Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 71
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the efficacy, safety, and tolerability of GDC-0810 compared with fulvestrant in postmenopausal women with advanced or metastatic estrogen receptor positive (ER+)/ human epidermal growth factor receptor 2 negative (HER2-) breast cancer resistant to AI therapy. The development of GDC-0810 has been halted by the Sponsor and the enrollment in this study has been discontinued. Participants currently enrolled in the study who are experiencing clinical benefit may continue receiving GDC-0810 as a single agent or fulvestrant until disease progression (PD), unmanageable toxicity, withdrawal of consent, exhaustion of GDC-0810 drug supply, or termination of the study by the Sponsor.

Detailed description:

Arms:
arm 1: Participants will receive 500 milligrams (mg) of fulvestrant as two intramuscular injections (250 mg each) on Day 1 and Day 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle until disease progression, unmanageable toxicity, withdrawal of consent, exhaustion of GDC-0810 drug supply, or termination of study by the Sponsor. arm 2: Participants will receive three 200 mg tablets (total dose = 600 mg) of GDC-0810 orally once daily until disease progression, unmanageable toxicity, withdrawal of consent, exhaustion of GDC-0810 drug supply, or termination of study by the Sponsor.

Interventions: intervention 1: Fulvestrant intervention 2: GDC-0810
Intervention descriptions: intervention 1: Fulvestrant at a dose of 500 mg as two intramuscular injections will be administered on Day 1 and Day 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle. intervention 2: GDC-0810 will be administered as tablets at a dose of 600 mg orally once daily.

Protocol document:
Prot_SAP_000.pdf: 
Official Title: 
A Phase II, Open-Label, Randomized Study of GDC-0810 Versus 
Fulvestrant in Postmenopausal Women With Advanced or Metastatic 
ER+ /HER2- Breast Cancer Resistant to Aromatase Inhibitor Therapy 
NCT Number: 
NCT02569801 
Document Date: 
Protocol Version 2: 24-January-2017 


 
Title
24-Jan-2017 17:11:42
Date and Time (UTC)
Company Signatory
Approver's Name
FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
GDC-0810—Genentech, Inc. 
Protocol GO29689, Version 2 
PROTOCOL 
TITLE: 
A PHASE II, OPEN-LABEL, RANDOMIZED STUDY 
OF GDC-0810 VERSUS FULVESTRANT IN 
POSTMENOPAUSAL WOMEN WITH ADVANCED 
OR METASTATIC ER+ /HER2 − BREAST CANCER 
RESISTANT TO AROMATASE INHIBITOR 
THERAPY 
PROTOCOL NUMBER: GO29689 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-000106-19 
IND NUMBER: 
116019 
TEST PRODUCT: 
GDC-0810 (RO7056118) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1: 27 May 2015 
Version 2:  See electronic date stamp below. 
 


 
GDC-0810—Genentech, Inc. 
2/Protocol GO29689, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol GO29689 has been amended to reduce the number of required study 
procedures as a result of Sponsor decision to halt the development of GDC-0810 and 
halt enrollment.  The decision to halt the development of GDC-0810 is not due to safety 
concerns.  Following the halt of enrollment, the study team was unblinded and therefore 
monitoring of active patients can be conducted by the Medical Monitor.  The Internal 
Monitoring Committee (IMC) will no longer be required to monitor ongoing efficacy and 
safety, given the IMC concluded that safety profiles observed from patients treated in 
Study GO29689 were consistent with the known safety profiles for GDC-0810 and 
fulvestrant and no new safety findings had been identified.  The Sponsor will continue to 
monitor clinical safety data in real time. 
As a result of the decision to halt develop of GDC-0810, the following changes have 
been made: 
• 
Enrollment has been discontinued.  Therefore, no further patients will be enrolled.  
• 
Patients experiencing clinical benefit may continue to receive GDC-0810 as a single 
agent or fulvestrant until progression of disease, unacceptable toxicity, consent 
withdrawal, GDC-0810 drug supply has been exhausted, or the Sponsor terminates 
the study.   
• 
Limited physical examination, vital signs, liver function test, creatinine adverse 
events, concomitant medication, and study drug compliance will be collected at least 
monthly and as clinically indicated.  
• 
Hematology, ECOG, blood chemistry (except creatinine and liver function tests), 
urinalysis, bone scans, and CT/MRI scans will be collected per institutional 
guidelines and as clinically indicated.  
• 
Patient-reported outcome questionnaires will be discontinued.   
• 
Survival information from patients who discontinued from the treatment phase of the 
study will no longer be collected. 
• 
The IMC will longer be required to monitor ongoing patient safety.  
• 
The Sponsor will continue to monitor clinical safety data in real time.   
• 
No new or potential safety risks have been identified; however, on the basis of 
accumulated clinical experience, dose modification guidelines have been updated.  
• 
Collection of fasting lipid panel has been removed because it is not essential for 
ongoing safety monitoring. 
• 
Based on accumulated clinical experience and the addition of elevation of hepatic 
transaminases as a potential risk in the GDC-0810 Investigator’s Brochure, 
Version 3, Grade ≥3 elevation of ALT or AST has been added as adverse event of 
special interest to align with the other ongoing GDC-0810 study (GO29642). 


GDC-0810—Genentech, Inc. 
3/Protocol GO29689, Version 2 
• 
Clinical and nonclinical summaries have been update to align with the GDC-0810 
Investigator’s Brochure, Version 4. 
Note:  Exclusion criteria were not updated to align with GDC-0810 Investigator’s 
Brochure recommendations given discontinuation of study enrollment. 
• 
The definition of the end of study has been revised because of the Sponsor’s 
decision to halt the development of GDC-0810 (see Section 3.2). 
• 
Post-trial access to GDC-0810 has been revised because of the Sponsor’s decision 
to halt the development of GDC-0810. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
GDC-0810—Genentech, Inc. 
23/Protocol GO29689, Version 2 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 30 
PROTOCOL SYNOPSIS .................................................................................... 31 
1. 
BACKGROUND .......................................................................................... 42 
1.1 
Background on Estrogen Receptor-Positive 
Breast Cancer........................................................................ 42 
1.2 
Background on GDC-0810 .................................................... 42 
1.2.1 
Summary of Nonclinical Data ................................................ 43 
1.2.2 
Summary of Phase I Clinical Data ......................................... 43 
1.3 
Background on Fulvestrant.................................................... 45 
1.4 
Study Rationale and Benefit-Risk Assessment...................... 46 
2. 
OBJECTIVES.............................................................................................. 47 
2.1 
Efficacy Objectives ................................................................ 47 
2.2 
Safety Objectives................................................................... 47 
2.3 
Pharmacokinetic Objectives .................................................. 47 
2.4 
Exploratory Objectives........................................................... 47 
3. 
STUDY DESIGN ......................................................................................... 48 
3.1 
Description of Study .............................................................. 48 
3.2 
End of Study.......................................................................... 49 
3.3 
Rationale for Study Design.................................................... 49 
3.3.1 
Patient Population ................................................................. 49 
3.3.2 
GDC-0810 Dose and Schedule ............................................. 50 
3.3.3 
Control Treatment.................................................................. 50 
3.3.4 
Open-Label Design................................................................ 50 
3.3.5 
Collection of Archival Tumor Tissue ...................................... 51 
3.3.6 
Optional Collection of Tumor Biopsies at Disease 
Progression ........................................................................... 51 
3.3.7 
Collection of a Blood Sample for Mutation 
Detection in Tumor DNA........................................................ 51 
3.3.8 
Optional Collection of a Blood Sample for Whole 
Genome Sequencing............................................................. 52 
3.3.9 
Pharmacokinetic Evaluation Schedule .................................. 52 


GDC-0810—Genentech, Inc. 
24/Protocol GO29689, Version 2 
3.3.10 
Patient-Reported Outcome Questionnaires........................... 52 
3.3.11 
DNA for Exploratory Pharmacogenetic 
Polymorphisms...................................................................... 53 
3.4 
Outcome Measures ............................................................... 53 
3.4.1 
Primary Efficacy Outcome Measure ...................................... 53 
3.4.2 
Secondary Efficacy Outcome Measures................................ 54 
3.4.3 
Safety Outcome Measures .................................................... 54 
3.4.4 
Pharmacokinetic Outcome Measures.................................... 54 
3.4.5 
Exploratory Outcome Measures ............................................ 54 
4. 
MATERIALS AND METHODS .................................................................... 55 
4.1 
Patients.................................................................................. 55 
4.1.1 
Inclusion Criteria.................................................................... 55 
4.1.2 
Exclusion Criteria................................................................... 57 
4.2 
Method of Treatment Assignment.......................................... 59 
4.3 
Study Treatment.................................................................... 60 
4.3.1 
Formulation, Packaging, and Handling.................................. 60 
4.3.1.1 
GDC-0810 ............................................................................. 60 
4.3.1.2 
Fulvestrant............................................................................. 60 
4.3.2 
Dosage, Administration, and Compliance.............................. 60 
4.3.2.1 
GDC-0810 ............................................................................. 60 
4.3.2.2 
Fulvestrant............................................................................. 61 
4.3.3 
Investigational Medicinal Product Accountability ................... 61 
4.3.4 
Post-Trial Access to GDC-0810............................................. 62 
4.4 
Concomitant Therapy ............................................................ 62 
4.4.1 
Permitted Therapy ................................................................. 62 
4.4.2 
Prohibited Therapy ................................................................ 63 
4.5 
Study Assessments ............................................................... 64 
4.5.1 
Informed Consent Forms and Screening Log........................ 64 
4.5.2 
Medical History and Demographic Data ................................ 64 
4.5.3 
Physical Examinations........................................................... 64 
4.5.4 
Vital Signs.............................................................................. 65 
4.5.5 
Tumor and Response Evaluations......................................... 65 


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25/Protocol GO29689, Version 2 
4.5.5.1 
Response Evaluations in Patients with Bone-
Only Disease ......................................................................... 66 
4.5.6 
Endometrial Thickness Assessment...................................... 67 
4.5.7 
Electrocardiograms................................................................ 67 
4.5.8 
Patient-Reported Outcomes .................................................. 68 
4.5.9 
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 69 
4.5.10 
Assay Methods...................................................................... 71 
4.5.10.1 
Mutational Analysis for ESR1 ................................................ 71 
4.5.10.2 
ER, PgR, and HER2 Analysis................................................ 71 
4.5.10.3 
Circulating Tumor DNA Analysis ........................................... 72 
4.5.10.4 
Messenger RNA Expression Profiling.................................... 72 
4.5.10.5 
Tumor Somatic Mutation Analysis ......................................... 72 
4.5.10.6 
Copy Number Analysis .......................................................... 72 
4.5.10.7 
Plasma Biomarker Analyses.................................................. 72 
4.5.10.8 
Plasma Pharmacokinetic Samples ........................................ 72 
4.5.10.9 
Pharmacogenetic Polymorphism Assay ................................ 72 
4.5.10.10 
Sample for Whole Genome Sequencing................................ 73 
4.5.11 
Timing of Study Assessments ............................................... 73 
4.5.11.1 
Screening and Pretreatment Assessments............................ 73 
4.5.11.2 
Assessments during Treatment............................................. 73 
4.5.11.3 
Study Drug Discontinuation Visit ........................................... 74 
4.5.11.4 
Follow-Up Assessments ........................................................ 74 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 74 
4.6.1 
Patient Discontinuation.......................................................... 74 
4.6.2 
Study Drug Discontinuation ................................................... 75 
4.6.3 
Study and Site Discontinuation.............................................. 75 
5. 
ASSESSMENT OF SAFETY....................................................................... 76 
5.1 
Safety Plan ............................................................................ 76 
5.1.1 
Safety Monitoring................................................................... 76 
5.1.2 
Internal Monitoring Committee............................................... 76 
5.1.3 
Identified Safety Risks Associated With GDC-
0810 ...................................................................................... 77 


GDC-0810—Genentech, Inc. 
26/Protocol GO29689, Version 2 
5.1.3.1 
Gastrointestinal Toxicities (Diarrhea, Nausea and 
Vomiting) ............................................................................... 77 
5.1.4 
Potential Safety Risks Associated with GDC-
0810 ...................................................................................... 77 
5.1.4.1 
Changes in the Female Reproductive Organs 
and Uterotrophic Effects ........................................................ 77 
5.1.4.2 
Venous Thromboembolic Events........................................... 78 
5.1.4.3 
Renal Dysfunction ................................................................. 79 
5.1.4.4 
Phototoxicity .......................................................................... 79 
5.1.4.5 
Elevation of Hepatic Transaminases ..................................... 79 
5.1.4.6 
General Guidance for GDC-0810 Dose 
Modifications.......................................................................... 80 
5.1.5 
Safety Risks Associated with Fulvestrant .............................. 83 
5.1.5.1 
General Guidance for Fulvestrant Dose 
Modifications.......................................................................... 84 
5.2 
Safety Parameters and Definitions ........................................ 84 
5.2.1 
Adverse Events ..................................................................... 84 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 85 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 86 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 86 
5.3.1 
Adverse Event Reporting Period ........................................... 86 
5.3.2 
Eliciting Adverse Event Information ....................................... 87 
5.3.3 
Assessment of Severity of Adverse Events ........................... 87 
5.3.4 
Assessment of Causality of Adverse Events ......................... 88 
5.3.5 
Procedures for Recording Adverse Events............................ 88 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 89 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 89 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 89 
5.3.5.4 
Abnormal Laboratory Values ................................................. 90 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 90 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 91 
5.3.5.7 
Deaths ................................................................................... 91 


GDC-0810—Genentech, Inc. 
27/Protocol GO29689, Version 2 
5.3.5.8 
Preexisting Medical Conditions.............................................. 92 
5.3.5.9 
Lack of Efficacy or Worsening of Breast Cancer ................... 92 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 92 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 93 
5.3.5.12 
Adverse Events that Change Grade over Time ..................... 93 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 94 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 94 
5.4.1 
Emergency Medical Contacts................................................ 95 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 95 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................... 95 
5.4.2.2 
Events That Occur after Study Drug Initiation........................ 95 
5.4.3 
Reporting Requirements for Pregnancies.............................. 96 
5.4.3.1 
Pregnancies in Female Patients............................................ 96 
5.4.3.2 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 96 
5.5 
Follow-Up of Patients after Adverse Events .......................... 96 
5.5.1 
Investigator Follow-Up........................................................... 96 
5.5.2 
Sponsor Follow-Up ................................................................ 97 
5.6 
Post-Study Adverse Events................................................... 97 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 97 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 98 
6.1 
Determination of Sample Size ............................................... 98 
6.2 
Summaries of Conduct of Study............................................ 99 
6.3 
Summaries of Treatment Group Comparability ..................... 99 
6.4 
Efficacy Analyses .................................................................. 99 
6.4.1 
Primary Efficacy Endpoint...................................................... 99 
6.4.2 
Secondary Efficacy Endpoints............................................. 100 
6.4.2.1 
Objective Response Rate.................................................... 100 
6.4.2.2 
Duration of Objective Response.......................................... 100 


GDC-0810—Genentech, Inc. 
28/Protocol GO29689, Version 2 
6.4.2.3 
Clinical Benefit Rate ............................................................ 100 
6.5 
Safety Analyses................................................................... 101 
6.6 
Pharmacokinetic Analyses................................................... 101 
6.7 
Patient-Reported Outcome Analyses .................................. 101 
6.8 
Additional Exploratory Analyses .......................................... 102 
6.9 
Interim Analysis ................................................................... 102 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 103 
7.1 
Data Quality Assurance....................................................... 103 
7.2 
Electronic Case Report Forms............................................. 103 
7.3 
Electronic Patient-Reported Outcome Data......................... 104 
7.4 
Source Data Documentation................................................ 104 
7.5 
Use of Computerized Systems ............................................ 105 
7.6 
Retention of Records........................................................... 105 
8. 
ETHICAL CONSIDERATIONS.................................................................. 105 
8.1 
Compliance with Laws and Regulations .............................. 105 
8.2 
Informed Consent ................................................................ 105 
8.3 
Institutional Review Board or Ethics Committee.................. 107 
8.4 
Confidentiality...................................................................... 107 
8.5 
Financial Disclosure ............................................................ 107 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 108 
9.1 
Study Documentation .......................................................... 108 
9.2 
Protocol Deviations.............................................................. 108 
9.3 
Site Inspections ................................................................... 108 
9.4 
Administrative Structure....................................................... 108 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 109 
9.6 
Protocol Amendments ......................................................... 110 
10. REFERENCES ......................................................................................... 111 


GDC-0810—Genentech, Inc. 
29/Protocol GO29689, Version 2 
 
 
LIST OF TABLES 
Table 1 
Dose Management Guidelines for GDC-0810............................. 81 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 87 
Table 3 
Causal Attribution Guidance ....................................................... 88 
Table 4 
Expected Probability of Observing a Hazard Ratio 
of < 0.5, < 0.6, or  < 0.7 in the Final Analysis (All Patients)......... 99 
Table 5 
Interim Analysis (All Patients) ................................................... 103 
 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments for Patients on Arm A (GDC-0810) . 114 
Appendix 2 
Schedule of Assessments for Patients on  Arm B 
(Fulvestrant).............................................................................. 119 
Appendix 3 
Schedule of Pharmacokinetic Assessments (for Arm A only) ... 124 
Appendix 4 
Patient-Reported Outcome Measure:  QLQ-C30 ...................... 125 
Appendix 5 
Patient-Report Outcome Measure:  Modified QLQ-BR23 ......... 128 
Appendix 6 
Treatment Satisfaction Questionnaire for Medication ............... 130 
Appendix 7 
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication ............................... 133 
Appendix 8 
Eastern Cooperative Oncology Group Performance Status...... 144 
Appendix 9 
Substrates and Inhibitors of CYP Enzymes .............................. 145 


 
GDC-0810—Genentech, Inc. 
30/Protocol GO29689, Version 2 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, OPEN-LABEL, RANDOMIZED STUDY 
OF GDC-0810 VERSUS FULVESTRANT IN 
POSTMENOPAUSAL WOMEN WITH ADVANCED 
OR METASTATIC ER+ /HER2 − BREAST CANCER 
RESISTANT TO AROMATASE INHIBITOR 
THERAPY 
PROTOCOL NUMBER: GO29689 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-000106-19 
IND NUMBER: 
116019 
TEST PRODUCT: 
GDC-0810 (RO7056118) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
  
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy to 
PPD at the address provided in your study binder. 
 
 


 
GDC-0810—Genentech, Inc. 
31/Protocol GO29689, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, OPEN-LABEL, RANDOMIZED STUDY OF GDC-0810 
VERSUS FULVESTRANT IN POSTMENOPAUSAL WOMEN WITH 
ADVANCED OR METASTATIC ER + /HER2 −  BREAST CANCER 
RESISTANT TO AROMATASE INHIBITOR THERAPY 
PROTOCOL NUMBER: 
GO29689 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-000106-19 
IND NUMBER: 
116019 
TEST PRODUCT: 
GDC-0810 (RO7056118) 
PHASE: 
II 
INDICATION: 
Advanced or Metastatic ER+ /HER2 −  Breast Cancer 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
The development of GDC-0810 has been halted and enrollment discontinued; therefore, the 
primary objectives will not be met. 
Efficacy Objectives 
The co-primary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of GDC-0810 compared with fulvestrant in the intent-to-treat (ITT) 
population as measured by progression-free survival (PFS) 
• 
To evaluate the efficacy of GDC-0810 compared with fulvestrant in patients with detectable 
ESR1 mutations as measured by PFS 
The secondary efficacy objective for this study is as follows: 
• 
To assess the clinical activity of GDC-0810 versus fulvestrant, as measured by objective 
response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and overall 
survival (OS) 
Safety Objectives 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of GDC-0810 compared with fulvestrant, focusing on 
the nature, frequency, and severity of serious and non-serious adverse events 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objective for this study is as follows: 
• 
To assess the pharmacokinetics of GDC-0810 in patients with advanced or MBC resistant 
to aromatase inhibitor (AI) therapy 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To estimate the frequency of ESR1 mutations in patients with advanced or metastatic 
breast cancer (MBC) resistant to AI therapy 
• 
To assess the potential relationship between GDC-0810 exposure (as measured by PK 
variables) and tumor response 


 
GDC-0810—Genentech, Inc. 
32/Protocol GO29689, Version 2 
• 
To assess the potential relationship between GDC-0810 exposure (as measured by PK 
variables) and safety 
• 
To assess disease and treatment-related symptoms, patient function, and health 
status/health-related quality of life (HRQoL) with GDC-0810 and fulvestrant as measured by 
the European Organization for Research and Cancer (EORTC) Quality of Life 
Questionnaire (QLQ-C30) and its breast cancer module (QLQ-BR23) 
• 
To evaluate patients’ treatment satisfaction with medication using a modified version of the 
Treatment Satisfaction Questionnaire for Medication (TSQM) for use in breast cancer 
• 
To assess whether dynamic (non-inherited) biomarkers, including but not limited to 
estrogen receptor (ER)/progesterone receptor (PgR)/human epidermal growth factor 
receptor 2 (HER2) expression, luminal A/B status, PIK3CA mutations, AKT1 mutations, 
p53 mutations, Ki67 levels, ER target gene expression and PI3K target gene expression, 
are predictive of response to study treatment, susceptibility to developing adverse events, 
or progression to a more severe disease state, can provide evidence of treatment activity, 
or can increase the knowledge and understanding of disease biology  
• 
When post-progression tissue is available, to evaluate the relationship between GDC-0810 
exposure and changes in levels of biomarkers, including but not limited to the dynamic 
(non-inherited) biomarkers described above 
• 
To use whole genome sequencing to assess whether non-dynamic (inherited) 
polymorphisms in the genome might be predictive of response to study treatment, 
susceptibility to developing adverse events, or progression to a more severe disease state, 
or can increase the knowledge and understanding of disease biology 
• 
To explore the role of polymorphisms in drug metabolism enzyme and transporter genes in 
the pharmacokinetics, safety, and efficacy of GDC-0810 in patients with advanced or MBC, 
if indicated by PK data 
Study Design 
Description of Study 
This is a multicenter, international, randomized, open-label, Phase II trial with two study arms.  
A total of approximately 152 patients with advanced or metastatic ER + /HER2 − breast cancer 
who have experienced recurrence or progression of their disease while receiving AI therapy for 
advanced or metastatic disease or who have relapsed within 6 months after completing 
adjuvant AI therapy will be enrolled in this study.  Patients who are enrolled in Arm A will receive 
GDC-0810, administered at 600 mg by mouth (PO) daily.  Patients who are enrolled in Arm B 
will receive fulvestrant, administered at 500 mg intramuscularly on Days 1 and 15 of Cycle 1, 
and Day 1 of each subsequent 28-day cycle thereafter. 
A permuted block randomization scheme will be used to ensure an approximate 1:1 allocation 
of patients who receive GDC-0810 (Arm A) versus patients who receive fulvestrant (Arm B) with 
respect to two stratification factors per local assessment: geographic region (United States, 
European Union, and Rest of World) and presence or absence of visceral disease. 
Patients may have either measurable disease (per Response Evaluation Criteria in Solid 
Tumors, version 1.1 [RECIST v1.1]) and/or non-measurable, but evaluable, locally advanced or 
metastatic disease with at least one evaluable bone lesion.  Locally advanced disease must not 
be amenable to resection or other local therapy with curative intent. 
Patients will receive study treatment in 28-day cycles until documented radiographic disease 
progression, intolerable toxicity, elective withdrawal from the study, study completion, or study 
termination.  Tumor assessments will be conducted for all patients at screening, per 
institutional guidelines, and as clinically indicated.   
Enrollment in Study GO29689 has been discontinued; therefore, no further patients will be 
enrolled in this study.  Any patient currently enrolled in Study GO28689 experiencing 
clinical benefit may continue to receive GDC-0810 as a single agent or fulvestrant until 
disease progression (as assessed by the investigator based on radiographic findings or clinical 
symptoms), unmanageable toxicity, patient withdrawal of consent, GDC-0810 drug supply 
has been exhausted, or the Sponsor terminates the study.  All patients who are discontinued 
from study treatment will return for a study drug discontinuation visit within 30 days after the last 


 
GDC-0810—Genentech, Inc. 
33/Protocol GO29689, Version 2 
dose of study treatment and will be followed for adverse events for at least 28 days after the last 
dose of study treatment. 
Number of Patients 
A total of approximately 152 patients with advanced or metastatic ER + /HER2 − breast cancer 
who have experienced recurrence or progression of their disease while receiving AI therapy for 
advanced or metastatic disease or who have relapsed within 6 months after completing 
adjuvant AI therapy will be enrolled in this study. 
Target Population 
Patients with ER + HER2−, locally advanced or MBC will be enrolled in the study. 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Disease-Specific Inclusion Criteria 
• 
Postmenopausal women with histologically or cytologically confirmed invasive, 
ER + /HER2 −  (defined by local guidelines) metastatic or inoperable (not amenable to 
resection or other local therapy with curative intent), locally advanced breast cancer 
Postmenopausal is defined as meeting at least one of the following criteria: 
– Prior bilateral oophorectomy 
– Age ≥ 56 years and natural amenorrhea with ≥ 1 year since last menses 
– Age < 56 years with amenorrhea ≥ 1 year since last menses, and serum estradiol levels 
(< 20 pg/mL) and follicle stimulating hormone (FSH) levels (> 40 mIU/mL) in the 
postmenopausal range 
– Age < 56 years after hysterectomy with one or both ovaries left in place, or with 
tamoxifen-induced amenorrhea together with a tamoxifen discontinuation of ≥ 1 year and 
serum estradiol levels (< 20 pg/mL) and FSH levels (> 40 mIU/mL) in the 
postmenopausal range 
– Age < 56 years after medical menopause on luteinizing hormone-releasing hormone 
(LHRH) agonist (on stable dose ≥ 1 year), with amenorrhea ≥ 1 year since last menses 
and serum estradiol levels (< 20 pg/mL) in the postmenopausal range irrespective of 
FSH/LH levels  
– Women with therapy-induced amenorrhea must agree to remain abstinent or use single 
or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per 
year during the treatment period and for at least 28 days after the last dose of GDC-0810 
or at least 1 year after the last dose of fulvestrant.  Abstinence is only acceptable if it is in 
line with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
– Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include tubal ligation, male sterilization, and certain intrauterine devices.  Alternatively, 
two methods (e.g., two barrier methods such as a condom and a cervical cap) may be 
combined to achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide. 
• 
Patients for whom endocrine therapy (e.g., fulvestrant) is recommended and treatment with 
cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or 
local treatment guidelines 
• 
Radiologic/objective evidence of recurrence or progression to the most recent systemic 
therapy for breast cancer 
• 
Radiologic/objective evidence of breast cancer recurrence or progression while on or within 
6 months after the end of adjuvant treatment with an AI, or progression while on or within 
1 month after the end of prior AI treatment for locally advanced or MBC.  The AI (letrozole, 
anastrozole, or exemestane) does not have to be the most recent treatment before 
randomization, but patients must have received at least 4 weeks of treatment with an AI. 


 
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• 
Patients must have measurable disease by RECIST v1.1 or non-measurable, evaluable 
disease with at least one evaluable bone lesion by RECIST v1.1 based on radiologic scans 
within 28 days of Day 1 of Cycle 1.  Bone lesions that have been irradiated are not 
evaluable. 
General Inclusion Criteria 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years  
• 
ECOG Performance Status of 0 or 1 
• 
Consent to the collection of a formalin-fixed paraffin-embedded (FFPE) block or a minimum 
of 10 freshly cut unstained tumor slides (submission of 15−20 is strongly encouraged) from 
archival tumor tissue or a newly collected (“fresh”) tumor sample for protocol-mandated 
exploratory assessments   
• 
Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 28 days prior to Day 1 of Cycle 1: 
– Absolute neutrophil count ≥ 1500/μL 
– Platelet count ≥ 90,000/μL 
– Hemoglobin ≥ 9.0 g/dL (90 g/L) 
– Albumin ≥ 3.0 g/dL (30 μmol/L) 
– Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
– Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase 
(ALP) ≤ 1.5 × ULN, with the following exceptions: 
Patients with documented liver metastases:  AST and/or ALT ≤ 5.0 × ULN 
Patients with documented bone metastases:  ALP ≤ 5.0 × ULN 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min based on 
Cockroft−Gault glomerular filtration rate (GFR) estimation 
(140 − age) × (weight in kg) × (0.85 if female) 
72 × (serum creatinine) 
International normalized ratio (INR) < 1.5 and activated partial thromboplastin time 
(aPTT) < 1.5 × ULN; for patients requiring therapeutic anticoagulation therapy, a 
stable INR ≤ 2.5 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Disease-Specific Exclusion Criteria 
• 
HER2-positive disease (immunohistochemistry [IHC] 3 + staining, fluorescence in situ 
hybridization [FISH] positive, and/or chromogenic in situ hybridization [CISH] positive) 
• 
Prior treatment with fulvestrant 
• 
Prior anti-cancer therapy within 2 weeks prior to Cycle 1 Day 1 
• 
Prior radiation therapy within 2 weeks prior to Cycle 1 Day 1 
• 
Prior treatment with > 1 cytotoxic chemotherapy regimens or > 2 endocrine therapies for 
advanced or metastatic disease 
• 
Ongoing, acute treatment-related toxicity that has not resolved to Grade ≤ 1 or been 
deemed stable by the investigator   
• 
Concurrent hormone replacement therapy 
• 
Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab 
therapy; use of bisphosphonate therapy or denosumab for other reasons (e.g., bone 
metastasis, osteoporosis, etc.) is allowed. 
• 
Known untreated or active central nervous system (CNS) metastases (progressing or 
requiring anticonvulsants or corticosteroids for symptomatic control); a computed 
tomography (CT) scan or magnetic resonance imaging (MRI) of the brain will be performed 
at screening if required by the local health authority 


 
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Patients with a history of treated CNS metastases are eligible, provided they meet all of the 
following criteria:  
– Evaluable or measurable disease outside the CNS is present. 
– Radiographic demonstration of improvement upon the completion of CNS-directed 
therapy and no evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study  
– No history of intracranial hemorrhage or spinal cord hemorrhage  
– Screening CNS radiographic study is ≥ 8 weeks since completion of radiotherapy and 
≥ 4 weeks since the discontinuation of corticosteroids  
• 
History of other malignancy within the previous 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
patients who have undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to be at low risk for recurrence; patients with 
slow-growing, benign tumors are allowed 
General Exclusion Criteria 
• 
Inability or unwillingness to swallow pills or receive IM injections 
• 
History of malabsorption syndrome, short bowel syndrome, gastric resection, or other 
condition that would interfere with enteral absorption 
• 
History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) 
• 
Active bowel inflammation (e.g., diverticulitis) 
• 
History of endometrial cancer or atypical endometrial hyperplasia 
• 
Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or 
current known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV) 
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 [anti-HBc]) or hepatitis C (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 are positive for anti-HBc are eligible only if testing is also positive for 
hepatitis B surface antibody and polymerase chain reaction (PCR) is negative for HBV 
DNA. 
– Patients who are positive for HCV serology are eligible only if testing for HCV RNA is 
negative. 
• 
Active autoimmune disease that is not controlled for at least 6 months by stable doses of 
nonsteroidal or steroidal (< 10 mg of prednisone per day) anti-inflammatory drugs or active 
inflammatory disease, including small or large intestine inflammation such as Crohn’s 
disease or ulcerative colitis, which requires immunosuppressive therapy 
• 
Clinically significant cardiac or pulmonary dysfunction, including the following: 
– Current uncontrolled Grade ≥ 2 hypertension or unstable angina 
– Symptomatic congestive heart failure of New York Heart Association Class II, III or IV 
– Serious cardiac arrhythmia requiring treatment, with the exceptions of atrial fibrillation 
and paroxysmal supraventricular tachycardia or conduction abnormality that has been 
treated and for which the patient is no longer at risk for serious arrhythmia (e.g., 
Wolff-Parkinson-White syndrome treated with surgical ablation) 
– History of acute coronary syndrome or unstable angina within 6 months prior to Cycle 1, 
Day 1 
• 
History of congenital long QT syndrome or corrected QT interval (QTcF) > 470 msec 
• 
Immunocompromised status due to current known active infection with HIV or due to the 
use of immunosuppressive therapies for other conditions 
• 
Need for current chronic corticosteroid therapy (≥ 10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids)  


 
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• 
Inhaled corticosteroids are allowed 
• 
Pregnancy, lactation, or breastfeeding 
• 
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic disease) 
• 
Major surgical procedure or significant traumatic injury within 28 days prior to Day 1 of 
Cycle 1 or anticipation of the need for major surgery during the course of study treatment 
• 
Inability, in the opinion of the investigator, to comply with study and follow-up procedures 
Length of Study 
The enrollment duration is projected to be approximately 22 months after the first patient is 
enrolled.  The last PFS event for the primary PFS analysis is projected to occur approximately 
26 months after the first patient is enrolled. 
End of Study 
The end of this study is defined as the date when the last patient, last visit occurs, GDC-0810 
drug supply is exhausted, or when the Sponsor decides to stop the study. 
Outcome Measures 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measures for this study, for all patients as well as the subset of 
patients with ESR1 mutations, are as follows: 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression 
as determined by the investigator per RECIST v1.1 or death from any cause on study, 
whichever occurs first 
Secondary Efficacy Outcome Measures 
The secondary outcome measures for this study are the following: 
• 
OS, defined as the time from randomization to the time of death from any cause  
• 
Objective response (PR plus complete response [CR]) as determined by the investigator 
per RECIST v1.1  
• 
DOR, defined as the time from the first occurrence of a documented objective response 
until first observation of disease progression, as determined by the investigator per RECIST 
v1.1, or death from any cause on study, whichever occurs first 
• 
Clinical benefit, defined as PR, CR, or stable disease (SD), lasting for at least 24 weeks 
from the time of randomization 
Safety Outcome Measures 
The safety and tolerability of GDC-0810 will be assessed using the following: 
• 
The incidence, nature, and severity of adverse events reported during the adverse event 
reporting period, graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.0 (NCI CTCAE, v4.0) 
• 
Incidence, nature and severity of serious adverse events 
• 
Incidence of adverse events leading to study treatment discontinuation, modification or 
interruption 
• 
Clinically significant changes in vital signs, physical findings, and clinical laboratory results 
during and following GDC-0810 or fulvestrant administration during the adverse-event 
reporting period 
Pharmacokinetic Outcome Measures 
Sparse PK samples will be collected and may be analyzed using population PK methods to 
estimate apparent clearance, volume of distribution, absorption rate constant, and other 
appropriate measures as data allow, and plasma concentrations will be summarized by visit.   


 
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Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Assessment of RNA in pre- and post-treatment tumor specimens, including assessment of 
PI3K and ER target gene expression signatures, ER, PgR, and HER2 status and luminal 
A/B status 
• 
Alterations of DNA in pre- and post-treatment tumor specimens, including ESR1 mutations, 
PIK3CA mutations, AKT1 mutations, and TP53 mutations  
• 
Assessment of Ki67 levels in pre- and post-treatment tumor specimens 
• 
Alterations in ctDNA from peripheral blood, including but not limited to ESR1, PIK3CA and 
AKT1 
• 
Assessment of mean change in disease/treatment-related symptoms, function and health 
status/HRQoL scales of the EORTC QLQ-C30 and the EORTC QLQ-BR23 breast module 
• 
Assessment of mean treatment satisfaction on the subscales (side effects, convenience, 
and global satisfaction) of a modified version of the TSQM 
• 
Whole genome sequencing data will be analyzed in the context of this study and explored in 
aggregate with other studies to better understand disease pathobiology and guide the 
development of new therapeutic approaches.  Given the complexity and exploratory nature 
of these analyses, whole genome sequencing data and analyses will not be shared with 
investigators or study participants unless required by law. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The test product for this study is GDC-0810.  GDC-0810 will be supplied by the Sponsor as 
white oblong tablets containing 200 mg GDC-0810 free acid.  The 600-mg dose of GDC-0810 
will be taken orally once per day until disease progression or intolerable toxicity.  GDC-0810 is 
supplied as 200-mg tablets; therefore, patients will take three 200-mg tablets daily to receive a 
600-mg dose.  Each 600-mg dose should be taken within 30 minutes after a meal, and efforts 
should be made by patients to take the dose at the same approximate time each day.  If a dose 
is missed (i.e., not taken within 8 hours after the scheduled dosing time), the patient should 
resume dosing with the next scheduled dose.  Missed or vomited doses will not be made up. 
Comparator 
The comparator for this study is fulvestrant.  Fulvestrant will be supplied by the Sponsor per 
country-specific requirements.  For countries in which the Sponsor is supplying fulvestrant, it will 
be supplied in sterile, single-patient, prefilled syringes containing 50 mg/mL fulvestrant as a 
5-mL injection.  Fulvestrant 500 mg will be administered in the clinic as two intramuscular 
injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day 
cycle.  
Non-Investigational Medicinal Products 
None 
Statistical Methods 
The primary and secondary efficacy analyses will include all randomized patients, with patients 
grouped according to the treatment assigned at randomization. 
Primary Analysis 
The primary efficacy endpoint is PFS, defined as the time from randomization to the first 
occurrence of disease progression, as determined by investigator review of tumor assessments 
using RECIST v1.1 or death on study from any cause.  The primary efficacy analyses will be 
performed on all randomized patients as well as on patients with ESR1 LBD mutations detected 
in circulating cell-free DNA, with patients allocated to the treatment arm assigned at 
randomization.  
For patients without disease progression or death as of the clinical data cutoff date, their PFS 
will be censored at the time of last tumor assessment (or censored at the date of randomization, 
if no tumor assessment was performed after the baseline visit).  For patients who start other 
anti-cancer treatment prior to the documented PFS event, the primary PFS analysis will include 


 
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PFS events after other anti-cancer treatment.  PFS sensitivity analysis will be performed, 
censoring PFS on the last tumor assessment prior to starting other anti-cancer therapy. 
The two-sided log-rank test stratified by the stratification factors will be used as the primary 
analysis.  The Kaplan-Meier approach will be used to estimate median PFS for each treatment 
arm.  Cox proportional hazards models stratified by the stratification factors will be used to 
estimate a hazard ratio and its 90% confidence interval (CI).  The results from the unstratified 
analysis will also be provided. 
Exploratory analysis for PFS may be performed on patient subgroups by demographic disease 
characteristics. 
Determination of Sample Size 
The trial is designed to evaluate the clinical activity and safety of GDC-0810 compared with 
fulvestrant in patients with ER-positive locally advanced or MBC.  It is for hypothesis generation, 
and is not powered to detect minimum clinically meaningful difference between treatment arms.  
A total of approximately 152 patients will be enrolled in this study.  It is assumed that the 
median duration of PFS in the fulvestrant control arm is 5.5 months and 8.5 months in the 
GDC-0810 arm.  The final analysis of all randomized patients will be triggered by the 
occurrence of approximately 95 PFS events, which is expected to occur 26 months after the first 
patient is randomized.  Table 3 shows expected probabilities of observing a hazard ratio of less 
than 0.5, 0.6 and 0.7 in the final analysis in all randomized patients under varying assumptions 
for the true underlying hazard ratio.  Note that formal hypothesis testing is limited.  Rather than 
testing treatment differences at a statistically significant type I error level of 5%, 90% CI for the 
hazard ratio will be calculated. 
At a target hazard ratio of 0.6, the corresponding 90% CI based on 95 PFS events is (0.43, 0.84) 
which is considered to provide meaningful precision. 
Interim Analyses  
The IMC will convene for an interim safety analysis to review unblended summaries of the 
safety and PK data after the first 20 patients are randomized and have completed two 28-day 
cycles of therapy. 
In addition, after occurrence of approximately 62 PFS events in all patients, the IMC may 
convene to perform an interim analysis for safety and efficacy.  This interim efficacy analysis 
likely will not be informative for the ESR1 mutant subset because of the insufficient number of 
patients with ESR1 mutant tumors who are projected to have experienced disease progression 
by that time.  The activity of GDC-0810 versus fulvestrant in the ESR1 mutant subset will be 
assessed at interim only if a reasonable number of PFS events is available in the subset (for 
example, 30 PFS events).  
Table 4 shows the probability of observing a hazard ratio of less than 0.5, less than 0.6, or 0.7 
at interim analysis under varying assumptions of the true underlying hazard ratio for all patients. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AI 
aromatase inhibitor 
ALT 
alanine transaminase 
anti-HBc 
hepatitis B core antibody 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
BID 
bis en die (twice daily) 
CBR 
clinical benefit rate 
CI 
confidence interval 
CISH 
chromogenic in situ hybridization 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EMEA 
Europe, the Middle East, and Africa 
EORTC 
European Organization for Research and Cancer 
ePRO 
electronic patient-reported outcome 
ER 
estrogen receptor 
ER +  
estrogen receptor positive 


 
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Abbreviation 
Definition 
E.U. 
European Union 
18F NaF 
F-18 sodium fluoride 
FDA 
Food and Drug Administration 
FES-PET 
fluoroestradiol positron emission tomography 
FFPE 
formalin-fixed paraffin-embedded 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hormone receptor 
HRQoL 
health-related quality of life 
ICF 
Informed Consent Forms 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
IM 
intramuscular 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISH 
in situ hybridization 
ITT 
intent to treat  
IV 
intravenous 
IWRS 
Interactive Web Response System 
LBD 
ligand-binding domain 
LH 
luteinizing hormone 
LHRH 
luteinizing hormone-releasing hormone 
MBC 
metastatic breast cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 


 
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Abbreviation 
Definition 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PgR 
progesterone receptor 
PK 
pharmacokinetic 
PO 
by mouth; orally 
PR 
partial response 
PRO 
patient-reported outcome 
QD 
once daily 
QLQ-BR23 
Quality Of Life Questionnaire Breast Cancer Module 
QLQ-C30 
Quality of Life Questionnaire 
qRT-PCR 
quantitative real-time PCR 
QTcF 
QT interval corrected using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase II dose 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
SNP 
single nucleotide polymorphism 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
upper limit of normal 
U.S. 
United States 
VTE 
venous thromboembolic event 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON ESTROGEN RECEPTOR-POSITIVE 
BREAST CANCER  
Breast cancer is the most common form of cancer and the leading cause of cancer 
death in women worldwide, accounting for more than 1,300,000 new cases and nearly 
500,000 cancer deaths annually (Jemal et al. 2011).  Approximately 80% of all breast 
cancers express and are dependent on the estrogen receptor (ER) for tumor growth and 
progression.  Modulation of estrogen activity and/or synthesis is the mainstay of 
therapeutic approach in postmenopausal women with ER-positive (ER+) breast cancer.  
However, despite the effectiveness of available hormonal therapies such as tamoxifen, 
aromatase inhibitors (AIs; e.g., anastrozole, letrozole, and exemestane) and full 
ER antagonists/degraders (e.g., fulvestrant), many patients ultimately relapse or develop 
resistance to these agents.  As such, there is a need for new ER-targeting therapies with 
increased anti-tumor activity to further delay disease progression and/or overcome 
resistance to the currently available hormonal therapies and ultimately prolong survival 
in postmenopausal women with ER+ advanced breast cancer. 
Despite becoming refractory to AIs or tamoxifen, growth and survival of resistant tumor 
cells remain dependent on ER signaling; therefore, patients with ER+ breast cancer can 
still respond to second- or third-line hormonal treatment after progression on prior 
hormonal therapy (Di Leo et al. 2010; Baselga et al. 2012).  Importantly, there is growing 
evidence that in the endocrine-resistant state, the ER can signal in a ligand-independent 
manner (Miller et al. 2010; Van Tine et al. 2011).  An agent with a dual mechanism of 
action (ER antagonism plus degradation) has the potential to target both 
ligand-dependent and independent ER signaling, and consequently, improve treatment 
outcomes in late-stage, ER+ breast cancer.  Furthermore, recent studies have identified 
mutations in ESR1 affecting the ligand-binding domain (LBD) of the ER-α protein (Segal 
and Dowsett 2014).  In preclinical models, mutant receptors drive ER-dependent 
transcription and proliferation in the absence of estrogen and reduce the efficacy of 
ER antagonists, suggesting that LBD-mutant forms of the ER are involved in mediating 
clinical resistance to endocrine therapy and that more potent ER antagonists may be of 
substantial therapeutic benefit (Li et al. 2013; Robinson et al. 2013; Toy et al. 2013).  
1.2 
BACKGROUND ON GDC-0810  
GDC-0810 is a small-molecule, therapeutic agent that competes with estrogens for 
binding to the ER with low nanomolar potency.  In MCF-7 breast cancer cells, the 
activity of GDC-0810 differentiates from that of first generation ER antagonists, such 
as tamoxifen, fully antagonizing the response of ER to estrogens and inducing 
proteosomal degradation of ERα.  In other ER+ breast cancer cell lines, such as 
HCC1500, MDA-MB-330, and Cama1 cells, GDC-0810 attenuates the transcriptional 
and proliferative response of ER to estrogens without inducing significant ERα 
degradation.  GDC-0810 has a non-steroidal structure and displays good oral 


 
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bioavailability in all nonclinical species tested, unlike fulvestrant, which has a steroidal 
structure and exhibits poor bioavailability.  
1.2.1 
Summary of Nonclinical Data 
GDC-0810 is a potent ER-α antagonist resulting in robust inhibition of ER signaling and 
inhibition of breast tumor cell proliferation.  In vivo, GDC-0810 exhibited dose 
dependent anti-tumor activity in both tamoxifen-sensitive and tamoxifen-resistant MCF7 
xenograft models of ER+ breast cancer.  In all models, the efficacious dose range was 
10 − 100 mg/kg/day, and all doses were well tolerated.  Efficacy in tamoxifen-resistant 
xenograft models correlated with efficient antagonist activity on ER target genes and 
reduction of ER-α tumor levels.  Fulvestrant appeared to be less efficacious than 
GDC-0810 in these models. 
1.2.2 
Summary of Phase I Clinical Data 
GDC-0810 is currently being studied in Study GO29642 (formerly known as 
ARN-810-001), a Phase Ia/Ib/IIa open-label, dose-finding, safety, pharmacokinetic (PK), 
and proof-of-concept trial of single-agent GDC-0810 and in combination with palbociclib 
or luteinizing hormone-releasing hormone (LHRH) agonist in postmenopausal women 
with locally advanced or metastatic ER+ breast cancer.  
As of 1 October 2014, enrollment in the Phase I dose-escalation portion of 
Study GO29642 was completed with 41 patients enrolled at doses from 100 mg to 
800 mg.  Nine dose-escalation cohorts of 3 − 6 patients each were enrolled.  Patients 
received between 100 and 800 mg total daily dose, given once daily (QD) or divided 
twice daily (BID), with fasting and without fasting.  As of 15 April 2016, a total of 
39 patients have discontinued the study:  36 (88%) due to disease progression, 1 (2%) 
due to non-treatment-related cardiac arrest, 1 (2%) due to treatment-related nausea, 
and 1 (2%) withdrew consent due to ongoing diarrhea.  At the time of the data cutoff 
(15 April 2016), with a median follow-up of 4 months (range:  1−26 months), 
16 of 41 (39%) patients were on study ≥ 6 months; among those patients previously 
treated with fulvestrant, 6 of 17 (35%) were on study ≥ 6 months.  In addition, robust ER 
target engagement across all doses was demonstrated by 18F-fluoroestradiol positron 
emission tomography (FES-PET) scans, and there were two confirmed partial responses 
(PRs) as of the data cutoff. 
As of 15 April 2016, 1 of 6 patients had experienced a dose-limiting toxicity (DLT) of 
Grade 3 diarrhea in the 800-mg QD fasting cohort, which resolved with dose 
modification and antidiarrheal therapy.  A maximum tolerated dose (MTD) was not 
determined.  However, given the high proportion of gastrointestinal (GI) adverse events, 
doses of 800 mg were deemed intolerable in the clinical setting of breast cancer.  
A recommended Phase II dose (RP2D) of 600 mg QD administered under fed conditions 
(i.e., 30 minutes after eating a meal) was selected based on the overall safety, 
tolerability, and PK profile of GDC-0810.  


 
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As of 15 April 2016, adverse events of any grade related to study drug occurring at 
> 20% frequency in the Phase I study were diarrhea (76%), nausea (66%), fatigue 
(59%), vomiting (34%), decreased appetite (29%),flatulence (27%), abdominal pain 
(24%), anemia (24%), dyspepsia (24%), hot flushes (24%), hypertriglyceridaemia 
(24%), muscle spasms (24%), and aspartate aminotransferase increase (22%) 
(n=41 patients treated at doses from 100 mg to 800 mg).  Diarrhea was mostly Grade 1, 
intermittent in nature, and manageable with dose modifications, dietary adjustments, 
and treatment with loperamide as needed.  As of 15 April 2016, the median treatment 
duration is 123 days (range 28−790 days) for patients in the Phase Ia study. 
As of 9 September 2016, 107 patients had been enrolled in the combined Phase Ib 
Cohort D1 and Phase IIa dose-expansion portions of Study GO29642.  Phase IIa 
investigated GDC-0810 at the RP2D of 600 mg QD administered within 30 minutes 
after a meal.  Phase Ib Cohort D1 investigated GDC-0810 at 600 mg in combination 
with an LHRH agonist.  Six patients were enrolled in Cohort D1, thus the 107 patients 
are predominantly from the Phase IIa portion of Study GO29642.  Adverse events of 
any grade related to study drug occurring at > 20% frequency in the Phase IIa study 
were diarrhea (44%), nausea (38%), fatigue (36%), and hot flush (21%).  
Administering GDC-0810 within 30 minutes after a meal may have lowered the 
incidence of GI toxicities (diarrhea, nausea, vomiting) observed in Phase IIa, compared 
with the GI toxicities from Phase Ia when GDC-0810 was administered under fasting or 
nonfasting conditions.  Safety data for the Phase IIa study remain preliminary with a 
median treatment duration of 77 days (range 1−547 days). 
As of 9 September 2016, 4 patients had been enrolled in the Phase 1b dose-escalation 
combination Cohort C1 that examined GDC-0810 at 400 mg in combination with 
palbociclib at 125 mg.  Adverse events of any grade related to study drug occurring at 
>20% frequency in Cohort C1 were diarrhea (50%), nausea (75%), fatigue (50%), hot 
flush (25%), decreased appetite (25%), and gastrooesophageal reflux disease (25%).  
Safety data for Cohort C1 remain preliminary with a median treatment duration of 
134 days (range 56−138 days). 
As of 9 September 2016, among the potential risks of GDC-0810, regardless of 
relatedness to study drug, no cases of endometrial cancer or phototoxicity were reported 
in either portion of Study GO29642.  Acute renal failure was reported in 
2 (1.3%) patients across all phases of Study GO29642 (combined n=148), neither case 
was considered related to GDC-0810.  Regardless of relatedness, 9 (6.1%) venous 
thromboembolic events (VTEs) were reported across all phases of Study GO29642.  
Adverse event terms were pulmonary embolism and deep vein thrombosis.  Grades 
ranged between 2 and 4.  All patients were anti-coagulated following diagnosis of their 
thromboses.  As described in the Investigator’s Brochure, Version 4 (January 2017), the 
only identified risks for GDC-0810 are diarrhea, vomiting, and nausea.  For a full 
discussion of the adverse event profile of GDC-0810, refer to Section 6 of the 
Investigator’s Brochure. 


 
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Adverse events observed for GDC-0810 thus far are similar to those that have been 
observed with other endocrine agents and are amenable to monitoring, are manageable, 
and are reversible. 
See the GDC-0810 Investigator's Brochure for additional details on nonclinical and 
clinical studies. 
1.3 
BACKGROUND ON FULVESTRANT 
Fulvestrant belongs to a class of reversible steroidal ER antagonists that directly 
compete with estrogen for ER binding, and is devoid of the partial agonist properties of 
tamoxifen.  Upon binding to the ER, it blocks estrogen signaling and downregulates the 
cellular levels of both the ER and progesterone receptor (PgR) (Howell et al. 2000).  The 
affinity of fulvestrant for the ER is approximately 100 fold greater than that of tamoxifen 
(Howell et al. 2000). 
Fulvestrant (250 mg via intramuscular [IM] injection once monthly) was approved by the 
Food and Drug Administration (FDA) in 2002 and by the European Medicines Agency 
(EMA) in 2004 (as well as in many other countries) for the treatment of hormone 
receptor (HR)-positive metastatic breast cancer (MBC) in postmenopausal women with 
disease progression following anti-estrogen therapy.  In multicenter Phase III studies, 
fulvestrant was found to be at least equivalent to anastrozole (a non-steroidal AI) in the 
second-line setting (Howell et al. 2002; Osborne et al. 2002).  Fulvestrant is also as 
active as tamoxifen for the first-line treatment of advanced breast cancer (Howell et al. 
2004) and displays a level of activity in patients in the post-AI metastatic disease setting 
similar to that of the non-steroidal AI exemestane (Chia et al. 2008).  High-dose 
fulvestrant (500 mg via IM injection once monthly) has been shown to be associated with 
significantly longer time to progression for the first-line treatment of women with 
advanced HR-positive breast cancer compared with anastrozole (Robertson et al. 2009).  
The 500-mg dose of fulvestrant was recently demonstrated to provide superior 
progression-free survival (PFS) in women with ER-positive advanced breast cancer than 
the 250-mg dose (Di Leo et al. 2010).  Both doses were well tolerated in these studies 
and produced fewer estrogenic effects than tamoxifen and less arthralgia than 
anastrozole (Osborne et al. 2002).  These results led to the approval of fulvestrant 
500 mg IM on Days 1, 15, 29 and once monthly thereafter as the recommended dose in 
the United States (U.S.), European Union (E.U.), Canada, Argentina, and Israel as of 
May 2011 for postmenopausal women with disease progression following anti-estrogen 
therapy.  These studies demonstrate that fulvestrant is an important treatment option for 
patients with advanced breast cancer and, as such, is considered appropriate control 
therapy for the present study. 


 
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1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Fulvestrant is an accepted, standard-of-care therapy for the patient population targeted 
by this study (see Section 4.1.1).  In a study of fulvestrant in a population with breast 
cancer who had previously received endocrine therapy, the most common adverse 
events reported were injection-site pain (11.6%), nausea (9.7%), and bone pain (9.4%). 
Fulvestrant should be used with caution in patients with hepatic impairment.  Because 
fulvestrant is administered intramuscularly, it should also be used with caution in patients 
with bleeding diatheses, thrombocytopenia, or anticoagulant use. 
GDC-0810 is a potent, orally bioavailable ER-α antagonist that is being developed for 
the treatment of postmenopausal women with ER+ advanced or MBC whose disease 
has recurred or progressed following treatment with hormonal therapy.  In murine MCF-7 
xenograft models, GDC-0810 has demonstrated robust tumor regression in both 
tamoxifen-sensitive and tamoxifen-resistant models, with superior tumor growth 
inhibition than fulvestrant at clinically relevant exposures.  GDC-0810 is currently being 
tested in a Phase I/IIa study in postmenopausal women with ER+ /human epidermal 
growth factor receptor 2 (HER2) − advanced and MBC.   
As of15 April 2016, a total of 41 patients had been treated with GDC-0810 doses 
ranging from 100 − 800 mg.  Robust ER target engagement across all doses was 
demonstrated by FES-PET scans.  Sixteen of 41 (39%) evaluable patients in this heavily 
pre-treated patient population (median 4 prior systemic treatments, range 1 − 14) had 
total time on study > 6 months, which is comparable to the 24-week clinical benefit rate 
(CBR) of 32% − 42% achieved by fulvestrant in patients with ER + advanced or MBC after 
one prior endocrine therapy (Chia et al. 2008; Di Leo et al. 2010; Johnston et al. 2013).  
Additionally, 2 patients with ESR mutations have achieved a partial response by 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 since the data cut at 
GDC-0810 doses of 300 mg BID and 400 mg BID. 
At 600 mg by mouth (PO) daily under nonfasting conditions, GDC-0810 has been well 
tolerated with most adverse events from Grade 1 to 2 in severity (see Section 1.2.2 for a 
summary of clinical safety).   
Specific eligibility criteria designed to minimize risk of GI toxicity and other potential risks 
are included in Section 4.1.2, and robust safety monitoring and risk mitigation strategies 
for all expected or potential safety risks are described in Section 5.1.  The 
implementation of appropriate dose-modification and treatment guidelines, appropriate 
choice of inclusion/exclusion criteria, and real-time safety monitoring and assessments 
combine to form the monitoring and risk mitigation system. 
In summary, clinical benefit has been observed in patients with refractory breast cancer. 
The safety profile remains acceptable and is consistent with other established endocrine 
therapies. The overall risk-benefit ratio of GDC-0810 is considered favorable for the 
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2. 
OBJECTIVES 
The development of GDC-0810 has been halted and enrollment discontinued; therefore, 
the primary objectives will not be met. 
2.1 
EFFICACY OBJECTIVES 
The co-primary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of GDC-0810 compared with fulvestrant in the 
intent-to-treat (ITT) population as measured by PFS 
• 
To evaluate the efficacy of GDC-0810 compared with fulvestrant in patients with 
detectable ESR1 mutations as measured by PFS 
 
The secondary efficacy objective for this study is as follows: 
• 
To assess the clinical activity of GDC-0810 versus fulvestrant, as measured by 
objective response rate (ORR), duration of response (DOR), CBR, and overall 
survival (OS) 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of GDC-0810 compared with fulvestrant, 
focusing on the nature, frequency, and severity of serious and non-serious adverse 
events 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The PK objective for this study is as follows: 
• 
To assess the pharmacokinetics of GDC-0810 in patients with advanced or MBC 
resistant to AI therapy 
 
2.4 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To estimate the frequency of ESR1 mutations in patients with advanced or MBC 
resistant to AI therapy 
• 
To assess the potential relationship between GDC-0810 exposure (as measured by 
PK variables) and tumor response 
• 
To assess the potential relationship between GDC-0810 exposure (as measured by 
PK variables) and safety 
• 
To assess disease and treatment-related symptoms, patient function, and health 
status/health-related quality of life (HRQoL) with GDC-0810 and fulvestrant as 
measured by the European Organization for Research and Cancer (EORTC) Quality 
of Life Questionnaire (QLQ-C30) and its breast cancer module (QLQ-BR23) 


 
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• 
To evaluate patients’ treatment satisfaction with medication using a modified version 
of the Treatment Satisfaction Questionnaire for Medication (TSQM) for use in breast 
cancer 
• 
To assess whether dynamic (non-inherited) biomarkers, including but not limited to 
ER/PgR/HER2 expression, luminal A/B status, PIK3CA mutations, AKT1 mutations, 
p53 mutations, Ki67 levels, ER target gene expression and PI3K target gene 
expression, are predictive of response to study treatment, susceptibility to 
developing adverse events, or progression to a more severe disease state, can 
provide evidence of treatment activity, or can increase the knowledge and 
understanding of disease biology  
• 
When post-progression tissue is available, to evaluate the relationship between 
GDC-0810 exposure and changes in levels of biomarkers, including but not limited 
to the dynamic (non-inherited) biomarkers described above 
• 
To use whole genome sequencing to assess whether non-dynamic (inherited) 
polymorphisms in the genome might be predictive of response to study treatment, 
susceptibility to developing adverse events, or progression to a more severe 
disease state, or can increase the knowledge and understanding of disease biology 
• 
To explore the role of polymorphisms in drug metabolism enzyme and transporter 
genes in the pharmacokinetics, safety, and efficacy of GDC-0810 in patients with 
advanced or MBC, if indicated by PK data 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a multicenter, international, randomized, open-label, Phase II trial with two study 
arms.  A total of approximately 152 patients with advanced or metastatic 
ER + /HER2 − breast cancer who have experienced recurrence or progression of their 
disease while receiving AI therapy for advanced or metastatic disease or who have 
relapsed within 6 months after completing adjuvant AI therapy will be enrolled in this 
study.  Patients who are enrolled in Arm A will receive GDC-0810, administered at 
600 mg PO daily.  Patients who are enrolled in Arm B will receive fulvestrant, 
administered at 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and Day 1 of each 
subsequent 28-day cycle thereafter. 
A permuted block randomization scheme will be used to ensure an approximate 1:1 
allocation of patients who receive GDC-0810 (Arm A) versus patients who receive 
fulvestrant (Arm B) with respect to two stratification factors per local assessment:  
geographic region (United States, European Union, and Rest of World) and presence or 
absence of visceral disease. 
Patients may have either measurable disease (per RECIST v1.1) and/or 
non-measurable, but evaluable, locally advanced or metastatic disease with at least one 
evaluable bone lesion.  Locally advanced disease must not be amenable to resection or 


 
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other local therapy with curative intent (see Section 4.1.1 and Section 4.1.2 for detailed 
inclusion and exclusion criteria). 
Patients will receive study treatment in 28-day cycles until documented radiographic 
disease progression, intolerable toxicity, elective withdrawal from the study, study 
completion, or study termination.  Tumor assessments will be conducted for all patients 
at screening, per institutional guidelines, and as clinically indicated.  A schedule of 
study assessments is provided in Appendix 1 and Appendix 2. 
Enrollment in Study GO29689 has been discontinued; therefore, no further patients 
will be enrolled in this study.  Any patient currently enrolled in Study GO28689 
experiencing clinical benefit may continue to receive GDC-0810 as a single agent or 
fulvestrant until disease progression (as assessed by the investigator based on 
radiographic findings or clinical symptoms), unmanageable toxicity, patient 
withdrawal of consent, GDC-0810 drug supply has been exhausted, or the Sponsor 
terminates the study.  All patients who are discontinued from study treatment will return 
for a study drug discontinuation visit within 30 days after the last dose of study treatment 
and will be followed for adverse events for at least 28 days after the last dose of study 
treatment.  
3.2 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs, 
GDC-0810 drug supply is exhausted, or when the Sponsor decides to stop the study.  
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Patient Population 
Female patients with HER2 − ER+, locally recurrent, or MBC for which chemotherapy is 
not indicated will be enrolled in this study.  This patient population is usually treated with 
multiple rounds of single-agent endocrine therapy prior to receiving cytotoxic 
chemotherapy.   
Enrollment in this study is limited to patients who experienced recurrent disease or 
disease progression while receiving an AI for the treatment of breast cancer or who have 
relapsed within 6 months after completing adjuvant AI therapy.  In addition, these 
patients may not have received more than one prior chemotherapy regimen or more 
than two lines of endocrine therapy in the advanced or metastatic disease setting.  The 
requirement for prior treatment with an AI identifies patients who have become resistant 
to endocrine therapy and would be an appropriate population for fulvestrant therapy.  
The allowance of up to one prior cytotoxic chemotherapy regimen in the metastatic 
setting is consistent with prior studies with fulvestrant in a similar patient population.  
Patients treated with one prior metastatic chemotherapy regimen are not expected to be 
predisposed to having more severe drug-related toxicities.  The inclusion criteria of 


 
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Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 − 1 has been 
selected to test a more homogenous patient population. 
Patients will be stratified according to geographic region (United States, European Union, 
and Rest of World), because potential differences in first- and second-line treatment 
regimens that are considered local standard-of-care could affect trial outcomes.  Patients 
will also be stratified according to presence or absence of visceral disease, as the 
presence of visceral disease is a known unfavorable risk factor for ER+ breast cancer 
that significantly decreases expected survival (Koenders et al. 1992). 
3.3.2 
GDC-0810 Dose and Schedule 
The dose and schedule of GDC-0810 will be 600 mg PO once daily continuously in 
28-day cycles, administered under fed conditions (within 30 minutes after eating a meal).  
In the single-agent Phase Ia study of GDC-0810, only 1 patient out of a total of 
6 patients enrolled at the 800-mg, PO, once daily fasting cohort experienced a DLT 
(Grade 3 diarrhea), which resolved with dose modification and antidiarrheal therapy.  
However, as additional patients treated with 800 mg PO QD experienced Grade 2 
nausea, vomiting, and diarrhea, this dose level was considered intolerable, and thus the 
MTD of GDC-0810 was not formally determined.  As there was a trend for increased 
exposure and better tolerability under nonfasted conditions, an RP2D of 600 mg QD 
administered under fed conditions (i.e., within 30 minutes after a meal) was selected 
based on the overall safety/tolerability and PK/pharmacodynamic (PD) profile of 
GDC-0810.  See the Investigator’s Brochure for further details. 
3.3.3 
Control Treatment 
Treatment for ER+, HER2 −  breast cancer usually consists of multiple lines of 
single-agent endocrine therapy, followed by cytotoxic chemotherapy once all endocrine 
therapy options have been exhausted or symptomatic or rapid disease progression 
warrants the use of cytotoxic chemotherapy.  Fulvestrant has been approved by the 
U.S. FDA and EMA for the treatment of HR+ or ER+, locally advanced or MBC in 
postmenopausal women with disease progression following prior anti-estrogen therapy 
(Howell et al. 2002; Osborne et al. 2002; Di Leo et al. 2010). 
The dose and schedule of fulvestrant will be 500 mg via IM injection on Days 1 and 15 of 
Cycle 1, and Day 1 of each subsequent 28-day cycle thereafter, which is the approved 
recommended dose and schedule in the United States, European Union, Canada, 
Argentina, and Israel (as of May 2011). 
3.3.4 
Open-Label Design 
Fulvestrant must be administered via an IM injection, and the two required injections per 
dose are associated with localized pain and other potential injection-related risks 
(e.g., bleeding, bruising, infection).  Sham injections would result in added risk to 
patients enrolled on the GDC-0810 arm, and are therefore undesirable.  An 


 
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acknowledged risk of the open-label design is the potential for bias by patients and 
investigators that is related to knowledge of the treatment assignment.  As a result, all 
radiographic scans done as part of response assessments will be collected and held 
centrally and may be reviewed retrospectively to generate an independent response 
assessment to corroborate the investigator’s assessment. 
3.3.5 
Collection of Archival Tumor Tissue 
Archival tissue (or fresh biopsy tissue if archival tissue is not available) will be required 
from all patients for study entry.  If available, both primary and metastatic tissue will be 
collected.  ER+  breast cancer is a heterogeneous disease.  Therefore, all patients may 
not be equally likely to benefit from treatment with GDC-0810.  Potential predictive 
biomarkers (including, but not limited to, the following:  expression of Ki67, expression of 
ER, expression of PgR, ESR1 mutation status, and alterations in the ER- and 
PI3K-pathway signaling) will be assessed in tumor samples collected prior to dosing in 
an effort to identify those patients with ER-driven pathogenesis who are most likely to 
respond to GDC-0810.  As these biomarkers may also have prognostic value, their 
potential association with disease progression will also be explored.  
3.3.6 
Optional Collection of Tumor Biopsies at Disease Progression 
Understanding the mechanisms of resistance to GDC-0810 is critical for the 
development of novel agents that target the ER and may provide an opportunity to 
develop next-generation agents to prevent resistance.  If post-progression tumor 
biopsies can be obtained with minimal risk and discomfort to the patients, it is strongly 
recommended that tissue be collected from patients who specifically consent to this 
optional procedure.  These tissue samples will be assessed for acquired 
ESR1 mutations and alterations in ER- and PI3K-pathway signaling that may help 
elucidate potential mechanisms of resistance. 
3.3.7 
Collection of a Blood Sample for Mutation Detection in Tumor 
DNA 
There is increasing evidence that tumor DNA representing the mutational status of tumor 
cells can be obtained through the isolation of circulating DNA from blood specimens of 
patients with cancer (Diehl et al. 2008; Maheswaran et al. 2008).  Multiple assays are in 
development to identify mutations in PIK3CA, ESR1, and PI3K and ER-pathway related 
genes in circulating tumor DNA (ctDNA).  This will be correlated with mutations detected 
in submitted tumor specimens.  Several small retrospective studies have examined the 
discordance rate between paired samples from the primary tumor and the metastatic 
biopsy (Dupont Jensen et al. 2011; Gonzalez-Angulo et al. 2011; Sanchez et al. 2011).  
Loss or gain of PIK3CA mutation in metastatic lesions has been observed in up to 33% of 
patients with MBC (Dupont Jensen et al. 2011).  In addition, recent studies have identified 
mutations in ESR1 (e.g., ERα) affecting the LBD of the ER (Segal and Dowsett 2014).  
In nonclinical models, mutant receptors are able to drive ER-dependent transcription and 
proliferation in the absence of estrogen, suggesting that LBD-mutant forms of the ER are 


 
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involved in mediating clinical resistance to endocrine therapy (Li et al. 2013; Robinson 
et al. 2013; Toy et al. 2013).  Identifying potential discordances in the PIK3CA and ESR1 
status of the primary and metastatic lesions through the analysis of archival tumor 
samples and ctDNA, which would represent the most recently collected tissue sample, 
may help clarify the prognostic and predictive significance of PIK3CA and ESR1 
mutations in patients treated with the experimental regimens.  This information may also 
be helpful in the development of a potential companion diagnostic for GDC-0810. 
3.3.8 
Optional Collection of a Blood Sample for Whole Genome 
Sequencing 
An optional blood sample will also be collected from all patients as a source of normal 
(germline) DNA for targeted sequencing to determine whether or not sequence variants 
detected in tumor tissue are somatic mutations or single nucleotide polymorphisms 
(SNPs).   
DNA will also be collected from all patients for next-generation whole genome 
sequencing.  As described above, ER+ breast cancer is a heterogeneous disease; 
therefore, all patients may not be equally likely to benefit from treatment with GDC-0810.  
Genomics is increasingly informing our understanding of disease pathobiology and 
rationale for the development of new therapeutic approaches.  Whole genome 
sequencing provides comprehensive characterization of the genome and, along with 
clinical data collected in this study, may increase the opportunity for making these 
discoveries.  Data obtained from whole genome sequencing will also be used to explore 
whether specific inherited polymorphisms are predictive of response to GDC-0810, 
susceptibility to developing adverse events, or progression to a more severe disease 
state. 
3.3.9 
Pharmacokinetic Evaluation Schedule 
PK samples (as outlined in Appendix 3) will be collected in all patients to enable a further 
understanding of GDC-0810 pharmacokinetics and identification of potential sources of 
variability influencing GDC-0810 PK.  The PK data will also be used to explore potential 
relationships of exposure (PK variables) to efficacy and safety in the study. 
3.3.10 
Patient-Reported Outcome Questionnaires 
As of protocol amendment version 2, patient reported outcomes questionnaires will no 
longer be required. 
In MBC, the main goals of treatment are to prolong survival and maintain or improve the 
quality of life (Cardoso et al. 2012).  Patient-reported outcome (PRO) measures provide 
an understanding of a patient’s quality of life and the impact of treatment on patients 
while undergoing therapy.  PROs of disease/treatment-related symptoms, function, and 
global health status will be assessed using the EORTC QLQ-C30 (Appendix 4) in 
conjunction with the QLQ-BR23 breast cancer module (Appendix 5).  The EORTC 
QLQ-C30 and its breast cancer−specific module, the QLQ-BR23, are validated and 


 
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reliable self-report measures (Aaronson et al.1993; Sprangers et al. 1996; Osoba et al. 
1997). 
The modified version of the TSQM (Appendix 6) is a validated and reliable self-report 
questionnaire that assesses overall patient satisfaction with their study treatment 
(Atkinson et al. 2004).  The modified version of the TSQM was tailored and approved for 
use in breast cancer patients. 
3.3.11 
DNA for Exploratory Pharmacogenetic Polymorphisms 
Blood samples will be used for the evaluation of genetic polymorphisms of drug 
metabolic enzymes (including, but not limited to CYP2C9, CYP3A4/5, and UGT1A1) and 
transporters (e.g., OATP1B1) and genetic variants that could contribute to potential 
safety and efficacy concerns.  For sample handling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.  Only in circumstances where there is 
concern for the collection of this genetic material for the above evaluations can this 
assessment be considered not mandatory as part of study assessments in this study.  
Results of any analyses from these samples will be reported outside the clinical study 
report. 
It is established that genetic variants of drug-metabolizing enzymes and transporters can 
affect the pharmacokinetics of drugs, which affect their safety and efficacy.  For example, 
patients who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1, which facilitates the metabolism and excretion of SN-38 
(the active metabolite of irinotecan), are at a higher risk for adverse effects associated 
with the use of standard doses of irinotecan (O’Dwyer and Catalano 2006).  Although 
in vitro studies can help elucidate the roles of enzymes in the metabolism of the drug, 
these results are not always predictive of in vivo metabolism for a number of reasons, 
such as differences in drug concentrations that the enzymes encounter in vitro and in 
vivo.  For this reason, a blood sample for DNA isolation is to be collected from all 
patients dosed with GDC-0810 in this study for potential pharmacogenetic analysis of 
genes or biomarkers that may affect the pharmacokinetics, safety, or response to 
GDC-0810.  The decision to analyze the samples will be based on a review of the 
pharmacokinetics and response data. 
3.4 
OUTCOME MEASURES  
3.4.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study, for all patients as well as the 
subset of patients with ESR1 mutations, is as follows: 
• 
PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator per RECIST v1.1 (See Appendix 7) or 
death from any cause on study, whichever occurs first 
 


 
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3.4.2 
Secondary Efficacy Outcome Measures 
The secondary outcome measures for this study are the following: 
• 
OS, defined as the time from randomization to the time of death from any cause  
• 
Objective response (PR plus complete response [CR]) as determined by the 
investigator per RECIST v1.1 (see Appendix 7) 
• 
DOR, defined as the time from the first occurrence of a documented objective 
response until first observation of disease progression, as determined by the 
investigator per RECIST v1.1 (see Appendix 7), or death from any cause on study, 
whichever occurs first 
• 
Clinical benefit, defined as PR, CR, or stable disease (SD), lasting for at least 
24 weeks from the time of randomization 
 
3.4.3 
Safety Outcome Measures 
The safety and tolerability of GDC-0810 will be assessed using the following: 
• 
The incidence, nature, and severity of adverse events reported during the adverse 
event reporting period (see Section 5.3.1), graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE, 
v4.0) 
• 
Incidence, nature and severity of serious adverse events 
• 
Incidence of adverse events leading to study treatment discontinuation, modification 
or interruption 
• 
Clinically significant changes in vital signs, physical findings, and clinical laboratory 
results during and following GDC-0810 or fulvestrant administration during the 
adverse-event reporting period 
 
3.4.4 
Pharmacokinetic Outcome Measures 
 
Sparse PK samples will be collected as outlined in Appendix 3 and may be analyzed 
using population PK methods to estimate apparent clearance, volume of distribution, 
absorption rate constant, and other appropriate measures as data allow, and plasma 
concentrations will be summarized by visit.  Please refer to Section 6.6 for additional 
information. 
3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Assessment of RNA in pre- and post-treatment tumor specimens, including 
assessment of PI3K and ER target gene expression signatures, ER, PgR, and 
HER2 status and luminal A/B status 
• 
Alterations of DNA in pre- and post-treatment tumor specimens, including 
ESR1 mutations, PIK3CA mutations, AKT1 mutations, and TP53 mutations  
• 
Assessment of Ki67 levels in pre- and post-treatment tumor specimens 


 
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• 
Alterations in ctDNA from peripheral blood, including but not limited to ESR1, 
PIK3CA and AKT1 
• 
Assessment of mean change in disease/treatment-related symptoms, function and 
health status/HRQoL scales of the EORTC QLQ-C30 (Appendix 4) and the EORTC 
QLQ-BR23 breast module (Appendix 5) 
• 
Assessment of mean treatment satisfaction on the subscales (side effects, 
convenience, and global satisfaction) of a modified version of the TSQM 
(Appendix 6) 
• 
Whole genome sequencing data will be analyzed in the context of this study and 
explored in aggregate with other studies to better understand disease pathobiology 
and guide the development of new therapeutic approaches.  Given the complexity 
and exploratory nature of these analyses, whole genome sequencing data and 
analyses will not be shared with investigators or study participants unless required 
by law. 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Patients with ER + HER2 − , locally advanced or MBC will be enrolled in the study.   
4.1.1 
Inclusion Criteria 
Patients must meet all of the following criteria for study entry: 
Disease-Specific Inclusion Criteria 
• 
Postmenopausal women with histologically or cytologically confirmed invasive, 
ER + /HER2 −  (defined by local guidelines) metastatic or inoperable (not amenable 
to resection or other local therapy with curative intent), locally advanced breast 
cancer 
Postmenopausal is defined as meeting at least one of the following criteria: 
– 
Prior bilateral oophorectomy 
– 
Age ≥ 56 years and natural amenorrhea with ≥ 1 year since last menses 
– 
Age < 56 years with amenorrhea ≥ 1 year since last menses, and serum 
estradiol levels (< 20 pg/mL) and follicle stimulating hormone (FSH) levels 
(> 40 mIU/mL) in the postmenopausal range 
– 
Age < 56 years after hysterectomy with one or both ovaries left in place, or with 
tamoxifen-induced amenorrhea together with a tamoxifen discontinuation of 
≥ 1 year and serum estradiol levels (< 20 pg/mL) and FSH levels (> 40 mIU/mL) 
in the postmenopausal range 
– 
Age < 56 years after medical menopause on luteinizing LHRH agonist (on 
stable dose ≥ 1 year), with amenorrhea ≥ 1 year since last menses and serum 
estradiol levels (< 20 pg/mL) in the postmenopausal range irrespective of 
FSH/LH levels  


 
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– 
Women with therapy-induced amenorrhea must agree to remain abstinent or 
use single or combined non-hormonal contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at 
least 28 days after the last dose of GDC-0810 or at least 1 year after the last 
dose of fulvestrant.  Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
– 
Examples of non-hormonal contraceptive methods with a failure rate of < 1% 
per year include tubal ligation, male sterilization, and certain intrauterine 
devices.  Alternatively, two methods (e.g., two barrier methods such as a 
condom and a cervical cap) may be combined to achieve a failure rate of < 1% 
per year.  Barrier methods must always be supplemented with the use of a 
spermicide. 
• 
Patients for whom endocrine therapy (e.g., fulvestrant) is recommended and 
treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, 
as per national or local treatment guidelines 
• 
Radiologic/objective evidence of recurrence or progression to the most recent 
systemic therapy for breast cancer 
• 
Radiologic/objective evidence of breast cancer recurrence or progression while on 
or within 6 months after the end of adjuvant treatment with an AI, or progression 
while on or within 1 month after the end of prior AI treatment for locally advanced or 
MBC.  The AI (letrozole, anastrozole, or exemestane) does not have to be the most 
recent treatment before randomization, but patients must have received at least 
4 weeks of treatment with an AI. 
• 
Patients must have measurable disease by RECIST v1.1 or non-measurable, 
evaluable disease with at least one evaluable bone lesion by RECIST v1.1 based on 
radiologic scans within 28 days of Day 1 of Cycle 1.  Bone lesions that have been 
irradiated are not evaluable. 
 
General Inclusion Criteria 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years  
• 
ECOG Performance Status of 0 or 1 (see Appendix 8) 
• 
Consent to the collection of a formalin-fixed paraffin-embedded (FFPE) block or a 
minimum of 10 freshly cut unstained tumor slides (submission of 15−20 is strongly 
encouraged) from archival tumor tissue or a newly collected (“fresh”) tumor sample 
for protocol-mandated exploratory assessments   
• 
Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 28 days prior to Day 1 of Cycle 1: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelet count ≥ 90,000/μL 


 
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– 
Hemoglobin ≥ 9.0 g/dL (90 g/L) 
– 
Albumin ≥ 3.0 g/dL (30 μmol/L) 
– 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
– 
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline 
phosphatase (ALP) ≤ 1.5 × ULN, with the following exceptions: 
Patients with documented liver metastases:  AST and/or ALT ≤ 5.0 × ULN 
Patients with documented bone metastases:  ALP ≤ 5.0 × ULN 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min based 
on Cockroft−Gault glomerular filtration rate (GFR) estimation 
(140 − age) × (weight in kg) × (0.85 if female) 
72 × (serum creatinine) 
International normalized ratio (INR) < 1.5 and activated partial thromboplastin 
time (aPTT) < 1.5 × ULN; for patients requiring therapeutic anticoagulation 
therapy, a stable INR ≤ 2.5 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Disease-Specific Exclusion Criteria 
• 
HER2-positive disease (immunohistochemistry [IHC] 3 + staining, fluorescence in 
situ hybridization [FISH] positive, and/or chromogenic in situ hybridization [CISH] 
positive) 
• 
Prior treatment with fulvestrant 
• 
Prior anti-cancer therapy within 2 weeks prior to Cycle 1 Day 1 
• 
Prior radiation therapy within 2 weeks prior to Cycle 1 Day 1 
• 
Prior treatment with > 1 cytotoxic chemotherapy regimens or > 2 endocrine therapies 
for advanced or metastatic disease 
• 
Ongoing, acute treatment-related toxicity that has not resolved to Grade ≤ 1 or been 
deemed stable by the investigator   
• 
Concurrent hormone replacement therapy 
• 
Symptomatic hypercalcemia requiring continued use of bisphosphonate or 
denosumab therapy; use of bisphosphonate therapy or denosumab for other 
reasons (e.g., bone metastasis, osteoporosis, etc.) is allowed (see Section 4.4.1). 
• 
Known untreated or active central nervous system (CNS) metastases (progressing 
or requiring anticonvulsants or corticosteroids for symptomatic control); a computed 
tomography (CT) scan or magnetic resonance imaging (MRI) of the brain will be 
performed at screening if required by the local health authority 
Patients with a history of treated CNS metastases are eligible, provided they meet 
all of the following criteria:  


 
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– 
Evaluable or measurable disease outside the CNS is present. 
– 
Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic study  
– 
No history of intracranial hemorrhage or spinal cord hemorrhage  
– 
Screening CNS radiographic study is ≥ 8 weeks since completion of 
radiotherapy and ≥ 4 weeks since the discontinuation of corticosteroids  
• 
History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I 
uterine cancer, or patients who have undergone potentially curative therapy with no 
evidence of disease and are deemed by the treating physician to be at low risk for 
recurrence; patients with slow-growing, benign tumors are allowed 
 
General Exclusion Criteria 
• 
Inability or unwillingness to swallow pills or receive IM injections 
• 
History of malabsorption syndrome, short bowel syndrome, gastric resection, or 
other condition that would interfere with enteral absorption 
• 
History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) 
• 
Active bowel inflammation (e.g., diverticulitis) 
• 
History of endometrial cancer or atypical endometrial hyperplasia 
• 
Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, or current known active infection with hepatitis B virus (HBV), or hepatitis C 
virus (HCV) 
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 [anti-HBc]) or hepatitis C (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 are positive for anti-HBc are eligible only if testing is also positive 
for hepatitis B surface antibody and polymerase chain reaction (PCR) is 
negative for HBV DNA. 
– 
Patients who are positive for HCV serology are eligible only if testing for HCV 
RNA is negative. 
• 
Active autoimmune disease that is not controlled for at least 6 months by stable 
doses of nonsteroidal or steroidal (< 10 mg of prednisone per day) anti-inflammatory 
drugs or active inflammatory disease, including small or large intestine inflammation 
such as Crohn’s disease or ulcerative colitis, which requires immunosuppressive 
therapy 
• 
Clinically significant cardiac or pulmonary dysfunction, including the following: 
– 
Current uncontrolled Grade ≥ 2 hypertension or unstable angina 


 
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– 
Symptomatic congestive heart failure of New York Heart Association Class II, 
III or IV 
– 
Serious cardiac arrhythmia requiring treatment, with the exceptions of atrial 
fibrillation and paroxysmal supraventricular tachycardia or conduction 
abnormality that has been treated and for which the patient is no longer at risk 
for serious arrhythmia (e.g., Wolff-Parkinson-White syndrome treated with 
surgical ablation) 
– 
History of acute coronary syndrome or unstable angina within 6 months prior to 
Cycle 1, Day 1 
• 
History of congenital long QT syndrome or corrected QT interval (QTcF) > 470 msec 
• 
Immunocompromised status due to current known active infection with HIV or due to 
the use of immunosuppressive therapies for other conditions 
• 
Need for current chronic corticosteroid therapy (≥ 10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids)  
Inhaled corticosteroids are allowed 
• 
Pregnancy, lactation, or breastfeeding 
• 
Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic disease) 
• 
Major surgical procedure or significant traumatic injury within 28 days prior to Day 1 
of Cycle 1 or anticipation of the need for major surgery during the course of study 
treatment 
• 
Inability, in the opinion of the investigator, to comply with study and follow-up 
procedures 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
After written informed consent has been obtained and eligibility has been established 
and approved, the study site will obtain the patient’s identification number and treatment 
assignment from the Interactive Web Response System (IWRS).  Patients will be 
randomized to receive either GDC-0810 or fulvestrant in an approximate 1:1 ratio 
through the use of a permuted block randomization method. 
Randomization will be stratified by the following criteria: 
• 
Visceral versus non-visceral disease: 
– 
Visceral disease: metastatic disease in the lung, liver, adrenal glands, brain, 
heart, pericardium, pleura, peritoneum, or other organs of the chest, abdomen 
and pelvis 
– 
Non-visceral disease: absence of metastatic disease in visceral organs. Pleural 
effusions and/or ascites. Disease involving lymph nodes and disease involving 
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• 
Geographical region: 
– 
United States 
– 
European Union 
– 
Rest of World (remaining countries) 
 
The Sponsor, the investigators, and the patients will be unblinded to treatment 
assignment. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
GDC-0810 
GDC-0810 will be supplied by the Sponsor as white oblong tablets containing 200 mg 
GDC-0810 free acid packaged in 30-ct, 60cc high-density polyethylene bottles with 
child-resistant closures and tamper-proof heat induction seals.  The drug product 
container includes a desiccant packet.  Each bottle of study drug will be labeled with the 
lot number, the Sponsor’s name, and directions for patient use and storage.  
For further information on the formulation and handling of GDC-0810, see the pharmacy 
manual and the GDC-0810 Investigator's Brochure. 
4.3.1.2 
Fulvestrant 
Fulvestrant will be obtained by the site and provided as standard of care therapy, except 
where it is required by local regulations to be supplied by the Sponsor.  For countries in 
which the Sponsor is supplying fulvestrant, it will be supplied in sterile single-patient, 
prefilled syringes containing 50 mg/mL fulvestrant, as a 5-mL injection.  For details 
regarding the storage of fulvestrant, please refer to the fulvestrant package insert or 
local prescribing information. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
GDC-0810 
GDC-0810 is intended for oral administration. The 600-mg dose of GDC-0810 will be 
taken orally once per day until disease progression or intolerable toxicity.  GDC-0810 is 
supplied as 200-mg tablets; therefore, patients will take three 200-mg tablets daily to 
receive a 600-mg dose.  Each 600-mg dose should be taken within 30 minutes after a 
meal, and efforts should be made by patients to take the dose at the same approximate 
time each day.  If a dose is missed (not taken within 8 hours after the scheduled dosing 
time), the patient should resume dosing with the next scheduled dose.  Missed or 
vomited doses will not be made up. 
On clinic visit days that require a predose blood draw for PK sampling and/or laboratory 
assessments (see Appendix 1 and Appendix 2), patients will be instructed to take their 
morning, oral study-treatment dose in the clinic after the completion of the pre-treatment 


 
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assessments.  For all other days, the daily study treatment dose should be taken at 
home. 
A sufficient number of GDC-0810 tablets should be provided to the patient to last until 
the next visit.  Patients will be instructed to bring their bottles of study drug and their 
medication diary with them to each study visit. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.2.2 
Fulvestrant 
Fulvestrant 500 mg will be administered in the clinic as two IM injections of 250 mg each 
on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle until 
disease progression or intolerable toxicity.  For more details regarding the dosing 
instructions and safety profile of fulvestrant, please refer to the fulvestrant (Faslodex®) 
Package Insert or Summary of Product Characteristics (SmPC). 
The fulvestrant dose level cannot be modified.  Guidelines for dosage modification and 
treatment interruption or discontinuation of fulvestrant are provided in Section 5.1.5.1. 
Any overdose or incorrect administration of fulvestrant should be noted on the 
Fulvestrant Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of fulvestrant should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(GDC-0810 and fulvestrant) will be provided by the Sponsor where required by local 
health authority regulations.  The study site will acknowledge receipt of IMPs using the 
IWRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 


 
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4.3.4 
Post-Trial Access to GDC-0810 
The Sponsor (Genentech) is a member of the Roche group and is subject to Roche’s 
global policies.  The Sponsor will offer post-trial access to the study drug (GDC-0810) 
free of charge to eligible patients in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, as outlined below.   
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
• 
The data suggest that the study drug is not effective for ER+ breast cancer 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for ER+ breast cancer 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
Patients treated with anti-seizure medications should have levels monitored regularly. 
Palliative and supportive care for disease-related symptoms may be administered at the 
investigator’s discretion.  Patients who experience toxicities should have their symptoms 
treated as clinically indicated.  Anti-emetics and anti-diarrheal medications should not be 


 
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administered prophylactically before initial treatment with study drug.  At the discretion of 
the investigator, prophylactic anti-emetic and/or anti-diarrheal medication(s) may be 
used as per standard clinical practice before subsequent doses of study drug. 
Pain medications administered per standard clinical practice are allowed.  Bone-sparing 
agents (e.g., bisphosphonates, denosumab) for palliation of bone metastases or for the 
treatment of osteoporosis/osteopenia are allowed, but initiation of such agents or 
modification of the pre-study bisphosphonate or denosumab treatment regimen require 
the approval of the Medical Monitor and should be avoided where possible. 
GDC-0810 was shown to inhibit human CYP2B6 and CYP2C enzymes in vitro; 
therefore, drug-drug interactions with co-administered CYP2B6 and CYP2C substrates 
cannot be excluded and should be avoided where possible.  Note that many of these 
medications are also metabolized by other CYP enzymes which are not inhibited by 
GDC-0810 (e.g., CYP3A4), thus attenuating the potential for drug-drug interactions to 
some extent.  If there is clinical need for a particular CYP2B6 or CYP2C substrate drug, 
dose adjustments and/or use of alternative medications are recommended.  
 A list of possible CYP2B6 and CYP2C substrates can be found in Appendix 9. 
4.4.2 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited for at least 14 days prior to 
Cycle 1 Day 1 dosing and during the study treatment:  
• 
Therapy intended for the treatment of cancer (regulatory-approved or experimental), 
including chemotherapy, radiation therapy, immunotherapy, biologic therapy, herbal 
therapy, radiopharmaceutical therapy, or endocrine therapy. 
Local radiotherapy is not permitted.  It is understood that there may be extreme 
circumstances requiring local radiotherapy in which the investigator does not 
believe that the symptoms are a result of disease progression (e.g., impending 
fracture), and the radiation field does not encompass a target/non-target lesion.  
In such cases, the investigator must obtain approval from the Medical Monitor, 
and such patients should have a tumor assessment of the lesion(s) before they 
actually receive the radiotherapy.  If a patient received radiation therapy and a 
target or non-target lesion is included in the field of radiation, the lesion(s) will 
become unevaluable for tumor response. 
Further reasons for avoiding local radiotherapy include the difficulty in 
distinguishing new symptomatic pain or worsening of lytic bone lesions from 
disease progression.  Radiation therapy to a specific site renders that lesion 
unevaluable for tumor response.  Previous clinical experience also suggests that 
new bone pain is frequently a symptom of disease progression.  Bone pain 
secondary to study treatment can be treated with pain medications, nonsteroidal 
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Use of the following concomitant therapies is prohibited for at least 7 days prior to 
Cycle 1 Day 1 dosing and during the study treatment: 
• 
Hematopoietic growth factors (e.g., erythropoietins, G-CSF, and GM-CSF) are not to 
be administered prophylactically.  Use of these agents should be reserved for cases 
of severe neutropenia and anemia per the labeling of these agents and require the 
approval of the Medical Monitor. 
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective ER modulators (e.g., raloxifene) are 
prohibited. 
• 
Owing to their narrow therapeutic index and the potential for drug-drug interactions, 
concomitant therapy with warfarin or phenytoin is prohibited.  Please see 
Appendix 9 for further information. 
 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1, Appendix 2, and Appendix 3 for the schedule of assessments 
performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
(ICFs) 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 randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases that have occurred within the 
previous 5 years before Cycle 1 Day 1, surgeries, breast cancer history (including tumor 
characteristics such as HR status, location of metastases, prior cancer therapies, 
surgeries and procedures), menopausal status, smoking history, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity in accordance 
with the applicable laws (e.g., health authority requirements). 
4.5.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
GI, genitourinary, and neurological systems, as well as measurements of weight and 


 
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height (height is measured at screening only).  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. 
An assessment of the patient’s ECOG Performance Status (see Appendix 8) will be 
completed at screening and as specified in the Schedule of Assessments (see 
Appendix 1 and Appendix 2). 
At subsequent visits (or as clinically indicated), symptom-directed physical examinations 
should be performed.  Particular attention should be given to symptoms related to 
adverse events of special interest (e.g., diarrhea).  Detailed information about any 
diarrhea symptoms (e.g., urgency, loss of stool continence, impact on lifestyle) as well 
as management (e.g., dietary changes, fluids, probiotics, use of anti-diarrheals) should 
be assessed. Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs, collected at screening, per institutional guidelines, and as clinically 
indicated and at each subsequent visit, will include measurements of heart rate, systolic 
and diastolic blood pressure (while the patient is in a seated position), and oral or 
tympanic temperature. 
4.5.5 
Tumor and Response Evaluations 
Tumor assessments will be performed at screening, per institutional guidelines, and 
when clinically indicated. All known measurable sites of disease must be documented at 
screening and re-assessed at each subsequent tumor evaluation.  A documented 
standard-of-care tumor assessment performed within 28 days before Cycle 1 Day 1 may 
be used for the screening assessment, provided it meets the requirements described 
below.   
Response assessments will be performed by the investigator, on the basis of physical 
examinations and imaging scans (Appendix 7).  
CT scans are the preferred imaging modality for tumor assessments.  Tumor 
assessments should include a diagnostic quality, contrast-enhanced CT scan of the 
chest, abdomen, and pelvis at baseline. CT scans of the neck should be included if 
clinically indicated.  A CT for tumor assessment may be acquired on a PET/CT scanner 
if it is of full diagnostic quality and includes intravenous (IV) contrast. 
In patients for whom a CT scan is contraindicated due to a CT IV contrast allergy, a CT 
of the chest without contrast and MRI of the abdomen and pelvis with contrast are 
recommended.  MRI of the chest may only be performed with the approval of the 
Sponsor.  In these patients, at screening, tumor assessments should include a 


 
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diagnostic quality, contrast-enhanced MRI scan of the chest (if approved), abdomen, 
and pelvis.  MRI scans of the neck should be included if clinically indicated.  
The same imaging method used at screening must be used throughout the study.  
To be suitable for RECIST assessments, CT/MRI scans should ideally have a maximum 
thickness of 5 mm and minimal gaps.  Subsequent tumor assessments should include 
CT/MRI scans of the chest, pelvis, and abdomen and other known sites of disease.  
In addition to the scheduled on-protocol CT/MRI scans, CT/MRI scans may be repeated 
at the investigator’s discretion at any time if progressive disease is suspected. 
A technetium bone scan should be performed at screening (up to 28 days prior to 
Cycle 1 Day 1) to evaluate for the presence of bone metastases.  Positive areas on bone 
scans should be evaluated by X-ray, CT scan, or MRI prior to randomization (up to 
28 days prior to Cycle 1 Day 1).  Bone scans should be repeated in the event of clinical 
suspicion of progression of existing bone lesions, the development of new bone lesions, 
and in the assessment of a CR, if any disease was evident at screening.  For adequate 
assessment of bone lesions, it is expected that the radiologist will adjust window leveling 
accordingly.   
To ensure a valid comparison of tumor data and uniformity in the assessment of tumor 
response during the study, the following procedures must be implemented at the study 
site: 
• 
All lesions identified at baseline (target and non-target) will be reassessed using the 
same method throughout the course of the study. 
• 
All CT scans and MRIs obtained for all patients enrolled at the center should be 
reviewed by the local radiologist who, together with the investigator, will determine 
the local assessment of response and progression.  All bone scans obtained from 
the patients with bone metastases should be reviewed similarly. 
• 
All radiological data (CT scan, MRI and bone scan, etc.) and photos for skin lesions 
obtained at baseline, during treatment period and the follow-up period must be sent 
to a central imaging vendor contracted by the Sponsor within 2 weeks of imaging. 
• 
Tumor response and progression will be assessed and will be the basis for the 
efficacy analyses (along with survival information).  The main analysis of the trial will 
be based on the local radiology review results. 
 
Patients who discontinue study treatment for any reason other than disease progression 
will continue to undergo tumor response evaluations until progressive disease or 
initiation of other anti-cancer therapy. 
4.5.5.1 
Response Evaluations in Patients with Bone-Only Disease 
For patients with bone-only disease not visible on the CT or MRI scans being performed 
as part of the tumor assessments, a bone scan should be repeated at every tumor 
assessment  (± 7 days for flexibility in the event of isotope shortage), and when clinically 


 
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indicated.  Abnormalities found on subsequent bone scans should be evaluated by 
CT scan, MRI, or X-ray to ascertain the presence of bone destruction versus a healing 
reaction.  In the absence of measurable disease at baseline, the following will be 
considered progression among patients with lytic or mixed (lytic + sclerotic) bone lesions: 
• 
The appearance of one or more new lytic lesions in bone 
• 
The appearance of one or more new lesions outside of bone 
• 
Unequivocal progression of existing bone lesions 
 
Pathologic fracture, new compression fracture, or bone metastasis complications will not 
be considered as evidence of disease progression unless one of the above-mentioned 
criteria is also fulfilled.   
Patients with symptoms of rapidly progressing disease without radiological (or 
photographical) evidence will not be considered to have progressed for efficacy analyses.  
For patients with bone-only disease, response will be determined based on radiographic 
findings or clinical symptoms (Appendix 7) with the following extension:  the overall 
lesion response at each assessment will be based solely on non-target lesion responses.  
Specifically, in the absence of new lesions, the overall lesion response at each 
assessment will be one of the following:  CR, SD, unknown (i.e., missing data), or 
progressive disease.  All assessments not qualifying for CR, progressive disease, or 
unknown would be classified as SD.  In the presence of any new lesions, the overall 
lesion response will be progressive disease. 
If a patient presents with both irradiated and non-irradiated bone lesions, only the 
non-irradiated lesions should be followed for tumor assessments unless progression is 
documented after radiation. 
In the event that it is not feasible to perform a bone scan, or it is anticipated that it will 
not be feasible to perform bone scans throughout the study, F-18 sodium fluoride 
(18F NaF) PET scans may be substituted.  In this case, an 18F NaF PET scan must be 
performed at screening and, in patients with bone-only disease not visible on the CT or 
MRI scans being performed as part of the tumor assessments, must be repeated at 
every tumor assessment.   
4.5.6 
Endometrial Thickness Assessment 
To assess for any potential effect of study treatment on the uterus, transvaginal 
ultrasound scans will be performed to monitor endometrial thickness at screening, at the 
study drug discontinuation visit, and as clinically indicated.  Transvaginal ultrasounds 
are not required for patients who have had a hysterectomy. 
4.5.7 
Electrocardiograms 
An electrocardiogram (ECG; 12-lead) is required at screening and at the study drug 
discontinuation visit, and may be repeated during the study as clinically indicated. 


 
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All ECG recordings should be performed using a standard high-quality, high-fidelity 
digital electrocardiograph machine equipped with computer-based interval 
measurements.  Lead placement should be as consistent as possible.  ECG recordings 
must be performed after the patient has been resting in a supine position for at least 
10 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.   
If at a particular postdose 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.  An unscheduled PK sample should be obtained, and the Medical 
Monitor should be notified.  Standard-of-care treatment may be instituted per the 
discretion of the investigator.  A decision on study drug discontinuation should be made, 
as described in Section 5.1.5.  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). 
Clinically significant abnormalities observed during screening will be recorded on the 
General Medical History and Baseline Conditions eCRF.  New or worsened clinically 
significant abnormalities and/or QTcF prolongations that meet the criteria described 
above will be recorded on the Adverse Event eCRF. 
4.5.8 
Patient-Reported Outcomes 
With the initiation of protocol amendment version 2, patient-reported outcomes will no 
longer be collected.  
The EORTC QLQ-C30, QLQ-BR23, and a modified version of the TSQM will be 
collected to more fully characterize the clinical profile of GDC-0810 and fulvestrant. 
The EORTC QLQ-C30 (see Appendix 4) and the QLQ-BR23 (see Appendix 5) are 
validated and reliable self-report measures (Aaronson et al. 1993; Sprangers et al. 1996; 
Osoba et al. 1997).  The EORTC QLQ-C30 (version 3) consists of 30 questions that 
assess the following:  global health status/HRQoL, five aspects of patient functioning 
(physical, emotional, role, cognitive, and social); three symptom scales (fatigue, nausea 
and vomiting, and pain); and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties) with a recall period of “the last week.” 
The EORTC QLQ-BR23 breast cancer module also uses a recall period of “the past 


 
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week,” and consists of 23 additional items assessing disease/treatment symptoms 
(systemic therapy side effects, breast symptoms, arm symptoms, and hair loss) and 
aspects of patient functioning (body image, sexual functioning, and future perspective). 
The modified version of the TSQM (see Appendix 6) is a validated instrument consisting 
of 11 questions that measure patients’ satisfaction with medication.  The 11 items 
incorporate 3 domains:  side effects, convenience, and global satisfaction.  The original 
version of the TSQM also contains a three-item subscale of effectiveness of treatment.  
The original TSQM had not previously been used in a cancer population, and during a 
validation study, cancer patients clearly indicated that they were not able to interpret or 
respond to the items on the effectiveness subscale. 
The PRO instruments will be translated as required in the local language and completed 
in their entirety by the patient.  To ensure instrument validity and that data standards 
meet health authority requirements, PRO questionnaires scheduled for administration 
during a clinic visit must be completed by the patient at the investigational site at the 
start of the clinic visit prior to other study assessments and before administration of 
study treatment.  Interviewer assessment is allowed, but can only be conducted by a 
member of the clinic staff, if the patient is unable to complete the measure on their own.  
Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site. 
An electronic PRO (ePRO) data collection modality will be employed.  To capture PRO 
data during study treatment, patients will complete the questionnaires on a validated 
ePRO tablet at the site.  The ePRO device and instructions for completing the PRO 
questionnaires electronically will be provided by the investigator staff.  The data will be 
transmitted via a pre-specified transmission method (e.g., Web or wireless) automatically 
after entry to a centralized database at the ePRO vendor.  The data can be accessed 
securely by appropriate study personnel via the Internet.    
Please see Appendix 1 for the schedule of PRO assessments.  It should take 
approximately 10 minutes to complete the PRO assessments at each timepoint.   
4.5.9 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis (see Appendix 1 and Appendix 2 for the collection schedule): 
• 
Hematology:  red blood cell count, hemoglobin, hematocrit, white blood cell count 
with differential (neutrophils, bands, eosinophils, basophils, lymphocytes, and 
monocytes), and platelet count 
Reporting the differential as absolute counts is preferred, but percent is accepted 
• 
Coagulation:  aPTT and INR 


 
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• 
Serum or plasma chemistry:  glucose, blood urea nitrogen or urea, creatinine, 
sodium, potassium, chloride, magnesium, bicarbonate, calcium, total protein, 
albumin, total bilirubin, ALP, AST, and ALT 
• 
Urinalysis (macro):  specific gravity, pH, glucose, protein, ketones, and blood, with 
reflex microscopic analysis done if macro is abnormal 
 
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor for analysis (see Appendix 1, Appendix 2, and Appendix 3 
for the collection schedule): 
• 
Plasma samples for ctDNA isolation for exploratory research on candidate 
biomarkers, including but not limited to the following:  ESR1 mutations, PIK3CA 
mutations, and AKT1 mutations 
• 
Plasma sample to be banked for potential, future blood-based companion diagnostic 
development 
• 
Plasma samples for PK analysis 
• 
Blood for pharmacogenetic assessment (where approved by local regulatory 
authorities) 
• 
Archival or newly collected (fresh) tumor tissue samples for DNA and/or RNA 
extraction for exploratory NGS or other research on candidate biomarkers, 
including but not limited to the following:  ESR1 mutation status, PIK3CA mutation 
status, ER/PgR and HER2 expression, LumA/B subtype, Ki67 IHC assay, and other 
assessments related to ER and PI3K signaling pathways 
Sites must confirm the availability of a representative FFPE tumor specimen 
before initiating screening procedures. 
In the event that multiple tissue blocks are available for a given patient 
(e.g., primary tumor and metastatic site), the most recently collected tumor 
sample must be submitted; both primary and metastatic tissue should be 
submitted where possible. 
Tumor blocks are preferred, but in the event that local regulations prevent the 
shipment of tumor blocks, 10 unstained, serially cut, 5-μM thick slides are 
requested (15 − 20 slides are preferred).  Minimum tissue requirements are 
further described in the laboratory manual.  Cytological, fine-needle aspiration, 
and bone biopsy samples are not acceptable. 
 
 
 
 
 
 
  


 
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• 
If available, fresh tumor tissue samples collected at the time of disease progression  
Tissue collection at the time of disease progression is not required for study 
participation. The tissue specimen will be requested for those patients who sign 
the Optional Research Informed Consent, and will be used for DNA and/or RNA 
extraction for exploratory research on mechanisms of resistance, including but 
not limited to the following:  ESR1 mutation status, PIK3CA mutation status, and 
other assessments related to ER and PI3K signaling pathways. 
• 
Optional blood sample for whole genome sequencing using an appropriate 
next-generation sequencing (NGS) platform 
 
Laboratory manuals and supply kits will be provided for all central laboratory 
assessments. For detailed sampling procedures, storage conditions, and shipment 
instructions, see the laboratory manual. 
 Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.10 
Assay Methods 
4.5.10.1 
Mutational Analysis for ESR1 
Somatic mutations in the LBD of the ESR1 gene confer ligand independence and are 
found in approximately 40% of metastatic breast cancers but are rare in primary breast 
cancers.  ctDNA obtained from plasma offers a robust mutation detection alternative to 
tissue that can be collected with less inconvenience and risk to patients, particularly 
those with bone metastases that are difficult to biopsy.  Quantitative real-time PCR 
(qRT-PCR) assays or NGS assays designed to interrogate the LBD of ESR1 offer a 
sensitive and quantitative method to detect mutations from ctDNA. DNA will be extracted 
from plasma samples and subjected to NGS and/or qRT-PCR assays that detect the 
wild-type allele, as well as mutations that include, but are not limited to, the following 
amino acid changes:  D538(G), Y537(S, N, C), E380(Q), L536(Q, H, P, R), S463P and 
P535H.  Assays may also be run on metastatic tumor tissue if such tissue is available.  
Assays from all samples will be run in a central laboratory on analytically validated NGS 
and/or qRT-PCR platforms, and mutation calls will be made using appropriate cutoffs 
and automated software.  The information about the spectrum and the prevalence of 
ESR1 mutations may help with the development of a companion diagnostic for 
GDC-0810. 
4.5.10.2 
ER, PgR, and HER2 Analysis 
PgR, ER, and HER2 status will be determined at a central laboratory using standardized 
immunohistochemical and/or FISH procedures, or will be determined using an 
analogous RNA-based method. 


 
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4.5.10.3 
Circulating Tumor DNA Analysis 
ctDNA will be extracted from plasma samples collected from patients and used for the 
detection of oncogenic mutations and DNA methylation using appropriate technologies.  
The prevalence of the mutations measured at baseline and after treatment may provide 
information on response or resistance to therapy. 
4.5.10.4 
Messenger RNA Expression Profiling 
In cases where there is sufficient archival tissue to isolate RNA, gene expression may be 
performed using gene expression assays conducted using appropriate technologies.  
Analysis may include, but is not limited to, a panel of genes that is important for intrinsic 
subtyping, breast cancer biology, and immune-related and ER signaling.  The goal will 
be to generate a database of expression status to examine whether there are gene 
expression patterns associated with clinical response to GDC-0810. 
4.5.10.5 
Tumor Somatic Mutation Analysis 
In cases where there is sufficient material to isolate DNA, NGS may be performed using 
an appropriate NGS platform, such as Illumina or an equivalent. The goal will be to 
determine whether the somatic mutations are associated with clinical response to 
GDC-0810. 
4.5.10.6 
Copy Number Analysis 
The level of copy number alterations in cancer-related genes may be determined using 
DNA-based technologies, either cytogenetically, using chromosomal in situ hybridization 
(ISH), NGS platforms, reverse transcription-PCR−based platforms or by using equivalent 
technologies.  For cytogenetic assays, detection may be either fluorescence-based 
(FISH assay) or chromogenic-based (CISH).  Data on the increased copy number of 
ER- or PI3K pathway−activating genes may provide information on response or 
resistance to therapy. 
4.5.10.7 
Plasma Biomarker Analyses 
Assays that assess the expression of soluble, systemic cytokines, and chemokines from 
the plasma of patients will be completed using appropriate methodologies, such as 
ELISA-based, mass spectrometry-based, or equivalent technologies. 
4.5.10.8 
Plasma Pharmacokinetic Samples 
Plasma concentrations of GDC-0810 will be measured in a designated bioanalytical 
laboratory using a validated liquid chromatography tandem mass spectrometry assay.  
Plasma samples may be used for the exploratory evaluation of safety and/or response 
biomarkers, the identification and profiling of potential GDC-0810-related metabolites, 
ex-vivo protein binding and/or PK or PD assay development purposes.  
4.5.10.9 
Pharmacogenetic Polymorphism Assay 
If approved by the local regulatory authority, pharmacogenetic polymorphisms will be 
assayed using multiplex PCR, allele-specific PCR, direct sequencing, or other 
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measures to better understand the impact of genetic variants on drug metabolism, 
exposure, adverse events, and/or response. 
A blood sample will also be utilized as a source of normal DNA to determine whether 
sequence variants in the ESR1 gene and in other relevant oncogenes in the tumor DNA 
are somatic mutations or SNPs. 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.10.10 
Sample for Whole Genome Sequencing 
A single blood sample will be collected for whole genome sequencing from patients who 
consent to this optional assessment, and may be sent to one or more laboratories for 
analysis using an appropriate NGS platform.  Whole genome sequencing data and 
associated clinical data may be shared with researchers who are not participating in the 
study or submitted to government or other health-research databases for broad sharing 
with other researchers.  Study participants will not be identified by name or any other 
personally identifying information. 
4.5.11 
Timing of Study Assessments 
4.5.11.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  ICFs for patients who are 
not subsequently enrolled will be maintained at the study site. 
Screening and pretreatment tests and evaluations will be performed within 28 days 
preceding Cycle 1, Day 1 (defined as the day of the first dose of study drug), unless 
otherwise specified.  Tests that are performed as standard of care before obtaining 
informed consent may be used for screening and baseline assessments, provided that 
they have been performed within this timeframe.  All screening evaluations must be 
completed and reviewed to confirm that patients meet all eligibility criteria before the first 
administration of study drug.  
4.5.11.2 
Assessments during Treatment 
All assessments will be performed per institutional guidelines or as clinically indicated, 
unless otherwise noted.  On treatment days, assessments should be performed before 
study drug administration unless otherwise noted.  When laboratory assessments are 
performed, results of local laboratory assessments must be reviewed, and the review 
documented, before study drug administration. 
If a visit is scheduled on a holiday that precludes a protocol-specified procedure, the 
procedure should be performed on the nearest following date.  Subsequent 
protocol-specified procedures should remain synchronized with Day 1 of the most recent 
cycle, unless otherwise noted.  


 
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Refer to the Study Flowchart provided in Appendix 1 and Appendix 2 for the schedule of 
treatment period assessments. 
4.5.11.3 
Study Drug Discontinuation Visit 
All patients who are discontinued from study drug will return for a study drug 
discontinuation visit within 30 days after the last dose of study treatment.  The treatment 
completion visit procedures and assessments should be performed after permanent 
discontinuation of study drug.  The visit at which disease progression is recorded may 
serve as the study drug discontinuation visit, provided that all tests required at the study 
drug discontinuation visit are performed.  Assessment of disease progression based on 
clinical examination must be confirmed by radiographic assessment prior to or at the 
study drug discontinuation visit and before initiating new anti-cancer therapy. 
Refer to the Study Flowchart in Appendix 1 and Appendix 2 for the schedule of 
assessments to be performed at the study drug discontinuation visit. 
4.5.11.4 
Follow-Up Assessments 
All patients will be followed for safety for at least 28 days after the last administration of 
study therapy.  Ongoing adverse events related to study treatment will be followed until 
the event has resolved to baseline (pretreatment) grade, the event is assessed by the 
investigator as stable, new anti-tumor treatment is initiated, the patient is lost to follow-up, 
the patient withdraws consent, or it has been determined that the study treatment or 
participation is not the cause of the adverse event.  
The schedule of follow-up visits and assessments is provided in Appendix 1 and 
Appendix 2. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
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 withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance, defined as failure to comply with the protocol requirements 
for assessments of safety and efficacy of the study medications, as well as failure to 
comply with study drug administration 
 


 
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Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Drug Discontinuation 
Patients must discontinue study drug if they experience any of the following: 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if the patient continues to receive study drug 
• 
Pregnancy 
• 
Documented disease progression or relapse 
• 
Unacceptable toxicity 
• 
Use of another anti-cancer therapy 
• 
Patient or investigator decision 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.  
4.6.3 
Study and Site 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.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice (GCP) 
• 
No study activity (i.e., all patients have completed and all obligations have been 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The GDC-0810 entire safety profile is not known at this time.  Human experience is 
currently limited, and the identified and potential risks of GDC-0810 described below are 
based on nonclinical data (in vitro and in vivo), clinical data from the first 41 patients 
enrolled on Study GO29642 Phase Ia (single-agent, dose-escalation study), and 
published data on similar molecules.  The safety of participating patients will be 
addressed through appropriate choice of inclusion/exclusion criteria, the implementation 
of appropriate dose-modification and treatment guidelines, and real-time safety 
monitoring and assessments on individual adverse-event reports. 
Prior to halt of enrolment, an IMC monitored the safety of the two study arms.  Safety 
profiles observed from the treated patients were consistent with the known safety 
profiles of GDC-0810 and fulvestrant, and no new safety findings had been identified. 
No further patients will be enrolled in this study and the remaining patients on study 
will be re-consented.  Following unblinding of the study team, halt of enrollment, given 
the IMC concluded that the safety profiles were consistent with the known profiles of 
the two drugs, and no further increase in the sample size, the IMC will no longer 
monitor individual patient safety; instead, the Sponsor will continue to monitor clinical 
safety data in real time. 
5.1.1 
Safety Monitoring 
Safety will be evaluated through the monitoring of all serious and non-serious adverse 
events defined and graded according to NCI CTCAE, v4.0, as well as laboratory test 
findings.  General safety assessments will include serial interval histories, physical 
examinations, and specific laboratory studies, including serum chemistry and blood 
counts (see Appendix 1 for the schedule of study assessments).  All serious adverse 
events and protocol-defined adverse events of special interest will be reported to the 
Sponsor in an expedited fashion (see Section 5.2).  
The potential safety issues anticipated in this trial, as well as measures intended to avoid 
or minimize such toxicities, are outlined in the following sections. 
5.1.2 
Internal Monitoring Committee 
As of protocol version 2 and unblinding of the study team, the IMC will no longer be 
required to monitor the ongoing safety of the study; however, the study team will 
continue to monitor clinical safety data in real time (see Section 5.1).  


 
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5.1.3 
Identified Safety Risks Associated With GDC-0810 
5.1.3.1 
Gastrointestinal Toxicities (Diarrhea, Nausea and Vomiting) 
GI toxicities such as diarrhea, nausea and vomiting have been commonly observed in 
patients receiving single-agent GDC-0810.  As of a data cutoff of 9 September 2016, 
safety data was available from 107 patients treated with GDC-0810 600 mg in the 
Phase IIa and non-palbociclib containing Phase 1b components of Study GO29642.  
Treatment-related diarrhea, nausea, and vomiting were observed in 44%, 38%, and 
13% of the 107 patients, respectively.  Most of these GI events were Grade 1 or 2 in 
severity and occurred as early as in the first cycle of treatment.  These GI events were 
typically manageable with dietary modifications (e.g., taking GDC-0810 with food), and 
supportive care as needed (e.g., loperamide for diarrhea).  Dose interruption was 
required in 11 of the 60 patients who experienced diarrhea, among the 107 patients. 
Patients with active inflammatory bowel disease, short bowel syndrome, or gastric 
resection are excluded from this study.  Patients should be closely monitored for signs 
and symptoms related to GI effects.  Patients experiencing nausea, vomiting, and 
diarrhea should be treated as per Table 1.  
Any cases of Grade  ≥ 2 diarrhea/vomiting or Grade  ≥ 3 nausea, regardless of 
seriousness or causality, should be reported immediately to the Sponsor (see 
Section 5.2.3). 
5.1.4 
Potential Safety Risks Associated with GDC-0810 
5.1.4.1 
Changes in the Female Reproductive Organs and 
Uterotrophic Effects 
GDC-0810 exhibited mixed antagonist/agonist activity in the rat uterus that was 
intermediate between tamoxifen and raloxifene.  In adult ovariectomized rats, an 
increase in uterine weight and endometrial cell height was observed following treatment 
with GDC-0810 (refer to the GDC-0810 Investigator's Brochure, Version 4 for further 
details). 
As of the data cutoff of 9 September 2016, safety data from 148 patients treated with 
GDC-0810 in the Phase Ia, IIa, and non-palbociclib containing Ib components of 
Study GO29642 were reviewed.  Among 36 patients with a baseline transvaginal 
ultrasound scan of the uterus and at least one follow up scan, 29 (81%) patients showed 
an increase in the thickness of endometrium in their most recent postbaseline scan 
compared with their baseline thickness.  The median change in thickness from screening 
to most recent measurement was 3 mm (range −1.7 to 44 mm), and the mean was 5 mm.  
Two of the 148 patients experienced Grade 1 adverse events of vaginal hemorrhage.  
One event followed an endometrial biopsy and was considered unrelated to GDC-0810.  
The second event was considered related to GDC-0810 and a cyst was noted on 
ultrasound, which may have been the cause of bleeding.  Endometrial polyps were 
reported as adverse events in 3 patients. 


 
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Among the 148 patients, reproductive organ adverse events (occurring under the 
MedDRA SOC reproductive system and breast disorders), regardless of relatedness 
included vaginal discharge that was reported in 27 (18%) patients, ranging from 
Grade 1 to 2 in severity and was of Grade 1 severity in 25 of 27 patients.  
Every precaution should be taken to ensure that no pregnant woman receives 
GDC-0810. 
Given the potential effect of GDC-0810 on the uterus, patients with a history of 
endometrial cancer or atypical endometrial hyperplasia are excluded from participating in 
this study.  Transvaginal ultrasound scans will be performed in patients to monitor 
endometrial thickness (at baseline, at the study drug discontinuation visit, and as 
clinically indicated). No action is required for asymptomatic endometrial thickening.  
Patients experiencing any abnormal vaginal bleeding post-study treatment are advised 
to seek consultation with their gynecologist for complete gynecological workup.  Any 
cases of treatment-emergent Grade  ≥ 2 vaginal or uterine hemorrhage regardless of 
seriousness or causality should be reported immediately to the Sponsor (see 
Section 5.2.3). 
All patients will be made aware of the potential risk to their reproductive tract at the time 
of consent.  See Table 1 for management of vaginal or uterine hemorrhage. 
5.1.4.2 
Venous Thromboembolic Events 
An increased risk of VTE is known to be associated with some endocrine therapies such 
as tamoxifen. 
As of a data cutoff of 9 September 2016, safety data from 148 patients treated with 
GDC-0810 in the Phase Ia, IIa, and non-palbociclib containing Ib components of 
Study GO29642 were reviewed.  Among the 148 patients, 9 experienced at least one 
adverse event of thromboembolism (defined by MedDRA SMQ narrow of embolic and 
thrombotic events, venous).  Preferred terms were deep vein thrombosis, pulmonary 
embolism and venous thrombosis.  Events ranged from Grade 2 to 4 in severity, and all 
were treated with anticoagulation. 
Patients should be advised to seek immediate medical attention if they become aware of 
any symptoms of pulmonary embolism or deep vein thrombosis, such as acute onset of 
chest pain, shortness of breath, or swelling in extremities.  Investigators should manage 
and treat patients suspected to have a VTE according to Table 1. 
Thromboembolic events (e.g., pulmonary embolism, deep vein thrombosis) of Grade ≥ 2, 
regardless of seriousness or causality, should be reported immediately to the Sponsor 
(see Section 5.2). 
See Table 1 for guidelines on the management of VTEs. 


 
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5.1.4.3 
Renal Dysfunction 
Nonclinical toxicity studies have demonstrated minimal-to-mild microscopic findings in 
animal kidneys (kidney tubular degeneration, dilation, mineralization), which were 
completely reversible upon cessation of study drug.  As of 9 September 2016, the 
adverse event term of acute kidney injury was reported in 2 (1.3%) patients across all 
phases of Study GO29642 (combined n=148), neither case was considered related to 
GDC-0810.  
Renal function tests will be closely monitored, and GDC-0810 treatment should be held 
for Grade  ≥ 2 creatinine elevation.  GDC-0810 may be resumed if creatinine improves to 
normal or baseline value, whichever is higher. 
5.1.4.4 
Phototoxicity 
An in vitro study demonstrated the potential of GDC-0810 for phototoxicity.  As of 
9 September 2016, no adverse events of photosensitivity reactions have been reported in 
the Phase Ia/IIa of Study GO29642. 
Patients should be advised to take precautionary measures regarding sun exposure, 
with daily sunscreen use and wearing of protective clothing (i.e., sunglasses, hat, and 
long sleeves) when outdoors. 
5.1.4.5 
Elevation of Hepatic Transaminases 
Endocrine therapy of metastatic breast cancer has been associated with changes in 
hepatic enzyme levels and rare instances of severe events including hepatic necrosis 
(fulvestrant [Faslodex®] Package Insert; tamoxifen [Nolvadex®] Package Insert).  
In cynomolgus monkeys, increased liver weight and hepatocyte hypertrophy have been 
observed after administration of GDC-0810.   
Hepatic transaminase elevation has been observed in patients receiving GDC-0810.  
As of the data cutoff of 9 September 2016, safety data from 148 patients treated with 
GDC-0810 in the Phase Ia, IIa, and non-palbociclib containing Ib components of 
Study GO29642 were reviewed.  Among the 148 patients, 7 patients experienced at 
least 1 Grade ≥ 3 adverse event under the higher level MedDRA term of liver function 
analyses.  Among these 7 patients, 5 had evidence of metastases in their liver.  Of the 
remaining 2, 1 patient who was enrolled in the Phase IIa (600 mg QD, with food) 
experienced a maximum Grade 3 transaminase elevation (both ALT and AST).  ALP 
and bilirubin were not elevated above the normal range.  The patient experienced three 
episodes of transaminase elevation.  Each resolved after treatment interruption of 
GDC-0810.  The third elevation occurred at the reduced dose of 400 mg OD of 
GDC-0810, leading to the withdrawal of treatment.  The second patient experienced 
Grade 3 liver enzyme elevation during a respiratory tract infection on concomitant 
antibiotics. 


 
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Patients presenting with jaundice, coagulopathy, abdominal pain, or other symptoms 
suggestive of hepatic pathology should have their liver function tests checked and 
imaging of the liver performed.  If liver enzymes are elevated with no obvious 
malignant cause found, a hepatologist specialist should be consulted. 
Patients experiencing hepatic transaminase elevation of Grade ≥ 3, regardless of 
seriousness or causality, should be reported immediately to the Sponsor (see 
Section 5.2). 
Patients experiencing hepatic enzyme elevation should be treated and managed per 
standard of care and Table 1. 
5.1.4.6 
General Guidance for GDC-0810 Dose Modifications  
The GDC-0810 dose-reduction instructions provided here are intended to serve as 
recommended guidelines to allow ongoing treatment for patients experiencing clinical 
benefit without signs or symptoms of progression, while monitoring patient safety.  In 
addition to these guidelines, more conservative drug interruptions or dose reductions for 
the management of adverse events are permitted at the discretion of the investigator 
when deemed to be in the best interest of the patient. 
GDC-0810 should be held in the presence of Grade  ≥ 2 creatinine elevation 
Any Grade  ≥ 3 adverse events potentially attributed to the study drug.  Further detailed 
guidelines are provided in Section 5.1.3, 5.1.4.1−5.1.4.5, and Table 1. 
 
Patients who have had treatment interruptions due to adverse events may restart daily 
dosing as per the investigator’s discretion when toxicity has resolved to Grade ≤ 1 or 
baseline.  However, any patient whose treatment is interrupted for an adverse event that 
is related to study drug and who does not restart treatment within 28 days will be 
withdrawn from study treatment.   
Dose reductions for toxicity will be allowed at the investigator’s discretion, and in 
consultation with the Sponsor Medical Monitor.  No more than two dose reductions will 
be allowed.  Doses reduced for drug-related toxicity should generally not be re-escalated.  
However, intrapatient re-escalation back to the previous dose level may be permitted at 
the discretion of the investigator and in consultation with the Sponsor Medical Monitor.  
GDC-0810 dose reductions may occur in increments of 200 mg.  Therefore, the possible 
GDC-0810 doses permitted are 600 mg, 400 mg, and 200 mg. 


 
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Table 1 
Dose Management Guidelines for GDC-0810 
Toxicity 
Dose Modification and Management Guidelines 
Gastrointestinal Toxicities 
General 
• Patients should be closely monitored for GI symptoms and their effects on 
their wellbeing.  Patients experiencing nausea, vomiting, and diarrhea 
should be treated and managed per standard of care and per protocol 
guidelines, including use of anti-diarrheal agents and appropriate 
supportive care including hydration and dietary modification if clinically 
indicated.  
• Remind patients to take GDC-0810 30 minutes after the largest meal of the 
day (preferably the evening).  
Diarrhea 
General 
At first report of any grade diarrhea: 
• Initiate loperamide 4 mg, followed by 2 mg after each unformed stool.  
Daily dose should not exceed local recommendations in any 24-hour period. 
 
• Infectious or alternate etiology should be excluded.  
• Grade ≥ 2 diarrhea is identified as an AESI requiring expedited reporting 
from study sites regardless of seriousness.  
Grade 1 
• Manage with adequate anti-diarrheal agents (e.g., loperamide) and 
maximum supportive care according to local standards and practices.  
• Closely monitor for resolution.  
• If diarrhea does not resolve after 14 consecutive days, hold GDC-0810 until 
complete resolution of diarrhea.  
• Upon resolution, if Grade 1 diarrhea had persisted for > 1 week with no 
alternate etiology, consider starting loperamide 2 mg 1−2 times daily as 
secondary prophylaxis (i.e., use of loperamide to prevent further diarrhea).  
Grade 2 
• Manage with adequate anti-diarrheal agents (e.g., loperamide) and 
maximum supportive care according to local standards and practices.  
• Closely monitor for resolution.  
• Hold treatment with GDC-0810 until resolution to Grade ≤ 1.  
• If Grade 2 diarrhea is recurrent after improvement to Grade 1, despite 
maximum medical management, reduce GDC-0810 by one dose level.  
• Upon resolution, if Grade 2 diarrhea is recurrent with no alternate etiology, 
consider starting loperamide 2 mg 1−2 times daily as secondary prophylaxis 
(i.e., use of loperamide to prevent further diarrhea).  


 
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Toxicity 
Dose Modification and Management Guidelines 
Grade ≥ 3 
• Manage with adequate anti-diarrheal agents (e.g., loperamide) and 
maximum supportive care according to local standards and practices.  
• Closely monitor for resolution.  
• Hold treatment with GDC-0810 until resolution to Grade ≤ 1.  
• At resolution of first occurrence, reduce the dose of GDC-0810 by one dose 
level on improvement to Grade ≤ 1.  
• At resolution of second occurrence, reduce dose of GDC-0810 by one dose 
level on improvement to Grade ≤ 1.  
• On third occurrence discontinue GDC-0810. 
• At any occurrence of Grade 4 diarrhea, consider discontinuation.  
• Upon resolution, consider starting loperamide 2 mg 1−2 times daily as 
secondary prophylaxis (i.e., use of loperamide to prevent further diarrhea).  
Nausea and/or Vomiting 
General 
• Grade ≥ 2 vomiting and Grade ≥ 3 nausea are identified as AESIs requiring 
expedited reporting from study sites regardless of seriousness.  
Grade 1 − 2 
• Manage with anti-emetics and supportive care according to local standards 
and practices.  
• If persistent despite maximal medical therapy, hold treatment with 
GDC-0810 until resolution to Grade ≤ 1.  
Grade ≥ 3 
• Manage with anti-emetics and supportive care.  
• Hold treatment with GDC-0810 until resolution to Grade ≤ 1.  
• Reduce GDC-0810 dose by one dose level when treatment resumes.  
Vaginal or Uterine Hemorrhage 
General 
• Grade ≥ 2 vaginal or uterine hemorrhage is identified as an AESI requiring 
expedited reporting from study sites regardless of seriousness.  
• Prior to enrollment, screening scan of the uterus with transvaginal 
ultrasound must be performed.  Due to the potential risks of changes in the 
female reproductive tract and uterotrophic effects, patients with a history of 
endometrial polyps, endometrial cancer, atypical endometrial hyperplasia, 
or other significant endometrial disorders should be excluded unless they 
have undergone total hysterectomy, and there is no evidence of active 
disease.  


 
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Toxicity 
Dose Modification and Management Guidelines 
Grade 1 
• Seek consultation with gynecologist or other specialist for differential 
diagnosis and appropriate management.  
• Transvaginal ultrasound should be considered.  
Grade ≥ 2 
• As Grade 1.  
• Hold dosing with GDC-0810 until resolution to Grade ≤ 1.  
• Discuss with study Medical Monitor for appropriate dose modification and 
management.  
Venous Thromboembolic Events (including Pulmonary Embolism): 
General 
• Patients should be advised 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 VTEs are identified as AESIs requiring expedited reporting from 
study sites regardless of seriousness.  
Grade 1 − 2 
• Manage and treat patients according to institutional guidelines and local 
standards of care.  
• May consider anti-coagulation and/or IVC filter based upon local best 
standards and practices after an individual assessment of risk benefit for 
each patient.  
Grade ≥ 3 
• As Grade 1−2.  
• Hold dosing with GDC-0810 until the patient is stable.  
• Discuss with study Medical Monitor for appropriate dose modification and 
management.  
Elevation of Hepatic Transaminases: 
General 
• Patients presenting with jaundice, coagulopathy, abdominal pain, or other 
symptoms suggestive of hepatic pathology should have their liver function 
tests checked and imaging of the liver performed.  If the liver enzymes are 
elevated with no obvious malignant cause found, a hepatologist specialist 
should be consulted.  
• Patients experiencing hepatic enzyme elevation should be treated and 
managed per standard of care.  
Per Section 5.3.5.6, investigators must report the occurrence of abnormal 
liver function tests meeting Hy’s law criteria as an adverse event. 
Grade ≥ 3  
• Hold study drug until resolution to baseline or below ULN.  
AESI = adverse event of special interest (see Section 5.2.3); DVT = deep vein thrombosis; 
GI = gastrointestinal; IVC = inferior vena cava; PE = pulmonary embolism; VTE = venous 
thromboembolic event; ULN = upper limit of normal. 
 
5.1.5 
Safety Risks Associated with Fulvestrant 
In a Phase III randomized, double-blind, clinical trial that compared a 500-mg dose of 
fulvestrant with a 250-mg dose in 736 postmenopausal women with advanced breast 
cancer who had disease recurrence on or after adjuvant endocrine therapy or 
progression following endocrine therapy for advanced disease, the most frequently 
reported adverse events in the 500-mg group were injection-site pain (11.6% of patients), 


 
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nausea (9.7%), and bone pain (9.4%); in the 250-mg group, they were nausea (13.6%), 
back pain (10.7%), and injection-site pain (9.1%).  In the pooled safety population from 
clinical trials comparing fulvestrant 500 mg to 250 mg, postbaseline increase of 
Grade ≥ 1 AST, ALT, or ALP were observed in > 15% of patients, with Grade 3 − 4 
increases in 1% − 2% of patients.  Because fulvestrant is administered intramuscularly, it 
should be used with caution in patients with bleeding diatheses, thrombocytopenia, or 
anticoagulant use. 
For more details regarding the safety profile of fulvestrant, please refer to the fulvestrant 
(e.g., FASLODEX®) Package Insert or SmPC. 
5.1.5.1 
General Guidance for Fulvestrant Dose Modifications 
The fulvestrant dose level cannot be modified.  In general, the investigator may consider 
continuing fulvestrant if the observed adverse event is not thought to be fulvestrant 
related.  
If a scheduled dose coincides with a holiday or inclement weather or other conditions 
that preclude dosing, dosing should commence on the nearest following date.  
Subsequent dosing should continue on the original 28-day schedule. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious 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 guidelines for GCP, 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), except as described in 
Section 5.3.5.9  
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
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• 
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 
criteria; 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 
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5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious 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 include the following: 
• 
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 ≥ 2 diarrhea or vomiting 
• 
Grade ≥ 3 nausea 
• 
Grade ≥ 2 vaginal or uterine hemorrhage (Grade 2 is defined as moderate bleeding; 
medical intervention indicated) 
• 
Grade ≥ 2 thromboembolic event (including pulmonary embolism) 
• 
Grade ≥3 elevation of ALT or AST 
 
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 Section 5.4 to Section 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 the 
last dose of study drug.  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment 
(see 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 (v4.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 2 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), 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 or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 3): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 3 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
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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 or decreases in severity will be captured on the 
Adverse Event 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 if 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 5.3.5.4 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 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious 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 malignant 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 


 
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reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").  
If the death is attributed to progression of malignant breast cancer, "malignant disease 
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 modified RECIST v1.1.  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., in-patient 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 
• 
Hospitalization for outpatient care outside of normal clinical operating hours that is 
required per protocol or per local standard of care 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available 
 
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 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded 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). 
No safety data related to overdosing of GDC-0810 are available. 
5.3.5.12 
Adverse Events that Change Grade over Time 
When a patient experiences an adverse event that later increases in grade, the 
increased grade should be recorded on the Adverse Event eCRF.  In general, 
subsequent adverse-event grade decreases (with the exception of resolution) should not 
be recorded on the Adverse Event eCRF, as maximum grade is of primary interest for 
safety reporting. However, any additional upgrades and downgrades of diarrhea outside 
of the initial and maximum grade should be recorded on the Adverse Event Grade 
Changes eCRF to more fully assess the impact of time and/or supportive care on 
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5.3.5.13 
Patient-Reported Outcome Data  
Adverse-event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  The methods for collecting and 
analyzing PRO data are different from those for the ascertainment of observed or 
volunteered adverse events.  Because of these differences, PRO data will not be 
reported as adverse events, and no attempt will be made to resolve any noticeable 
discrepancies between PRO data and observed or volunteered adverse events.  
The PRO data will be presented in separate tables, figures, and data listings from the 
adverse-event data, and will be included in the appropriate section of the final study 
report. 
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 (see Section 5.4.2 for further details) 
• 
Non-serious adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC). 


 
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5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
Primary (PPD) Medical Monitor contact information: 
Medical Monitors: 
, M.D. (primary) 
 
, M.D. (secondary, Europe) 
 
, M.D. (secondary, Asia/Pacific) 
Telephone Nos.: 
 (North America) 
 
 (Europe and Asia/Pacific) 
Facsimile Nos.: 
 (North America) 
 
 (Europe and Asia/Pacific) 
 
Alternate (Genentech) Medical Monitor contact information for all sites: 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No.: 
 (
, USA) 
Alternate Telephone No.: 
 (
, USA) 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious 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 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 to Genentech via PPD at the following contact 
information: 
Email: 
rtpsafety@ppdi.com 
Telephone Nos.: 
800.201.8725 (North America) 
 
44.1223.374.240 (Europe and Asia/Pacific) 
Facsimile Nos.: 
888.488.9697 (North America) 
 
44.1223.374.102 (Europe and Asia/Pacific) 
 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 28 days after the last dose of study drug.  
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 
Safety Risk Management by the EDC system. 


 
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In the event that the EDC system is unavailable, the 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), by faxing the form using the fax number or email address 
provided above in Section 5.4.2.1.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Patients will be instructed to immediately inform the investigator if they become pregnant 
during the study or within 28 days after the last dose of study drug or 1 year after the 
last dose of fulvestrant.  A Pregnancy Report eCRF should be completed by the 
investigator immediately (i.e., no more than 24 hours after learning of the pregnancy) 
and submitted via the EDC system.  A pregnancy report will automatically be generated 
and sent to Safety Risk Management.  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 the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), by 
faxing 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. 
5.4.3.2 
Congenital Anomalies/Birth Defects and Abortions 
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).  Any abortion should be reported in the same 
fashion (as the Sponsor considers abortions to be medically significant). 
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 


 
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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.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
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 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.   
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the 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 non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
GDC-0810 Investigator's Brochure 
• 
SmPC for fulvestrant 
 


 
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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 
Primary and secondary efficacy analyses will include all randomized patients, with 
patients allocated to the randomized treatment arm.  In addition to the all-randomized 
patient population (the ITT population), analysis of PFS, ORR, and CBR will be repeated 
in the patient subsets defined by their ESR1 mutation status. 
Safety analyses will include all patients who received at least one dose of the study 
treatment, with patients allocated to the treatment arm associated with the regimen 
actually received. 
There will be no adjustments made for multiple comparisons when analyzing the primary 
and secondary endpoints. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The trial is designed to evaluate the clinical activity and safety of GDC-0810 compared 
with fulvestrant in patients with ER-positive locally advanced or MBC.  It is for hypothesis 
generation, and is not powered to detect minimum clinically meaningful difference 
between treatment arms.  
A total of approximately 152 patients will be enrolled in this study.  It is assumed that the 
median duration of PFS in the fulvestrant control arm is 5.5 months and 8.5 months in 
the GDC-0810 arm.  The final analysis of all randomized patients will be triggered by the 
occurrence of approximately 95 PFS events, which is expected to occur 26 months after 
the first patient is randomized. Table 4 shows expected probabilities of observing a 
hazard ratio of less than 0.5, 0.6 and 0.7 in the final analysis in all randomized patients 
under varying assumptions for the true underlying hazard ratio.  Note that formal 
hypothesis testing is limited.  Rather than testing treatment differences at a statistically 
significant type I error level of 5%, 90% confidence intervals (CI) for the hazard ratio will 
be calculated. 
At a target hazard ratio of 0.6, the corresponding 90% CI based on 95 PFS events is 
(0.43, 0.84) which is considered to provide meaningful precision.  


 
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Table 4 
Expected Probability of Observing a Hazard Ratio of < 0.5, < 0.6, 
or  < 0.7 in the Final Analysis (All Patients) 
 
95 PFS Events in ITT Population 
True HR 
Observed HR <  0.50 
Observed HR <  0.60 
Observed HR <  0.70 
0.4 
0.86 
0.98 
0.99 
0.5 
0.50 
0.81 
0.95 
0.6 
0.19 
0.50 
0.77 
0.7 
0.05 
0.23 
0.50 
0.8 
0.01 
0.08 
0.26 
HR = hazard ratio; ITT = intent to treat; PFS = progression-free survival. 
  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study treatment administration and discontinuation from the study will be 
summarized by treatment arm.  The incidence of study treatment discontinuation for 
reasons other than disease progression will be assessed. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables, stratification factors, and other baseline characteristics will be 
summarized by treatment groups. 
Descriptive summaries of continuous data will present the group mean, standard 
deviation, median, minimum and maximum.  Descriptive summaries of discrete data will 
present the category counts as frequencies and percentages. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include all randomized patients, with 
patients grouped according to the treatment assigned at randomization. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS, defined as the time from randomization to the first 
occurrence of disease progression, as determined by investigator review of tumor 
assessments using RECIST v1.1 or death on study from any cause.  The primary 
efficacy analyses will be performed on all randomized patients as well as on patients 
with ESR1 LBD mutations detected in circulating cell-free DNA, with patients allocated to 
the treatment arm assigned at randomization.  
For patients without disease progression or death as of the clinical data cutoff date, their 
PFS will be censored at the time of last tumor assessment (or censored at the date of 
randomization, if no tumor assessment was performed after the baseline visit).  For 
patients who start other anti-cancer treatment prior to the documented PFS event, the 
primary PFS analysis will include PFS events after other anti-cancer treatment.  PFS 


 
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sensitivity analysis will be performed, censoring PFS on the last tumor assessment prior 
to starting other anti-cancer therapy. 
The two-sided log-rank test stratified by the stratification factors will be used as the 
primary analysis.  The Kaplan-Meier approach will be used to estimate median PFS for 
each treatment arm.  Cox proportional hazards models stratified by the stratification 
factors will be used to estimate a hazard ratio and its 90% CI.  The results from the 
unstratified analysis will also be provided. 
Exploratory analysis for PFS may be performed on patient subgroups by demographic 
disease characteristics. 
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1 
Objective Response Rate 
The analysis of ORR will only include patients who have measurable disease at baseline 
(and will thus exclude patients with bone-only disease).  An estimate of the response 
rate and its 90% CI will be calculated using the Blyth-Still-Casella method for each 
treatment arm.  Response rate in the treatment arms will be compared using the 
stratified Mantel-Haenszel test. CIs for the difference in ORRs between the two arms will 
be determined using the normal approximation to the binomial distribution. 
6.4.2.2 
Duration of Objective Response 
DOR is defined as the time from first observation of an objective response until first 
observation of disease progression as assessed by the investigator according to 
RECIST v1.1 or death from any cause.  The analysis of DOR will include only patients 
who achieved an objective response.  
DOR will be estimated using the Kaplan-Meier methodology, with patients grouped 
according to the treatment arm assigned at randomization.  Comparisons between 
treatment arms using stratified and unstratified log rank test will be made for descriptive 
purposes.  Because the determination of DOR is based on a nonrandomized subset of 
all patients, formal hypothesis testing will not be performed. 
6.4.2.3 
Clinical Benefit Rate 
CBR is defined as the percentage of patients who experience a CR, PR, or SD lasting 
for at least 24 weeks since randomization.  An estimate of CBR and its 90% CI will be 
calculated using the Blyth-Still-Casella method for each treatment arm.  The CBRs in the 
treatment groups will be compared using the stratified Mantel-Haenszel test.  CIs for the 
difference in CBR between the two arms will be determined using the normal 
approximation to the binomial distribution. 


 
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6.5 
SAFETY ANALYSES 
The safety analyses will include all randomized patients who received at least one dose 
of study drug, with patients grouped according to the treatment actually received.  Safety 
will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in vital signs, and GDC-0810 exposure. 
Drug exposure will be summarized, which includes duration of treatment, number and 
intensity of dose.  
Verbatim descriptions of adverse events will be mapped to thesaurus terms.  
Adverse-event data will be listed by study site, treatment arm, patient number, and study 
day.  All adverse events occurring during or after the first dose of study treatment will be 
summarized by thesaurus term, appropriate thesaurus levels, treatment arm, and 
NCI CTCAE v4.0 grade.  In addition, serious adverse events, severe adverse events 
(Grade ≥ 3), adverse events of special interest, and adverse events leading to study drug 
discontinuation or interruption will be listed separately and summarized accordingly.  
Multiple occurrences of the same event will be counted once at the maximum severity.   
Deaths reported during the study will be summarized by treatment arm, including 
reasons leading to death.  
Relevant laboratory and vital sign (heart rate, blood pressure, and temperature) data will 
be displayed by time, with NCI CTCAE Grades 3 and 4 values identified, where 
appropriate.  Additionally, all laboratory data will be summarized by NCI CTCAE v4.0 
grade. 
6.6 
PHARMACOKINETIC ANALYSES  
As outlined in Appendix 3, plasma PK samples will be obtained for GDC-0810 and 
plasma concentrations will be summarized by visit.  Population PK analysis may be 
performed to characterize the PK in this study.  Additionally, population PK/PD analysis 
may be performed to assess potential correlations of exposure with dose, demographics, 
PD, safety, and efficacy outcomes.  The results of these population analyses may be 
reported separately from the clinical study report. 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES  
The percentage of participants randomized to each treatment group who complete each 
measure at baseline and each subsequent assessment point (i.e., PRO completion rates) 
will be calculated and compared.  Summary statistics (mean, standard deviation, median, 
and range) of absolute scores and the change from baseline will be reported for all items 
and subscales of the EORTC QLQ-C30 and QLQ-BR23 according to the EORTC 
scoring manual (Fayers et al. 2001).  Descriptive statistics (means) will be used to 
display the results of the modified version of the TSQM subscales (side effects, 
convenience, and global satisfaction), and responses obtained while receiving 


 
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GDC-0810 treatment will be compared to responses obtained to patients receiving 
fulvestrant (Atkinson et al. 2004). 
In the event of incomplete data, if the scale has more than 50% of the constituent items 
completed, a pro-rated score will be computed consistent with the scoring manuals and 
validation papers of the measure.  For subscales with less than 50% of the items 
completed, the subscale will be considered missing.  
6.8 
ADDITIONAL EXPLORATORY ANALYSES  
The analysis of OS will be conducted in all randomized patients.  Data for patients who 
are alive at the time of analysis data cutoff will be censored at the last date they were 
known to be alive.  Data from patients without postbaseline information will be censored 
at the date of randomization plus 1 day.  The OS curve for each treatment arm will be 
estimated by the Kaplan-Meier methodology, and the hazard ratio and its 90% CI will be 
estimated by the Cox proportional-hazards model. 
Exploratory biomarker analyses may be performed in an effort to understand the 
association of these markers with study-treatment response.  
Whole genome sequencing data will be analyzed in the context of this study and 
explored in aggregate with other studies to better understand disease pathobiology and 
guide the development of new therapeutic approaches. 
Blood samples may be used for the evaluation of genetic polymorphisms of drug 
metabolic enzymes, such as CYP3A4/5 and UGT1A1; transporters, such as OATP1B1 
and BCRP; and genetic variants, which could contribute to potential drug-safety 
assessments. 
6.9 
INTERIM ANALYSIS 
The IMC will convene for an interim safety analysis to review unblended summaries of 
the safety and PK data after the first 20 patients are randomized and have completed 
two 28-day cycles of therapy. 
In addition, after occurrence of approximately 62 PFS events in all patients, the IMC may 
convene to perform an interim analysis for safety and efficacy.  This interim efficacy 
analysis likely will not be informative for the ESR1 mutant subset because of the 
insufficient number of patients with ESR1 mutant tumors who are projected to have 
experienced disease progression by that time.  The activity of GDC-0810 versus 
fulvestrant in the ESR1 mutant subset will be assessed at interim only if a reasonable 
number of PFS events is available in the subset (for example, 30 PFS events).  
Table 5 shows the probability of observing a hazard ratio of less than 0.5, less than 0.6, 
or 0.7 at interim analysis under varying assumptions of the true underlying hazard ratio 
for all patients.  


 
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Table 5 
Interim Analysis (All Patients) 
 
62 PFS Events in ITT 
True HR 
Observed HR < 0.50 
Observed HR < 0.60 
Observed HR < 0.70 
0.4 
0.81 
0.94 
0.99 
0.5 
0.50 
0.76 
0.91 
0.6 
0.24 
0.5 
0.73 
0.7 
0.09 
0.27 
0.50 
0.8 
0.03 
0.13 
0.30 
HR = hazard ratio; ITT = intent to treat; PFS = progression-free survival. 
  
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor and a CRO will share responsibility for the 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 CRO will request data clarification from the sites, 
which the sites will resolve electronically in the EDC system.   
The Sponsor will perform oversight of the data management of this study.  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 on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 


 
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7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA  
Patients will use an ePRO device to capture PRO data.  The data will be transmitted 
electronically to a centralized database at the ePRO vendor.  This electronic device is 
designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with FDA regulations for electronic records (21 Code of Federal Regulations, 
Part 11).  The data can be reviewed by site staff via secure access to a web portal.  Only 
identified and trained users may view the data, and their actions become part of the 
audit trail.  The Sponsor will have view access only.  Regular data transfers will occur 
from the centralized database at the vendor to the database at the Sponsor. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, 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 7.6. 
To facilitate source data verification, 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. 


 
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7.5 
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. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), ICFs, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at least 
15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the 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). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample ICFs, such as a 
Child’s Informed Assent Form or Home 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 ICFs or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 


 
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IRB/EC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
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, the 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 of 1996 (HIPAA).  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. 


 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated.  In addition, any 
patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
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. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
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. 


 
GDC-0810—Genentech, Inc. 
108/Protocol GO29689, Version 2 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, ICFs, 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 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and will be managed by a CRO.  The CRO will 
provide clinical operations management, data management, and medical monitoring 
support to the Sponsor.  Approximately 45 sites in North America, Europe, and Asia 
Pacific will participate to enroll approximately 152 patients. 
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s unique identification number and treatment 
assignment from the IWRS.  The IWRS will manage GDC-0810 and fulvestrant inventory 
at all sites.  IWRS will be required to randomize patients, to monitor enrollment and 
patient status, and to manage study treatment requests and shipments. 
PRO data will be elicited from all patients in the study to more fully characterize the 
patient profile.  The PRO data will be collected electronically in the local languages of 
each participating country (see Section 4.5.8).   
Patient data will be recorded via an EDC system from Medidata Solutions through use of 
eCRFs (see Section 7.2).   


 
GDC-0810—Genentech, Inc. 
109/Protocol GO29689, Version 2 
Central laboratories will provide kits for PK, pharmacogenomic, tissue, whole blood, and 
plasma sample analyses to be conducted at central laboratories or Genentech or 
third-party laboratories. 
An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient scans in a standardized fashion throughout the trial.  
The review facility will retain copies of scans for potential centralized assessments of 
response or progression in the future. 
9.5 
PUBLICATION 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, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
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 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 


 
GDC-0810—Genentech, Inc. 
110/Protocol GO29689, Version 2 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
GDC-0810—Genentech, Inc. 
111/Protocol GO29689, Version 2 
10. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:365−76. 
Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment 
satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), 
using a national panel study of chronic disease. Health Qual Life Outcomes 
2004;2:12. 
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal 
hormone-receptor positive advanced breast cancer. N Engl J Med 2012 
9;366:520 − 9. 
Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol 2012;(23 Supplement 7):vii11–19.  
Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial 
of fulvestrant compared with exemestane after prior nonsteroidal aromatase 
inhibitor therapy in postmenopausal women with hormone receptor-positive, 
advanced breast cancer: results from EFECT. J Clin Oncol 2008;26:1664 − 70. 
Diehl F, Schmidt K, Durkee KH, et al. Analysis of mutations in DNA isolated from plasma 
and stool of colorectal cancer patients. Gastroenterology 2008;135:489 − 98. 
Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial 
comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women 
with estrogen receptor-postiive advanced breast cancer. J Clin Oncol 2010; 
28:4594 − 600. 
Dupont Jensen J, Laenkholm AV, Knoop A, et al. PIK3CA mutations may be discordant 
between primary and corresponding metastatic disease in breast cancer. Clin 
Cancer Res 2011;17:667 − 77. 
Faslodex® (fulvestrant) injection Package Insert, AstraZeneca.  
Fayers PM, Aaronson NK, Bjordal K, et al. On behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: 
European Organisation for Research and Treatment of Cancer, Brussels 2001. 
Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale KA, et al. PI3K pathway mutations 
and PTEN levels in primary and metastatic breast cancer. Mol Cancer 
Therapeutics 2011;10:1093 − 101. 
Howell A, Osborne CK, Morris C, et al. ICI 182,780 (Faslodex): development of a novel, 
“pure” antiestrogen. Cancer 2000;89:817 − 25. 


 
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112/Protocol GO29689, Version 2 
Howell A, Robertson FJ, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is 
as effective as anastrozole in postmenopausal women with advanced breast 
cancer progressing after prior endocrine treatment. J Clin Oncol 
2002;20:3396 − 403. 
Howell A, Roberston JF, Abram P, et al. Comparison of fulvestrant versus tamoxifen for 
the treatment of advanced breast cancer in postmenopausal women previously 
untreated with endocrine therapy: a multinational, double-blind, randomized trial. 
J Clin Oncol 2004;22:1605 − 13. 
Jemal A, Bray F, Center MM, et al. Global cancer statistics. Ca Cancer J Clin 2011; 
61:69 − 90. 
Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus 
exemestane alone after progression on non-steroidal aromatase inhibitors in 
postmenopausal patients with hormone receptor-positive locally advanced or 
metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised 
trial. Lancet Oncol 2013;14:989 − 98. 
Koenders PG, Beex, LV, Kloppenborg PW, et al. Human breast cancer: survival from 
first metastasis. Breast Cancer Study Group 1992;21:173 − 80. 
Li S, Shen D, Shao J, et al. Endocrine-therapy-resistant ESR1 variants revealed by 
genomic characterization of breast-cancer-derived xenografts. Cell Rep 
2013;4:1116 − 30. 
Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in 
circulating lung-cancer cells. N Engl J Med 2008;359:366 − 77. 
Miller TW, Hennessy BT, González-Angulo AM, et al. Hyperactivation of 
phosphatidylinositol-3 kinase promotes escape from hormone dependence in 
estrogen receptor-positive human breast cancer. J Clin Invest 2010;120:2406 − 13. 
Nolvadex® (tamoxifen) Package Insert, AstraZeneca. 
O’Dwyer PJ and Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT) 1A1 
and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin 
Oncol 2006;24:4534 − 8. 
Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the 
efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal 
women with advanced breast cancer progressing on prior endocrine therapy: 
results of a North American trial. J Clin Oncol 2002;20:3386 − 95. 
Osoba D, Aaronson N, Zee B, et al. Modification of the EORTC QLQ-C30 (version 2.0) 
based on content validity and reliability testing in large samples of patients with 
cancer. The Study Group on Quality of Life of the EORTC and the Symptom 
Control and Quality of Life Committees of the NCI of Canada Clinical Trials Group. 
Qual Life Res 1997;6:103−8. 


 
GDC-0810—Genentech, Inc. 
113/Protocol GO29689, Version 2 
Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus 
anastrozole 1 mg as first-line treatment for advanced breast cancer: results from 
the FIRST study. J Clin Oncol 2009;27:4530 − 5. 
Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant 
metastatic breast cancer. Nat Genet 2013;45:1446 − 5. 
Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined 
phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen 
receptor-positive breast cancer. Breast Cancer Res 2011;13(2):R21. 
Segal CV and Dowsett M. Estrogen receptor mutations in breast cancer – new focus on 
an old target. Clin Can Res 2014;20:1724 − 6. 
Sprangers MA, Groenvold M, Arraras JI, et al. The European Organization for Research 
and Treatment of Cancer breast cancer-specific quality-of-life questionnaire 
module: first results from a three-country field study. J Clin Oncol 1996; 
14:2756−68. 
Toy Q, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in 
hormone-resistant breast cancer. Nat Genet 2013;45:1439 − 45. 
Van Tine BA, Crowder RJ, Ellis MJ. ER and PI3K independently modulate endocrine 
resistance in ER-positive breast cancer. Cancer Discov 2011;1:287 − 8. 
 


 
GDC-0810—Genentech, Inc. 
114/Protocol GO29689, Version 2 
Appendix 1  
Schedule of Assessments for Patients on Arm A (GDC-0810) 
 
Screening a
Cycle 1 
Cycle 2 Cycle 3 Cycle 4
Cycles 5 +
Study Drug  
Discontinuation b 
Day
(Window) − 28 to  − 1
1 
15
(+1) c
1 
(+1) c 
1 
(±1) c 
1 
(±3) c 
1 
(±3) c 
Within 30 days  
after last dose 
Informed consent d 
x 
 
 
 
 
 
 
 
Medical history and demographic data e 
x 
 
 
 
 
 
 
 
Concomitant medications f 
x 
x 
x 
x 
x 
x 
x g 
x 
Adverse events h 
x 
x 
x 
x 
x 
x 
x g 
x 
Vital signs i 
x 
x 
x 
x 
x 
x 
x 
x 
Complete physical examination, height, weight  j 
x 
 
 
 
 
 
 
 
Limited physical examination k 
 
x 
x 
x 
x 
x 
x 
x 
ECOG performance status 
x 
x 
x 
x 
x 
x 
x 
x 
Single 12-lead ECG 
x 
As clinically indicated 
x 
Endometrial thickness assessment l 
x 
As clinically indicated 
x 
Tumor assessment m 
x 
x g 
x 
Bone scan n 
x 
x g 
 
Drug accountability 
 
x 
x 
x 
x 
x 
x 
x 
CBC with differential o 
x 
x 
x 
x 
x 
x 
x g 
x 
Coagulation (INR, aPTT) p 
x 
As clinically indicated (see footnote) 
 
Blood chemistry q 
x q 
x 
x 
x 
x 
x 
x g 
x  
FSH and estradiol 
x r 
 
 
 
 
 
 
 
Urinalysis s 
x 
As clinically indicated 
 


 
 
Appendix 1  
Schedule of Assessments for Patients on Arm A (GDC-0810) (cont.) 
GDC-0810—Genentech, Inc. 
115/Protocol GO29689, Version 2 
 
Screening a
Cycle 1 
Cycle 2 Cycle 3 Cycle 4
Cycles 5 +
Study Drug  
Discontinuation b 
Day
(Window) − 28 to  − 1
1 
15
(+1) c
1 
(+1) c 
1 
(±1) c 
1 
(±3) c 
1 
(±3) c 
Within 30 days  
after last dose 
Archival (or fresh) FFPE tumor tissuet 
x 
 
 
 
 
 
 
 
Plasma sample for ctDNA and plasma 
biomarkers u 
 
x 
 
 
x 
 
x 
x 
Plasma sample for potential CDx v 
 
x 
 
 
x 
 
 
 
Plasma sample for PK analysis w 
 
x 
 
 
x 
 
 
 
Blood sample for  
pharmacogenetics x 
 
x 
 
 
 
 
 
 
Optional blood sample for WGS y 
 
x 
 
 
 
 
 
 
Optional tumor biopsy at progression z 
 
 
 
 
 
 
 
x 
GDC-0810 administration aa 
 
x 
x 
x 
x 
x 
x 
 


 
 
Appendix 1  
Schedule of Assessments for Patients on Arm A (GDC-0810) (cont.) 
GDC-0810—Genentech, Inc. 
116/Protocol GO29689, Version 2 
aPTT = activated partial thromboplastin time; CBC = complete blood count; CDx = companion diagnostic; CT = computed tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; EORTC = European 
Organization for Research and Cancer; FFPE = formalin-fixed, paraffin-embedded; FSH = follicle stimulating hormone; INR = international 
normalized ratio; PK = pharmacokinetic; PRO = patient-reported outcome; TSQM = Treatment Satisfaction Questionnaire for Medication; 
q12 = every 12 (weeks); QLQ-BR23 = Quality Of Life Questionnaire Breast Cancer Module; QLQ-C30 = Quality Of Life Questionnaire; 
WGS = whole genome sequencing. 
Notes:  All assessments should be performed within the indicated window unless otherwise specified.  On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified.  Patients should receive their first dose of study treatment on the day of 
randomization if possible, but no later than 5 business days after randomization. 
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.   
b Patients who discontinue study drug for any reason other than death will return to the clinic for a treatment discontinuation visit within 
30 days after the last dose of study drug.  Patients must be followed for safety assessment for at least 28 days after completion of study drug.  
The visit at which response assessment shows disease progression may be used as the study drug discontinuation visit, provided that all 
tests required at the study drug discontinuation visit are performed. 
c The visit window for Cycle 1 Day 15 and Cycle 2 Day 1 is  + 1 day, because fulvestrant administration should not occur prior to 
Cycle 1 Day 15 or Cycle 2 Day 1.  The visit window for Cycle 3 Day 1 is  + 1 day, and the visit window for Day 1 of Cycles 4 and up 
is ± 3 days.  Visits are based on a 28-day cycle.  If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend that 
precludes the procedure within the allotted window, the procedure must be performed on the nearest following date.  The date of 
Cycle 1 Day 1 should be used to calculate all subsequent target visit dates.  
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Medical history includes clinically significant diseases within the previous 5 years before Cycle 1 Day 1, smoking history and breast cancer 
history (including tumor characteristics such as hormone receptor status, prior cancer therapies, surgeries and procedures).  Demographic 
data include age, sex, and self-reported race/ethnicity where allowed by local regulatory authorities. 
f Concomitant medications include prescription medication, over-the-counter preparations, and herbal or homeopathic remedies and 
supplements used within 7 days prior to the screening visit through the study drug discontinuation visit.  After the study drug discontinuation 
visit, only medications administered for ongoing or new treatment-related adverse events or as anti-cancer therapy will be collected. 
g To be performed per institutional guidelines and/or as clinically indicated except physical examination, ECOG, vital signs creatinine liver 
function tests, adverse events, concomitant medication, and study drug compliance should be monitored at each cycle. 


 
 
Appendix 1  
Schedule of Assessments for Patients on Arm A (GDC-0810) (cont.) 
GDC-0810—Genentech, Inc. 
117/Protocol GO29689, Version 2 
h 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 last dose of study 
drug.  After this period, investigators should report any deaths, serious adverse events, or other adverse events of concern that are believed 
to be related to prior treatment with study drug.  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.  Please note, additional information will be collected if diarrhea is reported as an adverse event. 
i Vital signs include measurements of heart rate, systolic and diastolic blood pressures while the patient is in a seated position, and oral or 
tympanic temperature.  Record abnormalities on the Adverse Event eCRF. 
j Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.   
k Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF. 
l Transvaginal ultrasounds should be performed to monitor endometrial thickness during the study at screening, at the study drug 
discontinuation visit, and additionally when clinically indicated (e.g., to evaluate vaginal bleeding).  Transvaginal ultrasounds are not 
required for patients who have had a hysterectomy. 
m Perform tumor assessments at screening per institutional guidelines and additionally when clinically indicated for all patients.  Screening 
assessments must include CT scans of the chest, abdomen and pelvis; CT scans of the neck and brain imaging should be included if 
clinically indicated.  A documented standard-of-care tumor assessment performed within 28 days before Cycle 1 Day 1 may be used for the 
screening assessment, provided it meets the above requirements.  The same imaging method used at screening must be used throughout 
the study.  Response assessments will be performed by the investigator, on the basis of physical examinations and imaging scans.  Bone 
disease identified on bone imaging should be evaluated radiographically by CT scan, magnetic resonance imaging (MRI), or X-ray.  The 
same modality used at screening should be used throughout the study. 
n An isotope bone scan (e.g., technetium) will be performed at screening and should be repeated in the event of clinical suspicion of 
progression of existing bone lesions and/or the development of new bone lesions or for confirmation of complete response for all patients.  
For patients with bone-only disease not visible on the CT or MRI scans being performed as part of the tumor assessments, bone scans 
should be repeated when clinically indicated until disease progression. 
o Includes white blood cell (WBC) count with differential (neutrophils, eosinophils, basophils, lymphocytes, and monocytes), red blood cell 
(RBC) count, hemoglobin, hematocrit, and platelet count.  Reporting the differential as absolute counts is preferred, but percent is accepted.  
Pre-dose laboratory samples may be drawn within 2 days prior to the cycle visit (except Cycle 1 Day 1, which must be drawn at that visit). 
p aPTT and INR should be collected at screening and as clinically indicated thereafter.  For patients taking warfarin or its equivalent, aPTT and 
INR should be measured twice in the first week of administration and then as clinically indicated.  


 
 
Appendix 1  
Schedule of Assessments for Patients on Arm A (GDC-0810) (cont.) 
GDC-0810—Genentech, Inc. 
118/Protocol GO29689, Version 2 
q Blood chemistry includes the following:  glucose, blood urea nitrogen or urea, creatinine, sodium, potassium, chloride, magnesium, 
bicarbonate, calcium, total protein, albumin, total bilirubin, alkaline phosphatase, AST, and ALT.  Samples for blood chemistry should be 
drawn predose, and may be drawn within 2 days prior to the cycle visit (except Cycle 1 Day 1, which must be drawn at that visit).  Screening 
blood chemistry should be drawn after fasting (≥ 8 hours) at treatment and at the Study Drug Discontinuation Visit, but may be drawn 
nonfasting at all other time points. 
r FSH and estradiol to be collected only when required to assess study eligibility (see Section 4.1.1). 
s Urinalysis includes dipstick macro (specific gravity, pH, glucose, protein, ketones and blood).  A reflex microscopic urinalysis (RBCs, WBCs, 
casts, etc.,) should be performed if the macroscopic analysis is abnormal. 
t Archival tumor tissue blocks or a minimum of 10 (15 − 20 preferred) freshly cut unstained slides from the most recent tumor tissue will be 
collected at screening for molecular characterization of the tumor tissue including, but not limited to, ESR1 mutations. 
u A plasma sample will be collected for ctDNA and plasma biomarkers, including but not limited to ESR1 mutations, PIK3CA mutations, and 
AKT1 mutations on Day 1 of Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, and every 3 cycles thereafter, timed to coincide roughly with 
response assessments.  On Cycle 1 Day 1, sample should be collected prior to study drug treatment.   
v A plasma sample will be collected and banked for potential future blood-based companion diagnostic development. On Cycle 1 Day 1, 
sample should be collected prior to study drug treatment. 
w See Appendix 3  for detailed schedule.  
x A pharmacogenomics sample will be collected where approved by local regulatory authorities.  On Cycle 1 Day 1, samples should be 
collected prior to study drug treatment. 
y Collection of a blood sample for whole genome sequencing (see Section 4.5.10) is not required for study participation but is strongly 
encouraged and will be collected from patients who sign the Optional Research portion of the Informed Consent form.  A blood sample will be 
collected as a source of normal DNA to determine whether sequence variants detected in tumor tissue are somatic mutations or single 
nucleotide polymorphisms.  A portion of this sample will be used for WGS (see Section 4.5.10).  Sample should be collected prior to study 
drug treatment.  Not applicable for a site that has not been granted regulatory approval for WGS sampling. 
z Tumor biopsy collection at the time of disease progression is not required for study participation but is strongly encouraged and will be 
collected from patients who sign the Optional Research portion of the Informed Consent Form. 
aa GDC-0810 will be taken orally once daily beginning on Cycle 1 Day 1.  GDC-0810 will be administered in the clinic on each day that a clinic 
visit is scheduled, after the predose assessments and procedures, and at home on all non-clinic visit days.  A sufficient number of study drug 
tablets will be provided to last until the next visit.  Patients will also receive a medication diary.  Instruct the patient to record the time and date 
she takes each treatment dose in the diary and to return all unused tablets at each study visit, to assess compliance. Collect and review the 
medication diary and unused tablets and assess compliance at each visit after each visit.  At the study drug discontinuation visit, do not 
dispense any additional study drug tablets or provide a new medication diary. 
 


 
GDC-0810—Genentech, Inc. 
119/Protocol GO29689, Version 2 
Appendix 2  
Schedule of Assessments for Patients on Arm B (Fulvestrant) 
 
Screening a
Cycle 1 
Cycle 2 Cycle 3 Cycle 4
Cycles 5+ 
Study Drug 
Discontinuation b 
Day
(Window)
− 28 to  − 1 
1 
15 
(+1) c
1 
(+1) c 
1 
(± 1) c 
1 
(± 3) c 
1 
(± 3) c 
Within 30 days after 
last dose 
Informed consent d 
x 
 
 
 
 
 
 
 
Medical history and demographic data e 
x 
 
 
 
 
 
 
 
Concomitant medications f 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events g 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs h 
x 
x 
x 
x 
x 
x 
x 
x 
Complete physical examination, height, 
weight j 
x 
 
 
 
 
 
 
 
Limited physical examination k 
 
x 
x 
x 
x 
x 
x 
x 
ECOG performance status 
x 
x 
x 
x 
x 
x 
x 
x 
Single 12-lead ECG 
x 
As clinically indicated 
Endometrial thickness assessment l 
x 
As clinically indicated 
x 
Tumor assessment m 
x 
x i, n 
x 
Bone scan n 
x 
Per clinical indication n 
 
CBC with differential o 
x 
x 
x 
x 
x 
x 
x i 
x 
Coagulation (INR, aPTT) p 
x 
As clinically indicated (see footnote) 
 
Blood chemistry q 
x q 
x 
x 
x 
x 
x 
x i 
x q 
FSH and estradiol r 
x r 
 
 
Urinalysis s 
x 
As clinically indicated 
 
Archival (or fresh) FFPE tumor tissue t 
x 
 
 
 
 
 
 
 


 
 
Appendix 2  
Schedule of Assessments for Patients on Arm B (Fulvestrant) (cont.) 
GDC-0810—Genentech, Inc. 
120/Protocol GO29689, Version 2 
 
Screening a
Cycle 1 
Cycle 2 Cycle 3 Cycle 4
Cycles 5+ 
Study Drug 
Discontinuation b 
Day
(Window)
− 28 to  − 1 
1 
15 
(+1) c
1 
(+1) c 
1 
(± 1) c 
1 
(± 3) c 
1 
(± 3) c 
Within 30 days after 
last dose 
Plasma sample for ctDNA and plasma 
biomarkers u 
 
x 
 
 
x 
 
x 
x 
Plasma sample for potential CDx v 
 
x 
 
 
x 
 
 
 
Optional blood sample for WGS w 
 
x 
 
 
 
 
 
 
Optional tumor biopsy at progression x 
 
 
 
 
 
 
 
x 
Fulvestrant administration y 
 
x 
x 
x 
x 
x 
x 
 
 


 
 
Appendix 2  
Schedule of Assessments for Patients on Arm B (Fulvestrant) (cont.) 
GDC-0810—Genentech, Inc. 
121/Protocol GO29689, Version 2 
aPTT = activated partial thromboplastin time; CBC = complete blood count; CDx = companion diagnostic; CT = computed tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; EORTC = European 
Organization for Research and Cancer; FFPE = formalin-fixed, paraffin-embedded; FSH = follicle stimulating hormone; INR = international 
normalized ratio; PK = pharmacokinetic; PRO = patient-reported outcome; q12 = every 12 (weeks); QLQ-BR23 = Quality Of Life Questionnaire 
Breast Cancer Module; QLQ-C30 = Quality of Life Questionnaire; TSQM = Treatment Satisfaction Questionnaire for Medication; WGS  = whole 
genome sequencing. 
Notes:  All assessments should be performed within the indicated window unless otherwise specified.  On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified. Patients should receive their first dose of study treatment on the day of 
randomization if possible, but no later than 5 business days after randomization. 
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.   
b Patients who discontinue study drug for any reason other than death will return to the clinic for a treatment discontinuation visit within 
30 days after the last dose of study drug.  Patients must be followed for safety assessment for at least 28 days after completion of study 
drug.  The visit at which response assessment shows disease progression may be used as the study drug discontinuation visit provided 
that all tests required at the study drug discontinuation visit are performed. 
c The visit window for Cycle 1 Day 15 and Cycle 2 Day 1 is  + 1 day since fulvestrant administration should not occur prior to Cycle 1 Day 15 
or Cycle 2 Day 1.  The visit window for Cycle 3 Day 1 is  ± 1 day and the visit window for Day 1 of Cycles 4 and up is  ± 3 days.  Visits are 
based on a 28-day cycle.  If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend that precludes the 
procedure within the allotted window, the procedure must be performed on the nearest following date. The date of Cycle 1 Day 1 should be 
used to calculate all subsequent target visit dates.  
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Medical history includes clinically significant diseases within the previous 5 years before Cycle 1 Day 1, smoking history and breast cancer 
history (including tumor characteristics such as hormone receptor status, prior cancer therapies, surgeries, and procedures).  Demographic 
data include age, sex, and self-reported race/ethnicity where allowed by local regulatory authorities. 
f Concomitant medications include prescription medication, over-the-counter preparations, and herbal or homeopathic remedies and 
supplements used within 7 days prior to the screening visit through the study drug discontinuation visit.  After the study drug discontinuation 
visit, only medications administered for ongoing or new treatment-related adverse events or as anti-cancer therapy will be collected. 
 
 


 
 
Appendix 2  
Schedule of Assessments for Patients on Arm B (Fulvestrant) (cont.) 
GDC-0810—Genentech, Inc. 
122/Protocol GO29689, Version 2 
g 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 last dose of study 
drug. After this period, investigators should report any deaths, serious adverse events, or other adverse events of concern that are believed 
to be related to prior treatment with study drug.  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.  Please note, additional information will be collected if diarrhea is reported as an adverse event. 
h Vital signs include measurements of heart rate, systolic and diastolic blood pressures while the patient is in a seated position, and oral or 
tympanic temperature.  Record abnormalities on the Adverse Event eCRF. 
i To be performed per institutional guidelines and/or as clinically indicated except physical examination, ECOG, vital signs creatinine 
liver function tests, adverse events, concomitant medication, and study drug compliance should be monitored at each cycle. 
j Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.   
k Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF. 
l Transvaginal ultrasounds should be performed to monitor endometrial thickness during the study at screening, at the study drug 
discontinuation visit, and additionally when clinically indicated (e.g., to evaluate vaginal bleeding).  Transvaginal ultrasounds are not 
required for patients who have had a hysterectomy. 
m Perform tumor assessments at screening per institutional guidelines and additionally when clinically indicated for all patients.  Screening 
assessments must include CT scans of the chest, abdomen and pelvis; CT scans of the neck and brain imaging should be included if 
clinically indicated.  A documented standard-of-care tumor assessment performed within 28 days before Cycle 1 Day 1 may be used for the 
screening assessment, provided it meets the above requirements.  The same imaging method used at screening must be used throughout 
the study.  Response assessments will be performed by the investigator, on the basis of physical examinations and imaging scans.  Bone 
disease identified on bone imaging should be evaluated radiographically by CT scan, MRI, or X-ray.  The same modality used at screening 
should be used throughout the study. 
n An isotope bone scan (e.g., technetium) will be performed at screening and should be repeated in the event of clinical suspicion of 
progression of existing bone lesions and/or the development of new bone lesions or for confirmation of complete response for all patients.  
For patients with bone-only disease not visible on the CT or MRI scans being performed as part of the tumor assessments, bone scans 
should be when clinically indicated until disease progression.  
 


 
 
Appendix 2  
Schedule of Assessments for Patients on Arm B (Fulvestrant) (cont.) 
GDC-0810—Genentech, Inc. 
123/Protocol GO29689, Version 2 
o Includes white blood cell (WBC) count with differential (neutrophils, eosinophils, basophils, lymphocytes, and monocytes), red blood cell 
(RBC) count, hemoglobin, hematocrit, and platelet count.  Reporting the differential as absolute counts is preferred, but percent is 
accepted.  Pre-dose laboratory samples may be drawn within 2 days prior to the cycle visit (except Cycle 1 Day 1, which must be drawn at 
that visit). 
p aPTT and INR should be collected at screening and as clinically indicated thereafter.  For patients taking warfarin or its equivalent, aPTT 
and INR should be measured twice in the first week of administration and then as clinically indicated. 
q Blood chemistry includes the following:  glucose, blood urea nitrogen or urea, creatinine, sodium, potassium, chloride, magnesium, 
bicarbonate, calcium, total protein, albumin, total bilirubin, alkaline phosphatase, AST and ALT.  Samples for blood chemistry should be 
drawn predose, and may be drawn within 2 days prior to the cycle visit (except Cycle 1 Day 1, which must be drawn at that visit).  
Screening blood chemistry should be drawn after fasting (≥ 8 hours) at treatment and at the study drug discontinuation visit, but may be 
drawn nonfasting at all other timepoints.  
r FSH and estradiol to be collected only when required to assess study eligibility (see Section 4.1.1). 
s Urinalysis includes dipstick macro (specific gravity, pH, glucose, protein, ketones and blood).  A reflex microscopic urinalysis (RBCs, 
WBCs, casts, etc.,) should be performed if the macroscopic analysis is abnormal. 
t Archival tumor tissue blocks or a minimum of 10 (15 − 20 preferred) freshly cut unstained slides from the most recent tumor tissue will be 
collected at screening for molecular characterization of the tumor tissue, including but not limited to ESR1 mutations. 
u A plasma sample will be collected for ctDNA and plasma biomarkers, including but not limited to ESR1 mutations, PIK3CA mutations, and 
AKT1 mutations on Day 1 of Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, and every 3 cycles thereafter, timed to coincide roughly with 
response assessments.  On Cycle 1 Day 1, the sample should be collected prior to study drug treatment.  
v A plasma sample will be collected and banked for potential future blood-based companion diagnostic development.  On Cycle 1, Day 1, 
sample should be collected prior to study drug treatment. 
w Collection of a blood sample for whole genome sequencing (see Section 4.5.10) is not required for study participation but is strongly 
encouraged and will be collected from patients who sign the Optional Research portion of the Informed Consent Form.  A blood sample will 
be collected as a source of normal DNA to determine whether sequence variants detected in tumor tissue are somatic mutations or single 
nucleotide polymorphisms.  A portion of this sample will be used for WGS (see Section 4.5.10).  Not applicable for a site that has not been 
granted regulatory approval for WGS sampling. 
x Tumor biopsy collection at the time of disease progression is not required for study participation but is strongly encouraged and will be 
collected from patients who sign the Optional Research portion of the Informed Consent Form. 
y Fulvestrant will be administered in the clinic as two intramuscular injections of 250 mg each (total dose 500 mg) on Days 1 and 15 of 
Cycle 1 and Day 1 of each subsequent 28-day cycle. 
 


 
GDC-0810—Genentech, Inc. 
124/Protocol GO29689, Version 2 
Appendix 3  
Schedule of Pharmacokinetic Assessments (for Arm A only) 
Study Visit 
Timepoint 
Assessment 
Predose 
GDC-0810 PK 
Cycle 1, Day 1  
3 hours postdose 
GDC-0810 PK 
Predose 
GDC-0810 PK 
Cycle 3, Day 1  
(± 1 day) 
3 hours postdose 
GDC-0810 PK 
Notes:  Predose samples should be collected within 30 minutes 
before administration of GDC-0810.  All other sample draw times 
are  ± 5 minutes.  The plasma sample will be split into two equal 
aliquots:  a primary sample and a back-up sample. 
Detailed instructions for PK plasma sample preparation and 
shipping will be provided to the study sites in a separate Laboratory 
Manual. 
Record exact date and time of all study drug doses and PK sample 
collections. 
 
 


 
GDC-0810—Genentech, Inc. 
133/Protocol GO29689, Version 2 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions and/or lymph nodes will be categorized as measurable or 
non-measurable as described below. 
MEASURABLE TUMOR LESIONS 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 
• 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be  ≥ 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and at follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement. 
                                            
 
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. 
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
134/Protocol GO29689, Version 2 
NON-MEASURABLE TUMOR LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 but < 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
• 
Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions.  
However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
• 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
135/Protocol GO29689, Version 2 
Target Lesions:  Specifications by Methods of Measurements 
• 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed.  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 Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the 
study.  Imaging-based evaluation should always be the preferred option. 
 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
136/Protocol GO29689, Version 2 
and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised. 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to 
a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan). 
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, but in addition should 
lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
137/Protocol GO29689, Version 2 
reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  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. 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
• 
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. 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
138/Protocol GO29689, Version 2 
• 
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 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to < 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm. 
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan 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 CRF, 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 measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (BML is equivalent to a “less than” sign.) (Note:  It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well 
and BML should also be ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, 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 in this instance should be the maximum 
longest diameter for the coalesced lesion. 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
139/Protocol GO29689, Version 2 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While 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 and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
PD:  Unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
 
Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, 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. 
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in some 
Phase III trials when it is not a criterion of study entry to have measurable disease.  The 
same general concepts apply here as noted above; however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that can 
be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread, or may be described in 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
140/Protocol GO29689, Version 2 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is seen, 
the patient should be considered to have had overall PD at that point.  While it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 
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 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan 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. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly, possible “new” disease).  New lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm:  
• 
A negative FDG-PET scan at baseline with a positive3 FDG-PET scan during the 
study is a sign of PD based on a new lesion.  
• 
In the case of no FDG-PET scan at baseline and a positive FDG-PET scan during 
the study: 
                                            
 
3 A “positive” FDG-PET scan lesion means one that is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation-corrected image. 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
141/Protocol GO29689, Version 2 
If the positive FDG-PET scan during the study corresponds to a new site of 
disease confirmed by CT, this will be considered PD. 
If the positive FDG-PET scan during the study is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine whether 
there is truly progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET scan during the study corresponds to a preexisting site 
of disease on CT that is not progressing on the basis of the anatomic images, 
this will not be considered PD. 
 
EVALUATION OF RESPONSE 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
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 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-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. 
 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
142/Protocol GO29689, Version 2 
Table 2 
Timepoint Response:  Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised. 
 
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.  This would be most likely to happen 
in the case of PD.  For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint. 


 
 
Appendix 7  
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication (cont.) 
GDC-0810—Genentech, Inc. 
143/Protocol GO29689, Version 2 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
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. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion. 


 
GDC-0810—Genentech, Inc. 
144/Protocol GO29689, Version 2 
Appendix 8  
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
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% of 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 


 
GDC-0810—Genentech, Inc. 
145/Protocol GO29689, Version 2 
Appendix 9  
Substrates and Inhibitors of CYP Enzymes 
The following drugs are sensitive substrates or substrates of CYPs 2C8, 2C9 and 2C19 
with a low therapeutic window.  It is strongly recommended to consider alternate 
therapies, whenever possible.  It is not possible to produce an exhaustive list of 
medications that fall into these categories, so if in question, refer to the appropriate 
product label. 
CYP Enzymes  
Sensitive Substrates  
Substrates with Narrow 
Therapeutic Range  
CYP2B6 
Bupropion, efavirenz 
 
CYP2C8  
Repaglinide  
Paclitaxel  
CYP2C9  
Celecoxib  
Warfarin, phenytoin  
(neither drug should be used 
concomitantly with 
GDC-0810)  
CYP2C19  
Clobazam, lansoprazole, 
omeprazole, S-mephenytoin  
S-mephenytoin  
Source: FDA draft guidance on “Drug Interaction Studies Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations,” Feb 2012. Can be accessed from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm292362.pdf.