Conditions: Early Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 221
Healthy volunteers: no

Brief summary:
This is a randomized, multicenter, open-label, two-arm, Phase II study to evaluate the efficacy, safety, and pharmacokinetics of giredestrant versus anastrozole (in the window-of-opportunity phase) and giredestrant plus palbociclib compared with anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with untreated, estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, early breast cancer.

The study consists of a screening period of up to 28 days, a window-of-opportunity phase for 14 days, followed by a neoadjuvant treatment phase for 16 weeks (four 28-day cycles), surgery, and an end of study visit (28 days after the final dose of study treatment).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Giredestrant intervention 2: Anastrozole intervention 3: Palbociclib intervention 4: Surgery
Intervention descriptions: intervention 1: During the window-of-opportunity phase (first 2 weeks) giredestrant will be taken orally once per day (QD) as a single agent. During the neoadjuvant treatment phase, giredestrant will be taken orally QD on Days 1-28 of each 28-day cycle for a total of 4 cycles, in combination with palbociclib. intervention 2: During the window-of-opportunity phase (first 2 weeks), anastrozole 1 mg will be taken orally QD as a single agent. During the neoadjuvant treatment phase, anastrozole 1 mg will be taken orally QD on Days 1-28 of each 28-day cycle for a total of 4 cycles, in combination with palbociclib. intervention 3: During the neoadjuvant treatment phase, palbociclib 125 mg will be taken orally QD on Days 1-21 of a 28-day cycle for a total of 4 cycles. intervention 4: Surgery must be performed within a maximum of 14 days after the final cycle in the neoadjuvant treatment phase and ideally should occur as soon as possible after the last dose of study treatment.

Protocol document:
Prot_SAP_001.pdf: 
Official Title: 
A Randomized, Multicenter, Open-Label, Two-Arm, Phase II, 
Neoadjuvant Study Evaluating the Efficacy, Safety, and 
Pharmacokinetics of GDC-9545 Plus Palbociclib Compared With 
Anastrozole Plus Palbociclib for Postmenopausal Women With 
Estrogen Receptor-Positive and HER2-Negative Untreated Early 
Breast Cancer 
NCT Number: 
NCT04436744 
Document Date: 
Protocol Version 1: 08-April-2020 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (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 Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
GDC-9545—F. Hoffmann-La Roche Ltd
Protocol WO42133, Version 1
PROTOCOL
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
TWO-ARM, PHASE II, NEOADJUVANT STUDY 
EVALUATING THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF GDC-9545 PLUS 
PALBOCICLIB COMPARED WITH ANASTROZOLE
PLUS PALBOCICLIB FOR POSTMENOPAUSAL 
WOMEN WITH ESTROGEN RECEPTOR-POSITIVE 
AND HER2-NEGATIVE UNTREATED EARLY 
BREAST CANCER
PROTOCOL NUMBER:
WO42133
VERSION NUMBER:
1
EUDRACT NUMBER:
2020-001007-16
IND NUMBER:
132673
NCT NUMBER:
To be determined 
TEST PRODUCT:
GDC-9545 (RO7197597)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
08-Apr-2020 23:34:09
Title
Approver's Name
Company Signatory
Date and Time (UTC)
"Use of this document is governed by the terms of use on the first page of this document."


GDC-9545—F. Hoffmann-La Roche Ltd
2/Protocol WO42133, Version 1
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 21
1.1
Background on Hormone-Receptor Positive 
Breast Cancer........................................................................ 21
1.2
Background on Anastrozole in Early Breast 
Cancer................................................................................... 21
1.3
Background on CDK4/6 Inhibitors in Breast 
Cancer................................................................................... 22
1.4
Background on GDC-9545 .................................................... 23
1.4.1
Nonclinical Data..................................................................... 23
1.4.2
Clinical Data .......................................................................... 24
1.5
Study Rationale and BenefitRisk Assessment..................... 27
1.5.1
Rationale for Exploring GDC-9545 in Early 
Breast Cancer........................................................................ 27
1.5.2
Rationale for the Window-of-Opportunity Phase.................... 28
1.5.3
Rationale for the Neoadjuvant Phase.................................... 28
2.
OBJECTIVES AND ENDPOINTS ............................................................... 30
2.1
Efficacy Objectives ................................................................ 31
2.1.1
Primary Efficacy Objective..................................................... 31
2.1.2
Secondary Efficacy Objective................................................ 31
2.1.3
Exploratory Efficacy Objective............................................... 31
2.2
Safety Objectives................................................................... 31
2.3
Pharmacokinetic Objective .................................................... 32
2.4
Biomarker Objective .............................................................. 32
3.
STUDY DESIGN......................................................................................... 32
3.1
Description of the Study......................................................... 32
3.2
End of Study and Length of Study......................................... 36
3.3
Rationale for Study Design.................................................... 36
3.3.1
Rationale for GDC-9545 and Palbociclib Dose 
and Schedule......................................................................... 36
3.3.2
Rationale for Patient Population ............................................ 37
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3/Protocol WO42133, Version 1
3.3.3
Rationale for Control Group................................................... 37
3.3.4
Rationale for Biomarker Assessments................................... 37
3.3.4.1
Rationale for Changes in Ki67 as Primary 
Endpoint ................................................................................ 38
3.3.4.2
Rationale for the Collection of Plasma Samples 
for Somatic Tumor Mutation Analysis .................................... 39
3.3.4.3
Rationale for the Collection of Tissue Samples ..................... 39
3.3.5
Rationale for Non-Standard Clinical Outcome 
Assessments ......................................................................... 40
4.
MATERIALS AND METHODS .................................................................... 40
4.1
Patients.................................................................................. 40
4.1.1
Inclusion Criteria.................................................................... 40
4.1.2
Exclusion Criteria................................................................... 42
4.2
Method of Treatment Assignment.......................................... 44
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 45
4.3.1
Study Treatment Formulation and Packaging........................ 45
4.3.1.1
GDC-9545 ............................................................................. 45
4.3.1.2
Anastrozole............................................................................ 45
4.3.1.3
Palbociclib ............................................................................. 45
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 45
4.3.2.1
GDC-9545, Palbociclib, and Anastrozole............................... 46
4.3.2.2
Compliance............................................................................ 46
4.3.3
Investigational Medicinal Product Accountability ................... 47
4.3.4
Continued Access to GDC-9545............................................ 48
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 48
4.4.1
Permitted Therapy................................................................. 48
4.4.2
Cautionary Therapy ............................................................... 48
4.4.2.1
CYP3A4 Substrate with a Narrow Therapeutic 
Index...................................................................................... 48
4.4.2.2
Medications Associated with QT Interval 
Prolongation .......................................................................... 49
4.4.2.3
Herbal Therapies................................................................... 49
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GDC-9545—F. Hoffmann-La Roche Ltd
4/Protocol WO42133, Version 1
4.4.3
Prohibited Therapy ................................................................ 50
4.4.4
Prohibited Food ..................................................................... 51
4.5
Study Assessments ............................................................... 51
4.5.1
Informed Consent Forms and Screening Log........................ 51
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 51
4.5.3
Additional Restrictions ........................................................... 52
4.5.4
Physical Examinations........................................................... 52
4.5.5
Vital Signs.............................................................................. 52
4.5.6
Local-Regional Tumor Status ................................................ 52
4.5.7
Tumor and Response Evaluations......................................... 52
4.5.8
Tumor Staging....................................................................... 53
4.5.9
ECOG Performance Status ................................................... 53
4.5.10
Ki67 Assessment................................................................... 53
4.5.11
Surgical Treatment Plan ........................................................ 55
4.5.12
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 55
4.5.13
Electrocardiograms................................................................ 57
4.5.14
Clinical Outcome Assessments ............................................. 58
4.5.14.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 58
4.5.14.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 59
4.5.15
Blood Samples for Whole Genome Sequencing 
or Whole Exome Sequencing (Patients at 
Participating Sites)................................................................. 60
4.5.16
Optional Tumor Biopsies ....................................................... 61
4.5.17
Optional Samples for Research Biosample 
Repository ............................................................................. 61
4.5.17.1
Overview of the Research Biosample Repository.................. 61
4.5.17.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 62
4.5.17.3
Sample Collection.................................................................. 62
4.5.17.4
Confidentiality........................................................................ 63
4.5.17.5
Consent to Participate in the Research 
Biosample Repository............................................................ 63
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5/Protocol WO42133, Version 1
4.5.17.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 63
4.5.17.7
Monitoring and Oversight....................................................... 64
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 64
4.6.1
Study Treatment Discontinuation........................................... 64
4.6.2
Patient Discontinuation from the Study.................................. 65
4.6.3
Study Discontinuation............................................................ 65
4.6.4
Site Discontinuation............................................................... 65
4.6.5
Clinical Trial Conduct, in Light of COVID-19 or 
Other Significant Events with Global Impact.......................... 66
5.
ASSESSMENT OF SAFETY....................................................................... 66
5.1
Safety Plan ............................................................................ 66
5.1.1
Potential Risks Associated with GDC-9545........................... 67
5.1.1.1
Hepatoxicity........................................................................... 67
5.1.1.2
Gastrointestinal Toxicities...................................................... 67
5.1.1.3
Venous Thromboembolic Events (including 
Pulmonary Embolism)............................................................ 67
5.1.1.4
Bradycardia ........................................................................... 68
5.1.1.5
Renal Toxicity or Increased Creatinine.................................. 68
5.1.1.6
Changes in Female Reproductive Organs and 
Menopausal Symptoms ......................................................... 68
5.1.1.7
Female Fertility...................................................................... 69
5.1.1.8
Embryofetal Toxicity .............................................................. 69
5.1.1.9
Drug-Drug Interactions .......................................................... 69
5.1.2
Risks Associated with Palbociclib.......................................... 69
5.1.3
Risks Associated with Anastrozole........................................ 69
5.1.4
Management of Patients Who Experience 
Adverse Events ..................................................................... 69
5.1.4.1
Dose Modifications ................................................................ 69
5.1.4.2
Treatment Interruption ........................................................... 70
5.1.4.3
Management Guidelines........................................................ 71
5.2
Safety Parameters and Definitions ........................................ 73
5.2.1
Adverse Events ..................................................................... 73
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6/Protocol WO42133, Version 1
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 74
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 75
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 75
5.3.1
Adverse Event Reporting Period ........................................... 75
5.3.2
Eliciting Adverse Event Information....................................... 76
5.3.3
Assessment of Severity of Adverse Events ........................... 76
5.3.4
Assessment of Causality of Adverse Events ......................... 77
5.3.5
Procedures for Recording Adverse Events............................ 77
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 78
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 78
5.3.5.3
Persistent or Recurrent Adverse Events................................ 78
5.3.5.4
Abnormal Laboratory Values ................................................. 79
5.3.5.5
Abnormal Vital Sign Values ................................................... 79
5.3.5.6
Abnormal Liver Function Tests.............................................. 80
5.3.5.7
Deaths ................................................................................... 80
5.3.5.8
Preexisting Medical Conditions.............................................. 81
5.3.5.9
Lack of Efficacy or Worsening of Breast Cancer ................... 81
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 81
5.3.5.11
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse .......................................................... 82
5.3.5.12
Patient-Reported Outcome Data ........................................... 84
5.3.5.13
Safety Biomarker Data........................................................... 84
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 84
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 85
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 85
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 85
5.4.2.2
Events That Occur after Study Drug Initiation........................ 85
5.4.3
Reporting Requirements for Pregnancies.............................. 86
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GDC-9545—F. Hoffmann-La Roche Ltd
7/Protocol WO42133, Version 1
5.4.3.1
Pregnancies in Female Patients............................................ 86
5.4.3.2
Abortions ............................................................................... 86
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 87
5.5
Follow-Up of Patients after Adverse Events .......................... 87
5.5.1
Investigator Follow-Up........................................................... 87
5.5.2
Sponsor Follow-Up ................................................................ 87
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 87
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 87
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 88
6.1
Determination of Sample Size ............................................... 88
6.2
Summaries of Conduct of Study............................................ 89
6.3
Summaries of Treatment Group Comparability ..................... 89
6.4
Efficacy Analyses .................................................................. 89
6.4.1
Primary Efficacy Endpoint...................................................... 89
6.4.2
Secondary Efficacy Endpoints............................................... 89
6.4.3
Exploratory Efficacy Endpoints.............................................. 90
6.5
Safety Analyses..................................................................... 90
6.5.1
Analyses of Exposure, Adverse Event, 
Laboratory, and Vital Sign Data............................................. 90
6.5.2
Exploratory Analyses of Patient-Reported 
Outcome Data ....................................................................... 91
6.6
Pharmacokinetic Analyses..................................................... 91
6.7
Biomarker Analyses............................................................... 91
6.8
Optional Interim Analysis....................................................... 92
7.
DATA COLLECTION AND MANAGEMENT ............................................... 92
7.1
Data Quality Assurance......................................................... 92
7.2
Electronic Case Report Forms............................................... 92
7.3
Source Data Documentation.................................................. 92
7.4
Use of Computerized Systems .............................................. 93
7.5
Retention of Records............................................................. 93
8.
ETHICAL CONSIDERATIONS.................................................................... 94
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GDC-9545—F. Hoffmann-La Roche Ltd
8/Protocol WO42133, Version 1
8.1
Compliance with Laws and Regulations ................................ 94
8.2
Informed Consent.................................................................. 94
8.3
Institutional Review Board or Ethics Committee.................... 95
8.4
Confidentiality........................................................................ 96
8.5
Financial Disclosure .............................................................. 96
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 97
9.1
Study Documentation ............................................................ 97
9.2
Protocol Deviations................................................................ 97
9.3
Management of Study Quality ............................................... 97
9.4
Site Inspections ..................................................................... 97
9.5
Administrative Structure......................................................... 97
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 98
9.7
Protocol Amendments ........................................................... 99
10. REFERENCES ......................................................................................... 100
LIST OF TABLES
Table 1
Dose Reductions for Palbociclib ................................................. 70
Table 2
Guidelines for Management of Patients Who Experience 
Adverse Events Associated with GDC-9545............................... 71
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 76
Table 4
Causal Attribution Guidance ....................................................... 77
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 35
Figure 2
Study Treatment Regimens ........................................................ 46
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GDC-9545—F. Hoffmann-La Roche Ltd
9/Protocol WO42133, Version 1
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 105
Appendix 2
Schedule of Pharmacokinetic and Biomarker Samples ............ 109
Appendix 3
National Cancer Institute Patient-Reported Outcomes 
Common Terminology Criteria for Adverse Events 
(NCI PRO-CTCAE) Items.......................................................... 110
Appendix 4
Modified Response Evaluation Criteria in Solid Tumors: 
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer........................................................................... 112
Appendix 5
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 117
Appendix 6
Cancer Therapy Satisfaction Questionnaire.............................. 118
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GDC-9545—F. Hoffmann-La Roche Ltd
10/Protocol WO42133, Version 1
PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
TWO-ARM, PHASE II, NEOADJUVANT STUDY 
EVALUATING THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF GDC-9545 PLUS 
PALBOCICLIB COMPARED WITH ANASTROZOLE
PLUS PALBOCICLIB FOR POSTMENOPAUSAL 
WOMEN WITH ESTROGEN RECEPTOR-POSITIVE 
AND HER2-NEGATIVE UNTREATED EARLY 
BREAST CANCER
PROTOCOL NUMBER:
WO42133
VERSION NUMBER:
1
EUDRACT NUMBER:
2020-001007-16
IND NUMBER:
132673
NCT NUMBER:
To be determined 
TEST PRODUCT:
GDC-9545 (RO7197597)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
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 your local study monitor.
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GDC-9545—F. Hoffmann-La Roche Ltd
11/Protocol WO42133, Version 1
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL, TWO-ARM, 
PHASE II, NEOADJUVANT STUDY EVALUATING THE EFFICACY, 
SAFETY, AND PHARMACOKINETICS OF GDC-9545 PLUS 
PALBOCICLIB COMPARED WITH ANASTROZOLE PLUS 
PALBOCICLIB FOR POSTMENOPAUSAL WOMEN WITH 
ESTROGEN RECEPTOR-POSITIVE AND HER2-NEGATIVE 
UNTREATED EARLY BREAST CANCER
PROTOCOL NUMBER:
WO42133
VERSION NUMBER:
1
EUDRACT NUMBER:
2020-001007-16
IND NUMBER:
132673
NCT NUMBER:
To be determined 
TEST PRODUCT:
GDC-9545 (RO7197597)
PHASE:
II
INDICATION:
Hormone receptor-positive postmenopausal women with untreated
early breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of GDC-9545 plus palbociclib
compared with anastrozole plus palbociclib in postmenopausal patients with untreated estrogen 
receptor (ER)-positive and HER2-negative early breast cancer (EBC).  Specific objectives and 
corresponding endpoints for the study are outlined below.
In this protocol, “study treatment” refers to the combination of treatments that may be assigned 
to a patient during the study (i.e., GDC-9545, GDC-9545 plus palbociclib, anastrozole, and 
anastrozole plus palbociclib).
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of GDC-9545 compared 
with anastrozole on the basis of the following endpoint:

Central assessment of changes in Ki67 scores from baseline to Week 2 (Day 15 [1 day])
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the clinical efficacy of GDC-9545 
plus palbociclib compared with anastrozole plus palbociclib on the basis of the following 
endpoints:

Objective response rate by ultrasound, defined as the proportion of patients with a complete 
response or partial response, as determined by the investigator according to modified 
RECIST (mRECIST)

Complete cell cycle arrest (CCCA) rate defined as proportion of patients with centrally 
assessed Ki67 scores 2.7% stained nuclei upon treatment at Week 2
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GDC-9545—F. Hoffmann-La Roche Ltd
12/Protocol WO42133, Version 1
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of GDC-9545 plus
palbociclib compared with anastrozole plus palbociclib on the basis of the following endpoints:

Central assessment of changes in Ki67 scores from baseline to surgery and from Week 2 to 
surgery

CCCA rate as defined as proportion of patients with centrally assessed Ki67 scores 2.7% 
stained nuclei upon treatment at surgery or post-treatment biopsy

Pathological complete response rate (ypT0/is, ypN0) of GDC-9545 plus palbociclib 
compared with anastrozole plus palbociclib
Safety Objectives
The safety objective for this study is to evaluate the safety of GDC-9545 plus palbociclib 
compared with anastrozole plus palbociclib on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined in accordance to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
The exploratory safety objective for this study is to evaluate the tolerability of GDC-9545 plus
palbociclib compared with anastrozole plus palbociclib from the patient's perspective on the 
basis of the following endpoints:

Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptomatic treatment toxicities, as assessed through use of the NCI 
Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events
(PRO-CTCAE) instrument

Overall tolerability (i.e., bother experience due to side effects of treatment) as assessed 
through an overall treatment burden item

Change from baseline in symptomatic treatment toxicities and overall tolerability and/or side 
effect burden, as assessed through respective use of the PRO-CTCAE and the additional 
overall burden item

Expectations of therapy, feelings about side effects, and satisfaction with treatment from the 
patient perspective as assessed through use of the Cancer Therapy Satisfaction 
Questionnaire
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of GDC-9545
alone and when administered in combination with palbociclib on the basis of the following 
endpoint:

Plasma concentration of GDC-9545 at specified timepoints
Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to the study treatments (i.e., predictive biomarkers), are early 
surrogates of efficacy, are associated with acquired resistance to the study treatments, can 
provide evidence of activity of the study treatments (i.e., pharmacodynamic 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, plasma, and tumor tissue and efficacy, safety, 
PK, disease biology, or other biomarker endpoints
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GDC-9545—F. Hoffmann-La Roche Ltd
13/Protocol WO42133, Version 1

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 (PgR) protein levels and ER target genes 
through analysis of matched baseline, Week 2, and surgery tumor specimens
Study Design
Description of Study
This is a randomized, multicenter, open-label, two-arm, Phase II study to evaluate the efficacy, 
safety, and pharmacokinetics of GDC-9545 versus anastrozole (in the window-of-opportunity 
phase) and GDC-9545 plus palbociclib compared with anastrozole plus palbociclib (in the 
neoadjuvant phase) in postmenopausal women with untreated ER-positive HER2-negative 
EBC. Approximately 215 patients are expected be enrolled in this study, at approximately 
90 investigative sites globally.
Eligible patients will be randomly assigned in a 1:1 ratio to either the experimental arm 
(GDC-9545) or control arm (anastrozole).  Patients must have histologically confirmed invasive 
breast carcinoma, with measurable disease as per mRECIST with a primary tumor size 1.5 cm 
in longest diameter evaluated by ultrasound at screening.  The tumor size category at 
presentation should be cT1c (1.5 cm)cT4ac.
Patients will be randomized on the basis of Ki67 score with eligibility criteria determined from 
pretreatment tumor tissue sample tested by a central pathology laboratory or a local site.  Use 
of the central laboratory for Ki67 level testing is recommended and is the preferred method for 
determining eligibility and stratification.  A Ki67 score 5% stained nuclei is required for 
eligibility.  For the purpose of assessing eligibility, ER, PgR, and HER2 will be locally 
determined prior to beginning of study treatment.  ER and PgR will also be centrally assessed, 
but the results are not required prior to randomization.
Patients will be stratified by T status (cT1ccT2 vs. cT3cT4 ac), Ki67 score (20% vs. 20%), 
and PgR status (positive vs. negative).
The study consists of a screening period of up to 28 days, a window-of-opportunity phase for 
14 days, followed by a neoadjuvant treatment phase for 16 weeks (four 28-day cycles), surgery, 
and an end of study visit (28 days after the final dose of study treatment).  During the
window-of-opportunity phase, patients will receive either GDC-9545 or anastrozole as a single 
agent. During the neoadjuvant treatment phase, patients will receive four 28-day cycles of
GDC-9545 plus palbociclib or anastrozole plus palbociclib.
All patients will be required to provide a pretreatment tumor tissue sample during screening, a 
tumor biopsy sample during treatment, and a post-treatment tissue sample from the surgical 
specimen.
In the neoadjuvant treatment phase, before each cycle, a blood sample will be collected and 
physical examination performed.  Tumor assessments by ultrasound are mandatory at 
screening, and an additional tumor assessment by ultrasound must be performed after the final 
dose of neoadjuvant combination treatment (i.e., after Day 21 of Cycle 4 and prior to surgery).  
If there is suspicion of disease progression, any other method to evaluate the disease will be 
allowed at any time at investigator’s discretion.
Surgery must be performed within a maximum of 14 days after the final cycle in the neoadjuvant 
treatment phase and ideally should occur as soon as possible after the last dose of study 
treatment.  A surgical specimen will be obtained for analysis and will be analyzed by the local 
pathologist. If surgery is delayed, the patient is not operable or will not undergo surgery for 
other reasons, or does not complete 16 weeks (four cycles) of combination therapy, an optional 
biopsy may be performed as a separate procedure within 2 days from the end of the 
combination treatment.
All patients must return for the end of study visit 28 days after the final dose of study treatment 
regardless of the reason for treatment discontinuation.  Patients who experience disease 
progression or unacceptable toxicity will be treated as per local practice after the end of study 
visit.
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Patient treatment after the surgery will be at the investigator’s discretion.  Systemic 
chemotherapy and radiation therapy, if indicated, may be initiated after the end of study visit.  
Any post-surgery treatments are not part of the study and will not be provided by the Sponsor, 
and data will not be collected.
Patient-reported outcome instruments will be completed by patients to evaluate the experience 
of treatment from the patient's perspective as specified in the schedule of activities.
Patients who do not initially meet all eligibility criteria, other than HR status and Ki67, may be
re-screened once to meet eligibility.
Number of Patients
Approximately 215 patients are expected be enrolled in this study, at approximately 
90 investigative sites globally.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Postmenopausal 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 operable or inoperable invasive breast carcinoma, with all of the 
following characteristics:

cT1c (1.5 cm)cT4ac breast cancer at presentation
Primary tumor must be 1.5 cm in longest diameter by ultrasound.

Measurable disease by ultrasound as defined per mRECIST

Patients with multifocal tumors (more than one mass confined to the same quadrant 
as the primary tumor) if all lesions are sampled and confirmed as 
ER-positive/HER2-negative invasive breast cancer and at least one lesion is 
1.5 cm in longest diameter by ultrasound

Patients with multicentric tumors (multiple tumors involving more than one quadrant) if all 
discrete lesions are sampled and confirmed as ER-positive/HER2-negative invasive 
breast cancer and at least one lesion is 1.5 cm in longest diameter by ultrasound

Candidate for neoadjuvant treatment and considered appropriate for endocrine therapy

Willingness to undergo breast surgery (mastectomy or breast-conserving surgery) after 
neoadjuvant treatment

Willingness to provide three mandatory tumor samples as follows:

Pretreatment

During treatment at Cycle 0 Day 15 (+1 day) 

Posttreatment (from surgical specimen) or an optional biopsy (if surgery is not possible 
or delayed)

Documented ER-positive tumor in accordance to American Society of Clinical Oncology
(ASCO)/College of American Pathologists (CAP) guidelines, assessed locally and defined 
as 1% of tumor cells stained positive on the basis of the most recent tumor biopsy

Documented PgR status (positive or negative) as per local assessment

Documented HER2-negative tumor in accordance to 2018 ASCO/CAP guidelines, 
assessed locally on the most recent tumor biopsy

Ki67 score 5% analyzed centrally (recommended) or locally (by Sponsor pre-approved 
assay/scoring method)
Use of the central laboratory for Ki67 level testing for eligibility is recommended.
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For sites using the central laboratory to test for Ki67 eligibility, a tissue sample must be 
submitted to the central laboratory for enrollment by the immunohistochemistry-based 
central pathology laboratory Ki67 Clinical Trial Assay.

Postmenopausal status defined as one of the following: 

Documented bilateral surgical oophorectomy (14 days prior to first treatment on Day 1 
of Cycle 1 and recovery from surgery to baseline)

Age 60 years and 12 consecutive months with no menses without an alternative 
medical cause

Age 60 years and 12 continuous months of amenorrhea with no identified cause 
other than menopause, estradiol levels, and follicle-stimulating hormone levels in the 
postmenopausal range

Eastern Cooperative Oncology Group Performance Status 01

Adequate organ function as defined by the following criteria:

ANC 1.5 109/L (1500/L)

Platelet count 100 109/L (100,000/L)

AST and serum ALT 2 upper limit of normal (ULN)

Hemoglobin 90 g/L (9 g/dL)

Serum bilirubin 1.5 ULN with the following exception:
Patients with known Gilbert syndrome:  3 ULN

Serum creatinine 1.5 ULN or estimated creatinine clearance 60 mL/min as 
calculated per institutional guidelines

INR 1.5 ULN and aPTT 1.5 ULN
For patients requiring anticoagulation therapy with warfarin, a stable INR between 
2 and 3 is required.
For patients receiving heparin, PTT (or aPTT) between 1.5 and 2.5 ULN (or patient 
value before starting heparin treatment) is required.
If anticoagulation therapy is required for a prosthetic heart valve, stable INR between 
2.5 and 3.5 is permitted.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Stage IV (metastatic) breast cancer 

Inflammatory breast cancer (cT4d)

Bilateral invasive breast cancer

History of invasive breast cancer

History of ductal carcinoma in situ or lobular carcinoma in situ if they have received any 
systemic therapy for treatment or radiation therapy to the ipsilateral breast 
Patients treated with surgery alone may be eligible.

History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine 
cancer

Previous systemic or local treatment for the primary breast cancer currently under 
investigation (including excisional biopsy or any other surgery of the primary tumor and/or 
axillary lymph nodes, radiotherapy, cytotoxic, and endocrine treatments)

History of any prior treatment with aromatase inhibitors, tamoxifen, selective estrogen 
receptor downregulatorrs, or cyclin-dependent kinase 4 and 6 inhibitors
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
Major surgery within 4 weeks prior to randomization

Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C virus [HCV]), current alcohol 
abuse, cirrhosis, or positive test for viral hepatitis as defined below:
Active infection is defined as requiring treatment with antiviral therapy or presence of 
positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B 
core antibody [HBcAb]) or HCV antibody.  Unless required by local regulations, 
patients are not required to have HIV, HBV, or HCV assessments at screening if these 
assessments have not been previously performed.
Patients who test positive for HBcAb are eligible only if test results are also positive for 
hepatitis B surface antibody and polymerase chain reaction is negative for HBV DNA.
Patients who are positive for HCV serology are only eligible if testing for HCV RNA is 
negative.

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 anastrozole, or palbociclib or any of its excipients

Known issues with swallowing oral medication

History of documented hemorrhagic diathesis, coagulopathy, or thromboembolism

Active cardiac disease or history of cardiac dysfunction including any of the following:

History or presence of symptomatic bradycardia or resting heart rate 50 bpm at 
screening
Patients on stable dose of a -blocker or calcium channel antagonist for 
pre-existing baseline conditions (e.g., hypertension) may be permitted if resting 
heart is 50 bpm.

History of angina pectoris, symptomatic pericarditis, myocardial infarction, or any cardiac 
arrhythmias (e.g., ventricular, supraventricular, nodal arrhythmias, or conduction 
abnormality) within 12 months prior to study entry

History of documented congestive heart failure (New York Heart Association Class IIIV) 
or cardiomyopathy

Left ventricular ejection fraction 50% as determined by multiple-gated acquisition scan 
or echocardiogram

QT interval corrected through use of Fridericia’s formula (QTcF) 470 ms based on 
mean value of triplicate ECGs, history of long or short QT syndrome, Brugada syndrome 
or known history of corrected QT interval prolongation, or torsades de pointes

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, sick sinus syndrome, or evidence of prior myocardial infarction

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 long QT syndrome

Current treatment with medications that are well known to prolong the QT interval

Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major 
upper gastrointestinal surgery including gastric resection

Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination 
half-lives (whichever is longer) prior to randomization
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
Known HIV infection

Serious infection requiring oral or IV antibiotics, or other clinically significant infection within 
14 days prior to screening
Patients who fully recovered from serious and clinically significant infections within
14 days prior to screening are eligible.

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study

Assessed by the investigator to be unable or unwilling to comply with the requirements of 
the protocol
End of Study
The end of this study is defined as the date when the last patient, last visit, occurs or the date of 
Sponsor decision to end the study, whichever is earlier.  The end of the study is expected to 
occur approximately 6 months after the last patient is enrolled.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 19 months.
Investigational Medicinal Products
The investigational medicinal products for this study are GDC-9545 (test product), anastrozole
(comparator), and palbociclib.
Test Product (Investigational Drug)
During the window-of-opportunity phase (14 days), patients will receive either GDC-9545 30 mg 
orally (PO) once a day (QD) or anastrozole 1 mg PO QD as a single agent.  During the 
window-of-opportunity phase, GDC-9545 and anastrozole can be taken with or without food at 
approximately the same time each day.
During the neoadjuvant treatment phase, GDC-9545 30 mg PO QD or anastrozole 1 mg PO QD 
will be administered on Days 128 of each 28-day cycle in combination with palbociclib 125 mg
PO QD on Days 121 of each 28-day cycle for four cycles.  Starting with Day 1 of Cycle 0 and 
on Day 1 of each 28-day cycle thereafter, study treatment will be administered in the clinic after 
the study assessments, as indicated in the schedule of activities. All other doses will be taken 
at home on all non-clinic visit days.  If a GDC-9545 dose is missed, the dose should be made 
up unless the next dose is due within 6 hours.
GDC-9545, anastrozole, and palbociclib should be taken orally with food at approximately the 
same time each day as per study treatment regimen.  If palbociclib switches to tablet formation, 
study treatments may be taken with or without food.
Statistical Methods
Primary Analysis
The primary efficacy endpoint for this study is Ki67score change during the window-of-
opportunity phase, defined as the mean change of Ki67 score from baseline to Week 2.  Ki67 
score will be centrally assessed and measured in percentage score.  All Ki67 scores will be 
log-transformed before analysis, and 0.1 will be added to all raw Ki67 scores before 
log-transformation to handle zero raw Ki67 scores.
Mean Ki67 change at Week 2 will be summarized in original percentage scale for each arm, and 
corresponding 95% CI will be calculated by normal approximation.  The change in mean Ki67 
score between the experimental arm and control arm will be compared through the use of the 
z-test.  Patients with missing central Ki67 scores at baseline and/or Week 2 will be excluded 
from the analysis.
The analysis of the primary efficacy endpoint will take place when approximately 202 patients 
have been randomized and have complete central Ki67 scores for the analysis at both baseline 
and Week 2.
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Determination of Sample Size
The sample size is determined by the primary efficacy endpoint, central assessment Ki67 
change from baseline to Week 2.  Approximately 202 patients will need to be randomized in a 
1:1 ratio to either the experimental arm (GDC-9545) or control arm (anastrozole) to allow for 80% 
power to detect an 8% improvement for mean Ki67 change in 2 weeks from 75% in the control 
arm to 83% in the experimental arm at one-sided 10% level of significance.  This target 
improvement also corresponds to an effect size of 0.3.  Based on Cohen’s interpretation, an 
effect size of 0.3 represents a small to medium effect and a 21% non-overlap between the two 
treatment arms.
Patients with missing central Ki67 score at baseline and/or at Week 2 will be excluded from the 
analysis of the primary efficacy endpoint.  For both experimental and control arms, a 6% 
missing Ki67 rate is assumed.  Thus, a total of approximately 215 patients is projected to be 
enrolled to account for patients with missing Ki67 scores.
Interim Analyses 
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct an 
interim efficacy analysis.  The decision to conduct an optional interim analysis and the timing of 
the analysis will be documented in the Sponsor's trial master file prior to the conduct of the 
interim analysis.  The interim analysis will be performed and interpreted by the Sponsor study 
team personnel who will have full access to unblinded data.  Access to treatment assignment 
information will follow the Sponsor's standard procedures.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AI
aromatase inhibitor
ASCO
American Society of Clinical Oncology
ATAC
arimidex, tamoxifen, alone or in combination
CAP
College of American Pathologists
CBR
clinical benefit rate
CCCA
complete cell cycle arrest
CDK4/6
cyclin-dependent kinase 4 and 6
COVID-19
coronavirus disease 2019
CR
complete response
CTc
computed tomography
CTSQ
Cancer Therapy Satisfaction Questionnaire
DDI
drug-drug interaction
EBC
early breast cancer
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
FES
F-18 16-fluoroestradiol
FFPE
formalin-fixed, paraffin-embedded core
FSH
follicle-stimulating hormone
GI
Gastrointestinal
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hormone receptor
ICH
International Council for Harmonisation
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
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Abbreviation
Definition
LHRH
luteinizing hormonereleasing hormone
mRECIST
modified Response Evaluation Criteria in Solid Tumors
NCI
National Cancer Institute
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0
NET
neoadjuvant endocrine therapy
NGS
next generation sequencing
OCT
optimal cutting temperature
ORR
objective response rate
pCR
pathological complete response
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PK
pharmacokinetic
PO
Oral
PR
partial response
PRO
patient-reported outcome
PRO-CTCAE
Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events 
QD
once a day
QTcF
QT interval corrected through use of Fridericia's formula
RBR
Research Biosample Repository
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
SC
Steering Committee
SERD
selective estrogen receptor downregulatorr
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing
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1.
BACKGROUND
1.1
BACKGROUND ON HORMONE-RECEPTOR POSITIVE BREAST 
CANCER
Breast cancer is the most commonly diagnosed cancer in women, with an estimated 
global incidence of 2,088,849 new cases and 626,679 deaths reported in 2018 (Bray 
et al. 2018; IARC 2018).  Approximately 80% of all breast cancers express the estrogen 
receptor (ER), 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. The selective 
estrogen-receptor modulator, tamoxifen, and aromatase inhibitors (AIs) represent the 
cornerstone treatment for patients who are hormone receptor positive.
Selective ER downregulators (SERDs) have the potential to block endocrine-dependent 
and endocrine-independent ER signaling by ablation of ER and have been recognized to 
offer a therapeutic approach to ER-positive breast cancer in metastatic breast. 
Fulvestrant, the first generation SERD, binds, blocks, and degrades the ER, leading to 
complete inhibition of estrogen signaling through the ER. Fulvestrant has shown benefit 
over an AI (anastrozole) in frontline patients (Robertson et al. 2016; see Section 1.5.1). 
However, fulvestrant is hampered by intramuscular administration due to its poor 
physicochemical and pharmacokinetic (PK) properties.
GDC-9545, a second-generation SERD, is a novel, potent, orally bioavailable, small 
molecule therapeutic agent currently being developed for the treatment of patients with 
ER-positive breast cancer.
Tamoxifen and AI therapy are associated with significant side effects that often lead to 
early discontinuation of treatment.  Maximizing therapeutic benefit, while minimizing 
treatment related toxicities, is particularly important in hormone receptor (HR)-positive, 
HER2-negative early breast cancer (EBC) where treatment duration is usually for 
5 years or more.  Currently, only approximately 60% of patients manage to complete 
5 years of adjuvant endocrine therapy (Hagen et al. 2019).  Improved treatment options 
may decrease or eliminate the risk of recurrences after adjuvant therapy and provide 
more tolerable treatment options (see Section 1.5.3).
1.2
BACKGROUND ON ANASTROZOLE IN EARLY BREAST 
CANCER
The AIs anastrozole, letrozole and exemestane have been the standard-of-care 
endocrine therapy in postmenopausal women with HR-positive EBC for 15 years. AIs, 
given either for 5 years or for 2–3 years after 2–3 years of tamoxifen, produce greater 
reductions in recurrence than 5 years of tamoxifen alone (Dowsett et al 2010), as well as 
reduction in breast cancer mortality (EBCTCG 2015).
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In the Arimidex(anastrozole), tamoxifen, alone or in combination (ATAC) trial (Howell 
et al. 2005), anastrozole has been shown to be superior to tamoxifen when given for 
5 years as adjuvant treatment. After a median follow-up of 68 months, anastrozole
significantly prolonged disease-free survival (hazard ratio=0.87; 95% CI: 0.78 to 0·97;
p=0.01) and significantly reduced distant metastases (hazard ratio=0.86; 95% CI:
0.74 to 0·99; p=0.04) and contralateral breast cancers (42% reduction; 95% CI: 12 to 62;
p=0.01).  Anastrozole was also associated with fewer side-effects than tamoxifen, 
especially gynecological problems and vascular events, but arthralgia and fractures were 
increased.
Anastrozole has also been assessed in several neoadjuvant studies. The IMPACT trial 
evaluated change in expression of the proliferative marker Ki67 with anastrozole, 
tamoxifen, or combination in the neoadjuvant setting. The suppression of Ki67 was 
greater with anastrozole than with tamoxifen (p=0.004 and p0.001) but was similar 
between tamoxifen and the combination (p=0.600 and p=0.912, respectively; Smith et al. 
2005) (see Section 1.5.3).
1.3
BACKGROUND ON CDK4/6 INHIBITORS IN BREAST CANCER
Three cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, palbociclib, ribociclib, and 
abemaciclib, are now in widespread clinical use and have been approved as both 
firstline and secondline treatments in patients with HR-positive, HER2-negative breast 
cancer.  With the exception of abemaciclib, these agents are approved for use only in 
combination with endocrine agents, typically with an AI in the first-line setting or with
fulvestrant in patients who are AI-resistant. When given in combination with endocrine 
therapy, an approximate doubling of progression-free survival (PFS) in patients with 
advanced HR-positive, HER2-negative breast cancer, compared with endocrine therapy 
plus placebo, has been observed.  These consistently positive PFS results have been 
demonstrated in large Phase III trials in the frontline setting (PALOMA-2 [Finn et al. 2015]
for palbociclib plus letrozole; MONALEESA-2 [Slamon et al. 2018] for ribociclib plus 
letrozole; and MONARCH-3 [Goetz et al. 2017] for abemaciclib plus letrozole or 
anastrozole). More recently, the MONALEESA-7 trial was the first to show a statistically 
significant improvement in overall survival for a CDK4/6 inhibitor (ribociclib plus 
endocrine therapy) in breast cancer and the first to evaluate this treatment exclusively in 
premenopausal patients (Im et al. 2019).  Additionally, benefit was observed in 
populations previously treated with endocrine therapy for advanced disease (PALOMA-3 
[Cristofanilli et al. 2016] for palbociclib plus fulvestrant; MONARCH-2 [Sledge et al. 2017] 
for abemaciclib and fulvestrant; and MONALEESA-3 [Goetz et al. 2017] for ribociclib 
plus fulvestrant). 
In the neoadjuvant setting, the addition of CDK4/6 inhibitors to AIs has been shown to 
significantly decrease Ki67 expression and lead to potent cell cycle arrest effect.  Refer 
to Section 1.5.3 for the rationale for using CDK4/6 inhibitors in the neoadjuvant setting.
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CDK 4/6 inhibitors are currently being explored in the adjuvant and postneoadjuvant 
EBC setting.
1.4
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 of both wild-type and mutant ER with nanomolar potency.  Upon binding, 
GDC-9545 induces an inactive conformation to the ER ligand-binding domain, 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 
modulators such as tamoxifen that 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 ERs.
1.4.1
Nonclinical Data
Nonclinical studies comparing drug exposure and in vitro potency of GDC-9545 versus 
fulvestrant demonstrated that human steady-state total drug exposure of GDC-9545 at 
30 mg once a day (QD) is approximately 10-fold higher than the steady-state exposure 
of fulvestrant 500 mg intramuscular monthly.  Furthermore, the lower plasma protein 
binding of GDC-9545 provides higher free concentration of GDC-9545 than fulvestrant.  
In in vitro cell and biochemical assays, GDC-9545 exhibited up to 10-times higher 
potency than fulvestrant both in wild-type and ESR1mutant contexts.
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 
activating ESR1 mutation (ER. Y537S).  The efficacious dose range was 
0.110 mg/kg/day, and all doses were well tolerated.  On the basis of in vivo xenograft
models, maximal activity of GDC-9545 occurs at human dose equivalents greater than 
10 mg.  In three patient-derived xenograft models, no further ER depletion or inhibition of 
ER transcriptional activity was observed with the increase of dose from 2080 mg/kg, 
corresponding to clinical exposures of 30 mg and 100 mg, respectively. Fulvestrant, 
when dosed according to a clinically relevant dosing scheme, was less efficacious than 
GDC-9545 in the assessed xenograft models.  Taken together, GDC-9545 data 
demonstrated robust nonclinical activity in ER-positive breast cancer models of both 
ESR1wild type and ESR1-mutationbearing disease.
Refer to the GDC-9545 Investigator’s Brochure for details on toxicology and safety 
pharmacology studies.
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1.4.2
Clinical Data
GDC-9545 Experience in Early Breast Cancer
Study GO40987 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.  Patients are assigned to one of 
three treatment cohorts (10, 30, and 100 mg).  GDC-9545 is administered QD up to and 
including the day of surgery (if allowed per local process) for approximately 14 days.  All 
patients are required to provide a pretreatment and post-treatment tumor tissue sample.
As of 31 January 2020 preliminary data, approximately 28 patients have been enrolled 
and 24 patients have completed study treatment and surgery with no surgical 
complications attributed to GDC-9545.  To date, no patients treated have experienced 
any thromboembolic events or issues with wound healing.  No serious adverse events or 
Grade 3 adverse events related to GDC-9545 have been reported.  No patients 
withdrew from study due to adverse events.  Overall, all of the reported adverse events 
have been Grade 1 or 2 in severity and in keeping with the expected safety profile of 
drugs in this class and the GDC-9545 Phase I metastatic breast cancer study.
GDC-9545 Experience in Metastatic Breast Cancer
GDC-9545 is currently being evaluated in Study GO39932, a first-in-human,
Phase Ia/Ib, multicenter, open-label study evaluating the safety, pharmacokinetics, and 
activity of GDC-9545 as a single agent or in combination with palbociclib (luteinizing 
hormonereleasing hormone [LHRH] agonist) in patients with ER-positive
(HER2-negative) locally advanced or metastatic breast cancer.
As of the clinical cutoff date of 4 September 2019, 120 patients in Study GO39932 had 
received treatment as follows:  74 patients had been treated with single-agent 
GDC-9545 at doses of 10 mg (6 patients), 30 mg (10 patients), 90/100 mg (correlated to 
90 or 100 mg)(49 patients), and 250 mg (9 patients) (with or without LHRH agonist), and 
46 patients had been treated with GDC-9545 100 mg in combination with palbociclib 
125 mg (with or without LHRH agonist).  Overall, study patients had received a median 
of 113 doses of GDC-9545 (range: 3596 doses) and remained on GDC-9545 treatment 
for a median of 113 days (range: 3531 days). Enrollment is currently ongoing in the 
expansion stage, where an additional 30 patients will be dosed with GDC-9545 
monotherapy at 30 mg QD (see Section 3.3.1).
The majority of patients enrolled as of the clinical cutoff date had visceral (62%) and 
measurable disease (79%) at baseline, and a small proportion (18%) had bone-only 
disease at baseline.  Baseline ESR1 mutation status of wild-type or mutant was reported 
in 55% and 33% of patients, respectively.  The remaining patients had unknown ESR1
mutation status.  The majority of patients did not receive prior therapy with fulvestrant 
(83%) or a CDK4/6 inhibitor (71%).
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Based on the clinical cutoff date, clinical benefit, as measured by either radiographic 
partial response (PR) or at least 6 months of stable disease, was observed at all four 
single-agent GDC-9545 doses tested and in the GDC-9545 plus palbociclib combination 
cohort.  In the single-agent GDC-9545 30 mg cohort, there were 10 efficacy-evaluable 
patients (defined as any patient with at least one dose of study treatment) and 
7 response-evaluable patients with measurable disease per Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) at baseline.  In this cohort, the 
median for investigator-assessed PFS per RECIST v1.1 for the 10 efficacy-evaluable 
patients was 231 days (95% CI: 54, not evaluable), with 50% of patients reporting an 
event of disease progression or death.  The clinical benefit rate (CBR) in all patients in 
the 30 mg cohort was 50.0% and the objective response rate (ORR; confirmed response) 
in the 7 response-evaluable patients was 14.3% (1 patient).  The CBR was similar to that 
observed in patients treated at higher doses (e.g., at 90/10 0mg, CBR was 53.6% 
[95% CI: 38% to 69%; n36]).
Adverse Events, Regardless of Attribution
Of the 74 patients treated with single-agent GDC-9545 at doses ranging from 
10 to 250 mg, adverse events, regardless of attribution and occurring in 10% or more 
patients, included the following:  fatigue (24%), back pain (20%), arthralgia (19%), 
diarrhea (16%), nausea (16%), constipation (15%), pain in extremity (15%), cough (12%), 
and dizziness (11%).  Adverse events mapped into the cardiac disorder System Organ 
Class were experienced by 7 patients (9.5%), including adverse events of bradycardia 
(6 patients at 90/100 mg and 1 patient at 250 mg) and palpitation (1 patient at 90 mg and 
1 patient at 250 mg).  All cardiac-related events were Grade 1 and asymptomatic.  
No cardiac-related events have been reported at the GDC-9545 30-mg dose.
Of the 10 patients treated with single-agent GDC-9545 30 mg, the following adverse 
events occurred in 3 or more patients:  fatigue, nausea, constipation, back pain and 
vomiting (4 patients each), diarrhea, pain in extremity, gastroesophageal reflux disease, 
dyspepsia and myalgia (3 patients each).
Of the 46 patients treated with GDC-9545 100 mg in combination with palbociclib
125 mg, adverse events, regardless of attribution and occurring in 10% or more patients,
included the following:  neutropenia/neutrophil count decrease (67%); bradycardia (26%);
fatigue (24%); diarrhea (22%); nausea, constipation, dizziness, and anemia (17% each); 
asthenia 15%); thrombocytopenia (13%); and pruritus and visual impairment (11% each).
Overall in Study GO39932, Grade 3 adverse events were reported in 40 of 
120 safety-evaluable patients (33%), including 14 patients (19%) in single-agent
GDC-9545 cohorts, and 26 patients (57%) in the GDC-9545 plus palbociclib combination 
cohorts.  Grade 3 adverse events, regardless of attribution and occurring in 2 or more 
patients, were lymphopenia and diarrhea (3%) in single-agent GDC-9545 cohorts and 
neutropenia/neutrophil count decrease (50%) in GDC-9545 plus palbociclib combination 
cohorts.  No Grade 3 adverse events were reported in the GDC-9545 30-mg cohort.
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Serious adverse events were reported in 8 of 120 (6.7%) safety-evaluable patients, 
including 4 of 74 (5.4%) patients in the single-agent GDC-9545 cohort and 4 of 
46 (8.7%) patients in the GDC-9545 plus palbociclib combination cohort.  One case of 
Grade 3 migraine occurred in the 30 mg single-dose cohort.  Three Grade 3 serious 
adverse event cases occurred in the 90/100 mg single-dose cohort: appendiceal 
abscess, small intestinal obstruction, and fatigue.  In the GDC-9545 plus palbociclib 
cohort, one Grade 3 urinary tract infection occurred, and three Grade 4 cases occurred:  
neutropenia (2 cases) and thrombocytopenia.
Overall, no Grade 5 adverse events were reported.
Adverse Events Attributed to Study Treatment
Of the 74 patients treated with single-agent GDC-9545 at doses ranging from 
10250 mg, adverse events attributed to GDC-9545 have been mostly Grade 1 or 2 in 
severity. Adverse events attributed to GDC-9545 occurring in 5% or more patients 
included the following:  fatigue (19%); arthralgia (12%); nausea (11%); diarrhea (10%);
bradycardia (8%); hot flush, alanine aminotransferase increase, and aspartate 
aminotransferase increase (7% each); and constipation and dyspepsia (5% each). 
Of the 10 patients treated with single-agent GDC-9545 at 30 mg, adverse events 
attributed to GDC-9545 with Grade 1 or 2 severity occurring in 3 or more patients 
included fatigue, nausea, diarrhea, and dyspepsia (3 patients each). Three Grade 3 
events of fatigue, transaminase increase, and diarrhea were reported in patients treated 
with GDC-9545 100 mg. Only one patient experienced a treatment-related serious 
adverse event (Grade 3 fatigue) considered related to both GDC-9545 and disease 
progression.  No patients were withdrawn from treatment because of adverse events. 
Of the 46 patients treated with GDC-9545 100 mg in combination with palbociclib
125 mg, adverse events attributed to any study drug occurring in 5% or more patients 
included the following:  neutropenia/neutrophil count decrease (63%); bradycardia (24%); 
fatigue (20%); nausea (17%); diarrhea (15%); anemia, asthenia, and thrombocytopenia 
(13% each); pruritus (11%); hot flush, constipation, dizziness, and visual impairment
(9% each); and dry skin, vomiting, vision blurred, decreased appetite, insomnia, 
lymphocyte count decrease, photopsia, and alopecia (7% each).
A total of 4 patients exposed to the combination experienced serious adverse events 
(urinary tract infection, thrombocytopenia, and 2 serious cases of neutropenia), none of 
which were assessed as related to GDC-9545.  The only Grade 3 adverse event 
affecting 2 patients was neutropenia, including 2 patients with Grade 4 neutropenia.  
There were no adverse events with fatal outcome, and no patients treated with the 
combination experienced adverse events leading to discontinuation from treatment.
Overall, GDC-9545 was well tolerated at all dose levels with no trend for an increase in 
frequency or severity of adverse events. Seven (9.5%) patients who received 
single-agent GDC-9545 (all treated at 90 mg or higher dose) reported Grade 1 
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asymptomatic bradycardia/sinus bradycardia. No adverse event of bradycardia was 
reported at the 30-mg dose.  The mean heart rate decrease was approximately 3 bpm 
at the dose of 30 mg on Cycle 1 Day 15 and stabilized during the treatment.  
Combination therapy of GDC-9545 100 mg with palbociclib 125 mg in 46 patients has 
not identified any new safety signals or overlapping toxicities.  It is therefore anticipated 
that GDC-9545 30 mg administered with palbociclib 125 mg will be well tolerated (see 
Section 3.3.1).
Refer to the GDC-9545 Investigator’s Brochure for details regarding nonclinical and 
clinical studies.
1.5
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
The current trial is a proof of concept Phase II study in postmenopausal patients with 
ER-positive HER2-negative newly diagnosed EBC. The study will have two parts, a 
14-day window-of-opportunity phase followed by a 16-week neoadjuvant treatment
phase. 
1.5.1
Rationale for Exploring GDC-9545 in Early Breast Cancer
Despite the effectiveness of both tamoxifen and AI therapy, many patients ultimately
relapse or develop resistance to these agents. The resistance to endocrine therapy is 
often caused by ESR1 mutation (Angus et al. 2017). Whereas ESR1 mutations are 
relatively rare in primary breast cancer, they are more prevalent in metastatic cancers, 
especially in patients previously treated with AIs, 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 AIs and 
tamoxifen ineffective (Robinson et al. 2013; Jeselsohn et al. 2014).
In contrast to AIs and tamoxifen, selective ER degraders (SERDs) are efficacious 
against these ligand-independent, constitutively active ER-mutated receptors.  This was 
first shown in the SoFEA study (Johnston et al. 2013), a Phase III randomized study in 
postmenopausal patients with HR-positive locally advanced or metastatic breast cancer 
comparing fulvestrant plus anastrozole or placebo versus exemestane alone after 
progression on non-steroidal AIs.  Subgroup analysis revealed that patients with ESR1 
mutations had an improved PFS of 5.7 months with fulvestrant compared with 
2.6 months with exemestane (hazard ratio=0.52; 95% CI: 0.30 to 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 detection of ESR1 mutations. The FALCON study was a Phase III, 
randomized, double-blind study that treated patients with de novo locally advanced or 
metastatic HR-positive breast cancer with either fulvestrant or anastrozole (Robertson 
et al. 2016). Fulvestrant was associated with a statistically significant improvement in 
PFS compared with anastrozole (hazard ratio0.797; 95% CI: 0.637 to 0.999; p0.0486).  
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Median PFS was 16.6 months (95% CI: 13.83 to 20.99 months) with fulvestrant and 
13.8 months (95% CI: 11.99 to 16.59 months) with anastrozole (a difference in medians 
of 2.8 months).
Fulvestrant has poor PK properties, requiring bilateral intramuscular injection, which has 
prohibited it from being studied in large adjuvant trials.  Therefore, studies are needed 
that aim to evaluate new oral SERDS with superior bioavailability, pharmacokinetics, and 
more potent activity against the ER, including ESR1 mutations.  These novel agents 
have the potential to be more effective than AIs in preventing disease progression and 
thus may ultimately improve overall survival in women with ER-positive EBC.
There is a need to improve the tolerability of endocrine therapies, particularly since 
treatment is usually for 5 years or more. Currently approved therapies are associated 
with significant side effects that often lead to early discontinuation of treatment.
Tamoxifen may cause venous thromboembolism and uterine cancer (Mourits et al. 2001; 
Hernandez et al. 2009), and AIs cause accelerated bone loss and arthralgia (Muslimani 
et al. 2009). Currently, only approximately 60% of patients manage to complete 5 years 
of adjuvant endocrine therapy (Hagen et al. 2019).  Oral SERDs may provide a more 
tolerable treatment option that enables better adherence and thus maximizes therapeutic 
benefit and compliance.
1.5.2
Rationale for the Window-of-Opportunity Phase
In the window-of-opportunity phase, patients will be treated with either GDC-9545 or
anastrozole for 2 weeks, followed by a biopsy to assess Ki67 change from baseline.  
Studies using a window-of-opportunity are becoming the standard for developing new 
treatments in HRpositive EBC. These studies allow for access to tumor tissue before, 
during, and after treatment for pharmacodynamics and correlative evaluations; provide
critical insight into the optimal patient population, differences in activity and mechanisms
between agents; and influence of the tumor biology on sensitivity and molecular
mechanisms of response or resistance (Guerrero-Zotano and Arteaga 2017).
The primary efficacy endpoint of the study will be the reduction of Ki67, a 
well-established proliferation biomarker, after 2 weeks of treatment (compared with
baseline). 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). Refer to Section 3.3.4.1 for a summary of the available evidence regarding the 
predictive value of changes in Ki67 on long-term outcome in EBC.
1.5.3
Rationale for the Neoadjuvant Phase
In the neoadjuvant phase, patients will be treated with GDC-9545 plus the CDK4/6 
inhibitor palbociclib or with anastrozole plus palbociclib for 16 weeks.
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Neoadjuvant endocrine therapy (NET), given from 4 to 6 months, has been shown to 
effectively reduce tumor size and potentially reduce the extent of surgery 
(Guerrero-Zotano and Arteaga 2017). Aside from the potential clinical benefits achieved 
by downstaging, neoadjuvant therapy allows for direct and early observation of treatment 
response and provides prognostic information.  This is of immediate benefit to patients. 
Patients who were not initially candidates for chemotherapy but whose tumors do not 
respond to NET can be offered chemotherapy after surgery as an additional treatment 
option. Patients who were initially candidates for chemotherapy and who have a good 
response to NET may be able to continue adjuvant treatment without the addition of 
chemotherapy.
CDK4/6 inhibitors are already established as standard-of-care treatment in patients with 
advanced HR-positive, HER2-negative breast cancer (see Section 1.3. for a summary of 
the clinical evidence with CDK4/6 inhibitors in advanced breast cancer). These 
inhibitors are currently being actively explored in the EBC setting, including neoadjuvant, 
adjuvant, and post-neoadjuvant studies (Spring et al. 2019).
The addition of CDK4/6 inhibitors to AIs has been shown to significantly increase the 
antiproliferative effect (see Section 3.3.4.1 for a summary of the available evidence for 
Ki67 changes as a predictor of long-term outcome in adjuvant studies). In the 
neoadjuvant Phase II NeoPalAna study (Ma et al. 2017), the combination of palbociclib 
plus anastrozole achieved 87% complete cell cycle arrest (CCCA) compared with 26% 
with anastrozole alone (p0.001).  Similarly, in the PALLET trial, more patients on 
palbociclib plus letrozole achieved CCCA compared with letrozole alone (90% vs. 59%; 
p=0.001) (Johnston et al. 2019). The addition of abemaciclib to anastrozole was shown 
to significantly reduce Ki67 compared with anastrozole alone in the neoMONARCH
study (Martin et al. 2018).
The safety findings in the PALLET and neoMONARCH trials suggest that the tolerability 
of CDK4/6 inhibitors in the EBC setting is comparable with the experience from 
advanced breast cancer.  In the PALLET study, more patients had Grade 3 toxicity on 
palbociclib plus letrozole than on letrozole alone (49.8% vs. 17.0%; p0.001) mainly 
because of asymptomatic neutropenia (40.8% vs. 0%) (Johnston et al. 2019). Grade 3 
ALT increase was reported for 4% of patients in the palbociclib plus letrozole arm, 
versus 0% with letrozole alone arm. The most common adverse event reported in more 
than 20% of the patients receiving the combination of palbociclib and letrozole were 
fatigue (58.2%), neutrophil count decreased (54.7%), hot flushes (26.9%), and nausea 
(24.9%).
The secondary efficacy endpoint of this study is ORR of the primary breast tumor after 
16 weeks (four cycles) of neoadjuvant treatment, measured by ultrasound. Achieving a 
reduction in tumor size is associated with a benefit for patients because it often allows 
for less extensive surgery than originally planned (Guerrero-Zotano and Arteaga 2017).
The combination of palbociclib and AI showed clinical benefit with response rates of 41% 
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and 55.3% (both measured by ultrasound) in the NeoPalAna and PALLET trials after 
1416 weeks of neoadjuvant treatment (Ma et al. 2017; Johnston et al. 2019).
ORR is not a co-primary endpoint of the study because its validity in predicting long-term 
outcome in EBC has not yet been fully established, with prior studies showing 
inconsistent results (Semiglazov 2015). In the IMPACT study, there was no difference 
among the three arms with regard to objective response (anastrozole 37%, tamoxifen 
36%, and the combination 39%). ORR did not predict long-term outcome in the adjuvant 
ATAC study, in which anastrozole achieved a significantly superior disease-free survival 
compared with tamoxifen or the combination (Smith et al. 2005). In contrast, the P024 
study demonstrated a significantly higher clinical response with the AI letrozole 
compared with tamoxifen (55% vs. 36%; p0.01).  The safety and activity of CDK4/6 
inhibitors in combination with endocrine therapy observed in patients with ER-positive, 
HER2-negative breast cancer demonstrated in the NeoPalAna, PALLET, and 
neoMONARCH studies warrants the investigation of the combination of GDC-9545 with 
palbociclib in this group of patients.
The anticipated or potential adverse events associated with administration of GDC-9545 
in combination with palbociclib therapy are expected to be clinically monitorable,
manageable, and reversible in patients (see Section 5). The study will also evaluate 
patient-reported tolerability for symptoms that have been associated with treatment and 
are self-reportable.
This study will provide critical pharmacodynamic data and rich biomarker data to help 
select patients whose tumors will respond or have resistance, will augment our current 
understanding of the safety of this combination, and will provide early evidence of 
efficacy in the curative setting—a setting where new therapies with an improved 
therapeutic index are needed. 
Improved treatment options for ER-positive, HER2-negative breast cancer may provide 
more effective and tolerable treatment, decrease or eliminate the risk of late recurrences 
after adjuvant therapy, and thus, ultimately achieve an increased cure rate for patients 
with ER-positive, HER2-negative EBC.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of GDC-9545 plus
palbociclib compared with anastrozole plus palbociclib in postmenopausal patients with 
untreated ER-positive and HER2-negative EBC.  Specific objectives and corresponding 
endpoints for the study are outlined below.
In this protocol, “study treatment” refers to the combination of treatments that may be 
assigned to a patient during the study (i.e., GDC-9545, GDC-9545 plus palbociclib, 
anastrozole, and anastrozole plus palbociclib).
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2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of GDC-9545 
compared with anastrozole on the basis of the following endpoint:

Central assessment of changes in Ki67 scores from baseline to Week 2
(Day 15 [1 day])
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the clinical efficacy of 
GDC-9545 plus palbociclib compared with anastrozole plus palbociclib on the basis of 
the following endpoints:

ORR by ultrasound, defined as the proportion of patients with a complete response 
(CR) or PR, as determined by the investigator according to modified 
RECIST (mRECIST)

CCCA rate defined as proportion of patients with centrally assessed Ki67 scores
2.7% stained nuclei upon treatment at Week 2
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of GDC-9545
plus palbociclib compared with anastrozole plus palbociclib on the basis of the following 
endpoints:

Central assessment of changes in Ki67 scores from baseline to surgery and from 
Week 2 to surgery

CCCA rate as defined as proportion of patients with centrally assessed Ki67 scores 
2.7% stained nuclei upon treatment at surgery or post-treatment biopsy (see 
Section 4.5.10)

Pathological complete response (pCR) rate (ypT0/is, ypN0) of GDC-9545 plus 
palbociclib compared with anastrozole plus palbociclib
2.2
SAFETY OBJECTIVES
The safety objective for this study is to evaluate the safety of GDC-9545 plus palbociclib 
compared with anastrozole plus palbociclib on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined in accordance to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
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The exploratory safety objective for this study is to evaluate the tolerability of GDC-9545 
plus palbociclib compared with anastrozole plus palbociclib from the patient's 
perspective on the basis of the following endpoints:

Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptomatic treatment toxicities, as assessed through use of the 
NCI Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events
(PRO-CTCAE) instrument

Overall tolerability (i.e., bother experience due to side effects of treatment) as 
assessed through an overall treatment burden item

Change from baseline in symptomatic treatment toxicities and overall tolerability 
and/or side effect burden, as assessed through respective use of the PRO-CTCAE
and the additional overall burden item

Expectations of therapy, feelings about side effects, and satisfaction with treatment 
from the patient perspective as assessed through use of the Cancer Therapy
Satisfaction Questionnaire (CTSQ)
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the PK profile of GDC-9545 alone and 
when administered in combination with palbociclib on the basis of the following endpoint:

Plasma concentration of GDC-9545 at specified timepoints
2.4
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to the study treatments (i.e., predictive 
biomarkers), are early surrogates of efficacy, are associated with acquired resistance to 
the study treatments, can provide evidence of activity of the study treatments
(i.e., pharmacodynamic 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, plasma, and tumor tissue (listed in
Section 4.5.12) and efficacy, safety, PK, disease biology, 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 (PgR) protein levels and ER target 
genes through analysis of matched baseline, Week 2, and surgery tumor specimens
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a randomized, multicenter, open-label, two-arm, Phase II study to evaluate the 
efficacy, safety, and pharmacokinetics of GDC-9545 versus anastrozole (in the 
window-of-opportunity phase) and GDC-9545 plus palbociclib compared with 
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anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with 
untreated ER-positive HER2-negative EBC. Approximately 215 patients are expected 
be enrolled in this study, at approximately 90 investigative sites globally.
Eligible patients will be randomly assigned in a 1:1 ratio to either the experimental arm 
(GDC-9545) or control arm (anastrozole).  Patients must have histologically confirmed 
invasive breast carcinoma, with measurable disease as per mRECIST with a primary 
tumor size 1.5 cm in longest diameter evaluated by ultrasound at screening.  The 
tumor size category at presentation should be cT1c (1.5 cm)cT4ac.
Patients will be randomized on the basis of Ki67 score with eligibility criteria determined 
from pretreatment tumor tissue sample tested by a central pathology laboratory or a 
local site. Use of the central laboratory for Ki67 level testing is recommended and is the 
preferred method for determining eligibility and stratification (see Section 4.5.10). A Ki67 
score 5% stained nuclei is required for eligibility (see Section 4.1.1).  For the purpose 
of assessing eligibility, ER, PgR, and HER2 will be locally determined prior to beginning 
of study treatment.  ER and PgR will also be centrally assessed, but the results are not 
required prior to randomization.
Patients will be stratified by T status (cT1ccT2 vs. cT3cT4 ac) (Hortobagyi et al. 
2017), Ki67 score (20% vs. 20%), and PgR status (positive vs. negative).
The study consists of a screening period of up to 28 days, a window-of-opportunity
phase for 14 days, followed by a neoadjuvant treatment phase for 16 weeks (four 28-day 
cycles), surgery, and an end of study visit (28 days after the final dose of study 
treatment).  During the window-of-opportunity phase, patients will receive either
GDC-9545 or anastrozole as a single agent. During the neoadjuvant treatment phase, 
patients will receive four 28-day cycles of GDC-9545 plus palbociclib or anastrozole plus
palbociclib.
All patients will be required to provide a pretreatment tumor tissue sample during 
screening, a tumor biopsy sample during treatment, and a post-treatment tissue sample
from the surgical specimen (see Section 4.5.10).
In the neoadjuvant treatment phase, before each cycle, a blood sample will be collected 
and physical examination performed (see Appendix 1 and Appendix 2).  Tumor 
assessments by ultrasound are mandatory at screening, and an additional tumor 
assessment by ultrasound must be performed after the final dose of neoadjuvant 
combination treatment (i.e., after Day 21 of Cycle 4 and prior to surgery).  If there is 
suspicion of disease progression, any other method to evaluate the disease will be 
allowed at any time at investigator’s discretion (see Appendix 1).
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Surgery must be performed within a maximum of 14 days after the final cycle in the
neoadjuvant treatment phase and ideally should occur as soon as possible after the last 
dose of study treatment. A surgical specimen will be obtained for analysis and will be 
analyzed by the local pathologist. If surgery is delayed, the patient is not operable or will 
not undergo surgery for other reasons, or does not complete 16 weeks (four cycles) of 
combination therapy, an optional biopsy may be performed as a separate procedure 
within 2 days from the end of the combination treatment.
All patients must return for the end of study visit 28 days after the final dose of study 
treatment regardless of the reason for treatment discontinuation. Patients who 
experience disease progression or unacceptable toxicity will be treated as per local 
practice after the end of study visit.
Patient treatment after the surgery will be at the investigator’s discretion. Systemic 
chemotherapy and radiation therapy, if indicated, may be initiated after the end of study 
visit. Any post-surgery treatments are not part of the study and will not be provided by 
the Sponsor, and data will not be collected.
Patient-reported outcome (PRO) instruments will be completed by patients to evaluate 
the experience of treatment from the patient's perspective as specified in the schedule of 
activities (see Appendix 1).
Figure 1 presents an overview of the study design.  A schedule of activities is provided 
in Appendix 1 and Appendix 2.
Patients who do not initially meet all eligibility criteria, other than HR status and Ki67, 
may be re-screened once to meet eligibility.  The investigator will record reasons for 
screen failure in the screening log (see Section 4.5.1).
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3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit, occurs or the 
date of Sponsor decision to end the study, whichever is earlier. The end of the study is 
expected to occur approximately 6 months after the last patient is enrolled.
The Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 19 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for GDC-9545 and Palbociclib Dose and Schedule
This study will evaluate GDC-9545 30 mg taken orally (PO) QD as a single agent for 
2 weeks during the window-of-opportunity phase. This will be followed by the 
neoadjuvant phase that will evaluate GDC-9545 30 mg PO QD on Days 128 of each 
cycle plus palbociclib 125 mg PO QD on Days 121 of each 28−day cycle, beginning on 
Day 1 of Cycle 1.  The dose of palbociclib administered represents the currently 
approved dosage for the treatment of adult patients with HR-positive/HER2-negative
advanced or metastatic breast cancer.
Based on the totality of the nonclinical and clinical data, GDC-9545 30 mg taken PO QD 
in combination with palbociclib has been selected as the most appropriate Phase II dose 
and schedule to maximize efficacy while ensuring tolerability.
The Phase Ia/Ib Study GO39932 in metastatic breast cancer evaluated escalating doses 
of GDC-9545 from 10 mg PO QD to 250 mg PO QD.  Overall, GDC-9545 was shown to 
be well tolerated at all dose levels with no clear trend for an increase in frequency or 
severity of adverse events, except for Grade 1 asymptomatic bradycardia/heart rate 
decrease that was dose related. Preclinical in vivo xenograft models reveal that the 
maximal activity is saturated at doses above 10-mg human-dose equivalents.  Human 
steady-state total drug exposure of GDC-9545 at 30 mg QD is about 10-fold higher than 
the steady-state exposure of fulvestrant 500 mg intramuscular monthly, with higher 
in vitro potency. F-18 16-fluoroestradiol (FES)positron emission tomography (PET)
showed complete or near-complete (90%) suppression of FES uptake to background 
levels at 10 mg PO QD to 250 mg PO QD regardless of ESR1 mutation status.  Clinical 
activity as measured by CBR was approximately 50% at the dose of 30 mg QD.  
No evidence of additional benefit was observed at doses above 30 mg. Similar 
pharmacodynamic reductions in ER, PgR, and Ki67 protein levels and in ER-signaling 
activity as measured by gene expression were observed across all dose levels, 
regardless of ESR1 mutation status.
The combination of GDC-9545 and palbociclib was also evaluated in the GO39932 study. 
As of the cutoff date of 4 September 2019, 46 patients were treated with GDC-9545 
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100 mg PO QD and palbociclib 125 mg PO QD.  In general, the combination was well 
tolerated with an expected safety profile, and no safety signals were identified.
Refer to the GDC-9545 Investigator’s Brochure for additional information.
3.3.2
Rationale for Patient Population
Postmenopausal patients with untreated, ER-positive, HER2-negative early stage breast 
cancer will be enrolled in this study. 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, a breast tumor size of 
1.5 cm as measured by ultrasound is needed for the study. Premenopausal patients 
are excluded because the control arm treatment includes anastrozole, which is not 
indicated in patients with functioning ovaries.
3.3.3
Rationale for Control Group
Anastrozole is an AI approved by the U.S. Food and Drug Administration (FDA) in the 
adjuvant setting for EBC. The approval was based on the results of the ATAC trial, 
where 9,366 postmenopausal women with operable breast cancer were randomized to 
adjuvant treatment with anastrozole 1 mg QD, tamoxifen 20 mg QD, or a combination of 
the two treatments for 5 years or until recurrence of the disease (Howell et al. 2005).
Anastrozole has not been approved in the neoadjuvant setting; however, neoadjuvant 
trials have consistently shown superiority of anastrozole or letrozole over tamoxifen in 
Ki67 suppression and clinical response and have predicted the outcome of subsequent 
adjuvant studies (Dowsett et al. 2005a, 2005b, 2007; Ellis et al. 2008; see biomarker
Section 3.3.4.1 for additional details).
More recently, combinations of hormonal therapy with CDK4/6 inhibitors (palbociclib, 
ribociclib, or abemaciclib) have shown robust efficacy benefit in the ER-positive 
advanced breast cancer setting (see Section 1.3) and promising antiproliferative and 
clinical effects in EBC (see Section 1.5.3).
3.3.4
Rationale for Biomarker Assessments
ER-positive, HER2-negative 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.  Pharmacodynamic 
biomarkers will be assessed to demonstrate evidence of biologic activity of GDC-9545 in 
patients and to inform potential revisions to the PK sample collection schedule.
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
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Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
3.3.4.1
Rationale for Changes in Ki67 as Primary Endpoint
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 scores reflect the ability of 
endocrine agents to suppress proliferation (Dowsett et al. 2005a, 2005b; Ellis et al. 
2008). 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 scores was significantly 
greater 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; hazard ratio0.87; 95% CI: 0.78 to 0.97; p0.01) 
and time-to-recurrence (402 vs. 498; hazard ratio0.79; 95% CI: 0.70 to 0.90; 
p0.0005), and significantly reduced distant metastasis (324 vs. 375; hazard ratio0.86; 
95% CI: 0.74 to 0.99; p0.04) and contralateral breast cancers (35 vs. 59; 42% 
reduction, 95% CI: 12% to 62%; p0.01) (Baum et al. 2002; Howell et al. 2005; ATAC
et al. 2008).
The POETIC study, a Phase III randomized clinical study with approximately 
4000 patients with EBC, 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 (IHC) 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. The 
POETIC study demonstrated that Ki67 levels at baseline and at 2 weeks postoperative 
were prognostic of outcomes. At 5 years, patients with low Ki67 levels (10%) at 
2 weeks postoperative had a recurrence rate of 8.4%, and patients with high Ki67 (10%) 
levels at 2 weeks postoperative had a recurrence rate of 19.6% (Robertson et al. 2018).
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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% vs. 39.6% and PFS 6.5 months vs. 5.4 months, respectively) (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
Rationale for the Collection of Plasma Samples for Somatic 
Tumor Mutation Analysis
There is increasing evidence that circulating-tumor DNA obtained from blood specimens 
of patients with cancer 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 isolated from 
plasma using digital polymerase chain reaction, and/or targeted next-generation 
sequencing (NGS).
3.3.4.3
Rationale for the Collection of Tissue Samples
Tumor tissue samples from the same lesion will be collected pretreatment (archival or 
fresh), during treatment (fresh), and post-treatment at surgery (fresh). All tumor tissues 
will be assessed for ER and PgR protein levels, and proliferative index (Ki67).  
In addition, tumor tissue will enable assessment of ER pathway activity using RNA 
analysis of ER target genes (Guan et al. 2019).  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. This approach offers the opportunity to 
perform molecular subtyping that may inform breast cancer biology and response to 
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GDC-9545, endocrine therapy, or CDK4/6 inhibition. The collection of tissue samples 
may also support future diagnostic development.
3.3.5
Rationale for Non-Standard Clinical Outcome Assessments
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic adverse events.  Recent research has shown that clinicians may 
underreport the incidence and severity of symptoms experienced by patients receiving 
treatment for cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; 
Basch 2010; Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014).  Collecting 
symptomatic information directly from patients can provide a better understanding of 
treatment characteristics and their effects.  To evaluate the tolerability of GDC-9545 plus 
palbociclib, patients will be asked to report on their experience related to diarrhea, 
nausea, vomiting, joint pain, hot flush, rash, and fatigue treatment-related symptoms 
selected from the validated PRO-CTCAE item bank (see Appendix 3).  These symptoms 
were identified as being salient to patients' experience with GDC-9545 and palbociclib 
on the basis of preliminary safety data for GDC-9545 and published safety data for 
palbociclib. An item asking about overall side-effect burden will also be included.
To gather additional information about patients’ experiences with novel NET 
combinations in the EBC setting, patients will be asked to report their expectations, 
feelings about side effects, and satisfaction with treatment via the CTSQ.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 215 postmenopausal women with operable or inoperable, untreated 
ER-positive, HER2-negative EBC will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Postmenopausal 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 operable or inoperable invasive breast carcinoma, with all of 
the following characteristics:

cT1c (1.5 cm)cT4ac breast cancer at presentation
Primary tumor must be 1.5 cm in longest diameter by ultrasound.

Measurable disease by ultrasound as defined per mRECIST (see Appendix 4)

Patients with multifocal tumors (more than one mass confined to the same 
quadrant as the primary tumor) if all lesions are sampled and confirmed as 
ER-positive/HER2-negative invasive breast cancer and at least one lesion is 
1.5 cm in longest diameter by ultrasound
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
Patients with multicentric tumors (multiple tumors involving more than one 
quadrant) if all discrete lesions are sampled and confirmed as 
ER-positive/HER2-negative invasive breast cancer and at least one lesion is 
1.5 cm in longest diameter by ultrasound

Candidate for neoadjuvant treatment and considered appropriate for endocrine 
therapy

Willingness to undergo breast surgery (mastectomy or breast-conserving surgery) 
after neoadjuvant treatment

Willingness to provide three mandatory tumor samples (see Section 4.5.10 for tumor 
tissue sample requirements) as follows:

Pretreatment

During treatment at Cycle 0 Day 15 (+1 day)

Posttreatment (from surgical specimen) or an optional biopsy (if surgery is not 
possible or delayed; see Section 4.5.10)

Documented ER-positive tumor in accordance to American Society of Clinical 
Oncology (ASCO)/College of American Pathologists (CAP) guidelines (Allison et al. 
2020), assessed locally and defined as 1% of tumor cells stained positive on the 
basis of the most recent tumor biopsy

Documented PgR status (positive or negative) as per local assessment

Documented HER2-negative tumor in accordance to 2018 ASCO/CAP guidelines 
(Wolff et al. 2018), assessed locally on the most recent tumor biopsy

Ki67 score 5% analyzed centrally (recommended) or locally (by Sponsor
pre-approved assay/scoring method)
Use of the central laboratory for Ki67 level testing for eligibility is recommended.
For sites using the central laboratory to test for Ki67 eligibility, a tissue sample 
must be submitted to the central laboratory for enrollment by the IHC-based 
central pathology laboratory Ki67 Clinical Trial Assay (see Section 4.5.10 for 
additional details).

Postmenopausal status defined as one of the following: 

Documented bilateral surgical oophorectomy (14 days prior to first treatment 
on Day 1 of Cycle 1 and recovery from surgery to baseline)

Age 60 years and 12 consecutive months with no menses without an 
alternative medical cause

Age 60 years and 12 continuous months of amenorrhea with no identified 
cause other than menopause, estradiol levels, and follicle-stimulating hormone 
(FSH) levels in the postmenopausal range

Eastern Cooperative Oncology Group (ECOG) Performance Status 01
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
Adequate organ function as defined by the following criteria:

ANC 1.5109/L (1500/L)

Platelet count 100109/L (100,000/L)

AST and serum ALT 2upper limit of normal (ULN)

Hemoglobin 90 g/L (9 g/dL)

Serum bilirubin 1.5ULN with the following exception:
Patients with known Gilbert syndrome:  3ULN

Serum creatinine 1.5ULN or estimated creatinine clearance 60 mL/min as 
calculated per institutional guidelines

INR 1.5ULN and aPTT 1.5ULN
For patients requiring anticoagulation therapy with warfarin, a stable INR
between 2 and 3 is required.
For patients receiving heparin, PTT (or aPTT) between 1.5 and 2.5ULN 
(or patient value before starting heparin treatment) is required.
If anticoagulation therapy is required for a prosthetic heart valve, stable INR 
between 2.5 and 3.5 is permitted.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Stage IV (metastatic) breast cancer 

Inflammatory breast cancer (cT4d)

Bilateral invasive breast cancer

History of invasive breast cancer

History of ductal carcinoma in situ or lobular carcinoma in situ if they have received 
any systemic therapy for treatment or radiation therapy to the ipsilateral breast 
Patients treated with surgery alone may be eligible.

History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer

Previous systemic or local treatment for the primary breast cancer currently under 
investigation (including excisional biopsy or any other surgery of the primary tumor 
and/or axillary lymph nodes, radiotherapy, cytotoxic, and endocrine treatments)

History of any prior treatment with AIs, tamoxifen, SERDs, or CDK4/6 inhibitors

Major surgery within 4 weeks prior to randomization
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
Known clinically significant history of liver disease consistent with Child-Pugh
Class B or C, including hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C virus
[HCV]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis as defined 
below:
Active infection is defined as requiring treatment with antiviral therapy or 
presence of positive test results for hepatitis B (hepatitis B surface antigen 
[HBsAg] and/or total hepatitis B core antibody [HBcAb]) or HCV antibody.  
Unless required by local regulations, patients are not required to have HIV, 
HBV, or HCV assessments at screening if these assessments have not been 
previously performed.
Patients who test positive for HBcAb are eligible only if test results are also 
positive for hepatitis B surface antibody and polymerase chain reaction is 
negative for HBV DNA.
Patients who are positive for HCV serology are only eligible if testing for HCV 
RNA is negative.

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 anastrozole, or palbociclib or any of its excipients

Known issues with swallowing oral medication

History of documented hemorrhagic diathesis, coagulopathy, or thromboembolism 

Active cardiac disease or history of cardiac dysfunction including any of the following:

History or presence of symptomatic bradycardia or resting heart rate 50 bpm at 
screening
Patients on stable dose of a -blocker or calcium channel antagonist for 
pre-existing baseline conditions (e.g., hypertension) may be permitted if 
resting heart is 50 bpm.

History of angina pectoris, symptomatic pericarditis, myocardial infarction, or any 
cardiac arrhythmias (e.g., ventricular, supraventricular, nodal arrhythmias, or 
conduction abnormality) within 12 months prior to study entry

History of documented congestive heart failure (New York Heart Association 
Class IIIV) or cardiomyopathy

Left ventricular ejection fraction 50% as determined by multiple-gated 
acquisition scan or echocardiogram 

QT interval corrected through use of Fridericia’s formula (QTcF) 470 ms based 
on mean value of triplicate ECGs, history of long or short QT syndrome, 
Brugada syndrome or known history of corrected QT interval prolongation, or 
torsades de pointes
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
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, sick sinus syndrome, or evidence of prior myocardial 
infarction

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 long QT syndrome

Current treatment with medications that are well known to prolong the QT interval
(see Section 4.4.2.2)

Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or
major upper gastrointestinal (GI) surgery including gastric resection

Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug 
elimination half-lives (whichever is longer) prior to randomization

Known HIV infection

Serious infection requiring oral or IV antibiotics, or other clinically significant infection 
within 14 days prior to screening
Patients who fully recovered from serious and clinically significant infections
within 14 days prior to screening are eligible.

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study

Assessed by the investigator to be unable or unwilling to comply with the
requirements of the protocol
4.2
METHOD OF TREATMENT ASSIGNMENT
This is a randomized, open-label study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS).
Patients will be randomly assigned to one of two treatment arms:  experimental arm or 
control arm.  Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm.  
Randomization will be stratified according to the following criteria:

cT status: cT1ccT2 versus cT3cT4ac

Ki67 score: 20% versus 20%

PgR status: positive versus negative
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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are GDC-9545, anastrozole,
and palbociclib.
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
GDC-9545
GDC-9545 will be supplied by the Sponsor as 30-mg capsules packaged in high-density 
polyethylene bottles with a plastic child-resistant cap with induction seal and desiccant.  
For information on the GDC-9545 formulation, see the pharmacy manual and the 
GDC-9545 Investigator's Brochure.
4.3.1.2
Anastrozole
Anastrozole will be supplied by the Sponsor as 1-mg film-coated tablets. For information 
on the anastrozole formulation, see the local prescribing information for anastrozole.
4.3.1.3
Palbociclib
Palbociclib will be supplied by the Sponsor as 75-, 100-, and 125-mg hard gelatin 
capsules.  During the course of the study, the formulation may switch to 75, 100, and 
125-mg tablets.  For additional information on the palbociclib formulation and packaging, 
see the local prescribing information for palbociclib.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1 and outlined in Figure 1 and
Figure 2.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
To assess patient compliance with self-administration of study medication (GDC-9545, 
anastrozole, and palbociclib), site study staff will provide patients with detailed 
instructions and training for the handling and administration of study drugs.  Patients will 
receive and should be instructed to complete a medication diary.  Patients will be 
instructed to bring all unused study medication and their medication diaries to the clinic 
at specified study visits (see schedule of activities Appendix 1).  Compliance will be 
assessed by investigator site team staff (e.g., by counting returned tablets/ capsules, 
clinic visit patient interview notes, and reviewing patient diaries).
Details on treatment administration should be noted on the Study Drug Administration 
electronic Case Report Form (eCRF).  Cases of 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 5.1.4.
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Figure 2
Study Treatment Regimens
Ccycle; Dday.
4.3.2.1
GDC-9545, Palbociclib, and Anastrozole
GDC-9545, anastrozole, and palbociclib should be taken orally with food at 
approximately the same time each day as per study treatment regimen. If palbociclib 
switches to tablet formation (see Section 4.3.1.3), study treatments may be taken with or 
without food. The capsule or tablet should be swallowed whole and should not be 
chewed, crushed, or opened.
During the window-of-opportunity phase, GDC-9545 and anastrozole can be taken with 
or without food at approximately the same time each day. During the 
window-of-opportunity phase, starting on Cycle 0 Day 1, GDC-9545 30 mg PO QD or
anastrozole 1 mg PO QD will be administered as a single agent for 2 weeks.
During the neoadjuvant treatment phase, GDC-9545 30 mg PO QD or anastrozole 1 mg
PO QD will be administered on Days 128 of each 28-day cycle in combination with 
palbociclib 125 mg PO QD on Days 121 of each 28-day cycle for four cycles.  Starting
with Day 1 of Cycle 0 and on Day 1 of each 28-day cycle thereafter, study treatment will 
be administered in the clinic after the study assessments, as indicated in the schedule of 
activities (see Appendix 1 and Appendix 2). All other doses will be taken at home on all 
non-clinic visit days.  If a GDC-9545 dose is missed, the dose should be made up unless 
the next dose is due within 6 hours.
4.3.2.2
Compliance
At the beginning of study participation by a patient, site study staff will provide the patient 
with detailed instructions and training for the handling and administration of study 
treatment.  Patients will receive and should be instructed to complete a medication diary.  
Window-of-Opportunity                            Neoadjuvant Treatment
GDC-9545
Anastrozole
Palbociclib
2 weeks                                                   Cycles 14
C0D1                                   C0D14    CXD1                                                               CXD21             CXD28
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At each clinic visit, the medication diary as well as unused tablets or capsules and all 
containers or packaging (used or unused) of study treatment should be collected and 
reviewed for drug accountability.
Treatment compliance will be defined as the number of capsules or tablets taken divided 
by the expected number of capsules or tablets and reported as a percentage.  In case of 
dose reductions, the expected number of capsules or tablets should reflect the new dose 
level.  Capsules or tablets that are not returned will be considered to have been taken, 
unless otherwise specified in the patient’s diary and/or eCRF.  Note that dosing eCRFs 
should be completed using the following prioritization:  1) site pharmacy drug 
accountability logs (IMP disbursed minus IMP returned), 2) clinic visit patient interview 
notes, and 3) patient daily dosing diary.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by the 
protocol.
The study site should follow all instructions included with each shipment of IMP.  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.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and 
authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
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 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 accountability log.
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Refer to the pharmacy manual and/or the GDC-9545 Investigator's Brochure and the 
anastrozole and palbociclib local prescribing information for information on IMP handling, 
including preparation and storage, and accountability.
4.3.4
Continued Access to GDC-9545
Currently, the Sponsor does not have any plans to provide Roche IMP (GDC-9545) or 
any other study treatments 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
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, 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 initiation of study drug to treatment discontinuation or end of study visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
GDC-9545 is primarily glucuronidated via UGT1A4.  It is unlikely that any clinically 
relevant drug-drug interaction (DDI) will occur with GDC-9545 both as a perpetrator and 
as a victim.  Palbociclib is primarily metabolized by CYP3A and sulfotransferase enzyme 
SULT2A1.  In vivo, palbociclib is a time-dependent inhibitor of CYP3A.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Symptomatic anti-emetics and anti-diarrheal therapy may be administered at the
investigator’s discretion.

Bone-sparing agents (e.g., bisphosphonates, denosumab for the treatment of
osteoporosis/osteopenia) are allowed in the study provided patients are on stable
doses for at least 4 weeks prior to randomization.

Patients can be treated per standard of care except for use of any prohibited 
therapies.
All concomitant medication and/or therapies should be documented in the patient’s 
eCRF.
4.4.2
Cautionary Therapy
4.4.2.1
CYP3A4 Substrate with a Narrow Therapeutic Index
Co-administration of midazolam (sensitive CYP3A4 substrate) with multiple doses of 
palbociclib increased the midazolam plasma exposure by 61% in healthy subjects 
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compared with the administration of midazolam alone. Therefore, the dose of a 
sensitive CYP3A4 substrate with a narrow therapeutic index (e.g., alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, 
sirolimus, and tacrolimus) may need to be reduced, as palbociclib may increase its 
exposure (IbranceU.S. Package Insert).
The above list of CYP3A4 sensitive substrates with a narrow therapeutic index is not 
necessarily comprehensive. Thus, the investigator should consult the prescribing 
information for any concomitant medication as well as the internet reference provided 
below when determining whether a medication is a sensitive CYP3A4 substrate with a 
narrow therapeutic index and can be safely administered with palbociclib. Palbociclib 
local prescribing information should also be consulted for information on prohibited 
therapies and recommended dose adjustments for concomitant medications.
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf
4.4.2.2
Medications Associated with QT Interval Prolongation
Any concomitant medications known to affect QT interval duration, including, but not 
limited to, the following drugs and drug classes should be used with caution and an 
alternative therapy should be used when possible:  fluoroquinolones, antifungals 
(i.e., ketoconazole, itraconazole, and fluconazo le), antimalarials, amiodarone, cisapride, 
clarithromycin, erythromycin, methadone, amitriptyline, maprotiline, clomipramine, 
citalopram, escitalopram, venlafaxine, quinidine, and Class 1 and 3 antiarrhythmics.
Investigators should use medical judgement and exercise caution when considering the 
co-administration of drugs known to cause decrease in heart rate in patients already 
receiving treatment with GDC-9545, and an alternative therapy should be used when 
possible.
Medications Associated with Bradycardia
Investigators should use medical judgment and exercise caution when considering 
initiation of concomitant medication known to cause decreases in heart rate including,
but not limited to, -blockers and calcium channel antagonists. An alternative therapy
should be used when possible. Patients on a stable dose of a -blocker or calcium
channel antagonist for preexisting baseline conditions (e.g., hypertension) should be
monitored closely in case dose modification is warranted.
4.4.2.3
Herbal Therapies
Concomitant use of herbal therapies, especially St. John’s wort (strong CYP3A inducer), 
in combination with palbociclib is not recommended because their pharmacokinetics, 
safety profiles, and potential DDIs are generally unknown.  However, other herbal 
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therapies (excluding St. John’s wort) not intended for the treatment of cancer may be 
used during the study at the discretion of the investigator and must be reported as 
concomitant therapy in the eCRF.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited during study treatment as 
described below:

Strong CYP3A4 inhibitors, including, but not limited to, the following: atazanavir, 
ritonavir, lopinavir, telaprevir, telithomycin, indinavir, nelfinavir, saquinavir, 
clarithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, 
posaconazole, conivaptan, diltiazem, nefazodone, and mibefradil
If co-administration of palbociclib with a strong CYP3A4 inhibitor cannot be 
avoided, reduce the dose of palbociclib as per palbociclib local prescribing 
information.

Strong CYP3A4 inducers, including, but not limited to, the following: rifampin, 
carbamazepine, phenytoin, enzalutamide, oxcarbazepine, phenobarbital, nevirapine, 
hyperforin (St. John's Wort), and cyproterone
The above lists of CYP3A4 concomitant medications are not necessarily comprehensive. 
Thus, the investigator should consult the prescribing information for any concomitant 
medication as well as the internet reference provided below when determining whether a 
certain medication strongly inhibits or induces CYP3A4. Palbociclib and anastrozole
local prescribing information should also be consulted for information on prohibited 
therapies and recommended dose adjustments for concomitant medications. In addition, 
the investigator should contact the Medical Monitor if questions arise regarding 
medications not listed above.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
during study treatment.

Any concomitant therapy intended for the treatment of cancer (including, but not 
limited to, chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or 
radiotherapy) is prohibited until after the end of study visit. Adjuvant endocrine 
therapy may be used after surgery at the investigator’s discretion. Adjuvant 
chemotherapy, if indicated, may be initiated after the completion of the mandatory 
end-of-study visit.

Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate, oral contraception, hormone-eluting intrauterine 
devices, Gonadotropin-releasing hormone (GnRH) agonists and selective ER 
modulators (e.g., raloxifene) are prohibited until after the end of study visit.
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
Primary prophylactic use of hematopoietic growth factors (e.g., erythropoietins, 
granulocyte colony-stimulating factor, and granulocyte-macrophage
colony-stimulating factor) is not permitted; however, they may be used to treat 
treatment-emergent neutropenia or anemia as indicated by the current ASCO 
guidelines or as secondary prophylaxis if dose reduction or delay is not considered a 
reasonable alternative and with approval of the Medical Monitor.
Enrolled patients who subsequently require the use of any prohibited therapies must be 
discontinued from study treatment as outlined in Section 4.6.1.
4.4.4
Prohibited Food
Use of the following foods is prohibited as described below:

Consumption of grapefruit, grapefruit juice, grapefruit supplements, or Seville 
oranges (potent CYP3A4 enzyme inhibitors) is prohibited for at least 3 days prior to 
initiation of study treatment and during study treatment.
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1
and Appendix 2.  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 toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
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. Patients who do not initially meet all eligibility criteria, 
other than HR status and Ki67 score, may be re-screened once at the investigator's 
discretion.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including tumor size, tumor grade, nodal status, and ER/PgR/Ki67 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 
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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, as allowed by 
the local regulations.
4.5.3
Additional Restrictions
No food or fluids other than water will be allowed from 8 hours prior to the lipid panel test 
at screening and end of study visit.
4.5.4
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, GI, and neurologic systems.  
Bilateral breast examination including evaluation of local-regional lymphatics should be 
conducted as per Section 4.5.6. Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed, physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  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.
4.5.5
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  
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 (see Section 5.3.5.5).
4.5.6
Local-Regional Tumor Status
Assessment of primary tumor and regional lymph nodes must be performed by physical 
examination. Physical examination of breast and axilla will be mandatory at screening 
and prior to each cycle of neoadjuvant therapy, as indicated in Appendix 1.
4.5.7
Tumor and Response Evaluations
Before starting neoadjuvant treatment, the primary tumor site must be marked using a
method that is routine clinical practice (e.g., skin tattoo or surgical clip) to enable 
appropriate surgical excision in case of tumor regression during neoadjuvant therapy. 
Tumor response will be evaluated with ultrasound. Breast ultrasounds will be mandatory
at screening (within 28 days prior to randomization) and after final dose of neoadjuvant 
combination treatment (i.e., after Cycle 4 Day 21 and prior to surgery; see Appendix 1).
If with ultrasound examination at baseline there is evidence of suspicious axillary lymph 
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nodes, then fine-needle aspiration or core biopsy is required. Sonographic tumor 
measurements are to be recorded in the eCRF. Response assessments will be made 
by the investigator on the basis of ultrasound through use of mRECIST (see
Appendix 4). Confirmation of response will not be required.
At the investigator's discretion, assessments may be repeated at any time if progressive 
disease is suspected.
4.5.8
Tumor Staging
Baseline distant site tumor staging procedures are not mandatory and should be
performed as per local practice, in alignment with national guidelines and as clinically
indicated, within 28 days prior to randomization.
For reference, per National Comprehensive Cancer Network guidelines, staging 
procedures are based on clinical stage as follows:

Stages IIAIIB: Bone scan is to be performed in presence of bone pain and/or
elevated ALP; abdominal/pelvic PET/computed tomography (CT) scan in case of 
elevated ALP, abnormal liver function tests, abdominal symptoms, or abnormal 
physical examination; and chest PET/CT scan if pulmonary symptoms are present.

Stages IIIAIIIC: Bone scan and PET/CT scan of chest, abdomen, and pelvis is to 
be performed; liver imaging, and/or other radiographic modalities may be considered 
when clinically indicated to exclude metastatic disease.
4.5.9
ECOG Performance Status
Performance status will be completed at screening and as specified in the schedule of 
activities (see Appendix 1) using the ECOG Performance Status Scale (see Appendix 5) 
and recorded on the eCRF.
4.5.10
Ki67 Assessment
Biological response to the study treatment will be assessed by measuring changes in 
cell proliferation (Ki67 protein levels) using formalin-fixed, paraffin-embedded core
(FFPE) histopathology sections of the tumor biopsy specimens collected at the following 
timepoints:

Screening, prior to initiation of treatment. A representative FFPE tumor 
specimen from a primary breast tumor (not lymph nodes) in a paraffin block is 
preferred, or at least 1520 slides containing unstained, freshly cut, serial tissue 
sections should be submitted along with an associated de-identified pathology report 
prior to study enrollment.  Regardless if Ki67 testing to determine eligibility is 
performed by central or local laboratory, a tissue sample must be submitted to the 
central laboratory. For sites using the central laboratory for Ki67 testing of eligibility, 
a tissue sample must be submitted to the central laboratory for enrollment by the 
IHC-based central pathology laboratory Ki67 Clinical Trial Assay.  If local Ki67 testing 
of tumor tissue for eligibility is strongly preferred by a site, this may be permitted only
if testing will be performed using a Sponsor pre-approved IHC-based assay and 
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scoring method.  Sponsor approval is required before any local testing of Ki67 for 
eligibility is permitted.  If Sponsor-approved local Ki67 testing is used to determine 
eligibility and stratification, confirmation of shipment of the pretreatment tumor tissue 
sample to the central pathology laboratory is required prior to randomization.  If the 
central Ki67 result becomes available prior to a patient’s randomization, the site must 
defer to the central result to determine eligibility even if the approved local result 
determines otherwise.  If a high level of discordance is observed between the 
eligibility determined by the local Ki67 results and the central pathology laboratory 
results determined after randomization, the Sponsor may discontinue the use of local 
testing at a site or at study level for the purposes of determining eligibility.
Tumor tissue should be of good quality based on total and viable tumor content:  
Samples must contain a minimum of 500 viable tumor cells that preserve 
cellular context and tissue architecture regardless of needle gauge or retrieval 
method.  Samples collected via resection, core-needle biopsy (at least three 
cores, embedded in a single paraffin block), punch, or forceps biopsy are 
acceptable.  Fine-needle aspiration (defined as samples that do not preserve 
tissue architecture and yield cell suspension and/or smears), brushing, and 
lavage samples are not acceptable.
Archival tumor tissue from prior diagnostic FFPE cores may be used; however, 
if archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment fresh tumor biopsy is required.  A pretreatment 
tumor biopsy may also be performed if a patient's archival tissue test results do 
not meet eligibility criteria.  If a pretreatment tumor biopsy is determined to be 
required, two FFPE core-needle biopsies embedded in a single paraffin block 
and one freshly frozen optimal cutting temperature (OCT) core-needle biopsy 
will be required.

After 2 weeks of treatment and at the time of surgery. FFPE and non-FFPE 
samples will be prepared from the newly collected tumor biopsies and surgical 
resection.
Two FFPE core-needle biopsies embedded in a single paraffin block and one 
freshly frozen OCT core-needle biopsy are required on Day 15 (+1 day).
For the post-treatment tissue sample collected at surgery, an FFPE tumor block 
from surgical resection 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20 paraffin embedded, unstained 
slides from the surgical specimen are required.  A freshly frozen OCT tumor 
tissue sample at surgery is required, unless not clinically feasible.
If the patient has pCR at time of surgery, tumor surgical specimens will no 
longer required.
All tumor tissue samples collected during the study will be sent to one or several central 
laboratories or to the Sponsor or a designee for analysis.
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A detailed description of tissue quality requirements and procedures for collection, 
handling and shipping of tumor tissue samples will be provided in a separate laboratory 
manual.
4.5.11
Surgical Treatment Plan
Patients will be scheduled to undergo surgery after four cycles of neoadjuvant therapy. 
Surgery must take place within a maximum of 14 days after the last cycle in the 
neoadjuvant treatment phase and ideally as soon as possible after the last dose of study 
treatment. Patients may undergo breast-conserving surgery or mastectomy in 
accordance to routine clinical practice, and the procedure should be documented and 
reported in the eCRF.
Sentinel lymph node biopsy is not allowed prior to neoadjuvant therapy. Surgical 
management options for axillary lymph nodes include sentinel lymph node biopsy (after 
neoadjuvant treatment) and axillary lymph node dissection of Level I and II lymphatics at 
the moment of breast surgery.  The choice of the axillary procedure will be based on the 
clinical status of axilla, T stage, and local practice.
4.5.12
Laboratory, Biomarker, and Other Biological Samples
Laboratory samples should be collected according to the schedule of activities (see 
Appendix 1 and Appendix 2).  Results of the following assessments should be available 
for review at each clinic visit (as required per the schedule of activities) prior to dosing to 
inform dosing decisions: complete blood count with differential, total bilirubin, ALP, AST, 
ALT, creatinine, and BUN/urea.
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, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells)

Chemistry panel (serum or plasma): sodium, potassium, chloride, glucose, BUN or 
urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, 
ALP, ALT, AST, urate, and LDH

Fasting lipid panel: cholesterol, HDL, LDL, and triglycerides

Coagulation:  INR, aPTT, and PT

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and
blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, and bacteria)
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
HBV serology:  HBsAg, HBcAb, and (if HBsAg test is negative and total HBcAb test 
is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

FSH, for patients 60 years

Estradiol, for patients 60 years
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis (see Appendix 2), unless otherwise indicated:

Plasma samples for PK analysis

Blood and plasma samples for exploratory research on biomarkers and biomarker 
assay development

Archival (diagnostic) or newly collected tissue sample obtained prior to initiation of 
treatment for determination of baseline Ki67 scores and for exploratory research on
biomarkers and biomarker assay development (see Section 4.5.10 for tumor tissue 
sample requirements)

Mandatory tumor tissue samples obtained on Day 15 (+1 day) after single-agent 
treatment and at the time of surgery to evaluate changes in Ki67 scores and for 
exploratory research on biomarkers and biomarker assay development (see 
Section 4.5.10 for tumor tissue sample requirements)
Tumor tissue specimens may be used for centralized retrospective assessment to 
evaluate correlation between genes, proteins, DNA, and RNA relevant to the signaling 
pathways and sensitivity/resistance to the investigational agents.
Exploratory biomarker research may include, but will not be limited to, analysis of 
expression of ESR1 and ER target genes, signatures associated with breast cancer 
subtypes, immune-related genes, and PI3K signaling genes.  Research may involve 
extraction of DNA, cell-free DNA, or RNA; analysis of gene and/or protein expression; 
analysis of mutations, copy number, single nucleotide polymorphisms, and other 
genomic variants; and genomic profiling through use of NGS of a comprehensive panel 
of genes.  DNA extracted from blood and plasma may be compared with DNA extracted 
from tissue to identify somatic variants by distinguishing germline variants from somatic 
variants.  NGS methods may include whole genome sequencing (WGS) or whole exome 
sequencing (WES) of blood samples, but only at participating sites (see Section 4.5.15).
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
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Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.17), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions:

Blood, plasma, and tumor tissue samples collected for biomarker research and 
biomarker assay development will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed or earlier depending on local regulations.

Plasma samples collected for PK analysis may be needed for additional 
pharmacokinetics and its associated biomarker characterization and for PK assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or by 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 no later than 6 weeks 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 genomic variants, 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.
4.5.13
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and 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. Twelve-lead single 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.
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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 post-dose timepoint the mean QTcF is 500 ms and/or 60 ms
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and 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 5.1.4.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia).
4.5.14
Clinical Outcome Assessments
PRO data will be collected to more fully characterize the clinical profile of GDC-9545 
plus palbociclib compared with anastrozole plus palbociclib in patients enrolled in the 
study. PRO data will be collected at the clinic sites using select items of the 
PRO-CTCAE and the CTSQ measure in its entirety according to the schedule of 
assessments (see Appendix 1).
If after completion of the PROs (i.e., PRO-CTCAE) at the start of a treatment cycle it is 
determined that the dose of palbociclib should be delayed, the PROs will not be 
re-administered when the patient returns to the clinic following the delay. The timing of 
subsequent PRO assessments will be based on the actual Day 1 of the given GDC-9545 
cycle when palbociclib was administered.
4.5.14.1
Data Collection Methods for Clinical Outcome Assessments
PRO questionnaires, translated into local languages as appropriate, will be distributed by 
site personnel via paper booklets provided by the Sponsor for self-administration by 
patients at specified timepoints during the study (see Appendix 1).  PROs will be 
administered at the clinic before the patient receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of 
study treatment, unless otherwise specified. Following completion, site personnel will 
enter PRO data into the study database.
During clinic visits, PRO instruments should be administered as outlined below:

Patients’ health status should not be discussed prior to administration of the 
instruments.
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
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 5 minutes at each specified visit.

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions.

Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers.

Site staff should not interpret or explain questions, but may read questions verbatim 
upon request.

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments.

Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location. If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank.
4.5.14.2
Description of Clinical Outcome Assessment Instruments
PRO-CTCAE
The PRO-CTCAE is a validated item bank that is used to characterize the presence, 
frequency of occurrence, severity, and/or degree of interference with daily function of 
78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 
2015).  The PRO-CTCAE contains 124 questions that are rated either dichotomously 
(for determination of presence vs. absence) or on a 5-point Likert scale (for determination 
of frequency of occurrence, severity, and interference with daily function).  Treatment 
toxicities can occur with observable signs (e.g., vomiting) or non-observable symptoms 
(e.g., nausea).  The standard PRO-CTCAE recall period is the previous 7 days.
A subset of seven symptoms deemed most applicable to the current treatments has 
been selected for this study (i.e., diarrhea, nausea, vomiting, fatigue, joint pain, hot flush, 
and rash; see Appendix 3). Symptoms have been selected on the basis of being 
self-reportable, having a symptomatic equivalent in the PRO-CTCAE item library, and 
being associated with GDC-9545 or palbociclib based on preliminary safety or published 
studies.
An additional question based on item 5 of the Functional Assessment of Cancer Therapy: 
General instrument will be administered to provide an overall assessment of tolerability 
(i.e., side effect burden).
Cancer Therapy Satisfaction Questionnaire
The CTSQ (see Appendix 6) is a validated measure used to assess expectations, 
experience, and satisfaction with cancer treatments (Abetz et al. 2005; Trask et al. 2008).
It contains 16 items that are rated on 5-point Likert scales assessing domains regarding
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expectations, feelings about side effects, and overall satisfaction. The CTSQ uses a 
recall period of the last 4 weeks.
4.5.15
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites)
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to developing adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  Research will be
aimed at exploring inherited characteristics.  DNA extracted from blood may be 
compared with DNA extracted from tissue to identify somatic variants by distinguishing 
germline variants from somatic variants.  The samples may be sent to one or more 
laboratories for analysis.
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research 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 WGS or WES, this section of the protocol 
(Section 4.5.15) will not be applicable at that site.
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
WGS and WES provide a 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 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.
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).
Refer to Section 4.5.12 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses.
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4.5.16
Optional Tumor Biopsies
Consenting patients will undergo an optional tumor biopsy at screening and/or at end of 
treatment. At screening, for patients with an acceptable archival tumor tissue specimen, 
one freshly frozen OCT core-needle biopsy is requested.
If surgery is delayed or if the patient is not operable or will not undergo surgery for other 
reasons, an optional biopsy may be performed as a separate procedure within 2 days 
from the end of the combination treatment.  If a patient does not complete 16 weeks 
(four cycles) of combination therapy, an optional biopsy may be performed within 2 days 
from the end of the combination treatment, either from the surgical specimen, or if 
surgery is not performed within 2 days after the end of the combination treatment, from a 
separate biopsy. If an optional biopsy is performed within 2 days after the end of the 
combination treatment, two FFPE core-needle biopsies embedded in a single paraffin 
block and one freshly frozen OCT core-needle biopsy are required.
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient’s 
agreement to undergo optional biopsies.  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 Optional Biopsy Sample Informed Consent eCRF.
Samples may be used for exploratory biomarker research as described in Section 4.5.12.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.12 for details on duration of sample storage, 
use of samples after patient withdrawal, confidentiality standards for data, and 
availability of data from biomarker analyses.
4.5.17
Optional Samples for Research Biosample Repository
4.5.17.1
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
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
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
4.5.17.2
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 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 4.5.17) 
will not be applicable at that site.
4.5.17.3
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, serum, plasma, and 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 blood and tissue samples 
from medically indicated procedures (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) 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 WGS, WES, or other genomic analysis methods. Genomics is 
increasingly informing researcher’s understanding of disease pathobiology.  WGS and 
WES provide a 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).
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4.5.17.4
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.
4.5.17.5
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 
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.
4.5.17.6
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 
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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 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.
4.5.17.7
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.
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

Intolerable toxicity related to study treatment determined by the investigator to be 
unacceptable given the potential for treatment benefit and the severity of the event

Disease progression per investigator’s assessment

Non-compliance with protocol specified drug administration and follow-up tests

Concomitant use of any other (non-protocol) systemic anti-cancer therapy

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
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Patients will return to the clinic for an end of study visit 28 (3) days after the final dose 
of study drug (see Appendix 1 for additional details).
4.6.2
Patient Discontinuation from the Study
Patients will return to the clinic for an end of study visit 28 (3) days after the final dose 
of study drug.
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

Adverse event

Loss to follow-up

Progression of the disease

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the study.  
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 not be replaced.
Patients who are withdrawn or withdraw from study participation (and not just study
treatment) will not be followed up for any reason after consent has been withdrawn.
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
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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)
4.6.5
Clinical Trial Conduct, in Light of COVID-19 or Other 
Significant Events with Global Impact
Due to coronavirus disease 2019 (COVID-19) or other significant event with global 
impact (e.g., pandemic, natural disaster), there are challenges that could affect the 
conduct of clinical studies. In such situations, the Sponsor will provide further guidance 
where possible, and investigators will be requested to discuss individual patient 
considerations with the Medical Monitor.
Prospective protocol waivers remain unacceptable due to COVID-19 or other significant
events with global impact. It is critical to ensure that protocol deviations are fully 
documented, to enable appropriate evaluation of the effect on the clinical study.
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
GDC-9545 is not currently approved for any indication, and clinical development is 
ongoing. Palbociclib has not been approved for patients with ER-positive, 
HER2-negative early stage breast cancer (see Section 1.5).  Anastrozole has been 
approved for patients with ER-positive early stage breast cancer in the adjuvant setting. 
The combination of palbociclib plus an AI (anastrozole or letrozole) has been evaluated 
in neoadjuvant studies showing a favorable safety profile (see Section 1.5). The safety 
plan for patients in this study is based on clinical experience with palbociclib and AI in 
published clinical trials and authorized use, and on clinical experience with GDC-9545 in 
ongoing studies. The anticipated important safety risks and management plan for 
GDC-9545, are outlined below. Patients should be instructed to promptly contact the 
investigator if any adverse event develops.
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.  
Patients will undergo 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 dosage modification and treatment interruption or 
discontinuation, are provided below.
Refer to the GDC-9545 Investigator’s Brochure for a complete summary of safety 
information. Currently, there is no identified risk with GDC-9545; however, the summary 
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of potential risks are provided below. Refer to the local prescribing information for a 
complete summary of safety information for palbociclib and anastrozole.
In addition to these guidelines, more conservative dose modifications of any study 
treatment for the management of adverse events are permitted at the discretion of the 
investigator if deemed to be in the best interest of the patient.
5.1.1
Potential Risks Associated with GDC-9545
5.1.1.1
Hepatoxicity
Isolated events of increases in transaminases and bilirubin have been observed with 
treatment of GDC-9545 at low frequency and primarily at low grades, with a single 
Grade 3 event of transaminase increase being reported for single-agent GDC-9545 at a 
dose of 90/100 mg.
In the single-agent study (GO39932) in the GDC-9545 30 mg cohort, only 1 patient 
experienced a Grade 1 ALT increase, with no other relevant hepatic events reported in 
other patients at this dose.
Investigators should carefully monitor patients for hepatoxicity following study treatment 
and follow the recommended management guidelines as noted in Table 2.
5.1.1.2
Gastrointestinal Toxicities
GI effects such as nausea, vomiting, and diarrhea have been reported in association 
with anti-estrogenic class medications and were also observed in the Phase I study of 
GDC-9545. Most of these events were low grade in severity and resolved without 
intervention. Patients who receive treatment with GDC-9545 should be closely 
monitored for GI effects and any consequent sequelae such as changes in blood 
chemistry parameters or dehydration.  Supportive care should be followed per 
institutional guidelines.
Investigators should carefully monitor patients for GI effects following study treatment 
and follow the recommended management guidelines as noted in Table 2.
5.1.1.3
Venous Thromboembolic Events (including Pulmonary 
Embolism)
Thromboembolic events occur in patients with malignancies, and the risk may be 
increased by suppression of ER signaling.  Patients should be closely monitored for 
signs and symptoms of thrombosis and instructed to immediately seek medical attention 
if thrombosis is suspected.
As of 4 September 2019, no thromboembolic events related to GDC-9545 have been 
reported.
Investigators should carefully monitor patients for thromboembolic events following study 
treatment and follow the recommended management guidelines as noted in Table 2.
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5.1.1.4
Bradycardia
Seven (9.5%) patients who received single-agent GDC-9545 (all treated at 90 mg or 
higher dose) reported Grade 1 asymptomatic bradycardia/sinus bradycardia.  
No adverse event of bradycardia was reported at the 30-mg dose.  The mean heart rate 
decrease was approximately 3 bpm at the dose of 30 mg on Cycle 1 Day 15 and 
stabilized during the treatment.  No clinically significant ECG changes, exercise 
intolerance, or changes in systolic or diastolic blood pressure were reported because of 
heart rate decrease at the 30 mg dose level.  Follow-up data from patients treated at 
GDC-9545 30 mg with a post-treatment heart rate drop of 10 bpm or heart rate 
60 bpm showed complete reversibility upon discontinuation of GDC-9545 treatment.
Single ECGs will be collected routinely during this study (see Section 4.5.13 and 
Appendix 1).  Investigators should use medical judgment and exercise caution when 
considering the co-administration of drugs known to cause decrease in heart rate and/or 
bradycardia and/or prolongation of the QT interval and consider using alternative 
treatment if possible.  In patients with pre-existing baseline conditions for which they are 
already receiving a stable dose of -blockers or calcium channel antagonists, 
investigators should carefully monitor patients for worsening of bradycardia following 
study treatment and follow the recommended management guidelines as noted in
Table 2.
5.1.1.5
Renal Toxicity or Increased Creatinine
Based on nonclinical studies, dose-dependent renal toxicity was observed in rats at 
30 mg/kg and in monkeys at 60 mg/kg, correlating with clinical pathology findings 
consistent with renal injury.  As of 4 September 2019, no cases of acute kidney injury or 
adverse events of creatinine increase have been reported. No trends of increase in 
serum creatinine levels were observed in laboratory results to date.
Investigators should carefully monitor patients for renal toxicity or creatinine increase
following study treatment and follow the recommended management guidelines as noted 
in Table 2.
5.1.1.6
Changes in Female Reproductive Organs and Menopausal 
Symptoms 
Based on the anti-estrogenic pharmacological activity of GDC-9545, the following effects 
are anticipated to occur: loss of muscle and bone, hot flashes, vaginal dryness or 
discharge, irritation, mood swings, and decreased libido. These symptoms could 
potentially be more severe than those experienced by typical menopausal patients.
As of 4 September 2019, the following adverse events classified as “reproductive system 
and breast disorders” have been reported in patients who received single-agent 
GDC-9545 at 10250 mg: vulvovaginal dryness, vaginal discharge, and vulvovaginal 
pruritus (1 patient each [1.4%]); all were Grade 1. Hot flushes (all Grade 1 or 2 in 
severity) have been reported in 7 patients (9.5%).
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Refer to the GDC-9545 Investigator’s Brochure for further information.
5.1.1.7
Female Fertility
GDC-9545 has not been tested in male animals or humans.
In nonclinical studies, perturbation and the irreversible arrest of the estrus cycle was 
observed microscopically in early development. It is unknown whether a longer recovery 
period in animals would reveal whether the observed perturbation in the estrus cycle is 
reversible.  Refer to the GDC-9545 Investigator’s Brochure for further information.
5.1.1.8
Embryofetal Toxicity
On the basis of the anti-estrogenic pharmacological activity of GDC-9545, administration 
of GDC-9545 during pregnancy is expected to have an adverse effect and poses a risk 
to the human fetus, including birth defects and miscarriage.
5.1.1.9
Drug-Drug Interactions
Refer to Section 4.4 for further details on DDIs and recommendations regarding 
concomitant medications.
5.1.2
Risks Associated with Palbociclib
The important risks associated with palbociclib include hematological disorders, 
particularly neutropenia, interstitial lung disease/pneumonitis, infections, and embryofetal 
toxicity.  Other common adverse reactions include stomatitis, nausea, vomiting and 
diarrhea, changes in appetite, rash, alopecia, fatigue, pyrexia, and increases in 
transaminases.  Refer to the palbociclib local prescribing information for information on 
all the risks associated with palbociclib.
5.1.3
Risks Associated with Anastrozole
The important risks associated with anastrozole include ischaemic cardiovascular events, 
loss of bone mineral density, and increases in cholesterol.  Other common adverse 
reactions include anorexia, increases in cholesterol, somnolence, carpal tunnel 
syndrome, sensory disturbances, hot flushes, nausea, diarrhea, vomiting, increases in 
ALT/AST/ALP, rash, alopecia, allergic reactions, osteoporosis, musculoskeletal pain,
vaginal dryness/bleeding, and asthenia.  Refer to the anastrozole local prescribing 
information for information on all the risks associated with anastrozole.
5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
Dose Modifications
Dose Modification for GDC-9545
No dose modification will be permitted for GDC-9545.  See Section 5.1.4.3 for further 
details on management of adverse events.
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Dose Modification for Anastrozole
There are no dose modifications for anastrozole. See Section 5.1.3 for further details on 
management of adverse events.
Dose Modification for Palbociclib
Management of some adverse events may require dose reductions of palbociclib (see 
Table 1 for the palbociclib dose-reduction schedule).  In general, the investigator may 
consider continuing palbociclib if the observed adverse event is not thought to be 
palbociclib related.
Table 1
Dose Reductions for Palbociclib
Dose Level 
Palbociclib
Starting dose
125 mg
First dose reduction
100 mg
Second dose reduction
75 mg
Third dose reduction
Not permitted
5.1.4.2
Treatment Interruption
Study treatment may be temporarily suspended in patients who experience toxicity
considered related to study drug.
In general, decisions on interruption of any of the study treatment components 
(GDC-9545, anastrozole, and palbociclib) may be made independently of the others; that 
is, one study treatment component alone may be interrupted for adverse events
attributed to that medication without mandatory interruptions of the other study treatment 
component as outlined below.

For temporarily interruption of GDC-9545 or anastrozole:
–
If either GDC-9545 or anastrozole is temporarily interrupted because of toxicity, 
palbociclib may be continued as monotherapy for a maximum of 28 days.
–
If either GDC-9545 or anastrozole is interrupted and cannot be resumed after 
being withheld for 28 days, the patient should be discontinued from all study 
treatment as per Section 4.6.1 and scheduled for surgery (see Section 3.1).

For permanent discontinuation of GDC-9545 or anastrozole:

If either GDC-9545 or anastrozole is permanently discontinued for any reason, 
the patient should be discontinued from all study treatment as per Section 4.6.1
and scheduled for surgery (see Section 3.1).

For temporarily interruption of palbociclib:

If palbociclib is temporarily interrupted because of toxicity, GDC-9545 or 
anastrozole may be continued until the Cycle 4 in the neoadjuvant phase.
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
If palbociclib administration is withheld because of an adverse event on Day 1 of 
a given cycle, the palbociclib dosing cycle should not begin until the patient is 
able to resume administration, which will correspond to a delayed Day 1 visit.  
All subsequent visits in that cycle and future cycles will be based on the new 
Day 1 visit.

For permanent discontinuation of palbociclib:
–
If palbociclib is permanently discontinued, GDC-9545 and anastrozole 
administration may be continued until Cycle 4 in the neoadjuvant phase.
5.1.4.3
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 2.  
Additional guidelines are provided in the subsections below.
Table 2
Guidelines for Management of Patients Who Experience Adverse 
Events Associated with GDC-9545
Event
Action to Be Taken
Elevation of hepatic transaminases
General guidance

If patient presents with jaundice, coagulopathy, abdominal pain, or 
other symptoms suggestive of hepatic toxicity, perform liver function 
tests with additional evaluation per institutional guidelines.

If hepatic enzymes are elevated with no obvious malignant cause 
found, consult with hepatologist.

Treat patient with hepatic enzyme elevation according to local 
standard of care.
Grade 1 or 2

Continue GDC-9545.

Rule out alternative etiologies (e.g., disease progression, 
concomitant medications, or biliary obstruction).

Treat patient according to local standard of care.
Grade 3

Withhold GDC-9545.

Consult with hepatologist.

If event resolves to baseline or below ULN within 28 days, resume 
GDC-9545 at full dose.

If event does not resolve to baseline or below ULN within 28 days, 
permanently discontinue GDC-9545.
Grade 4 or meets 
criteria as defined by 
Hy’s Law (see 
Section 5.3.5.6)

Permanently discontinue GDC-9545.

Consult with hepatologist.
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Table 2
Guidelines for Management of Patients Who Experience Adverse 
Events Associated with GDC-9545 (cont.)
Event
Action to Be Taken
Gastrointestinal events (nausea, vomiting, diarrhea) 
General guidance

Monitor closely for GI symptoms.  If patient presents with nausea, 
vomiting, or diarrhea, manage according to local standard of care, 
including use of anti-diarrheal agents and supportive care such as 
hydration and dietary modification as appropriate.

Infectious or alternate etiologies should be ruled out.
Grade2

Manage and treat according to local standard of care.

If persistent despite appropriate medical therapy, withhold 
GDC-9545 until resolution to Grade 1. 
Grade 3

Withhold GDC-9545 until event resolves to Grade 1.

Manage and treat patient according to local standard of care.

Consider consulting with gastroenterologist.

Resume GDC-9545 at full dose once the event resolves to 
Grade 1.

If adverse event is recurring and patient cannot tolerate treatment, 
then permanently discontinue GDC-9545.
Venous thromboembolic events (including pulmonary embolism)
General guidance

Advise patient to seek immediate medical attention if they become 
aware of any symptoms of PE or DVT, such as acute onset of chest 
pain, shortness of breath, or swelling in extremities. 
Grade 2

Withhold GDC-9545 until patient is stable.

Manage and treat patient according to local standard of care.

Resume GDC-9545 at full dose once the patient is stable.

Permanently discontinue GDC-9545 for recurrent thromboembolic 
events.
Bradycardia
General guidance

Monitor patient closely for symptomatic bradycardia.
Grade 1

Continue GDC-9545.

Continue to monitor patient per schedule of activities (see 
Appendix 1).

If heart rate falls below 40 bpm, withhold GDC 9545 until heart rate 
returns to 40 bpm and patient remains asymptomatic.
Grade 2

Withhold GDC-9545 and consult with cardiologist.

Resume GDC-9545 at full dose once the event improves to 
Grade 1 and the heart rate returns to >40 bpm.

For recurrent Grade 2 bradycardia, permanently discontinue 
GDC-9545.
Grade 3

Permanently discontinue GDC-9545 and consult with cardiologist.
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Table 2
Guidelines for Management of Patients Who Experience Adverse 
Events Associated with GDC-9545 (cont.)
Event
Action to Be Taken
Renal toxicity or increased creatinine
Grade 1 or 2

Continue GDC-9545.

Manage patient according to local standard of care.
Grade 3

Permanently discontinue GDC-9545.

Manage patient according to local standard of care.

Consult with nephrologist.
Non-hematologic toxicity
Grade 1 or 2

Continue GDC-9545.

Rule out alternative etiologies.
Grade 3 

Withhold GDC-9545 until symptoms resolve to Grade 1, and then 
resume GDC-9545 at full dose.
Grade 4

Permanently discontinue GDC-9545.
DVT deep vein thrombosis; GI gastrointestinal; PE pulmonary embolism; ULN upper limit of 
normal.
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)
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
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)

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).
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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:

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)

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.

Grade 3 hepatitis or elevations in AST or ALT

Grade 3 renal toxicity

Grade 2 bradycardia

Grade 2 thromboembolic event
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 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).
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After initiation of study drug, all adverse events will be reported until 28 days after final
dose of study treatment.
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?” 
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 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 3
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 (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by 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.
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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 Table 4:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the 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 4
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.
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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.
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 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,”
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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.
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., ALP 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
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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an 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ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy’s Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
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 
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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”).
If the death is attributed solely 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 mRECIST. 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:

Hospitalization for respite care
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
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.

Hospitalization due solely to progression of the underlying cancer
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.
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
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.

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.
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
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.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The “Accidental overdose” and “Medication error” boxes 
would need to be checked for both entries.
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO-CTCAE or other PRO data by the 
Sponsor.  In addition, the Sponsor will make no attempt to reconcile patient reports of 
treatment-related symptoms (via PRO-CTCAE) with investigator reports of adverse
events.  Sites are not expected to review the PRO-CTCAE or other PRO data for 
adverse events.
5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
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)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information 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
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
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.
5.4.1
Medical Monitors and Emergency Medical Contacts
Contact Information for All Sites
Medical Monitor/Emergency Medical Contact:
, M.D., Ph.D.
(Primary)
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, all serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study treatment.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
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be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided 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 until 28 days after the final
study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Only postmenopausal female patients are permitted in the study.  Patients will be 
instructed to immediately inform the investigator if they become pregnant during the 
study or within 28 days after the final dose of study drug.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
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5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
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.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
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 the final dose of study treatment), 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 to investigators.
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 
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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 through use of the reference safety 
information in the documents listed below:
Drug
Document
GDC-9545
GDC-9545 Investigator’s Brochure
Palbociclib
Palbociclib Summary of Product Characteristics
Anastrozole
Anastrozole Summary of Product Characteristics
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
Efficacy analyses will consist of all randomized patients, unless specified otherwise.
Safety analyses will include all randomized patients who received any amount of study 
treatment.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size is determined by the primary efficacy endpoint, central assessment
Ki67 change from baseline to Week 2 (see details in Section 6.4.1). Approximately
202 patients will need to be randomized in a 1:1 ratio to either the experimental arm
(GDC-9545) or control arm (anastrozole) to allow for 80% power to detect an 8% 
improvement for mean Ki67 change in 2 weeks from 75% in the control arm to 83% in 
the experimental arm at one-sided 10% level of significance. This target improvement 
also corresponds to an effect size of 0.3. Based on Cohen’s interpretation (Cohen 1988), 
an effect size of 0.3 represents a small to medium effect and a 21% non-overlap 
between the two treatment arms.
Patients with missing central Ki67 score at baseline and/or at Week 2 will be excluded 
from the analysis of the primary efficacy endpoint. For both experimental and control 
arms, a 6% missing Ki67 rate is assumed. Thus, a total of approximately 215 patients is 
projected to be enrolled to account for patients with missing Ki67 scores.
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6.2
SUMMARIES OF CONDUCT OF STUDY
Study enrollment, duration, study drug discontinuation, and study discontinuation, as 
well as reasons for study drug discontinuation and study discontinuation, will be listed 
and summarized for each treatment arm.  Major protocol deviations, including major 
deviations of inclusion/exclusion criteria, will also be listed and summarized for each 
treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Evaluation of treatment group comparability between the treatment arms will include 
demographic summaries, stratification factors, patient treatment history, and other 
baseline disease characteristics.
Continuous data will be summarized using means, standard deviations, medians, and 
ranges.  Categorical data will be summarized by counts and proportions.
6.4
EFFICACY ANALYSES
Unless specified otherwise, the analysis population for an efficacy analysis will consist of 
all randomized patients, with patients grouped according to their assigned treatment.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint for this study is Ki67score change during the 
window-of-opportunity phase, defined as the mean change of Ki67 score from baseline 
to Week 2.  Ki67 score will be centrally assessed and measured in percentage score.
All Ki67 scores will be log-transformed before analysis, and 0.1 will be added to all raw 
Ki67 scores before log-transformation to handle zero raw Ki67 scores.
Mean Ki67 change at Week 2 will be summarized in original percentage scale for each 
arm, and corresponding 95% CI will be calculated by normal approximation. The 
change in mean Ki67 score between the experimental arm and control arm will be 
compared through the use of the z-test. Patients with missing central Ki67 scores at 
baseline and/or Week 2 will be excluded from the analysis.
The analysis of the primary efficacy endpoint will take place when approximately 
202 patients have been randomized and have complete central Ki67 scores for the 
analysis at both baseline and Week 2.
6.4.2
Secondary Efficacy Endpoints
ORR will be defined as the proportion of patients with a CR or PR, as determined by the 
investigator according to mRECIST (see Appendix 4). The analysis population for ORR 
will be all randomized patients with measurable disease at baseline.  Patients not 
meeting the criteria for ORR, including patients without any post-baseline tumor 
assessment, will be considered as non-responders.
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An estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson 
method for each treatment arm.  ORR will be compared between treatment arms using 
the stratified Cochran-Mantel-Haenszel test.  The stratification factors to be used will be 
the same as those used for randomization.  The difference in ORR between treatment 
arms will be calculated, and its 95% CI will be calculated using the normal approximation 
to the binomial distribution.
CCCA rate is defined as the proportion of patients with centrally measured Ki67 score 
2.7%.  CCCA rate at Week 2 will be summarized.  The difference in CCCA rates 
between treatment arms will be calculated, and its 95% CI will be calculated using the 
normal approximation to the binomial distribution. Patients with missing central baseline 
and/or Week 2 corresponding Ki67 score will be excluded from the analysis.
6.4.3
Exploratory Efficacy Endpoints
CCCA rate is defined as the proportion of patients with centrally measured Ki67 scores
2.7%. CCCA rate at surgery will be summarized. The difference in CCCA rates 
between treatment arms will be calculated, and its 95% CI will be calculated using the 
normal approximation to the binomial distribution. Patients with missing central baseline 
and/or Week 2 corresponding Ki67 scores will be excluded from the analysis.
pCR rate is defined as the proportion of patients who achieved pCR in breast and axilla 
(with pCR defined as the absence of any residual invasive cancer on hematoxylin and 
eosin evaluation of the resected breast specimen, and all sampled ipsilateral lymph 
nodes following completion of neoadjuvant systemic therapy [i.e., ypT0/is, ypN0 in the 
current American Joint Committee on Cancer staging system]) after completion of 
neo-adjuvant treatment.
The pCR rate will be analyzed using statistical methods similar to those used for ORR.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety-evaluable population, defined as all 
patients who receive any amount of study treatment, with patients grouped according to 
treatment received.
6.5.1
Analyses of Exposure, Adverse Event, Laboratory, and 
Vital Sign Data
The frequency, nature, and severity of treatment-emergent adverse events, adverse 
events leading to death, adverse events leading to study drug discontinuation and dose 
modification, serious adverse events, and adverse events of special interest will be 
summarized by treatment arm.  All deaths will be summarized.  Selected laboratory data 
will be summarized by treatment received and grade compared with baseline, and 
measurements outside of the normal range will be identified.  Relevant vital signs will be 
presented using summary statistics by treatment received. Drug exposure will also be 
summarized, including duration of treatment, cumulative dose, and dose intensity.
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Treatment-emergent adverse events are defined as adverse events that occur after the 
first dose of study treatment.  Adverse events will be summarized by mapped MedDRA 
preferred terms and appropriate MedDRA hierarchy.  Adverse event severity will be 
graded according to NCI CTCAE v5.0.  Multiple occurrences of the same event will be 
counted once at the maximum severity.
6.5.2
Exploratory Analyses of Patient-Reported Outcome Data
PRO-CTCAE
PRO-CTCAE analyses will be descriptive, with a focus on characterizing the pattern of 
symptomatic treatment toxicities during the course of the study.  The number and 
percentage of patients who report each symptom and the change from baseline by 
category (frequency of occurrence, severity, or interference) will be summarized at each 
assessment timepoint by treatment arm.  For items that are rated on a 5-point Likert 
scale, the maximum post-baseline score and change from baseline will be summarized 
by treatment arm.
Results from these exploratory analyses will be presented separately from the safety 
analyses.  PRO-CTCAE data will be analyzed at the item level in line with current NCI 
recommendations for data handling (Basch et al. 2014). Graphical representation of 
PRO-CTCAE data over time will also be provided. PRO-CTCAE data will be
summarized over time. These analyses will also apply to the “overall treatment burden” 
item.  The proportion of missing data at each assessment timepoint will also be 
summarized to facilitate interpretation of data.
CTSQ
CTSQ analyses will be descriptive, summarizing means for each domain score 
(Expectations of Therapy, Feelings about Side Effects, and Satisfaction with Therapy) by 
treatment arm. The proportions of missing data will also be presented. CTSQ data may 
also be analyzed in relation to clinical outcomes and PRO-CTCAE scores; item-level 
responses may be descriptively explored as well.
6.6
PHARMACOKINETIC ANALYSES
Individual and mean plasma concentration of GDC-9545 versus time data will be 
tabulated and plotted. Additional PK analyses may be conducted as appropriate and 
reported in a standalone report.
6.7
BIOMARKER ANALYSES
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.  Results will be presented in a separate report.
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6.8
OPTIONAL INTERIM ANALYSIS
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct an interim efficacy analysis. The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor's trial master 
file prior to the conduct of the interim analysis. The interim analysis will be performed 
and interpreted by the Sponsor study team personnel who will have full access to 
unblinded data.  Access to treatment assignment information will follow the Sponsor's 
standard procedures.
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.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data 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.
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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.
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 PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 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.
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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 
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 laws.
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.
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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.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  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.
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 9.7).
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. 
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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.
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 (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication (see Section 9.6).
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 (see Section 9.6).
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).
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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 
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
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks. 
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation. Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed. 
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
9.4
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.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
or delegate will provide clinical operations management, data management, and medical 
monitoring.
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Approximately 90 sites globally will participate to enroll approximately 215 patients.  
Randomization 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.
A Steering Committee (SC) will provide scientific oversight for the trial. Details on the 
composition and mandate of the SC will be provided in the SC Charter.
9.6
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 details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  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 
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 
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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.
9.7
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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Appendix 1
Schedule of Activities
Screening a
Window of 
Opportunity b
Neoadjuvant Treatment c
Surgery d
End of 
Studye
Cycle (28-day cycle)
0
1
2
3
4
Days
–28 to –1
D1
Biopsyf
D15 (1D)
D1
(+3D)
D15
(3D)
D1
(3D)
D15
(3D)
D1
(3D)
D1
(3D)
28 D 
(3D)
Informed consent g
x
Demographic data
x
Medical history and baseline 
conditions
x
PRO-CTCAE h
x
x
x
x
CTSQ h
x
Vital signs i
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
Height
x
Complete physical examination j
x
x
Limited physical examination k
x
x
x
x
x
Breast and axilla assessment l
x
x
x
x
x
x
x
Tumor staging m
x
ECOG
x
x
x
x
x
x
ECG (12- lead) n
x
x
x
x
x
x
x
x
Hematology o
x
x
x
x
x
x
x
x
x
Chemistry p
x
x
x
x
x
x
x
x
x
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Appendix 1: Schedule of Activities
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Screening a
Window of 
Opportunity b
Neoadjuvant Treatment c
Surgery d
End of 
Studye
Cycle (28-day cycle)
0
1
2
3
4
Days
–28 to –1
D1
Biopsyf
D15 (1D)
D1
(+3D)
D15
(3D)
D1
(3D)
D15
(3D)
D1
(3D)
D1
(3D)
28 D 
(3D)
Coagulation (INR, aPTT, PT)
x
x
Fasting lipid panel q
x
x
FSH r
x
Estradiol r
x
Urinalysis s
x
x
x
x
x
GDC-9545 or anastrozole
(QD Days 128 of each cycle)
Administered at clinic visits (Day 1 of each cycle); 
otherwise administered at home.
Palbociclib administration
(QD Days 121 of each cycle)
Administered at clinic visits (Day 1 of each cycle); 
otherwise administered at home.
Medication diary t
Complete when medication is taken at home or at clinic visit.
Ki67score assessment u
x
x
x
Tumor assessment (ultrasound) v
x
x
Plasma PK samples
See Appendix 2.
Biomarker samples (blood and 
tissue)
See Appendix 2.
Surgical treatment plan w
x
Concomitant medications x
x x
x x
x
x
x
x
x
x
Adverse events y
x y
x y
x
x
x
x
x
x
x y
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Appendix 1: Schedule of Activities
GDC-9545—F. Hoffmann-La Roche Ltd
107/Protocol WO42133, Version 1
CTSQCancer Therapy Satisfaction Questionnaire; D day; ECOGEastern Cooperative Oncology Group; FSHfollicle-stimulating hormone; 
PKpharmacokinetic; POoral; PRO patient-reported outcome; PRO-CTCAEPatient-Reported Outcomes Common Terminology Criteria for 
Adverse Events; QDonce a day.
Notes:  On treatment days that coincide with clinic visits, all assessments should be performed prior to dosing unless otherwise specified.
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening, unless otherwise indicated.
b Patients will receive either GDC-9545 30 mg PO QD or anastrozole 1 mg PO QD for 2 weeks.
c Patients will receive GDC-9545 30 mg PO QD (Days 128/cycle) plus palbociclib 125 mg PO QD (Days 121/cycle) or anastrozole 1 mg PO QD
(Days 121/cycle) plus palbociclib 125 mg PO QD (Days 121/cycle) for four cycles (16 weeks), for 28 days per cycle.  Starting with Day 1 of 
Cycle 1, and on Day 1 of each 28-day cycle thereafter, study treatment will be administered in the clinic, after the study assessments.
d Surgery will be performed within 14 days after the final treatment in the neoadjuvant treatment phase.  If surgery is delayed, if the patient is not 
operable or will not undergo surgery for other reasons, or does not complete 16 weeks (four cycles) of combination therapy, an optional biopsy 
may be performed as a separate procedure within 2 days from the end of the combination treatment (see Appendix 2).
e Patients who complete the study or who discontinue the study prematurely will return to the clinic for an end of study visit 28 (3) days after the 
final study treatment.
f
A fresh post-dose biopsy will be obtained on Day 15 (1 day).  Blood will be collected from the patient, along with additional samples (see 
Section 4.5.10 and 4.5.12).
g Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment.
h Questionnaires will be self-administered before the patient receives any information on disease status, prior to the performance of non-PRO
assessments, and prior to the administration of study treatment (see Section 4.5.14).
i
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.
j
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, and neurologic systems.
k Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.
l
Assessment of primary tumor and regional lymph nodes must be performed by physical examination at screening and prior to administration of 
each cycle of study treatment during neoadjuvant therapy (see Section 4.5.6).
m Tumor staging procedures are based on routine clinical practice (see Section 4.5.8).
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Appendix 1: Schedule of Activities
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108/Protocol WO42133, Version 1
n Patients should be resting in a supine position for at least 10 minutes prior to ECG recording. All ECGs will be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws).
o Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).
p Chemistry panel (serum or plasma) includes, sodium, potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, 
calcium, total and direct bilirubin, ALP, ALT, AST, urate, and LDH.
q Fasting lipid panel will assess cholesterol, HDL, LDL, and triglycerides (after8 hours of fasting).
r
Only for patients 60 years.
s Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, and bacteria).  Urinalysis should be performed as clinically indicated during study treatment.
t
Patients will receive a medication diary and should be instructed to complete the medication diary each day immediately after taking their all
study medication during each cycle (e.g., Cycles 04). The medication diary and unused capsules or tablets in their bottles should be collected 
and reviewed on Day 1 of each cycle for drug accountability.
u For sample biopsy details, refer to Appendix 2 and Section 4.5.10.
v Ultrasound should be performed at screening (within 28 days prior to randomization), between Day 21 of Cycle 4 of the neoadjuvant treatment 
phase and surgery, and as clinically indicated.
w See Section 4.5.11.
x 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 initiation of study drug until end of study visit.
y After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study 
treatment. After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study drug treatment (see Section 5.6).
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Appendix 2
Schedule of Pharmacokinetic and Biomarker Samples
Visit
Timepoint
Sample Type
Screening
(Day 28 to Day –1)
NA
Pre-treatment archival or fresh tumor 
tissue sample(s) for biomarkers a
Freshly frozen OCT pretreatment tumor 
tissue sample (optional) b
Cycle 0 Day 1 (Window of 
Opportunity)
Predose
Plasma for biomarkers
Blood for WGS c
Predose d
GDC-9545 PK (plasma)
3 (1) hours post-dose
GDC-9545 PK (plasma)
Cycle 0 Day 15 (1 D)
(Biopsy)
Predose d
GDC-9545 PK (plasma)
Postdose e
Fresh tumor tissue samples during 
treatment for biomarkers e
Plasma for biomarkers e
Cycle 2 Day 1(3 days)
Predose d
GDC-9545 PK (plasma)
Surgery f
NA
Fresh post-treatment tumor tissue 
samples for biomarkers g
Plasma for biomarkers f
End of study visit
28 days after the final 
dose of study treatment
GDC-9545 PK (plasma)
Plasma for biomarkers
FFPEformalin-fixed, paraffin-embedded; NAnot applicable; OCT optimal cutting 
temperature; PKpharmacokinetic; WGSwhole genome sequencing.
a See Section 4.5.10 for details on tumor tissue sample requirements.
b Optional pretreatment tumor biopsy for patients who have provided written informed consent, 
have an accepted archival tumor tissue sample, and if collection of tumor biopsy sample is 
deemed clinically feasible. One freshly frozen OCT core-needle biopsy is requested.
c Not applicable for a site that has not been granted approval for WGS.
d Same day as treatment administration (within 2 hours before dosing).
e During treatment, fresh tumor biopsy sample and plasma for biomarkers should be collected 
after the last dose of treatment during the window-of-opportunity phase of the study. Tumor 
biopsy collection must occur prior to entry into the neoadjuvant phase of the study and any 
palbociclib administration. See Section 4.5.10 for details on tumor tissue sample requirements.
f
Refer to Appendix 1.
g Fresh post-treatment tumor (FFPE and non-FFPE) tissue surgical and plasma samples should 
be obtained within a maximum of 14 days after the last cycle in the neoadjuvant treatment 
phase and ideally should occur as soon as possible after the last dose of study treatment. 
Post-treatment plasma sample for biomarkers should be collected prior to surgery. See 
Section 4.5.10 for details on tumor tissue sample requirements; see Section 4.5.16 for details 
on an optional tumor biopsy collected at end of treatment.
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors: Assessment of
Response of Neoadjuvant Therapy in Early Breast Cancer
Conventional response criteria may not be ideal for the assessment of response in the
setting of neoadjuvant therapy in early breast cancer. Therefore, Response Evaluation
Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) have been modified to specifically
address assessment of primary breast lesions along with axillary lymph node disease,
using a range of breast imaging modalities. Selected sections from the RECIST 1.1 1 are
presented below, with modifications and the addition of explanatory text as needed for
clarity.
RECIST v1.1
Modified RECIST Early Breast Cancer 
Neoadjuvant Therapy
Modalities
CT as primary modality, 
ultrasound not 
recommended
No CT; primary assessments by 
ultrasound and clinical examination
Lymph nodes
May be considered
target lesions based on
size criteria (15 mm in
SAD)
Only axillary lymph nodes assessed;
nodes that are considered abnormal on
imaging (based on morphological factors
including, but not limited to SAD) to be 
followed as non-target lesions
Possibility of having 
only non-target disease
Allowed
Not allowed; primary breast lesions must
be measurable by ultrasound
CT computed tomography; RECISTResponse Evaluation Criteria in Solid Tumors; SAD short 
axis dimension.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
To assess objective response or future progression, it is necessary to estimate the overall
tumor burden at baseline and to use this as a comparator for subsequent measurements.
All baseline evaluations should be performed as close as possible to the treatment start
and never more than 4 weeks before the beginning of the treatment.
Method of Measurement
Ultrasound and clinical exam will be used to assess response in this protocol, adhering to
response criteria as presented in this appendix.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:22847.
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Appendix 4: Modified Response Evaluation Criteria in Solid Tumors: Assessment of
Response of Neoadjuvant Therapy in Early Breast Cancer
GDC-9545—F. Hoffmann-La Roche Ltd
113/Protocol WO42133, Version 1
Target Lesions
Target lesions should be selected on the basis of their size (lesions with the longest
diameter) and should lend themselves to reproducible repeated measurements. Up to
2 lesions in the breast may be identified as target lesions. Per this protocol, target
lesions must be 1.5 cm. A sum of the diameters of all target lesions will be calculated 
and reported as the baseline sum of diameters. The baseline sum of diameters will be 
used as a reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. Lesions that meet the criteria for radiographically 
defined simple cysts should not be considered malignant lesions (neither target nor 
non-target) since they are, by definition, simple cysts. Pathologic axillary lymph nodes
are not to be designated at target lesions, and lymph node measurements are not to be
included in the sum of diameters (see below for more detail).
Bilateral breast imaging studies should be conducted as per schedule of activities in 
Appendix 1. Ultrasound must be used to characterize each target lesion at baseline and 
during the study and all measurement should be recorded in metric notation.
Non-TargetLesions
Non-target lesions may include any other measurable breast lesions not identified as
target lesions, as well as truly non-measurable lesions, such as diffuse skin thickening or
other lesions not measurable by reproducible imaging techniques.
Lymph nodes merit special mention since they are normal anatomical structures that may
be visible by imaging even if not involved by tumor. Axillary lymph nodes are known to
vary widely in size, and signs of abnormality in axillary lymph nodes on imaging include
other morphological findings often in addition to changes in nodal size. For these reasons,
pathologic axillary lymph nodes on imaging should be identified as non-target lesions at
baseline.  Change in short-axis dimension may be considered in the assessment of
pathology, but measurements are not required, and these lesions should be followed
qualitatively, as described below at each response assessment timepoint.
Signs of lymph node pathology on imaging include the following:

Increase in short axis dimension

Thickened cortex, either diffusely or asymmetrically enlarged

Thinning, or replaced fatty hilum

Irregular margins or spiculations

Rim enhancement

Decreased echogenicity of cortex

Perinodal edema
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Appendix 4: Modified Response Evaluation Criteria in Solid Tumors: Assessment of
Response of Neoadjuvant Therapy in Early Breast Cancer
GDC-9545—F. Hoffmann-La Roche Ltd
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EVALUATION OF RESPONSE
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor
response for target breast lesions:

Complete response (CR): disappearance of all target lesions

Partial response (PR): at least a 30% decrease in the sum of diameters of target
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD): at least a 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (nadir), including baseline

In addition to the relative increase of 20%, the sum must also demonstrate an
absolute increase of at least 5 mm.

The appearance of one or more new lesions is also considered progression.

Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum on study
Special Notes on the Assessment of Target Lesions
Target Lesions That Become Too Small to Measure. While on study, all lesions
recorded at baseline should have their actual measurements recorded at each
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions
that are recorded as target lesions at baseline become so faint on imaging that the
radiologist may not feel comfortable assigning an exact measure and may report them as
being too small to measure. When this occurs, it is important that a value be recorded on
the eCRF as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to accurately
measure, below measurable limit (BML) should be indicated.
To reiterate, however, if the radiologist is able to provide an actual measure, that measure 
should be recorded, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment. When non-nodal lesions fragment, the
longest diameters of the fragmented portions should be added together to calculate the
target lesion sum. Similarly, as lesions coalesce, a plane between them may be
maintained that would aid in obtaining maximal diameter measurements of each
individual lesion. If the lesions have truly coalesced such that they are no longer
separable, the vector of the longest diameter for the coalesced lesion should be recorded.
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Appendix 4: Modified Response Evaluation Criteria in Solid Tumors: Assessment of
Response of Neoadjuvant Therapy in Early Breast Cancer
GDC-9545—F. Hoffmann-La Roche Ltd
115/Protocol WO42133, Version 1
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response
for any non-target lesions identified at baseline. Although some non-target lesions may
actually be measurable, they need not be measured and, instead, should be assessed
only qualitatively at the timepoints specified in the protocol.

CR: disappearance of all non-target lesions
All lymph nodes must be non-pathologic in appearance

Non-CR/Non-PD: persistence of one or more non-target lesion(s)

PD: unequivocal progression of existing non-target lesions.
For pathologic axillary lymph nodes, this may be based on a combination of
morphological factors, including a potential increase in short-axis dimension.
Special Notes on Assessment of Progression of Non-Target Disease
To achieve unequivocal progression on the basis of the non-target disease, there must
be an overall level of substantial worsening in non-target disease in a magnitude that,
even in the presence of SD or PR in target disease, the overall tumor burden has
increased sufficiently to merit discontinuation of therapy. A modest increase in the size of
one or more non-target lesions is usually not sufficient to qualify for unequivocal
progression status. The designation of overall progression solely on the basis of change
in non-target disease in the face of SD or PR of target disease will therefore be extremely
rare.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important. There are no specific criteria for
the identification of new radiographic lesions; however, the finding of a new lesion should
be unequivocal, that is, not attributable to differences in scanning technique, change in
imaging modality, or findings thought to represent something other than tumor.
This is particularly important when the patient’s baseline lesions show PR or CR. For 
example, necrosis of a breast lesion may be reported on an ultrasound report as a “new”
cystic lesion, which it is not. A lesion identified during the study in an anatomical location
that was not scanned at baseline is considered a new lesion and will indicate disease
progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm
there is definitely a new lesion, then progression should be declared using the date of the
initial scan.
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Appendix 4: Modified Response Evaluation Criteria in Solid Tumors: Assessment of
Response of Neoadjuvant Therapy in Early Breast Cancer
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Timepoint Response (Overall Response)
Table 1 provides a summary of the overall response status calculation at each
protocol-specified timepoint for which a response assessment occurs.
Table 1
Timepoint Response: Patients with Target Lesions (with or 
without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR, or no non-target lesions 
identified at baseline
No
CR
CR
Non-CR/non-PD
No
PR
CR
NE
No
PR
PR
Any except PD
No
PR
SD
Any except PD
No
SD
NE (Any lesion)
Any except PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PD progressive disease; PRpartial response; 
SD stable disease.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not
evaluable at that timepoint. If only a subset of lesion measurements are made at an
assessment, usually the case is also considered not evaluable at that timepoint, unless a
convincing argument can be made that the contribution of the individual missing lesion(s)
would not change the assigned timepoint response. Similarly, if one or more non-target
lesions are not assessed, the response for non-target lesions should be “not evaluable”
except where there is clear progression in non-target lesions that are assessed.
Special Notes on Response Assessment
Patients with a global deterioration of health status requiring discontinuation of treatment
without objective evidence of disease progression at that time should be reported as
“symptomatic deterioration.” Every effort should be made to document objective
progression even after discontinuation of treatment. Symptomatic deterioration is not a
descriptor of an objective response; it is a reason for stopping study therapy. The
objective response status of such patients is to be determined by evaluation of target and
non-target disease as shown in Table 1.
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Appendix 5
Eastern Cooperative Oncology Group Performance Status Scale
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 6
Cancer Therapy Satisfaction Questionnaire
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Appendix 6: Cancer Therapy Satisfaction Questionnaire
GDC-9545—F. Hoffmann-La Roche Ltd
119/Protocol WO42133, Version 1
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