545 (RO7197597)
MEDICAL MONITOR:
 M.D., M.P.H.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by PPD.
Protocol Number: 
 Report Number: 
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PROTOCOL SYNOPSIS
TITLE:
A PHASE I, MULTICENTER, OPEN-LABEL PREOPERATIVE, 
SHORT-TERM WINDOW STUDY OF GDC-9545 IN 
POSTMENOPAUSAL WOMEN WITH STAGE IIII OPERABLE, 
ESTROGEN RECEPTOR-POSITIVE BREAST CANCER
PROTOCOL NUMBER:
GO40987
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003798-85
IND NUMBER:
132673
NCT NUMBER:
NCT03916744
TEST PRODUCT:
GDC-9545 (RO7197597)
PHASE:
Phase I
INDICATION:
Stage IIII Operable, Estrogen ReceptorPositive Breast Cancer
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the pharmacodynamics, pharmacokinetics, safety and biologic 
activity of GDC-9545 in patients with Stage I–III operable estrogen receptor (ER)-positive 
(HER2-negative) untreated breast cancer.  Specific objectives and corresponding endpoints 
for the study are outlined below.
Safety Objective
The safety objective for this study is to evaluate the safety and tolerability of GDC-9545 when 
administered in this patient population:

Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0
(NCI CTCAE v.5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results, including ECGs
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to evaluate the GDC-9545 PK profile on the 
basis of the following endpoint:

Plasma concentration of GDC-9545 at steady state
Activity Objective
The activity objective for this study is to make a preliminary assessment of the activity of 
GDC-9545 on the basis of the following endpoint:

Change from baseline in tumor cell proliferation measured by Ki67 expression between 
pre- and post-treatment samples
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Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to GDC-9545 (i.e., predictive biomarkers), can provide evidence of 
GDC-9545 activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the knowledge 
and understanding of disease biology and drug safety, on the basis of the following endpoints:

Relationship between biomarkers in blood and tumor tissue and safety, PK, activity, or other 
biomarker endpoints

Cancer-related biomarkers in tumor tissue including DNA mutational status, RNA 
expression levels, DNA copy number and protein expression

Modulation of ER and progesterone receptor (PR) protein levels and ER target genes 
through analysis of paired pre-dose and on-treatment fresh tumor biopsies
Study Design
Description of Study
This is a Phase I, open-label, multicenter, preoperative study to assess changes in Ki67 levels 
and to evaluate the pharmacodynamics, pharmacokinetics, safety, and biologic activity of 
GDC-9545 in postmenopausal patients with Stage I–III operable ER-positive (HER2-negative)
untreated breast cancer.  Approximately 75 patients are expected be enrolled in this study, at 
approximately 2030 investigative sites globally.
The study consists of a screening period of up to 28 days; a treatment period of approximately 
14 days, including a day for surgery; and a minimum follow-up period of 28 days.  Patients will
be assigned to one of three treatment cohorts (10, 30, and 100 mg).  GDC-9545 will be 
administered once daily up to and including the day of surgery (if allowed per local process) on 
Day 15 (2 days).
All patients will be required to provide a pretreatment tumor tissue sample.  Archival tumor 
tissue from prior diagnostic formalin-fixed, paraffin-embedded cores (FFPE) may be used; 
however, if archival tissue is not available or is determined to be unsuitable for required testing, 
the patient will undergo a tumor biopsy.  For the purpose of enrollment, ER, PR, and HER2 will 
be locally determined prior to beginning of study treatment.  Patients who are not evaluable for 
the primary activity analysis as defined in the protocol will be replaced.
Surgery will take place on Day 15 (2).  If surgery must be delayed 2 days, the Medical 
Monitor should be consulted.  Surgery should be performed within 24 hours after the last dose 
of GDC-9545, if possible, to best observe PD knockdown with GDC-9545 in the surgical 
specimen.  In lieu of surgical specimen, a biopsy on Day 14 may be obtained.  The surgical 
specimen is not required if biopsy is obtained on Day 14. 
All patients will be closely monitored for adverse events throughout the study and for at least 
28 days after the final dose of study treatment.  Adverse events will be graded according to 
NCI CTCAE v5.0.  In addition to the safety assessments conducted at scheduled clinic visits, 
patients will be contacted for a general assessment of adverse events at 24 hours post-surgery
by telephone, if applicable.
To assess the steady-state concentrations of GDC-9545, a blood sample will be taken 
at surgery.
If a patient misses more than one dose or the patient's surgery is delayed beyond the allowable 
window, the Medical Monitor should be consulted about possible replacement.
Number of Patients
Approximately 75 postmenopausal women with HER2-negative, ER-positive, Stage IIII 
operable untreated breast cancer will be enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Women age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment
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
Histologically confirmed invasive breast carcinoma, with all of the following characteristics:
–
Primary tumor 1.5 cm in largest diameter by ultrasound
–
Stage IIII operable breast cancer
–
Documentation confirming the absence of distant metastasis (M0) as determined by 
institutional practice (in patients where there may be a reasonable suspicion of 
advanced disease [e.g., large tumors, clinically positive axillary lymph nodes] signs and 
symptoms)

ER-positive tumor and HER2-negative breast cancer as per local laboratory testing

Postmenopausal status defined as one of the following:
–
Prior bilateral surgical oophorectomy
–
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 
levels in the postmenopausal range 

Breast cancer eligible for primary surgery

Submission of a representative tumor tissue specimen
A FFPE tumor specimen in a paraffin block (preferred) or approximately 15 slides containing 
unstained, freshly cut, serial sections must be submitted along with an associated pathology 
report prior to study enrollment.  If less than 12 slides are available, the patient may still be 
eligible for the study after Medical Monitor approval has been obtained.  Confirmation of 
available tissue sample is required prior to Day 1 of treatment.  If archival tumor tissue is 
unavailable or is determined to be unsuitable for required testing, tumor tissue must be 
obtained from a biopsy performed at screening.  A biopsy may also be performed at 
screening if a patient's archival tissue test results do not meet eligibility criteria.  Refer to the 
protocol for additional information on tumor specimens collected at screening.

Eastern Cooperative Oncology Group Performance Status 1 

Adequate organ function as defined by the following criteria:
–
ANC 1500/L 
–
Platelets 100,000/L
–
AST and serum ALT 3 upper limit of normal (ULN) 
–
Total serum bilirubin 1.5 ULN 
Inclusion of patients with increased serum indirect bilirubin (3 ULN) due to 
Gilbert’s syndrome is permitted.
–
Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate
50 mL/min/1.73 m2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Diagnosis of inflammatory breast cancer

Diagnosis of bilateral breast cancer

Concurrent use of hormone replacement therapies

Previous systemic or local treatment for the primary breast cancer currently under 
investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments)

Concurrent treatment with other experimental drugs or participation in another clinical trial 
with any investigational drug within 30 days prior to study entry

Current treatment with any systemic anti-cancer therapies

Major surgery within 4 weeks prior to enrollment

Radiation therapy within 2 weeks prior to enrollment
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
Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer

Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or upper 
gastrointestinal surgery including gastric resection

Known HIV infection

Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol 
abuse, or cirrhosis

Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study

History of allergy to GDC-9545 or any of its excipients

Any condition requiring anticoagulants, such as warfarin, heparin, or thrombolytic drugs

History of documented hemorrhagic diathesis or coagulopathy

History or presence of symptomatic bradycardia

Baseline heart rate 55 bpm prior to enrollment

History or presence of sick sinus syndrome

History or presence of an abnormal ECG that is clinically significant in the investigator’s 
opinion, including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction

QT interval corrected through use of Fridericia's formula 470 ms demonstrated by at least 
two ECGs 30 minutes apart

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular 
hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by 
diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long 
QT syndrome

Current treatment with medications that are well known to prolong the QT interval

History or presence of uncontrolled hypothyroidism

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease 
or condition that contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment complications
End of Study
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.
Length of Study
The total length of the study, from screening to end of the study, is expected to be 
approximately 30 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product for this study is GDC-9545.  GDC-9545 will be 
administered (orally) once daily continuing up to and including the day of surgery.  Patients are 
allowed to take their final dose of GDC-9545 in the morning on the day of surgery if allowed per 
local process.
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Statistical Methods
Primary Analysis
The final analysis will be performed after LPLV and subsequent data cleaning.  The safety 
analysis will be based on the safety-evaluable population, and activity analysis will be based on 
the patients who completed study treatment.  All summaries will be presented according to the 
assigned dose level and cohort.  In general, data will be summarized as warranted, and listings 
will be used in place of tables when the samples sizes are small.  Continuous variables will be 
summarized using means, standard deviations, median, and ranges; categorical variables will 
be summarized using counts and percentages.
Determination of Sample Size  
This study is intended to obtain preliminary safety, PK, PD, and activity information.  The 
sample sizes do not reflect any explicit power and type I error considerations.
The range of mean Ki67 expression changes are from 66% (Opportune) to 76% (IMPACT) for 
2-week treatment.  The planned enrollment for this study is approximately 75 patients.  At least 
15 patients per cohort will provide a more robust safety profile as well as sample size for 
preliminary assessment of activity based on Ki67 expression.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AI
aromatase inhibitors
AUC
area under the concentration-time curve
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating-tumor DNA
DDIs
drugdrug interaction
DLTs
dose-limiting toxicity
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
ER
estrogen receptor
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded cores
FNA
fine-needle aspiration
FSH
follicle-stimulating hormone
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
IC50
50% inhibitory concentration 
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LBD
ligand-binding domain
LPLV
last patient, last visit
MTD
maximum tolerated dose
NCI
National Cancer Institute
NGS
next-generation sequencing
PD
pharmacodynamic
PK
pharmacokinetic
PLD
phospholipidosis
PR
progesterone receptor
QTcF
QT interval corrected through use of Fridericia's
formula
RBR
Research Biosample Repository
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Abbreviation
Definition
SERD
selective estrogen receptor degraders
SERM
selective estrogen receptor modulator
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing
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1.
BACKGROUND
1.1
BACKGROUND ON BREAST CANCER
Breast cancer is the most frequent cancer diagnosed in women, with an estimated global 
incidence of 1.67 million new cases reported in 2012 (Ferlay et al. 2013).  Breast cancer
accounts for approximately 15% (approximately 522,000 cases) of all cancer deaths.  
Approximately 80% of all breast cancers express the estrogen receptor (ER) factor, and 
the vast majority of these 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-positive breast cancer.  However, despite the 
effectiveness of available endocrine therapies such as ER antagonists (e.g., tamoxifen) 
and aromatase inhibitors (e.g., anastrozole, letrozole, and exemestane) many patients 
ultimately relapse or develop resistance to these agents.
There is mounting evidence that ESR1 mutations are an important driver of resistance to 
endocrine treatment (Jeselsohn et al. 2015).  While ESR1 mutations are relatively rare in 
primary breast cancer, they are more prevalent in metastatic cancers, especially in 
patients previously treated with aromatase inhibitors, implying that the mutations are 
acquired (Reinert et al. 2018). ESR1 mutations result in the ER becoming constitutively 
active in the absence of estrogen ligand rendering endocrine therapies such as 
aromatase inhibitors (AI) and tamoxifen ineffective (Robinson et al. 2013;
Jeselsohn et al. 2014).
In contrast to AIs and tamoxifen, selective estrogen receptor degraders (SERD) or 
antagonists are efficacious against these ligand independent, constitutively active 
ER-mutated receptors and have shown substantial therapeutic benefit. This was first 
shown in the SoFEA trial, a Phase III randomized study in postmenopausal patients with 
hormone receptor-positive locally advanced or metastatic breast cancer comparing 
fulvestrant plus anastrozole or placebo versus exemestane alone after progression on 
non-steroidal aromatase inhibitors (Johnston et al. 2013).   Subgroup analysis of plasma
from the SoFEA trial revealed that patients with ESR1 mutations had an improved 
progression-free survival (PFS) of 5.7 months with fulvestrant compared to 2.6 months 
with exemestane (hazard ratio [HR]0.52; 95% CI: 0.30, 0.92; p0.02) (Fribbens et al. 
2016).  This suggested that unlike an AI (exemestane), a SERD (fulvestrant) was active 
in those patients harboring an ESR1 mutation.
A SERD (fulvestrant) has also shown benefit over an AI (anastrozole) in frontline 
patients prior to the formation of ESR1 mutations. The FALCON study was a Phase III, 
randomized, double-blind trial that treated de novo locally advanced or metastatic breast 
cancer hormone receptorpositive patients with either fulvestrant or anastrozole 
(Robertson et al. 2016).  Fulvestrant was associated with a statistically significant 
improvement in PFS compared with anastrozole (HR0.797; 95% CI: 0.637, 0.999; 
p0.0486).  Median PFS was 16.6 months (95% CI: 13.83, 20.99 months) with 
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fulvestrant and 13.8 months (95% CI: 11.99, 16.59 months) with anastrozole (difference 
in medians: 2.8 months).
Unfortunately, fulvestrant has poor pharmacokinetic (PK) properties, requiring 
intramuscular injection; therefore, new agents with superior bioavailability, 
pharmacokinetics, and more potent activity against the ER, including ESR1 mutations, 
are needed to further delay disease progression and/or overcome resistance to the 
currently available endocrine therapies and ultimately prolong survival in women with 
ER-positive breast cancer.
1.2
BACKGROUND ON GDC-9545
GDC-9545 is a potent, orally bioavailable, small-molecule therapeutic agent that is being 
developed for the treatment of patients with ER-positive breast cancer.  GDC-9545
antagonizes the effects of estrogens via competitive binding to the ligand-binding 
domain (LBD) of both wild-type and mutant ER with nanomolar potency.  Upon binding, 
GDC-9545 induces an inactive conformation to the ER LBD, as measured by 
displacement of co-activator peptides.  In addition to its direct antagonist properties, the 
mechanism of action of GDC-9545 includes reducing levels of ER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
such as tamoxifen, which display partial agonism.  GDC-9545 potently inhibits the 
proliferation of multiple ER-positive breast cancer cell lines in vitro, including cells 
engineered to express clinically relevant mutations in ER. 
In vivo, GDC-9545 exhibited dose-dependent anti-tumor activity in xenograft models of 
ER-positive breast cancer, including in a patient-derived xenograft model that harbors an 
ESR1 mutation (ER.Y537S).  The efficacious dose range was 0.110 mg/kg/day, and all 
doses were well tolerated. Fulvestrant, when dosed according to a clinically relevant 
dosing scheme, was less efficacious than GDC-9545 in the assessed xenograft models.  
Thus, GDC-9545 demonstrated robust nonclinical activity in ER-positive breast cancer 
models of ESR1-wildtypeand ESR1-mutationbearing disease.
1.2.1
Nonclinical 
1.2.1.1
Pharmacokinetics and Metabolism
After a single IV administration to rats, dogs, and monkeys, GDC-9545 was found to 
have a low to moderate clearance, a large volume of distribution, and a terminal 
elimination half-life of 724 hours.  Oral bioavailability was moderate in rats and dogs 
(41%55%) and low (17%) in monkeys.  In vitro data showed that plasma protein 
binding of GDC-9545 was high across all species, ranging from 98% to 99% bound. 
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In vitro metabolite identification experiments showed that UGT1A4-mediated 
glucuronidation was the major in vitro metabolic pathway of GDC-9545.  
The contribution from CYP450 isoforms was minor and included both CYP3A4 and 
CYP2C9. No human-specific metabolites in mouse, rat, rabbit, dog, monkey and human 
hepatocytes were detected.
In vitro CYP inhibition studies in human liver microsomes and induction studies in human 
hepatocytes suggest a low-to-moderate potential for drugdrug interactions (DDIs). 
GDC-9545 directly inhibited CYP3A4 with 50% inhibitory concentration (IC50) values of 
6.5 M (midazolam 1'-hydroxylation) and 26 M (testosterone 6-hydroxylation); IC50 for 
CYP2B6 and CYP2C8 inhibition were 13 M and 21 M, respectively. GDC-9545 
showed weak metabolism dependent inhibition of CYP2C9.
1.2.1.2
Toxicology
Four-week Good Laboratory Practice repeat-dose oral toxicity studies in female rats and 
monkeys with integrated assessments of neurologic (rats, monkey), respiratory 
(monkey), and cardiovascular (monkey) function were conducted to characterize the 
nonclinical safety profile of GDC-9545.
In the rat study, GDC-9545 was tolerated at all dose levels (10, 30, and 100 mg/kg) 
with adverse effects predominantly in the kidneys and liver at 100 mg/kg. Similar but 
minimal histopathologic findings were also observed in the kidney of 1 rat at 
30 mg/kg. Additional findings at 100 mg/kg included lymphoid depletion, thymic atrophy, 
decreased salivary and pancreatic zymogens, gastric erosion, and atrophy of fat in skin; 
all were considered likely secondary to stress or declining condition in this dose 
level. At 30 mg/kg, scattered skeletal muscle degeneration was also noted in 
myofibers affected by phospholipidosis (PLD).  Pharmacologically-mediated findings in 
reproductive organs included gross findings in the ovaries and uterus; organ weight 
changes in the ovaries, uterus, and pituitary gland; and microscopic findings in the 
ovaries, uterus, cervix, vagina, mammary gland, and clitoral gland. The maximum 
tolerated dose (MTD) in rats was considered to be 100 mg/kg.
In the monkey study (20, 60, and 200 mg/kg), the MTD was considered to be 60 mg/kg 
as the high dose of 200 mg/kg was not tolerated with 2 monkeys, which were euthanized 
early due to moribund condition. Adverse effects were primarily observed at the high 
dose level of 200 mg/kg, and lack of tolerability was attributed to kidney and liver 
injury and inanition. Pharmacologically mediated findings in reproductive organs 
included gross findings in the ovaries and uterus, organ weight changes in the ovaries 
and uterus, and microscopic findings in the ovaries, uterus, cervix, vagina, and 
mammary gland.
In both rats and monkeys, there was a dose-dependent PLD observed 
in numerous organs at exposures that were higher than those anticipated at the human 
starting dose in Phase I (at least 44-fold and 6-fold based on area under the 
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concentrationtime curve [AUC], respectively), with adverse organ effects largely 
confined to the kidney and liver.  Although associated with the observation of PLD, it is 
unclear whether these toxicities were caused by PLD.  In rats, PLD was not noted at 
10 mg/kg (18-fold exposure factor), but increased in incidence and severity from 30 to 
100 mg/kg.  In monkeys, dose-responsive PLD was present at all doses but was limited 
to minimal changes in the lung at 20 mg/kg (6-fold exposure factor).
The translatability of PLD from nonclinical species to patients is not certain 
(Reasor et al. 2006).  Drugs such as tamoxifen and palbociclib have not demonstrated 
any clinical concerns in spite of their PLD findings in nonclinical studies; thus, it is 
unclear whether GDC-9545-related PLD observed nonclinically will translate into a 
clinical finding in humans and whether this will have any clinical sequelae if it does.  
Although GDC-9545 was associated with PLD in multiple tissues in both rats and 
monkeys, there was no light microscopic evidence of involvement of critical organs 
such as heart, eyes, or neurons in these studies (Chatman et al. 2009).  There is 
currently no qualified biomarker for assessment of PLD in the clinical setting although 
bis(monoacylglycerol)phosphate is being suggested as a potential biomarker; however, 
the function of the organs in which GDC-9545related PLD may have been associated 
with toxicity in the 28-day rat and cynomolgus monkey studies (liver and kidney) is
readily monitorable in the clinic using standard laboratory assessments. 
No respiratory or neurobehavioral abnormalities were detected in rats or cynomolgus 
monkeys during the 4-week repeat-dose toxicity studies, with the exception of decreased 
locomotor activity that was only observed in rats at the high dose of 100 mg/kg/day.
Following 28-day oral administration to rats and monkeys, the increases in systemic 
exposure of GDC-9545 were dose proportional. Based on the nature and reversibility of 
clinical signs, clinical pathology, and histopathology findings, the severely toxic dose 
for 10% of animals (STD10) for rats was defined as 100 mg/kg, with corresponding 
maximum plasma concentration (Cmax) and AUC from 0 to 24 hours (AUC0-24) values of 
6560 ng/mL and 143,000 ng hr/mL, respectively. In monkeys, the highest non-severely 
toxic dose was defined as 60 mg/kg/day, with corresponding Cmax and AUC0-24 values of 
841 ng/mL and 16,200 ng hr/mL, respectively, due to the clinical signs and 
moribundities present at 200 mg/kg/day.
In summary, results from the nonclinical toxicity and safety pharmacology studies 
completed to date provide a robust characterization of the toxicity profile of GDC-9545 
and support administration to patients with cancer.  Overall, the nonclinical findings are 
consistent with the anti-estrogenic mode of action of GDC-9545.  
Refer to the GDC-9545 Investigator’s Brochure for additional details.
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1.2.2
Clinical Summary 
As of the data cutoff date of 1 February 2019, a total of 55 postmenopausal women with 
locally advanced or metastatic ER-positive (HER2-negative) breast cancer, including
29 patients in single-agent dose escalation, 6 patients in palbociclib-combination dose 
escalation, and 20 patients in single-agent dose expansion, had received at least one 
dose of GDC-9545 in Study GO39932. During dose escalation, 4 single-agent cohorts 
of 3 patients each were enrolled at 10-, 30-, 90-, and 250-mg doses, given once daily. 
To acquire additional PK, pharmacodynamic (PD), and safety data, up to 7 additional 
patients were enrolled to backfill single-agent dose-escalation cohorts at 10-, 30-, and 
90-mg doses. The single-agent dose escalation completed enrollment in October 2018. 
No dose limiting toxicities (DLTs), related serious adverse events, or adverse events of 
special interest were reported. The MTD was not determined. Two dose levels of 
GDC-9545 were chosen for the single-agent dose expansion, 100 and 250 mg LHRH 
agonist, and an escalation cohort combining 100 mg GDC-9545 with 125 mg palbociclib 
was enrolled.
GDC-9545 is tolerated well at all dose levels. The most frequently reported adverse 
events related to GDC-9545 in10% of patients were fatigue (15%), diarrhea and 
nausea (13%), and arthralgia (11%). Grade3 adverse events were reported in 
10 patients (18%), but all were considered unrelated to GDC-9545 by the investigators.
Two patients have experienced serious adverse events considered not related to 
GDC-9545 by the investigator.
In Study GO39932, GDC-9545 was rapidly absorbed with peak concentrations achieved
at 14 hours (mean time to maximum concentration) after single dose as well as at 
steady state. The geometric mean half-life after single dose ranged from 
26.241.4 hours, indicating that once-daily dosing is appropriate for GDC-9545. 
In general, plasma exposures of GDC-9545 increased with doses at 10, 30, 90, and 
250 mg after single and multiple doses.  The expansion cohort’s exposure was in line 
with escalation cohort exposure.  Pharmacodynamics was assessed by functional 
imaging with [18F]-fluoroestradiol-positron emission tomography and showed robust 
ER-target engagement across all doses.
Refer to the GDC-9545 Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
GDC-9545 is a potent, orally bioavailable ER-α antagonist and inducer of ER-
degradation that competes with estrogens for binding to the ER with low nanomolar
potency; it is being developed for the treatment of women with ER-positive breast cancer.  
GDC-9545 demonstrated robust nonclinical activity in ER-positive breast cancer models 
of ESR1-wildtype and ESR1-mutation bearing disease.  As described in Section 1.2.1.2, 
GDC-9545 was tolerated in safety pharmacology studies.  Specific eligibility criteria 
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designed to minimize potential risks are included in Section 4.1, and robust safety 
monitoring and risk mitigation strategies for all expected or potential safety risks are 
described in Section 5.  The implementation of appropriate dose-modification and 
treatment guidelines, appropriate choice of inclusion/exclusion criteria, real-time safety 
monitoring and assessments, and periodic assessment of aggregate safety data and 
benefitrisk ratio combine to form the monitoring and risk mitigation system.
A window of opportunity (“window”) study is a type of neoadjuvant study where women 
with newly diagnosed hormone receptor-positive breast cancer are treated with an 
experimental drug for 2 weeks prior to surgery.  These studies provide access to tumor 
tissue before, during, and after treatment for PD and correlative studies, providing critical 
insight into the optimal patient population, differences in activity and mechanisms 
between agents, influence of the tumor biology on sensitivity, and molecular 
mechanisms of response or resistance.  Window studies are becoming the standard in 
developing a new drug in hormone receptorpositive breast cancer to inform dose 
selection and provide early readout on biologic activity.
To ensure consistency with current therapeutic standards, this study requires that
definitive surgery take place 15 days (2 days) after the start of the study treatment.  
As such, a patient's participation in this study is not expected to delay surgery beyond 
the standard waiting period. Furthermore, there is no nonclinical, clinical, or mechanistic 
evidence to suggest that GDC-9545 has a relevant impact on operability or that it 
increases risks associated with surgery.
Detailed studies in the neoadjuvant setting in prospective randomized clinical trials have 
demonstrated the utility and validity of changes in Ki67 as a predictor of benefit from of 
endocrine therapy treatment and of long-term outcome (Dowsett et al. 2005a; Dowsett et 
al. 2005b; Polychronis et al. 2005; Dowsett et al. 2006; Dowsett et al. 2007; Smith et al.
2007; Ellis et al. 2008; Baselga et al. 2009; Jones et al. 2009) (see Section 3.3.4.1 for 
additional details).
Although Ki67 measurements in preoperative trials cannot replace the need for adjuvant 
trials with clinical endpoints, when used along with additional PD data and Phase I dose 
escalation/expansion safety and efficacy data, they can be highly instructive in selecting 
the optimal dose for Phase III studies and defining the most appropriate patient 
populations.
As of November 2018, GDC-9545 has been well-tolerated and shown evidence of 
activity including in those patients with ESR1 mutations (see Section 1.2.2). At all doses 
tested, patients with [18F]-fluoroestradiol positron emission tomography imaging have 
shown near-complete or complete responses.  In addition, there is early indication of 
ER-pathway reduction by PD markers in the few on-treatment biopsies obtained from the 
Phase I study.
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Overall, there is strong rationale to run a window of opportunity study to select the 
optimal dose of GDC-9545.  In addition, GDC-9545 has a tolerable safety profile that 
poses minimal risk for patients during treatment and for surgery.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the pharmacodynamics, pharmacokinetics, safety and biologic 
activity of GDC-9545 in patients with Stage I–III operable ER-positive (HER2-negative) 
untreated breast cancer.  Specific objectives and corresponding endpoints for the study 
are outlined below.
2.1
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of GDC-9545
when administered in this patient population:

Incidence and severity of adverse events, with severity determined according to 
NCI CTCAE v.5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results, including ECGs
2.2
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to evaluate the GDC-9545 PK profile on the basis of 
the following endpoint:

Plasma concentration of GDC-9545 at steady state
2.3
ACTIVITY OBJECTIVE
The activity objective for this study is to make a preliminary assessment of the activity of 
GDC-9545 on the basis of the following endpoint:

Change from baseline in tumor cell proliferation measured by Ki67 expression 
between pre- and post-treatment samples
2.4
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate
biomarkers that are predictive of response to GDC-9545 (i.e., predictive biomarkers), 
can provide evidence of GDC-9545 activity (i.e., PD biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoints:

Relationship between biomarkers in blood and tumor tissue (listed in Section 4.5.9)
and safety, PK, activity, or other biomarker endpoints

Cancer-related biomarkers in tumor tissue including DNA mutational status, RNA 
expression levels, DNA copy number and protein expression

Modulation of ER and progesterone receptor (PR) protein levels and ER target 
genes through analysis of paired pre-dose and on-treatment fresh tumor biopsies
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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase I, open-label, multicenter, preoperative study to assess changes in Ki67 
levels and to evaluate the pharmacodynamics, pharmacokinetics, safety, and biologic 
activity of GDC-9545 in postmenopausal patients with Stage I–III operable ER-positive 
(HER2-negative) untreated breast cancer.  Approximately 75 patients are expected be 
enrolled in this study, at approximately 2030 investigative sites globally.
The study consists of a screening period of up to 28 days; a treatment period of 
approximately 14 days, including a day for surgery; and a minimum follow-up period of 
28 days.  Patients will be assigned to one of three treatment cohorts (10, 30, and 
100 mg; see Figure 1).  GDC-9545 will be administered once daily up to and including 
the day of surgery (if allowed per local process) on Day 15 (2 days).
All patients will be required to provide a pretreatment tumor tissue sample.  Archival 
tumor tissue from prior diagnostic formalin-fixed, paraffin-embedded cores (FFPE) may 
be used; however, if archival tissue is not available or is determined to be unsuitable for 
required testing, the patient will undergo a tumor biopsy.  For the purpose of enrollment, 
ER, PR, and HER2 will be locally determined prior to beginning of study treatment.
Patients who are not evaluable for the primary activity analysis as defined in Section 6
will be replaced.
Surgery will take place on Day 15 (2).  If surgery must be delayed 2 days, the Medical 
Monitor should be consulted.  Surgery should be performed within 24 hours after the last 
dose of GDC-9545, if possible, to best observe PD knockdown with GDC-9545 in the 
surgical specimen. In lieu of surgical specimen, a biopsy on Day 14 may be obtained.  
The surgical specimen is not required if biopsy is obtained on Day 14.
All patients will be closely monitored for adverse events throughout the study and for at 
least 28 days after the final dose of study treatment (see Section 5.3.1).  Adverse events 
will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 (NCI CTCAE v5.0).  In addition to the safety 
assessments conducted at scheduled clinic visits, patients will be contacted for a 
general assessment of adverse events at 24 hours post-surgery by telephone, if 
applicable.
To assess the steady-state concentrations of GDC-9545, a blood sample will be taken at 
surgery (see Appendix 1).
If a patient misses more than one dose or the patient's surgery is delayed beyond the 
allowable window, the Medical Monitor should be consulted about possible replacement.
A schedule of activities is provided in Appendix 1.
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Figure 1
Sample Study Schema
QDonce a day
Note:  A biopsy on Day 14 may be obtained instead of a surgical specimen.  A surgical specimen
on Day 15 is not required if biopsy is obtained on Day 14.
a Post-surgery visit should be performed at Day 43 (1 week) or prior to the initiation of 
another anti-cancer therapy, whichever occurs first.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of the study is defined as the date when the last patient, last visit (LPLV) 
occurs. The total length of the study, from screening to end of the study, is expected to 
be approximately 30 months.
In addition, the Sponsor may decide to terminate the study at any time
(see Section 4.6.3).
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
Postmenopausal patients with Stage IIII HER2-negative, ER-positive, early stage 
breast cancer will be enrolled in this study.  This patient population is usually treated with 
surgery followed by anti-hormonal therapy, and/or chemotherapy, according to staging 
and biological features.  Nonclinical studies suggest that ER-positive breast cancer is 
reliant upon the estrogen pathway giving strong rationale to use an endocrine agent 
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such as a SERD.  Patients with HER2 over-expressing tumors are excluded as these 
patients would generally be considered for HER2-directed therapy.  Given the number of 
tumor biopsies required as part of this study, the trial will have to be confined to patients 
with a tumor size of at least 1.5 cm.
3.3.2
Rationale for GDC-9545 Dose and Schedule
GDC-9545 is a potent, orally bioavailable, small-molecule therapeutic agent that is being 
developed for the treatment of patients with ER-positive breast cancer.  Nonclinical 
anti-tumor activity has been seen in a number of single-agent and combination therapy 
studies. In addition, early clinical anti-tumor activity has been seen in ER-positive breast 
cancer.  GDC-9545 has demonstrated an acceptable toxicity profile in more than 20
metastatic ER-positive breast cancer patients treated to date.  The dose and schedule of 
GDC-9545 will be orally once daily continuously for 14 days (2) and the day of surgery 
(if allowed). GCD-9545 will be administered at 10, 30, and 100 mg.
The doses selected for the Phase I GO40987 study are 10, 30, and 100 mg (rounded 
from 90 mg to reduce pill burden on patients).  These three doses mirror doses studied 
in the ongoing Phase Ia/b dose-escalation/expansion GO39932 study and that have 
already cleared the DLT window in the latter study. The traditional safety and efficacy 
endpoints are being studied in the Phase Ia/b GO39932 study, while the endpoints for 
the GO40987 study are biomarkers aimed at defining dose-PD and dose-activity 
relationships to help guide selection of the recommended Phase II dose. 
3.3.3
Rationale for PK Sampling Schedule
During the dose escalation of the ongoing Study GO39932, the full PK profile of 
GDC-9545 has been evaluated as single dose and at steady state at 10, 30, 90, and 
250 mg daily. Therefore, only a single PK sample will be taken at steady state to 
confirm the PK exposure of 10, 30, and 100 mg GDC-9545 in this study.
3.3.4
Rationale for Biomarker Assessments
PD biomarkers will be measured in tissue to determine whether clinically achievable 
exposures are sufficient for producing the desired effect on the intended molecular target. 
The evaluation of dose-PD and dose-activity relationships across a range of GDC-9545 
doses will enable dose selection.
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Breast cancer is a heterogeneous disease (Cancer Genome Atlas Network 2012).  
Therefore, all patients may not be equally likely to benefit from treatment with GDC-9545.  
Predictive biomarker samples will be assessed in an effort to identify those patients who 
are most likely to respond to GDC-9545.  PD biomarkers will be assessed to 
demonstrate evidence of biologic activity of GDC-9545 in patients, to support selection 
of a recommended dose and dose regimen, and to inform potential revisions to the 
PK sample collection schedule.
3.3.4.1
Ki67 
Ki67 is a well-established proliferation biomarker with prognostic value in ER-positive
breast cancer (Anderson et al. 2011).  Efficacy of endocrine therapy relies on induction 
of cell-cycle arrest, and during neoadjuvant treatment, Ki67 levels reflect the ability of 
endocrine agents to suppress proliferation (Dowsett et al. 2005b; Ellis et al. 2011).  
There are numerous examples of endocrine agents used in small, short-term 
neoadjuvant studies whose Ki67 results parallel disease-free recurrence outcomes from 
large adjuvant studies or PFS in metastatic studies (Guerrero-Zotano and Arteaga 2017).
In the IMPACT trial, short-term changes of Ki67 during the neoadjuvant period of 
treatment of primary breast cancer with anastrozole or tamoxifen alone or in combination 
correlated with recurrence-free survival.  In this study, Ki67 was assessed at baseline, 
on Day 15, and at surgery after 12 weeks of treatment (Dowsett et al. 2005a, 2005b).  
For each treatment arm, the reduction in geometric mean Ki67 levels was significantly 
higher for anastrozole (76%) than for tamoxifen at both timepoints (p0.004, p0.001, 
respectively), but no differences were found between tamoxifen (59%) and the 
combination of anastrozole and tamoxifen (64%). These results mirrored the statistically 
significant (p0.004) recurrence-free survival outcome difference between anastrozole
and tamoxifen (4.3% at 10 years) in the much larger adjuvant ATAC trial (n9366) 
without the requirement of a long follow-up. In addition, after a median follow-up of 
68 months, anastrozole significantly prolonged disease-free survival (575 events with 
anastrozole vs. 651 with tamoxifen; HR0.87; 95% CI: 0.78, 0.97; p0.01) and 
time-to-recurrence (402 vs. 498; HR0.79; CI: 0.70, 0.90; p0.0005), and significantly 
reduced distant metastases (324 vs. 375; HR0.86; CI: 0.74, 0.99; p0.04) and 
contralateral breast cancers (35 vs. 59; 42% reduction, CI: 12%, 62%; p0.01) (Baum et 
al. 2002; Howell et al. 2005; Forbes et al. 2008)
The POETIC trial, a Phase III randomized clinical trial with approximately 4000 patients
with early breast cancer, prospectively tested whether short-term perioperative 
endocrine therapy with an AI followed by standard adjuvant therapy can improve 
outcome in postmenopausal women with ER-positive breast cancer, whether the 
proliferation marker Ki67 as measured by immunohistochemistry after 2 weeks of AI 
therapy will predict for recurrence-free survival and whether molecular profiling 2 weeks 
after starting endocrine therapy predicts better for long-term outcome than at diagnosis.  
Similar to the IMPACT study, an early evaluation of Ki67 levels after 2 weeks of 
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treatment were shown to correlate to 5-year recurrence rate (low Ki67 8.5% 5-year TTR, 
high Ki67 19.6% 5-year TTR) (Robertson et al. 2018).
The neoadjuvant NEWEST study helped establish the optimal dose of the ER antagonist 
fulvestrant (500 mg) on the basis of significantly greater suppression of Ki67 compared
with the lower dose of 250 mg after 4 weeks of treatment (p0.0001) (Kuter et al. 2012). 
Fulvestrant at 500 mg had a mean percent change from baseline of 78% at 4 weeks and 
77% at 16 weeks.  Fulvestrant at 250 mg had a mean percent change from baseline of
47% at 4 weeks and 63% at 16 weeks.  These early Ki67 differences mirrored the 
results of the Phase III CONFIRM trial in advanced breast cancer, which also showed 
superiority of the 500-mg dose over the 250-mg dose (CBR in patients with measurable 
disease 45.6% versus 39.6% and PFS 6.5 months versus 5.4 months) (Di Leo et al. 
2010).
In summary, reduction in Ki67 after neoadjuvant treatment with AIs and fulvestrant is a 
good marker of suppression of cellular proliferation, correlates with long-term efficacy 
outcomes, and mirrors results of large adjuvant or metastatic endocrine trials, which 
make it an attractive endpoint to assess in the present trial.
3.3.4.2
Pharmacodynamic Pathway Modulation
Pre- and on-study tumor biopsies from the same lesion will be collected to assess ER 
protein degradation and PR protein levels. Similar to Ki67, reduction of both ER and PR 
were significantly greater with the 500-mg dose of fulvestrant than the 250-mg dose after 
4 weeks of treatment in the NEWEST study (ER 50% vs. 14%, p0.0001, PR 81% vs.
46%, p0.0018) (Kuter et al. 2012). In addition, paired tumor biopsies will enable 
assessment of ER pathway suppression using RNA analysis of ER target genes.
3.3.4.3
Plasma Samples for Somatic Tumor Mutation Analysis
There is increasing evidence that circulating DNA obtained from blood specimens of 
cancer patients is representative of the DNA and mutational status of tumor cells 
(Diehl et al. 2008; Maheswaran et al. 2008).  Recent nonclinical and clinical data 
suggest that mutations in ESR1 and PIK3CA are associated with endocrine-resistant 
breast cancer (Shou et al. 2004; Miller et al. 2010; Robinson et al. 2013; Toy et al. 2013; 
Jeselsohn et al. 2014; Bosch et al. 2015).  To gain insights into potential causal 
relationships between the clinical activity of GDC-9545 and resistance mechanisms,
genes related to PI3K signaling and endocrine resistance as well as reported and 
unreported chromosomal alterations resulting from the tumorigenesis process may be 
assessed in circulating-tumor DNA (ctDNA) isolated from plasma using digital 
polymerase chain reaction, and/or targeted next-generation sequencing (NGS).
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3.3.4.4
Tumor Samples for Somatic Mutation Analysis
NGS techniques such as exome sequencing may offer a unique opportunity to identify 
biomarkers of response and/or resistance to GDC-9545.  For example, genes related to 
PI3K signaling and endocrine resistance as well as reported and unreported 
chromosomal alterations resulting from the tumorigenesis process may be assessed. 
3.3.4.5
Blood Sample for Next-Generation Sequencing
NGS technologies generate a large quantity of sequencing data.  Tumor DNA can 
contain both reported and unreported chromosomal alterations because of the 
tumorigenesis process.  To help control for sequencing calls in previously unreported 
genomic alterations, a predose blood sample will be taken to determine whether the 
alteration is somatic using targeted NGS.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 75 postmenopausal women with HER2-negative, ER-positive, Stage IIII 
operable untreated breast cancer will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Women age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Histologically confirmed invasive breast carcinoma, with all of the following 
characteristics:
–
Primary tumor 1.5 cm in largest diameter by ultrasound
–
Stage IIII operable breast cancer
–
Documentation confirming the absence of distant metastasis (M0) as 
determined by institutional practice (in patients where there may be a 
reasonable suspicion of advanced disease [e.g., large tumors, clinically positive 
axillary lymph nodes] signs and symptoms)

ER-positive tumor and HER2-negative breast cancer as per local laboratory testing

Postmenopausal status defined as one of the following:
–
Prior bilateral surgical oophorectomy
–
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 

Breast cancer eligible for primary surgery
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
Submission of a representative tumor tissue specimen
A FFPE tumor specimen in a paraffin block (preferred) or approximately 15 slides 
containing unstained, freshly cut, serial sections must be submitted along with an 
associated pathology report prior to study enrollment.  If less than 12 slides are 
available, the patient may still be eligible for the study after Medical Monitor 
approval has been obtained.  Confirmation of available tissue sample is required 
prior to Day 1 of treatment.  If archival tumor tissue is unavailable or is determined 
to be unsuitable for required testing, tumor tissue must be obtained from a biopsy 
performed at screening.  A biopsy may also be performed at screening if a patient's 
archival tissue test results do not meet eligibility criteria.  Refer to Section 4.5.9 for 
additional information on tumor specimens collected at screening.

Eastern Cooperative Oncology Group (ECOG) Performance Status 1 

Adequate organ function as defined by the following criteria:
–
ANC 1500/L 
–
Platelets 100,000/L
–
AST and serum ALT 3upper limit of normal (ULN)
–
Total serum bilirubin 1.5ULN 
Inclusion of patients with increased serum indirect bilirubin (3ULN) due 
to Gilbert’s syndrome is permitted.
–
Chronic Kidney Disease Epidemiology Collaboration estimated glomerular 
filtration rate 50 mL/min/1.73 m2 (Michels et al. 2010)
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Diagnosis of inflammatory breast cancer

Diagnosis of bilateral breast cancer

Concurrent use of hormone replacement therapies

Previous systemic or local treatment for the primary breast cancer currently under 
investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments)

Concurrent treatment with other experimental drugs or participation in another 
clinical trial with any investigational drug within 30 days prior to study entry

Current treatment with any systemic anti-cancer therapies

Major surgery within 4 weeks prior to enrollment

Radiation therapy within 2 weeks prior to enrollment

Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
or Stage I uterine cancer

Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or 
upper gastrointestinal (GI) surgery including gastric resection
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
Known HIV infection

Known clinically significant history of liver disease consistent with Child-Pugh Class 
B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), 
current alcohol abuse, or cirrhosis

Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study

History of allergy to GDC-9545 or any of its excipients

Any condition requiring anticoagulants, such as warfarin, heparin, or 
thrombolytic drugs

History of documented hemorrhagic diathesis or coagulopathy

History or presence of symptomatic bradycardia

Baseline heart rate 55 bpm prior to enrollment

History or presence of sick sinus syndrome

History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction

QT interval corrected through use of Fridericia's formula (QTcF) 470 ms 
demonstrated by at least two ECGs 30 minutes apart

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction, left 
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome

Current treatment with medications that are well known to prolong the QT interval

History or presence of uncontrolled hypothyroidism

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug or that 
may affect the interpretation of the results or render the patient at high risk from 
treatment complications
4.2
METHOD OF TREATMENT ASSIGNMENT 
Treatment assignment will be conducted using an interactive voice or web-based 
response system (IxRS).  After written informed consent has been obtained, all patients 
will receive a screening number, which will be assigned by the IxRS.  Following 
completion of the screening period and after all patient eligibility requirements are 
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confirmed, patients will be assigned to a cohort and given an identification number 
(a different number from the screening number) by the IxRS. 
Patients will be assigned to one of three treatment arms based on the following 
stratification factors: 

Tumor grade (1 and 2 vs. 3)

Nodal status (cytologically positive vs. radiologically or cytologically negative). 
If on ultrasound examination there is evidence of suspicious axillary lymph 
nodes at the baseline examination, then fine-needle aspiration (FNA) or core 
biopsy is required to confirm nodal status.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is GDC-9545.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
GDC-9545
GDC-9545 will be supplied by the Sponsor and will be provided in two different strengths, 
10-mg and 50-mg tablets, packaged in high-density polyethylene bottles with a plastic 
child-resistant cap with induction seal and desiccant.  For information on the formulation 
and handling of GDC-9545, see the pharmacy manual and the GDC-9545 Investigator's 
Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimen is summarized in Section 3.1.
Refer to the pharmacy manual for detailed instructions on storage and administration.
The research staff at each participating site will provide detailed instructions and training 
for the handling of GDC-9545 and its administration to each patient at the beginning of 
their study participation.  Patients will be instructed to complete a daily medication diary.
Patients will be asked to return any remaining study drug from the previous dosing days
as well as all used and unused tablet containers and medication diary.  
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of GDC-9545 overdose, medication error, drug 
abuse, or drug misuse, along with any associated adverse events, should be reported as 
described in Section 5.3.5.11.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.2.
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The full prescribed dose of GDC-9545 should be taken by mouth in the morning, at 
approximately the same time each day unless otherwise specified.  GDC-9545 may be 
taken with or without food.
GDC-9545 will be administered once daily continuing up to and including the day of 
surgery. Patients are allowed to take their final dose of GDC-9545 in the morning on the 
day of surgery if allowed per local process.  If surgery must be delayed 2 days, the 
Medical Monitor should be consulted.  Continuous dosing will begin on Day 1.  On Day 1,
GDC-9545 will be administered in the clinic.  All other doses of GDC-9545 will be 
administered on an outpatient basis.  
For missed doses, patients should just take the next scheduled dose, without 
compensating for the missed dose. If a patient misses more than one dose, the Medical 
Monitor should be consulted about possible replacement, if applicable.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (GDC-9545) will be provided by the 
Sponsor where required by local health authority regulations. The study site will 
acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to GDC-9545 
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide the Genentech IMP GDC-9545 or any other study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing GDC-9545 in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
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4.4
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to screening through 4 weeks following final dose of study drug.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Symptomatic anti-emetics, anti-diarrheal therapy, may be administered at the 
investigator’s discretion.  All concomitant medication and/or therapies should be 
documented in the patient’s eCRF.

Bone-sparing agents (e.g., bisphosphonates, denosumab for the treatment of 
osteoporosis/osteopenia are allowed in the study provided patients were on stable 
doses for at least 4 weeks prior to enrollment.
4.4.2
Cautionary Therapy
4.4.2.1
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
As a perpetrator of DDIs, GDC-9545 has been shown to have the potential to inhibit and 
activate human CYP3A4/5 enzymes in vitro. As a victim, GDC-9545 is primarily 
glucuronidated via UGT1A4 with minor contributions from CYP3A4 and 2C9 enzymes. 
Low potential for clinically relevant DDI is anticipated for GDC-9545 both as a 
perpetrator and as a victim. Although the potential for clinically significant DDI as a 
victim or perpetrator is anticipated to be low to moderate based on the 
physiologically-based pharmacokinetic simulations, caution should be taken with the 
coadministration of drugs with narrow therapeutic index (see the GDC-9545 
Investigator’s Brochure). 
4.4.2.2
Medications Given with Precaution due to Effects Related to
Decreases in Heart Rate
Caution should be taken with the coadministration of drugs known to cause decreases in 
heart rate (see Section 5.1.1.7).
4.4.2.3
Herbal Therapies
Herbal therapies, except phytoestrogen-containing herbal therapies, not intended for the 
treatment of cancer may be used during the study at the discretion of the investigator.
4.4.3
Prohibited Therapy
No other hormonal therapy, chemotherapy, immunotherapy, or experimental anti-cancer 
medications will be permitted while the patient is in the study. 
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Hormone replacement therapy, selective ER modulators (e.g., raloxifene), and 
phytoestrogen-containing herbal therapies are prohibited
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for any adverse events prior to Day 1; dosing will occur 
only if the clinical assessment and local laboratory test values are acceptable.
Laboratory tests collected within 72 hours of Day 1 and deemed acceptable by the 
investigator may be used to proceed with dosing on Day 1. Laboratory tests must be
collected prior to dosing on Day 1.  In addition to the safety assessments conducted at 
scheduled clinic visits, patients will be contacted for a general assessment of adverse 
events at 24 hours post-surgery by telephone, if applicable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, breast cancer history 
(including tumor size, tumor grade, nodal status and PR status), and reproductive status, 
will be recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
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genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.
A limited, symptom-directed physical examinations should be performed at the 
post-surgery visit and will include an assessment of the surgery wound. Changes from 
baseline abnormalities should be recorded in patient notes. New or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of pulse rate, systolic and diastolic blood pressure 
(while the patient is in a seated position), and temperature (per institutional practice).  
Record abnormalities observed at baseline on the General Medical History and Baseline
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
4.5.5
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status scale will be assessed at screening and per Appendix 4.
4.5.6
Tumor Evaluations
Bilateral breast ultrasounds will be obtained per institutional guidelines within 28 days 
prior to enrollment. Ultrasounds performed prior to surgery may be unilateral or bilateral 
at the discretion of the investigator. If on ultrasound examination there is evidence of 
suspicious axillary lymph nodes at the baseline examination, then FNA or core biopsy is 
required. Sonographic tumor measurements are to be recorded in the eCRF. The 
tumor site may be marked with a radiopaque clip or marker via radiographic guidance 
(e.g., ultrasound) prior to initiation of neoadjuvant therapy.
4.5.7
Biological Response Assessment.
The biological response to the study treatment will be assessed by measuring changes 
in cell proliferation (Ki67 expression) using FFPE histopathology sections of the tumor 
biopsy specimens taken at baseline and at day of surgery.
4.5.8
Surgical Treatment Plan 
The planned and actual surgical treatment (breast-conserving surgery or mastectomy) 
performed should be documented and reported in the eCRF. Patients should be 
reassessed after completion of GDC-9545 administration and prior to surgery.
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4.5.9
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells)

Chemistry panel (serum or plasma): bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, magnesium, 
AST, ALT, total and direct bilirubin, and ALP

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination if clinically indicated (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria)

FSH; for patients 60 years

Estradiol; for patients 60 years

Coagulation (PT. aPTT, and INR) 
The following samples will be sent to the Sponsor or a designee for analysis:

Plasma samples for PK analysis

Blood samples for analysis of ctDNA and plasma biomarkers

Blood samples for NGS

Archival (diagnostic) or newly collected tumor tissue sample obtained prior to 
initiation of treatment
A representative FFPE tumor specimen in a paraffin block (preferred) or 
approximately 15 unstained, serial sections, (freshly cut) must be submitted 
along with an associated pathology report.  Confirmation of available tissue 
sample is required prior to enrollment. If less than 15 slides are available, the 
patient may still be eligible for the study after Medical Monitor approval has 
been obtained.
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples should contain a minimum of 500 viable tumor cells per section that 
preserve cellular context and tissue architecture regardless of needle gauge or 
retrieval method. Samples collected via resection, core-needle biopsy (at least 
two cores, three preferable, embedded in a single paraffin block), or excisional, 
incisional, punch, or forceps biopsy are acceptable.  FNA (defined as samples 
that do not preserve tissue architecture and yield cell suspension and/or 
smears), brushing, cell pellets from pleural effusion, and lavage samples are 
not acceptable.
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required (at least three cores).  
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
An FFPE tumor block from surgical resection or tissue sample obtained on Day 14
is required.  If a tumor block cannot be submitted for various reasons (e.g., the 
tumor tissue is not sufficient at surgical resection or due to site restrictions), 
approximately 15 unstained slides from the surgical specimen are required. The 
surgical specimen is not required if biopsy is obtained on Day 14.
Exploratory biomarker research using blood, plasma, and tissue samples may include, 
but will not be limited to, protein-based analyses, copy number and mutational analysis 
of cancer-related genes, gene expression of ER target genes and signatures associated 
with breast cancer subtypes, immune-related and PI3K signaling, and analysis of ctDNA.
Exploratory biomarker research may involve extraction of DNA, ctDNA, or RNA; analysis 
of somatic mutations and chromosomal alterations; and use of NGS.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11, biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Plasma samples collected for PK analysis may be needed for additional exploratory 
research, such as PK or PD assay development and validation; therefore, these 
samples will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed.

Blood, plasma, and tumor tissue samples collected for biomarker research will be 
destroyed no later than 15 years after the final Clinical Study Report has been 
completed or earlier depending on local regulations

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than 18 months after final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site after eligibility determination.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests 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.
Data arising from sample analysis including data on mutations will be subject to the 
confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients 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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4.5.10
Electrocardiograms
Triplicate ECG recordings will be obtained at specified timepoints, as outlined in the
schedule of activities (see Appendix 1).  ECGs acquired on different days should be as 
closely time-matched as feasible.  Three interpretable ECG recordings (e.g., without 
artifacts) must be obtained at each timepoint (5 minutes).  The average of the three 
readings will be used to determine ECG intervals (e.g., PR, QRS, QT).  Single ECG 
recordings may be obtained at unscheduled timepoints as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws).  Circumstances that may induce changes 
in heart rate, including environmental distractions (e.g., television, radio, conversation),
should be avoided during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following should be recorded in the appropriate eCRF:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF based 
on the machine readings of the individual ECG tracings.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  If considered 
appropriate by the Sponsor, ECGs may be analyzed retrospectively at a central 
laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another triplicate ECG must be recorded, ideally within the next 
5 minutes, and triplicate ECG monitoring should continue until QTcF has stabilized on 
two successive ECGs.  The Medical Monitor should be notified.  Standard-of-care 
treatment may be instituted per the discretion of the investigator.  If a PK sample is not 
scheduled for that timepoint, an unscheduled PK sample should be obtained.  A decision 
on study drug discontinuation should be made, as described in Section 5.1.2.  The 
investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval
[see Appendix 2 and Appendix 3], severe bradycardia).
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4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

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
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's Institutional Review Board or Ethics Committee (IRB/EC) and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for RBR 
sampling, this section of the protocol (Section 4.5.11) will not be applicable at that site.
4.5.11.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to GDC-9545, diseases, or 
drug safety:

Leftover blood, plasma, and FFPE tissue samples (with the exception of remaining 
archival tissue blocks, which will be returned to sites) and any derivatives thereof 
(e.g., DNA, RNA, proteins, peptides), including leftover tissue samples from 
medically indicated procedures performed at the investigator's discretion during the 
course of the study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods. Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
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comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to 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 Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.11.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients 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 from RBR samples 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.
4.5.11.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
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and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient 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 
samples and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.11.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice 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 samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient 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.
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4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of 
the following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Adverse event that, in the investigator's or surgeon’s opinion, has the potential to 
delay surgery

Any other adverse event that cannot be adequately managed 

Protocol violation requiring discontinuation of study treatment

Patient is not compliant with study procedures

Patient is lost to follow-up
The primary reason for study treatment discontinuation should be documented on 
the appropriate eCRF.  Patients who discontinue study treatment prematurely will 
be replaced.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor

Adverse event

Loss to follow-up
Every effort should be made to obtain a reason for patient discontinuation from the study
but have not withdrawn consent.  The primary reason for discontinuation from the study 
should be documented on the appropriate eCRF.  If a patient requests to be withdrawn 
from the study, this request must be documented in the source documents and signed 
by the investigator.  Patients who withdraw from the study will be replaced.
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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
GDC-9545 is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on the anticipated mechanism of action, nonclinical data 
(in vitro and in vivo), published data on similar molecules, and clinical experience with 
GDC-9545.  The anticipated important safety risks for GDC-9545 are outlined below.  
Please refer to the GDC-9545 Investigator's Brochure for a complete summary of safety 
information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities (see 
Section 4.1.2).  Patients will undergo real-time safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  In 
addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided below.
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5.1.1
Potential Risks Associated with GDC-9545
5.1.1.1
Hepatotoxicity
Dose-dependent hepatic effects were observed in repeat-dose studies in both rats and 
monkeys given GDC-9545.  Microscopic changes and liver enzyme elevations were 
observed.  Changes were reversible at all dose levels assessed.  Please refer to the 
GDC-9545 Investigator’s Brochure for further information.
Liver enzyme elevation has been reported in association with some oral SERD 
molecules currently in early development (see GDC-9545 Investigator’s Brochure for 
further information).  Changes in liver enzymes have been reported with the oral 
selective estrogen receptor modulator (SERM) tamoxifen (reported as common, 
1% to 10%) and the injectable SERD fulvestrant (reported as very common, 10%) 
(eMC 2016a; 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 (1/1000 to 1/100) in patients receiving fulvestrant.
Guidelines for management of patients who develop hepatotoxicity are provided 
in Table 1.
5.1.1.2
Gastrointestinal Toxicities (Nausea, Vomiting, Diarrhea)
During repeat-dose testing of GDC-9545 with monkeys, vomiting, diarrhea, and soft 
stools were reported. Please refer to the GDC-9545 Investigator’s Brochure for further 
information.
GI toxicities have been reported in association with some oral SERD molecules currently 
in early development (see GDC-9545 Investigator’s Brochure for further information).  
The mechanism of action of SERD associated GI toxicities is not clear and without 
randomized data, it is impossible to be sure if there is a true treatment effect.  However, 
patients should be closely monitored for GI effects and any consequent sequelae such 
as changes in blood chemistry parameters or dehydration.
Guidelines for management of patients who develop GI toxicities are provided in Table 1.
5.1.1.3
Thromboembolic Events
No evidence of thrombosis, bleeding events, or wound closure issues were seen in 
nonclinical studies in rats and monkeys given GDC-9545.
Thromboembolic events may 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) (eMC 2016a).  There are no randomized placebo controlled 
data from oral SERD programs at present.
The SERM tamoxifen is reported to carry a 2- to 3-fold increased risk of thromboembolic 
events in the adjuvant setting (eMC 2016b).
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To date, no patients treated with GDC-9545 in ongoing Phase I Study GO39932 have
experienced any thromboembolic events or issues with wound healing. However, given
limited data, high-risk patients (e.g., patients with a history of bleeding diathesis,
coagulopathy, low platelet counts, or need for long-term anticoagulant therapy) are
excluded from this study to minimize unexpected risk to patients (see Section 4.1.2).
Guidelines for management of patients who develop thromboembolic toxicities are 
provided in Table 1.
5.1.1.4
Renal Dysfunction
Dose-dependent effects on the kidneys were observed in repeat-dose studies in both 
rats and monkeys given GDC-9545. Microscopic findings consistent with renal injury 
were observed along with mild increases in creatinine, urea, and phosphorus.  Some 
findings were reversible during the recovery phase in monkeys at the recovery dose 
assessed, but no reversibility was observed in rats.  Please refer to the GDC-9545 
Investigator’s Brochure for further information.
Renal failure or acute kidney injury are not listed as unwanted effects of fulvestrant
(eMC 2016a).
Renal function tests will be closely monitored in GDC-9545 studies with serum creatinine 
and BUN measurements.
Guidelines for management of patients with renal dysfunction are provided in Table 1.
5.1.1.5
Changes in Female Reproductive Organs and Menopausal 
Symptoms
GDC-9545-related effects in reproductive tissues consistent with expected 
pharmacology of GDC-9545 on ER degradation were observed at all doses in rats and 
monkeys in repeat-dose toxicity studies.  Changes observed included ovarian follicular 
cysts (including intracystic hemorrhage), decreased uterine weight, cervical and vaginal 
epithelial atrophy, and decreased pituitary gland weight.  Changes were partially 
reversible in monkeys and not reversible in rats during the follow-up period possibly due 
to the presence of pharmacologically active exposures of GDC-9545 at the end of the 
28-day recovery period.  Please refer to the GDC-9545 Investigator’s Brochure for 
further information.
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.  Please refer to the GDC-9545 Investigator’s 
Brochure for further information.
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Unlike GDC-9545, the SERM tamoxifen promotes the growth of endometrial tissue in 
vitro, acting as an agonist of ER in that tissue (Hu et al. 2015).  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.
Changes in reproductive organs and menopausal symptoms should be managed 
according to local standards of care.
It is recommended that a specialist gynecological opinion be sought in the event of any 
abnormal bleeding from the reproductive tract.
5.1.1.6
Female Infertility
GDC-9545 has not been tested in male animals.  Perturbation and arrest of the estrus 
cycle was observed microscopically in both female rats and monkeys.  This was not 
reversible during the follow-up period.
It is unknown whether a longer recovery period in animals would reveal whether the 
observed perturbation in the estrus cycle is reversible. While this finding remains 
incompletely explained pending further study with a longer recovery period, any patients
with concerns for future fertility should be made aware of this potential issue prior to 
coming onto this study. Their concerns, including fertility preservation, should be 
discussed prior to enrolling into any study with GDC-9545.  Please refer to the 
GDC-9545 Investigator’s Brochure for further information.
5.1.1.7
Bradycardia
During the nonclinical 4-week toxicity study in cynomolgus monkeys, GDC-9545 related 
reductions in heart rate or increases in RR interval were observed (surface and 
telemetry leads) on 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 
cynomolgus monkey and not considered adverse.
At the time of the completion of the dose escalation portion of Study GO39932, three 
patients (10%) in the 90 mg cohort, had reported Grade 1 asymptomatic bradycardia. 
Upon further review of clinical safety data (vital signs/ECGs) patients at all dose levels 
were noted to have decreased heart rate from baseline and/or Grade 1 bradycardia. In 
all patients, bradycardia/decreased heart rate was not accompanied with clinically 
significant ECG changes or exercise intolerance. 
Until there is a clear understanding of the clinical profile of bradycardia with GDC-9545, 
ECGs will continue to be collected during the study. Caution should be taken with the 
coadministration of drugs known to cause decreases in heart rate.
Guidelines for management of patients who develop bradycardia are provided in Table 1.
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5.1.1.8
DrugDrug Interactions
Please refer to the Section 4.4.2.1 for the potential DDI risks and the recommendations 
of the concomitant medications and foods.
5.1.2
Management of Patients Who Experience Adverse Events
If, in the investigator's or surgeon's opinion, an adverse event has the potential to delay 
surgery, GDC-9545 treatment should be discontinued and the patient withdrawn from 
the study (see Section 4.6.1). Patients who discontinue study treatment prematurely will 
be replaced.
5.1.2.1
Dose Modifications
There will be no dose reductions allowed for GDC-9545. GDC-9545 may be held or 
discontinued per Section 5.1.2.3.
5.1.2.2
Treatment Interruption
GDC-9545 treatment may be temporarily suspended as appropriate for managing of
toxicity considered to be related to study drug.  The investigator and the Medical Monitor 
will determine the acceptable length of treatment interruption.
If a patient misses more than one dose, the Medical Monitor should be consulted about 
possible replacement of the patient.
5.1.2.3
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 1.  
Additional guidelines are provided in the subsections below.
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Table 1
Guidelines for Management of Patients Who Experience Specific 
Adverse Events
Event
Action to Be Taken
Elevation of hepatic 
transaminases

Patients presenting with jaundice, coagulopathy, abdominal pain, or 
other symptoms suggestive of hepatic pathology should have their 
liver function tests checked and imaging of the liver performed.  
If the liver enzymes are elevated with no obvious malignant cause 
found, a hepatologist should be consulted. 

Patients experiencing hepatic enzyme elevation should be treated 
and managed per standard of care.

Discontinue GDC-9545 for Grade 3 events and consult with the 
Medical Monitor.
Gastrointestinal 
toxicities (nausea, 
vomiting, diarrhea)

Monitor patients closely for GI symptoms and the effects on their 
well-being.  Patients experiencing nausea, vomiting, and diarrhea 
should be managed according to local standards of care, including 
use of anti-diarrheal agents and appropriate supportive care 
including hydration and dietary modification as appropriate. 
Infectious or alternate etiology should be excluded.

Discontinue GDC-9545 for Grade 3 events and consult with the 
Medical Monitor. 
Venous thromboembolic 
events including 
pulmonary embolism

Patients should be advised to seek immediate medical attention if 
they become aware of any symptoms of pulmonary embolism or 
DVT, such as acute onset of chest pain, shortness of breath, or 
swelling in extremities.

Manage and treat patients according to local standards of care
(e.g., consider anti-coagulation and/or IVC filter).

Discontinue GDC-9545 for related VTE or pulmonary embolism and 
consult with the Medical Monitor.
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Table 1
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Renal toxicity (decrease 
in post-treatment GFR 
of 25% potentially 
attributed to GDC-9545)

Patients experiencing deterioration in renal function should be 
treated and managed according to local standard of care.

Discontinue GDC-9545 and consult with the Medical Monitor.
Bradycardia

Monitor patients closely for symptomatic bradycardia that may have 
effects on their well-being. 

Patients experiencing symptomatic bradycardia should be treated 
and managed per standard of care.

For Grade 2 bradycardia, withhold GDC-9545 and consult with the 
Medical Monitor.  GDC-9545 is not to be resumed without 
permission from the Medical Monitor. 

For Grade 3 bradycardia, discontinue GDC-9545 and consult with
the Medical Monitor.
Grade 3 adverse
events potentially 
attributed to GDC-9545

Discontinue GDC-9545 and consult with the Medical Monitor. 
DVT deep vein thrombosis; GFRglomerular filtration rate; GIgastrointestinal; IVCinferior 
vena cava; PEpulmonary embolism; ULNupper limit of normal; VTEvenous thromboembolic 
events.
5.1.2.4
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms and 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Therefore, it is critical that 
expert cardiology advice be sought to confirm any ECG changes and to ascertain the 
likelihood of a drug-induced arrhythmia versus the background occurrence of this 
arrhythmia.  In such a situation, saving all available ECG data is highly suggested.
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
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interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, 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.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event 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) (see Sections 5.3.5.8
and 5.3.5.9 for more information)

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)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)
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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient'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 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
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 immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

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

Any Grade of endometrial cancer

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 5.3.5.6)
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
Suspected transmission of an infectious agent by the study drug, as defined below:
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 patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.1.2 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient 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?"
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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v 5.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 2
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 living a
3
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v 5.0), 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 patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether 
an adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 3):

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
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
Presence of risk factors in the patient 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 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of 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 patient'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.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting 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).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event 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 Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
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5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events 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 adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event 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 consequent 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 adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event 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 serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
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5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event 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 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
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 adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event 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 precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  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 Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event 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 
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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 adverse event.
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 Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) 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 as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of breast cancer
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 Adverse Event 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 Adverse Event 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").
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If the death is attributed to progression of breast cancer, “breast cancer progression"
should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting 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.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST criteria.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious 
adverse event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Planned hospitalization required by the protocol for breast cancer surgery 

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
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
The patient has not experienced an adverse event
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse
(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

Intentional overdose:  intentional 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.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
GDC-9545, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
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
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with GDC-9545, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as 
described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

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.

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.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient: Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
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As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event 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.
5.4
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; 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 after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information for these events to the Sponsor immediately 
(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 serious adverse 
events to the local health authority and IRB/EC.
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the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study treatment are provided in Section 5.6.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
5.5.2
Sponsor Follow-Up
For serious adverse events and adverse events of special interest, 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.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 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 use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided in 
Section 5.4.2.1.
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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest 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 adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

GDC-9545 Investigator's Brochure
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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The final analysis will be performed after LPLV and subsequent data cleaning. The 
safety analysis will be based on the safety-evaluable population, and activity analysis will 
be based on the patients who completed study treatment. All summaries will be 
presented according to the assigned dose level and cohort. In general, data will be 
summarized as warranted, and listings will be used in place of tables when the samples 
sizes are small. Continuous variables will be summarized using means, standard 
deviations, median, and ranges; categorical variables will be summarized using counts 
and percentages.
6.1
DETERMINATION OF SAMPLE SIZE
This study is intended to obtain preliminary safety, PK, PD, and activity information. The 
sample sizes do not reflect any explicit power and type I error considerations.
The range of mean Ki67 expression changes are from 66% (Opportune) to 76% 
(IMPACT) for 2-week treatment (see Section 3.3.4.1). The planned enrollment for this 
study is approximately 75 patients. At least 15 patients per cohort will provide a more 
robust safety profile as well as sample size for preliminary assessment of activity based 
on Ki67 expression. In Table 4, two-sided 80% CIs for Ki67 expression changes are 
listed, based on different assumed observed changes. The CIs show clear shift pattern 
at the sample size of 15 patients. To better evaluate the Ki67 expression change at 30 
mg, the sample size is increased to 45.  The 80% CIs show clear separation at this 
patient sample size.
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Table 4
Two-Sided 80% Confidence Intervals for Ki67 Expression Change 
Assumed Observed Change
Sample size
60%
70%
80%
90%
15
(53.9%, 66.8%)
(62.9%, 77.9%)
(71.9%, 89.0%)
(80.9%, 100%)
20
(54.7%, 65.8%)
63.8%, 76.8%)
(72.9%, 87.8%)
(82.0%, 98.7%)
45
(56.4%, 63.8%)
(65.8%, 74.5%)
(75.2%, 85.1%)
(84.6%, 95.7%)
6.2
SUMMARIES OF CONDUCT OF STUDY
Summaries of study conduct will include all enrolled patients in the study. The number
of patients who enroll, discontinue, or complete the study will be summarized. Reasons 
for discontinuations and premature study withdrawal will be listed and summarized. 
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including, but not limited, to age, 
race/ethnicity, weight, type of malignancy, duration of malignancy, and baseline ECOG 
Performance Status) will be summarized using means, standard deviations, medians, 
and ranges for continuous variables and proportions for categorical variables, as 
appropriate. Summaries will be presented overall and by dose level.
6.4
SAFETY ANALYSES
For safety analyses, the analysis population will include all enrolled patients who receive 
at least one dose of study medication.
Study treatment discontinuation and reasons for patient discontinuations from the study 
will be described and summarized. Study drug administration data will be listed and any 
dose modifications will be flagged.
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results (including ECGs), changes in vital signs, and GDC-9545 exposure.
All adverse events occurring on or after treatment on Day 1 will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTCAE v5.0 toxicity grade.
Relevant laboratory and vital sign (pulse rate, blood pressure, and temperature) data will 
be displayed by time, with NCI CTCAE v5.0 Grade 3 and 4 values identified, where 
appropriate. Additionally, all laboratory data will be summarized by NCI CTCAE v5.0.
Safety data will be accumulated up to the end of the patient’s follow-up period.
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6.5
PHARMACOKINETIC ANALYSES
The sparse PK concentration data at the steady state will be summarized by dose level
and compared with the historical PK profiles from the Phase I study. 
Additional PK analyses may be conducted as appropriate.
6.6
ACTIVITY ANALYSES
The activity analysis population will consist of all patients who completed study treatment 
and who have tumor biopsy specimens available at baseline and at surgery for
assessment of activity.
The activity is defined as change from baseline in tumor cell proliferation measured by 
Ki67 expression between pre- and post-treatment samples. The activity will be 
summarized by dose level. 
On the assumption of a log normal distribution, Ki67 values will be log transformed 
before analysis.  Log(Ki67post) and log(Ki67pre) will be used to denote the mean of the 
logs of the post-treatment and pre-treatment values, respectively. A value of 0.1 will be 
added to every untransformed Ki67 value to avoid the mathematical anomaly that arises 
because the log of zero is minus infinity. The result of mean log changes and CI can be 
calculated and displayed on their original scale by back transformation.
6.7
BIOMARKER ANALYSES
Exploratory biomarker analyses may be performed in an effort to understand the
association of these markers with study treatment response. The biomarker analysis will
be descriptive in nature includes modulation of ER-target genes as well as ER and PR
protein levels.  
Although no formal statistical analysis of exploratory biomarkers will be performed, 
data may be analyzed in the context of this study and in aggregate with data from 
other studies.  
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
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The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and IxRS will be 
sent directly to the Sponsor, using the Sponsor's standard procedures to handle and 
process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
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 patient 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, patient-reported outcomes, 
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, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions 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.
7.4
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 health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper patient-reported outcome data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for at least 15 years after completion or 
discontinuation of the study or for the length of time required by relevant national or local 
health authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations.  
No records may 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.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national law.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
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A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient,
unless permitted or required by law.
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Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients 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 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on genomic variants, 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 Clinical Study Reports 
and other summary reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
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policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by Genentech, a member of the Roche Group.  
The Sponsor will provide clinical operations management, data management, and 
medical monitoring.
Approximately 2030 sites globally will participate to enroll approximately 75 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for more details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
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an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).
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10.
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Bosch A, Li Z, Bergamaschi A, et al. 1. PI3K inhibition results in enhanced estrogen 
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Cancer Genome Atlas Network 2012-Cancer Genome Atlas Network. Comprehensive 
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Chatman LA, Morton D, Johnson TO, et al. A strategy for risk management of 
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Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor 
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Di Leo A, Jerusalem G, Petruzelka 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.
Dowsett M, Ebbs SR, Dixon JM, et al. Biomarker changes during neoadjuvant 
anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-
2 in breast cancer-a study from the IMPACT trialists. J Clin Oncol 
2005a;23:247792.
Dowsett M, Smith IE, Ebbs SR, et al. Short-term changes in Ki67 during neoadjuvant 
treatment of primary breast cancer with anastrozole or tamoxifen alone or 
combined correlate with recurrence-free survival. Clin Cancer Res 
2005b;11:9518s.
Dowsett M, Smith IE, Ebbs SR, et al. Proliferation and apoptosis as markers of benefit in 
neoadjuvant endocrine therapy of breast cancer. Clin Cancer Res 
2006;12:102430s.
Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after short-
term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 
2007;99:16770.
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Ellis MJ, Suman VJ, Hoog J, et al. Randomized phase II neoadjuvant comparison 
between letrozole, anastrozole, and exemestane for postmenopausal women with 
estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes 
and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG 
Z1031. J Clin Oncol 2011;29:23429.
Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor-positive breast 
cancer based on postneoadjuvant endocrine therapy tumor characteristics. Natl 
Cancer Inst 2008;100:13808.
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[resource on the Internet]. 2016a [updated 23 September 2016; cited 1 March
2017]. Available from: https://www.medicines.org.uk/emc/medicine/14381.
[eMC] electronic Medicines Compendium. Tamoxifen 20 mg tablets [resource on the 
Internet]. 2016b [updated 8 July 2016; cited 1 March 2017]. Available from: 
https://www.medicines.org.uk/emc/medicine/30769.
Ferlay J., Soerjomataram I, Ervik M, et al. GLOBOCON 2012 v1. 0, Cancer incidence 
and mortality worldwide: IARC Cancer Base No. 11 [resource on the Internet]. 
Lyon, France: International Agency for Research on Cancer; 2013 [cited 16 August 
2016].  Available from: http://globocan.iarc.fr.
Forbes JF, Cuzick J, Buzdar A, et al. Effect of anastrozole and tamoxifen as adjuvant 
treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. 
Lancet Oncol 2008;9:4553
Fribbens C, O'Leary B, Kilburn L, et al. Plasma ESR1 Mutations and the Treatment of 
Estrogen Receptor-Positive Advanced Breast Cancer. J Clin Oncol 
2016;34:29618.
Guerrero-Zotano Al, Arteaga CL. Neoadjuvant Trials in ER+ Breast Cancer: A Tool for 
Acceleration of Drug Development and Discovery. Cancer Discov 2017 
Jun;7:56174.
Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or 
in Combination) trial after completion of 5 years' adjuvant treatment for breast 
cancer. Lancet 2005;365:602.
Hu R, Hilakivi-Clarke L, Clarke R. Molecular mechanisms of tamoxifen-associated 
endometrial cancer (Review). Oncol Lett 2015;9:1495-1501.
Jeselsohn R, Buchwalter G, De Angelis C, et al. ESR1 mutations—a mechanism for 
acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol 2015; 
12:57383.
Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active 
estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive 
breast cancer. Clin Cancer Res 2014; 20:175767.
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Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus 
exemestane alone after progression on non-steroidal aromatase inhibitors in 
postmenopausal patients with hormone-receptor-positive locally advanced or 
metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised 
trial. Lancet Oncol. 2013;14:98998.
Jones RL, Salter J, A'Hern R, et al. The prognostic significance of Ki67 before and after 
neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 
2009;116:5368.
Kuter I, Gee JM, Hegg R, et al. Dose-dependent change in biomarkers during 
neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a 
randomized Phase II study. Breast Cancer Res Treat 2012;133:23746.
Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in 
circulating lung-cancer cells. N Engl J Med 2008;359:366-77.
Michels WM, Grootendorst DC, Verduijn M, et al. Performance of the Cockcroft-Gault, 
MDRD, and new CKD-EPI formulas in relation to GFR, age, and body size. Clin J 
Am Soc Nephrol 2010;5:10039.
Miller TW, Hennessy BT, González-Angulo AM, et al. Hyperactivation of 
phosphatidylinositol-3 kinase promotes escape from hormone dependence in 
estrogen receptor-positive human breast cancer. J Clin Invest 2010;120:240613.
Polychronis A, Sinnett HD, Hadjiminas D, et al. Preoperative gefitinib versus gefitinib 
and anastrozole in postmenopausal patients with oestrogen-receptor positive and 
epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind 
placebo-controlled phase II randomised trial. Lancet Oncol 2005;6:38391.
Reasor MJ, Hastings KL, Ulrich RG. Drug-induced phospholipidosis: issues and future 
directions. Expert Opin Drug Saf 2006;5:56783.
Reinert T, Gonçalves R, Bines J. Implications of ESR1 Mutations in Hormone Receptor-
Positive Breast Cancer. Curr Treat Options Oncol 2018;19:24.
Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus 
anastrozole 1 mg for hormone receptor-positive advanced breast cancer 
(FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 
2016;388:29973005.
Robertson JFR, Dowsett M, Bliss JM, et al. Peri-operative aromatase inhibitor treatment 
in determining or predicting longterm outcome in early breast cancer – The 
POETIC* Trial (CRUK/07/015) [abstract]. SABCS17-GS1-03 2018; abstract GS1-03:
Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant
metastatic breast cancer. Nat Genet 2013;45:146651.
Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: 
increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast 
cancer. J Natl Cancer Inst 2004;96:926-35.
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Smith IE, Walsh G, Skene A, et al. A phase II placebo-controlled trial of neoadjuvant 
anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol 
2007;25:381622.
Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-
resistant breast cancer. Nat Genet 2013;45:143945.
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Appendix 1
Schedule of Activities
Screening
In–Clinic
Treatment
Surgery a
Post-Surgery 
Visit k
Day
(Window)
(Day 28 to 
Day 1)
1
8
(2)
15
(2)
43
(1 week)
Informed consent (Section 4.5.1) b
x
Medical history, demographic data and baseline conditions 
(Section 4.5.2)
x
Physical examination (Section 4.5.3)
x
x c
Height
x
Weight
x
Vital signs (Section 4.5.4)
x
x
x
x
x
ECOG performance status (Section 4.5.5)
x
x
x
x
Hematology (Section 4.5.9)
x d
x d
x
x
Chemistry (Section 4.5.9)
x d
x d
x
x
Coagulation (PT, aPTT, and INR) (Section 4.5.9) 
x d
x d
x
x
x
FSH (Section 4.5.9) e
x
Estradiol (Section 4.5.9) e
x
Triplicate 12-lead ECG (Section 4.5.10)
x
x
x f
x f
Tumor evaluation (Section 4.5.6)
x
Tumor tissue (Section 4.5.9)
x
x or 
biopsy on
Day 14
Confirmation of available tissue sample
x
Urinalysis (Section 4.5.9) 
x
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Appendix 1: Schedule of Activities
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Screening
In–Clinic
Treatment
Surgery a
Post-Surgery 
Visit k
Day
(Window)
(Day 28 to 
Day 1)
1
8
(2)
15
(2)
43
(1 week)
Plasma PK sample (Section 4.5.9) g
x or 
prior to biopsy 
on Day 14 
Blood sample for biomarkers (ctDNA) (Section 4.5.9)
x d
x or 
prior to biopsy 
on Day 14
x
Blood sample for biomarkers (NGS) (Section 4.5.9)
x d
Study drug compliance h
x
x
x
GDC-9545 dosing (Section 4.3.2)  i
x
x
Adverse events 
x
x 
x
x j
x
Concomitant medication
x
x
x
x
x
ctDNAcirculating-tumor DNA; ECOGEastern Cooperative Oncology Group; FSHfollicle-stimulating hormone; NGSnext-generation 
sequencing; PKpharmacokinetic.
a If surgery must be delayed 2 days, the Medical Monitor should be consulted.
b Signed informed consent must be provided prior to any study-specific evaluations.
c A limited, symptom-directed physical examinations should be performed at the post-surgery visit and will include an assessment of the surgery 
wound.
d Laboratory tests must be collected prior to dosing and preferably within 72 hours of Day 1.
e For patients 60 years only.
f
ECG should be performed if clinically indicated.
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g A single blood sample for PK needs to be collected prior to surgery or on Day 14 if biopsy obtained, and as close as possible to post-treatment 
biopsy collection.  The PK collection time and the dose administration time prior to PK collection should be recorded.
h Patients will receive and should be instructed to complete a medication diary (see Section 4.3.2).  The medication diary and unused drug and 
bottles of GDC-9545 should be collected and reviewed on Day 8 and at the surgery visit for drug accountability.
i
GDC-9545 will be orally self-administered on Days 114 (2 days).
j
Assessment of adverse events will also be done at 24 hours post-surgery (1 day) by telephone contact, if applicable.
k Post-surgery visit should be performed at Day 43(1 week) or prior to the initiation of another anti-cancer therapy, whichever occurs first.
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Appendix 2
Drugs with Known Torsades de Pointes Risk
Information available at www.azcert.org.
Amiodarone
Gatifloxacin
Sotalol
Anagrelide
Grepafloxacin
Sparfloxacin
Arsenic trioxide
Halofantrine
Sulpiride
Astemizole
Haloperidol
Sultopride
Azithromycin
Ibogaine
Terfenadine
Bepridil
Ibutilide
Terlipressin
Chloroquine
Levofloxacin
Terodiline
Chlorpromazine
Levomepromazine
Thioridazine
Cilostazol
Levomethadyl acetate
Vandetanib
Ciprofloxacin
Levosulpiride
Cisapride
Mesoridazine
Citalopram
Methadone
Clarithromycin
Moxifloxacin
Cocaine
Ondansetron
Disopyramide
Oxaliplatin
Dofetilide
Papaverine HCl
Domperidone
Pentamidine
Donepezil
Pimozide
Dronedarone
Probucol
Droperidol
Procainamide
Erythromycin
Propofol
Escitalopram
Quinidine
Flecainide
Roxithromycin
Fluconazole
Sevoflurane
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Appendix 3
Drugs Known to Increase QT Interval
Information available at www.azcert.org.
Alfuzosin
Gemifloxacin
Prothipendyl
Apomorphine
Granisetron
Rilpivirine
Aripiprazole
Hydrocodone - ER
Risperidone
Artenimol+piperaquine
Iloperidone
Romidepsin
Asenapine
Imipramine (melipramine)
Saquinavir
Atomoxetine
Isradipine
Sertindole
Bedaquiline
Ketanserin
Sorafenib
Bendamustine
Lapatinib
Sunitinib
Bortezomib
Lenvatinib
Tacrolimus
Bosutinib
Leuprolide
Tamoxifen
Buprenorphine
Lithium
Telavancin
Capecitabine
Melperone
Telithromycin
Ceritinib
Mifepristone
Tetrabenazine
Clomipramine
Mirabegron
Tiapride
Clozapine
Mirtazapine
Tizanidine
Crizotinib
Moexipril/HCTZ
Tolterodine
Cyamemazine
(cyamepromazine)
Nicardipine
Toremifene
Dabrafenib
Nilotinib
Trimipramine
Dasatinib
Norfloxacin
Tropisetron
Degarelix
Nortriptyline
Vardenafil
Delamanid
Ofloxacin
Vemurafenib
Desipramine
Osimertinib
Venlafaxine
Dexmedetomidine
Oxytocin
Vorinostat
Dolasetron
Paliperidone
Zotepine
Efavirenz
Panobinostat
Eribulin mesylate
Pasireotide
Ezogabine (Retigabine)
Pazopanib
Famotidine
Perflutren lipid microspheres
Felbamate
Perphenazine
Fingolimod
Pilsicainide
Flupentixol
Pipamperone
Foscarnet
Promethazine
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Appendix 4
Eastern Cooperative Oncology Group Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restrictions
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light housework or office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about 50% waking hours.
3
Capable of only limited self-care, confined to a bed or chair 50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair
5
Dead
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Appendix 5
American Joint Committee on Cancer TNM Classification of Malignant Tumors
Definition of Primary Tumor (T) – Clinical and Pathological
T Category
T Criteria
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis (DCIS)
Ductal carcinoma in situ
Tis (Paget)
Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast 
parenchyma.  Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and 
characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.
T1
Tumor 20 mm in greatest dimension
T1mi
Tumor 1 mm in greatest dimension
T1a
Tumor 1 mm but 5 mm in greatest dimension (round any measurement 1.01.9 to 2 mm)
T1b
Tumor 5 mm but 10 mm in greatest dimension
T1c
Tumor 10 mm but 20 mm in greatest dimension
T2
Tumor 20 mm but 50 mm in greatest dimension
T3
Tumor 50 mm in greatest dimension
T4
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the 
dermis alone does not qualify as T4
T4a
Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does 
not qualify as T4
T4b
Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d'orange) of the skin that does not meet 
the criteria for inflammatory carcinoma
T4c
Both T4a and T4b are present
T4d
Inflammatory carcinoma
Note:  Lobular carcinoma in situ (LCIS) is a benign entity and has been removed from TNM staging in AJCC Cancer Staging Manual 8th edition.
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Appendix 5: American Joint Committee on Cancer TNM Classification of Malignant Tumors
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Definition of Regional Lymph Nodes Clinical (cN)
cN Category
cN Criteria
cNX a
Regional lymph nodes cannot be assessed (e.g., previously removed)
cN0
No regional lymph node metastases (by imaging or clinical examination)
cN1
Metastases to movable ipsilateral Level I, II axillary lymph node(s)
cN1mi b
Micrometastases (approximately 200 cells, larger than 0.2 mm, but not larger than 2.0 mm
cN2
Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted; 
or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases
cN2a
Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures
cN2b
Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases
cN3
Metastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary lymph node involvement;
or in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases;
or in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
cN3a
Metastases in ipsilateral infraclavicular lymph node(s)
cN3b
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
cN3c
Metastases in ipsilateral supraclavicular lymph node(s)
Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of the metastasis by sentinel node biopsy or fine-needle 
aspiration/ core needle biopsy respectively.
a The cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no 
documentation of physical examination of the axilla.
b cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in 
cases treated with neoadjuvant therapy.
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Appendix 5: American Joint Committee on Cancer TNM Classification of Malignant Tumors
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Definition of Regional Lymph Nodes Pathological (pN)
pN Category
pN Criteria
pNX
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study)
pN0
No regional lymph node metastasis identified or ITCs only
pN0(i )
ITCs only (malignant cell clusters no larger than 0.2 mm) in regional lymph node(s)
pN0(mol )
Positive molecular findings by RT-PCR; no ITCs detected 
pN1
Micrometastases;
or Metastases in 1–3 axillary lymph nodes;
and/or clinically negative internal mammary nodes with micrometastases or micrometastases by sentinel lymph node biopsy 
pN1mi
Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)
pN1a
Metastases in 1–3 axillary lymph nodes, at least one metastasis larger than 2.0 mm
pN1b
Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs
pN1c
pN1a and pN1b combined
pN2
Metastases in 4–9 axillary lymph nodes; 
or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases
pN2a
Metastases in 4–9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)
pN2b
Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically 
negative axillary nodes
pN3
Metastases in 10 or more axillary lymph nodes;
or in infraclavicular (Level III axillary) lymph nodes;
or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level I, II axillary 
lymph nodes
or in more than three axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically 
negative ipsilateral internal mammary lymph nodes;
or in ipsilateral supraclavicular lymph nodes 
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Appendix 5: American Joint Committee on Cancer TNM Classification of Malignant Tumors 
 
GDC-9545—Genentech, Inc. 
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Definition of Regional Lymph Nodes − Pathological (pN) (cont.) 
pN Category 
pN Criteria 
pN3a 
Metastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); 
or metastases to the infraclavicular (Level III axillary lymph) nodes. 
pN3b 
pN1a and pN2a in the presence of cN2b (positive internal mammary lymph nodes by imaging)  
or pN2a in the presence of pN1b  
pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
ITC =  isolated tumor cell clusters; RT-PCR = reverse transcriptase polymerase chain reaction. 
Note:  (sn) and (f) suffixes should be added to the N category to denote confirmation of the metastasis by sentinel node biopsy or fine-needle 
aspiration/ core needle biopsy respectively, with no further resection nodes. 
 
 
Distant Metastases (M) 
M Category 
M Criteria 
M0 
No clinical or radiographic evidence of distant metastases a  
cM0(i + ) 
No clinical or radiographic evidence of distant metastases in presence of tumor cells or deposits no larger than 0.2 mm detected 
microscopically or by molecular techniques in circulating blood, bone marrow, or other non-regional nodal tissue in a patient 
without symptoms or signs of metastases 
M1 
Distant metastases detected by clinical and radiographic means (cM) and/or histologically proven metastases larger than 0.2 mm 
(pM) 
a Note that imaging studies are not required to assign the cM0 category.  
 
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Appendix 5: American Joint Committee on Cancer TNM Classification of Malignant Tumors
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90/Protocol GO40987, Version 4
Anatomic Stage/Prognostic Groups
Stage
T
N
M
0
Tis
N0
M0
IA
T1
N0
M0
IB
T0
N1mi
M0
T1
N1mi
M0
IIA
T0
N1
M0
T1
N1
M0
T2
N0
M0
IIB
T2
N1
M0
T3
N0
M0
IIIA
T0
N2
M0
T1
N2
M0
T2
N2
M0
T3
N1
M0
T3
N2
M0
IIIB
T4
N0
M0
T4
N1
M0
T4
N2
M0
IIIC
Any T
N3
M0
IV
Any T
Any N
M1
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Appendix 5: American Joint Committee on Cancer TNM Classification of Malignant Tumors
GDC-9545—Genentech, Inc.
91/Protocol GO40987, Version 4
Note:  T1 includes T1mi  
T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.  
M0 includes M0(i+)
The designation pM0 is not valid; any M0 is clinical.  
If a patient presents with M1 prior to neoadjuvant systemic therapy , the stage is Stage IV and remains Stage IV regardless of response to 
neoadjuvant therapy.  
Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed 
within 4 months of diagnosis in the absence of disease progression and provided the patient has not received neoadjuvant therapy. 
Staging following neoadjuvant therapy is denoted with a “ye” or “yp” prefix to the T and N.  No stage group is assigned if there is a complete 
pathological response (pCR) to neoadjuvant therapy for example, ypT0ypN0cM0.
Reference
Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 8th ed.  New York, NY: Springer, 2017;589631.
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