Clinical trial NCT01823835
Conditions: Breast Cancer
Sponsor: Genentech, Inc.
Start date: 2014-12-29; Completion date: 2020-03-13
Enrollment: 152 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a multi-institution, Phase Ia/Ib/IIa open-label, dose-finding, safety, pharmacokinetics (PK), and proof-of-concept study of GDC-0810 as a single agent and in combination with palbociclib and/or LHRH agonist. The study is divided into 3 phases: Phase Ia, Phase Ib, and Phase IIa. During Phase Ia (dose escalation phase), GDC-0810 single agent will be administered orally on a continuous daily dosing regimen with a Day -7 lead-in period for single dose PK evaluation prior to the start of daily treatment. The incidence of dose-limiting toxicities (DLTs) will be evaluated from Day -7 through the first cycle (28 days) of treatment (35 days total). Depending on safety and tolerability, participants will be assigned sequentially to escalating doses of GDC-0810 using standard 3 + 3 design. During Phase Ib (dose escalation and expansion phase), participants will receive GDC-0810 with palbociclib and/or LHRH agonist to determine the recommended Phase II dose (RP2D) and assess the safety and tolerability of concomitant administration. During Phase IIa (dose expansion phase), participants previously treated with an aromatase inhibitor (AI) will be treated at the RP2D to further characterize the safety, PK, pharmacodynamics, and anti-tumor activity of GDC-0810.

Detailed description:

Arms: arm 1: 100 mg GDC-0810 once daily (QD) in fasting state. arm 2: 200 mg GDC-0810 QD in fasting state. arm 3: 400 mg GDC-0810 QD in fasting state. arm 4: 600 mg GDC-0810 QD in fasting state. arm 5: 600 mg GDC-0810 QD in non-fasting state. arm 6: 300 mg GDC-0810 twice daily (BID) in fasting state. arm 7: 800 mg GDC-0810 QD in fasting state. arm 8: 800 mg GDC-0810 QD in non-fasting state. arm 9: 400 mg GDC-0810 BID in fasting state. arm 10: 600 mg GDC-0810 QD. Additionally, participants in this arm did not receive any prior treatment with fulvestrant and had confirmed ER-a (ESR1) mutation of the ligand binding domain (LBD). arm 11: 600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and confirmed ER-a (ESR1) mutation of the LBD. arm 12: 600 mg GDC-0810 QD. Additionally, participants in this arm did not receive any prior treatment with fulvestrant and had progressed following ≤1 prior therapy with an aromatase inhibitor (AI). arm 13: 600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and progressed following ≤1 prior therapy with an AI. arm 14: 400 mg GDC-0810 + 125 mg Palbociclib QD. arm 15: ≤600 mg GDC-0810 QD + LHRH agonist once monthly.
Interventions: intervention 1: GDC-0810 intervention 2: LHRH Agonist intervention 3: Palbociclib
Intervention descriptions: intervention 1: GDC-0810 administered orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, GDC-0810 drug supply exhausted, or study termination (up to 3 years). intervention 2: LHRH agonist administered once monthly until disease progression, unacceptable toxicity, withdrawal of consent, GDC-0810 drug supply exhausted, or study termination (up to 3 years). Choice of LHRH agonist will be an institutional choice approved for use in breast cancer. intervention 3: Palbociclib administered orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, GDC-0810 drug supply exhausted, or study termination (up to 3 years).

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: 
An Open-Label, Phase Ia/Ib/IIa Study of GDC-0810 Single Agent or in 
Combination With Palbociclib and/or an LHRH Agonist in Women 
With Locally Advanced or Metastatic Estrogen Receptor Positive 
Breast Cancer 
NCT Number: 
NCT01823835 
Document Date: 
Protocol Version 9: 25-January-2017 


 
Title
25-Jan-2017 04:31:48
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable 
Ethics Committee or Institutional Review Board.  It is understood that this information will not be 
disclosed to others without written authorization from Genentech except to the extent necessary to 
obtain informed consent from persons to whom the drug may be administered. 
 
GDC-0810—Genentech, Inc. 
Protocol GO29642, Version 9 
PROTOCOL 
TITLE: 
AN OPEN-LABEL, PHASE Ia/Ib/IIa STUDY OF 
GDC-0810 SINGLE AGENT OR IN COMBINATION 
WITH PALBOCICLIB AND/OR AN LHRH AGONIST 
IN WOMEN WITH LOCALLY ADVANCED OR 
METASTATIC ESTROGEN RECEPTOR POSITIVE 
BREAST CANCER 
PROTOCOL NUMBER: GO29642 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2014-004852-77 
IND NUMBER: 
116019 
TEST PRODUCT: 
GDC-0810 (RO7056118) 
MEDICAL MONITOR: 
 M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  17 December 2012 
DATES AMENDED: 
Version 2:  24 January 2013−Amendment 1 
Version 3:  8 February 2013−Amendment 2 
Version 4:  23 April 2013−Amendment 3 
Version 5:  11 October 2013−Amendment 4 
Version 6:  20 June 2014−Amendment 5 
Version 7:  2 January 2015−Amendment 6 
Version 8:  18 December 2015−Amendment 7 
Version 9:  See electronic date stamp below. 


GDC-0810—Genentech, Inc. 
2/Protocol GO29642, Version 9 
PROTOCOL AMENDMENT, VERSION 9: 
RATIONALE 
Protocol GO29642 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 into the study.  The decision to halt the development of GDC-0810 is not 
due to any safety concerns.  Adverse events observed for GDC-0810 alone or in 
combination with luteinizing hormone-releasing hormone (LHRH) agonist or palbociclib 
thus far are similar to those that have been observed with other endocrine agents and 
are amenable to monitoring, are manageable, and reversible. 
As a result of the decision to halt development of GDC-0810, the following changes have 
been made: 
• 
Enrollment in this study 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 in combination with LHRH agonist or palbociclib until progression of 
disease, unacceptable toxicity, consent withdrawal, GDC-0810 drug supply has 
been exhausted, or the Sponsor terminates the study.   
• 
Limited Physical exam, ECOG, vital signs, liver function tests, creatinine, adverse 
events, concomitant medication, study drug compliance will be collected at least 
monthly and as clinically indicated. 
• 
Hematology (for patients receiving GDC-0810 alone or in combination with LHRH 
agonist), 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. 
• 
Hematology will be collected at least monthly and as clinically indicated for patients 
receiving GDC-0810 in combination with palbociclib.  
• 
The frequency of transvaginal ultrasounds has been changed from every 6 months 
to as clinically indicated due to the low rate of adverse events observed and to align 
with the other ongoing GDC-0810 study (GO29689).  Collection of the transvaginal 
ultrasound at the end of treatment will continue. 
• 
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. 
• 
Clinical and nonclinical summaries have been update to align with the GDC-0810 
Investigator’s Brochure, Version 4. 
• 
The definition of the end of study has been revised because of the Sponsor’s 
decision to halt the development of GDC-0810. 
• 
Post-trial access to GDC-0810 has been revised because of the Sponsor’s decision 
to halt the development of GDC-0810. 


 
GDC-0810—Genentech, Inc. 
3/Protocol GO29642, Version 9 
 
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. 
21/Protocol GO29642, Version 9 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 28 
PROTOCOL SYNOPSIS .................................................................................... 29 
1. 
BACKGROUND ON ESTROGEN RECEPTOR POSITIVE 
BREAST CANCER...................................................................................... 44 
1.1 
GDC-0810 Single Agent Clinical Safety Summary ................ 45 
1.2 
Clinical PK Summary............................................................. 47 
2. 
BACKGROUND ON CYCLIN-DEPENDENT KINASES AND 
PALBOCICLIB (IBRANCE) ......................................................................... 47 
2.1 
Nonclinical Overview of Palbociclib ....................................... 48 
2.2 
Clinical Overview of Palbociclib............................................. 48 
2.3 
Background on Ovarian Ablation and LHRH 
Agonist................................................................................... 50 
3. 
STUDY RATIONALE FOR GDC-0810 AS A SINGLE AGENT 
AND RISK BENEFIT ASSESSMENT.......................................................... 50 
4. 
STUDY RATIONALE FOR GDC-0810 IN COMBINATION 
WITH PALBOCICLIB AND/OR LHRH AGONISTS AND RISK 
BENEFIT ASSESSMENT ........................................................................... 51 
5. 
STUDY RATIONALE FOR GDC-0810 IN COMBINATION 
WITH LHRH AGONIST AND RISK BENEFIT ASSESSMENT.................... 53 
5.1 
Clinical Dose Selection of Palbociclib.................................... 53 
5.2 
Clinical Dose Selection of LHRH Agonist .............................. 54 
6. 
STUDY OBJECTIVES................................................................................. 54 
6.1 
Primary Objectives ................................................................ 54 
6.1.1 
Phase Ia ................................................................................ 54 
6.1.2 
Phase IIa ............................................................................... 54 
6.1.3 
Phase Ib ................................................................................ 54 
6.2 
Secondary Objectives............................................................ 54 
6.2.1 
Exploratory Objectives........................................................... 55 
7. 
STUDY DESIGN ......................................................................................... 55 
7.1 
Phase IA................................................................................ 56 
7.2 
Phase IIA............................................................................... 57 


 
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7.3 
Phase IB................................................................................ 58 
8. 
PATIENT SELECTION................................................................................ 59 
8.1 
Phase IA................................................................................ 60 
8.1.1 
Phase Ia Inclusion Criteria..................................................... 60 
8.1.2 
Phase Ia Exclusion Criteria.................................................... 61 
8.2 
Phase IIa ............................................................................... 62 
8.2.1 
Phase IIa Inclusion Criteria.................................................... 62 
8.2.2 
Phase IIa Exclusion Criteria................................................... 65 
8.3 
Phase IB................................................................................ 66 
8.3.1 
Phase Ib Inclusion Criteria..................................................... 66 
8.3.2 
Phase Ib Exclusion Criteria.................................................... 68 
9. 
STUDY DRUG ............................................................................................ 69 
9.1 
GDC-0810 ............................................................................. 69 
9.1.1 
Description and Composition of the Drug 
Substance.............................................................................. 69 
9.1.2 
Study Drug Product ............................................................... 69 
9.1.3 
Packaging and Labeling ........................................................ 69 
10. STUDY TREATMENTS............................................................................... 70 
10.1 
Treatment Dose Assignment ................................................. 70 
10.1.1 
Phase Ia ................................................................................ 70 
10.1.2 
Phase IIa ............................................................................... 71 
10.1.3 
Phase Ib ................................................................................ 71 
10.1.3.1 
Cohort C1 .............................................................................. 71 
10.1.3.2 
Cohort D1 .............................................................................. 72 
10.2 
DLT Definition........................................................................ 73 
10.2.1 
Phase Ia ................................................................................ 73 
10.2.2 
Phase IIa ............................................................................... 73 
10.2.3 
Phase Ib ................................................................................ 73 
10.3 
Study Drug and Study Treatment Administration................... 76 
10.3.1 
Phase Ia ................................................................................ 76 
10.3.2 
Phase IIa ............................................................................... 77 
10.3.3 
Phase Ib ................................................................................ 77 


 
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10.4 
Dose Modifications ................................................................ 78 
10.4.1 
Dose Modifications for Phase Ia, Ib Cohort D, 
and IIa.................................................................................... 78 
10.4.2 
Dose Modifications for Phase Ib Cohort C1........................... 84 
10.4.3 
Concomitant Medications and Treatments ............................ 90 
10.4.3.1 
Drug Interactions of GDC-0810 ............................................. 90 
10.4.3.2 
Drug Interactions of Palbociclib ............................................. 90 
10.4.3.3 
Agents that may increase palbociclib plasma 
concentrations ....................................................................... 91 
10.4.3.4 
Agents that may decrease palbociclib plasma 
concentrations ....................................................................... 91 
10.4.3.5 
Drugs that may have their plasma concentrations 
altered by palbociclib ............................................................. 91 
10.4.3.6 
Drug Interactions of LHRH Agonists...................................... 91 
10.5 
Study Drug Accountability...................................................... 92 
10.6 
Measures of Treatment Compliance...................................... 94 
11. STUDY PROCEDURES AND GUIDELINES .............................................. 94 
11.1 
Clinical Assessments............................................................. 94 
11.1.1 
Demographics ....................................................................... 94 
11.1.2 
Medical History...................................................................... 94 
11.1.3 
Physical Examination ............................................................ 95 
11.1.4 
Vital Signs.............................................................................. 95 
11.1.5 
Performance Status............................................................... 95 
11.1.6 
Adverse Events ..................................................................... 95 
11.1.7 
Concomitant Medications and Treatments ............................ 95 
11.1.8 
Tumor Assessments.............................................................. 95 
11.1.9 
Endometrial Thickness Assessments (if 
applicable) ............................................................................. 96 
11.2 
Clinical Laboratory Measurements ........................................ 96 
11.3 
Electrocardiogram (ECG) ...................................................... 96 
11.3.1 
Phase Ia ................................................................................ 96 
11.3.2 
Phase IIa ............................................................................... 96 
11.3.3 
Phase Ib ................................................................................ 97 
11.4 
Pharmacokinetic Measurements ........................................... 97 


 
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11.4.1 
Phase Ia ................................................................................ 97 
11.4.2 
Phase IIa ............................................................................... 97 
11.4.3 
Phase Ib ................................................................................ 97 
11.5 
Correlative Studies ................................................................ 98 
11.5.1 
FES-PET ............................................................................... 98 
11.5.1.1 
Phase Ia ................................................................................ 98 
11.5.1.2 
Phase IIa ............................................................................... 99 
11.5.2 
Tumor Biopsies.................................................................... 100 
11.5.2.1 
Phase Ia .............................................................................. 100 
11.5.2.2 
Phase IIa ............................................................................. 100 
11.5.2.3 
Phase Ib .............................................................................. 100 
11.5.2.4 
Archival Tissue Collection.................................................... 101 
11.5.3 
Circulating Tumor DNA Analyses ........................................ 101 
11.5.4 
Pharmacogenomic (PGx) Evaluations................................. 101 
12. SAFETY ASSESSMENTS ........................................................................ 102 
12.1 
Safety Parameters and Definitions ...................................... 102 
12.1.1 
Adverse Events ................................................................... 102 
12.1.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 102 
12.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 103 
12.2 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 104 
12.2.1 
Adverse Event Reporting Period ......................................... 104 
12.2.2 
Eliciting Adverse Event Information ..................................... 104 
12.2.3 
Assessment of Severity of Adverse Events ......................... 105 
12.2.4 
Assessment of Causality of Adverse Events ....................... 105 
12.2.5 
Procedures for Recording Adverse Events.......................... 106 
12.2.5.1 
Diagnosis versus Signs and Symptoms............................... 106 
12.2.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 106 
12.2.5.3 
Persistent or Recurrent Adverse Events.............................. 107 
12.2.5.4 
Abnormal Laboratory Values ............................................... 107 
12.2.5.5 
Abnormal Vital Sign Values ................................................. 108 


 
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25/Protocol GO29642, Version 9 
12.2.5.6 
Abnormal Liver Function Tests............................................ 109 
12.2.5.7 
Deaths ................................................................................. 109 
12.2.5.8 
Preexisting Medical Conditions............................................ 110 
12.2.5.9 
Lack of Efficacy or Worsening of Breast Cancer ................. 110 
12.2.5.10 
Hospitalization or Prolonged Hospitalization........................ 110 
12.2.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 111 
12.2.5.12 
Adverse Events in Individuals Not Enrolled in the 
Study ................................................................................... 111 
12.3 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 111 
12.3.1 
Emergency Medical Contacts.............................................. 112 
12.3.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 112 
12.3.2.1 
Events That Occur prior to Study Drug Initiation.................. 112 
12.3.2.2 
Events That Occur after Study Drug Initiation...................... 112 
12.3.3 
Reporting Requirements for Pregnancies............................ 113 
12.3.3.1 
Pregnancies in Female Patients.......................................... 113 
12.3.3.2 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................. 114 
12.4 
Follow-Up of Patients after Adverse Events ........................ 114 
12.4.1 
Investigator Follow-Up......................................................... 114 
12.4.2 
Sponsor Follow-Up .............................................................. 114 
12.5 
Post-Study Adverse Events................................................. 114 
12.6 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 115 
13. PATIENT END OF TREATMENT ............................................................. 115 
14. PROTOCOL VIOLATIONS ....................................................................... 116 
15. STATISTICAL METHODS AND CONSIDERATIONS............................... 116 
15.1 
Planned Analyses................................................................ 116 
15.2 
Determination of Sample Size ............................................. 117 
15.2.1 
Phase Ia .............................................................................. 117 


 
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26/Protocol GO29642, Version 9 
15.2.2 
Phase IIa ............................................................................. 118 
15.2.3 
Phase Ib .............................................................................. 118 
15.3 
Safety Analyses................................................................... 119 
15.3.1 
Adverse Events ................................................................... 119 
15.3.2 
Clinical Laboratory Results.................................................. 120 
15.3.3 
Vital Signs............................................................................ 120 
15.3.4 
Concomitant Medications/Treatments ................................. 120 
15.3.5 
Endometrial Thickness ........................................................ 120 
15.3.6 
Ventricular Repolarization.................................................... 120 
15.4 
Pharmacokinetic Analyses................................................... 121 
15.5 
Anti-Tumor Activity .............................................................. 121 
15.6 
Exploratory Studies ............................................................. 122 
16. DATA COLLECTION, RETENTION, AND MONITORING ........................ 122 
16.1 
Data Collection Instruments................................................. 122 
16.2 
Data Management Procedures............................................ 123 
16.3 
Data Quality Control and Reporting..................................... 123 
16.4 
Archival of Data ................................................................... 123 
16.5 
Availability and Retention of Investigational 
Records ............................................................................... 123 
16.6 
Monitoring............................................................................ 124 
16.7 
Patient Confidentiality.......................................................... 124 
17. ADMINISTRATIVE, ETHICAL, REGULATORY 
CONSIDERATIONS.................................................................................. 124 
17.1 
Protocol Amendments ......................................................... 125 
17.2 
Protocol Deviations ............................................................. 125 
17.3 
Institutional Review Boards or Ethics Committee ................ 125 
17.3.1 
Informed Consent Form....................................................... 126 
17.4 
Reporting of Safety Issues and Serious Breaches 
of the Protocol or ICH GCP ................................................. 127 
17.5 
Sponsor Discontinuation Criteria ......................................... 127 
17.6 
Publications ......................................................................... 127 
18. REFERENCES ......................................................................................... 129 
19. APPENDICES........................................................................................... 133 


 
GDC-0810—Genentech, Inc. 
27/Protocol GO29642, Version 9 
 
 
LIST OF TABLES 
Table 1 
Single Agent Cohorts (Phase Ia and IIa)..................................... 56 
Table 2 
Combination Cohorts (Phase Ib)................................................. 56 
Table 3 
Dose Levels for Escalation for Phase Ia (Cohorts 1−9) .............. 71 
Table 4 
Dose Modification and Management Guidelines......................... 80 
Table 5 
Dose Modification Guidelines for Treatment-Related 
Non-Hematologic Toxicities ........................................................ 85 
Table 6 
Dose Modification Guidelines for Hematologic Toxicities............ 88 
Table 7 
Pre- and Post-Treatment Functional ER Imaging with FES-
PET/CT Schedule (Phase Ia)...................................................... 98 
Table 8 
Pre- and Post-Treatment Functional ER Imaging with FES-
PET/CT Schedule (Phase IIa)..................................................... 99 
Table 9 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 105 
Table 10 
Causal Attribution Guidance ..................................................... 106 
Table 11 
Probability of Escalation to the Next Dose ................................ 117 
Table 12 
Probability of Failing to Observe Toxicity .................................. 117 
Table 13 
Two-Sided Confidence Intervals for Phase IIa Cohorts ............ 118 
Table 14 
Probability of Safety-Signal Detection with 10 Patients............. 119 
 
 
LIST OF FIGURES 
Figure 1 
Palbociclib:  GDC-0810............................................................... 52 
Figure 2 
Phase IIa Schema....................................................................... 58 
Figure 3 
Cohorts C1, C2, and C3 (Dose Escalation and Expansion) 
Dosing Schema........................................................................... 59 
Figure 4 
Cohort D1 (Safety Run-In and Expansion) Dosing Schema ....... 59 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities: Phase Ia................................................ 133 
Appendix 2 
Schedule of Activities: Phase IIa............................................... 136 
Appendix 3 
Schedule of Activities: Phase Ib Cohorts C0 and C1 (Dose 
Escalation) ................................................................................ 139 
Appendix 4 
Schedule of Activities: Phase Ib Cohort D1 (Safety Run-In) ..... 143 
Appendix 5 
Laboratory Tests....................................................................... 147 
Appendix 6 
ECOG Performance Status....................................................... 148 
Appendix 7 
National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE)........................................ 149 
Appendix 8 
Restricted Medications or Treatments ...................................... 150 




GDC-0810—Genentech, Inc. 
29/Protocol GO29642, Version 9 
PROTOCOL SYNOPSIS 
TITLE: 
AN OPEN-LABEL, PHASE Ia/Ib/IIa STUDY OF GDC-0810 SINGLE 
AGENT OR IN COMBINATION WITH PALBOCICLIB AND/OR AN 
LHRH AGONIST IN WOMEN WITH LOCALLY ADVANCED OR 
METASTATIC ESTROGEN RECEPTOR POSITIVE BREAST 
CANCER 
PROTOCOL NUMBER: 
GO29642 
VERSION NUMBER: 
9 
EUDRACT NUMBER: 
2014-004852-77 
IND NUMBER: 
116019 
TEST PRODUCT: 
GDC-0810 (RO7056118) 
PHASE: 
Phase Ia/Ib/IIa 
INDICATION: 
Breast cancer 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
Primary Objective 
Phase Ia 
• 
To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose 
(RP2D)and assess the safety of single agent GDC-0810 in postmenopausal women with 
locally advanced or metastatic estrogen-receptor-positive (ER+) and human 
epidermal-growth-factor-negative (HER2−) breast cancer 
 
Phase IIa 
• 
To determine the anti-tumor activity of single agent GDC-0810 in postmenopausal women 
with locally advanced or metastatic ER+ (HER2−) breast cancer 
 
Phase Ib 
• 
To determine the RP2D and assess the safety and tolerability of concomitant administration 
of GDC-0810  with palbociclib and/or luteinizing hormone-releasing hormone (LHRH) 
agonist in women with locally advanced or metastatic ER+ (HER2−) breast cancer 
 
Secondary Objectives 
Phase Ia 
• 
To evaluate the pharmacokinetics of GDC-0810 single agent and its glucuronide 
metabolites following single and multiple dose treatments. 
 
Phase IIa 
• 
To evaluate the safety of GDC-0810 single agent when administered at the RP2Ds in 
women with locally advanced or metastatic ER+ (HER2−) breast cancer 
• 
To evaluate the effect of GDC-0810 single agent on ventricular repolarization in 
postmenopausal women participating in the Phase IIa portion of the study 
 


 
GDC-0810—Genentech, Inc. 
30/Protocol GO29642, Version 9 
Phase Ib 
• 
To evaluate the pharmacokinetics of GDC-0810 in combination with palbociclib and/or an 
LHRH agonist. 
 
• 
To evaluate the pharmacokinetics of palbociclib and/or an LHRH agonist in combination 
with GDC-0810  
 
Exploratory Objectives 
• 
To perform exploratory evaluation of biomarkers of PD response with [18F]-fluoroestradiol 
(FES)- positron emitting tomography (PET) in Phase Ia and Phase IIa 
• 
To perform exploratory evaluation of ER target gene expression 
• 
To perform exploratory evaluation of mechanisms of resistance to GDC-0810 
 
Study Design 
Description of Study 
This is a multi-institution Phase Ia/Ib/IIa open-label, dose-finding, safety, PK, and 
proof-of-concept study of GDC-0810 as a single agent and in combination with palbociclib 
and/or LHRH agonist. 
The study is divided into three phases:  Phase Ia, Phase Ib, and Phase IIa.  The Phase Ib 
palbociclib combination cohorts will be conducted in the U.S. only and the LHRH agonists 
combination cohorts will be conducted in the U.S. and South Korea.  The Phase Ia and IIa part 
of the study (single agent GDC-0810 cohorts) will be conducted in Spain, Netherlands South 
Korea and the U.S. 
Enrollment in Study GO29642 has been discontinued; therefore, no patients will be enrolled 
in the Phase Ib Cohorts C2, C3, and D2.  Any patient currently enrolled in Phase Ia, Ib 
Cohort C1, Ib Cohort D1, or IIa experiencing clinical benefit may continue to receive 
GDC-0810 as a single agent or combination with LHRH agonist or palbociclib until disease 
progression, unmanageable toxicity, patient withdrawal of consent, GDC-0810 drug supply 
has been exhausted, or the Sponsor terminates the study. 
Phase Ia 
Phase Ia consists of dose escalation in postmenopausal women with locally advanced or 
metastatic ER+ (HER2−) breast cancer and enrollment into dose escalation cohorts has been 
completed.   
During Phase Ia, GDC-0810 single agent was administered orally to postmenopausal women 
with locally advanced or metastatic ER+ (HER2−) breast cancer on a continuous daily dosing 
regimen with a Day −7 lead-in period for single dose PK evaluation prior to the start of daily 
treatment.  The incidence of DLTs will be evaluated from Day −7 through the first cycle 
(28 days) of treatment (35 days total).  Depending on safety and tolerability, patients will be 
assigned sequentially to escalating doses of GDC-0810 using standard 3 + 3 design.   
The starting dose will be 100 mg once daily.  Dosing will be based on flat milligram increments 
without adjustments for body size.  It is anticipated that dose levels will span the anticipated 
pharmacologically active dose range and be within the safety margin indicated by nonclinical 
toxicology studies.  The dosing regimen may be changed if the PK and safety data suggest that 
a discontinuous regimen or another dosing frequency (e.g., twice daily [BID]), with or without a 
fasting requirement, may be preferable for the Phase IIa portion of the study. 
Phase IIa 
Expansion cohorts consisting of a total of 100 postmenopausal women with locally advanced or 
metastatic ER+ (HER2−) breast cancer previously treated with an aromatase inhibitor (AI) will 
be treated at the RP2D to further characterize the safety, PK, PD, and anti-tumor activity of 
GDC-0810 as follows: 


 
GDC-0810—Genentech, Inc. 
31/Protocol GO29642, Version 9 
• 
Cohort A:  30 patients who have confirmed ER-α (ESR1) mutation of the ligand-binding 
domain (LBD), further divided into 2 subsets: 
Cohort A1:  20 patients who had no prior treatment with fulvestrant.  FES-PET will be 
obtained for PD analysis only in Cohort A1. 
Cohort A2:  10 patients where prior treatment with fulvestrant is allowed 
• 
Cohort B:  70 patients who have progressed following ≤ 1 prior therapy with an AI in the 
advanced/metastatic setting, further divided into 2 subsets: 
Cohort B1:  50 patients who had no prior treatment with fulvestrant 
Cohort B2:  20 patients where prior treatment with fulvestrant is allowed 
 
During the Phase Ib and Phase IIa portion of the study, there will be no PK week lead-in period 
(i.e., all eligible patients will start continuous daily dosing treatment on Cycle 1 Day 1). 
The effect of GDC-0810 on ventricular repolarization will be evaluated in all patients enrolled in 
the Phase IIa portion of the study. 
After enrollment is complete in Cohorts A2, B1, and B2 of the Phase IIa portion of the study, 
further enrollment in Cohort A1 may be discontinued.  Enrollment in the Phase IIa portion of 
the study is complete. 
All patients will be treated until disease progression, unacceptable toxicity, or patient withdrawal 
of consent. 
Phase Ib 
Enrollment in Study GO29642 has been discontinued; therefore, no patients will be enrolled 
in the Phase Ib Cohorts C2, C3, and D2.   
In Cohorts C1, C2, and C3 of the Phase Ib study (dose escalation and expansion), GDC-0810 
will be administered orally on Days 1−28 of a 28-day schedule and 125 mg palbociclib will be 
administered on Days 1−21 of a 28-day schedule to women with locally advanced or metastatic 
ER+ (HER2−) breast cancer.  In Cohorts C1 and C2 (dose escalation), patients will be assigned 
sequentially to escalating doses of GDC-0810 using standard 3 + 3 design.  If the MTD is 
exceeded at dose level C1 (or the dose level is deemed intolerable in the absence of dose 
limiting toxicities), de-escalation to dose level C0 may occur.  Palbociclib dose de-escalation 
below 75 mg/day is not allowed, but the schedule may be changed in consultation with the 
Medical Monitor for example to 75 mg/day 2 weeks on followed by 2 weeks off (2/2 schedule).  
The starting dose of GDC-0810 will be 400 mg daily, one dose level below the single agent 
RP2D.   
In Cohort C3, up to 6 pre- or perimenopausal women may be enrolled to receive a combination 
of GDC-0810 (28/0), LHRH every 4 weeks (Q4W), and palbociclib (21/7). 
In Phase Ib Cohort D1 (safety run-in cohort) and Cohort D2 (dose expansion), GDC-0810 will 
be administered orally on Days 1−28 of a 28-day schedule and an LHRH agonist administered 
monthly.  The GDC-810 dose for Cohort D1 will be 600 mg daily.  There will be no dose 
escalation of either study drug or study drug treatment.  No patients will be enrolled in 
Cohort D2. 
For Cohorts, C1, C2 and D1, the incidence of DLTs will be evaluated from Days 1 to 28 of 
Cycle 1.   
Number of Patients 
• 
Phase I:  21 to 42, depending on how many doses are needed to reach the MTD and/or 
RP2D 
• 
Phase IIa:  100 Target Population 
• 
Phase Ib:  Approximately 5 patients have been enrolled in the Phase Ib dose escalation 
cohorts (Cohorts C0 and C1).  No additional patients will be enrolled. 
Approximately 4 patients have been enrolled at the RP2D of GDC-0810 and palbociclib, and 
approximately 6 patients have been enrolled at 600 mg of GDC-0810 and an LHRH agonist  
 


 
GDC-0810—Genentech, Inc. 
32/Protocol GO29642, Version 9 
Target Population 
Phase Ia Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of either locally recurrent disease not amenable to resection or radiation therapy 
with curative intent, or metastatic disease, both progressing after at least 6 months of 
endocrine therapy for ER+ breast cancer 
• 
ER-positive tumor (staining in ≥ 1% cells by immunohistochemistry [IHC] as per local 
laboratory testing)  
• 
HER2-negative breast cancer as per local laboratory testing (IHC result of 0 or +1 for 
cellular membrane protein expression or a fluorescence in situ hybridization [FISH] result 
showing HER2/CEP17 ratio < 1.8 or an average of fewer than 4 copies of HER2 gene per 
nucleus for systems without an internal control probe)  
• 
At least 2 months must have elapsed from the use of tamoxifen  
• 
At least 6 months must have elapsed from the use of fulvestrant 
• 
At least 2 weeks must have elapsed from the use of any other anti-cancer hormonal therapy  
• 
At least 3 weeks must have elapsed from the use of any chemotherapy 
• 
Females, 18 years of age or older 
• 
Postmenopausal status defined as:  
Prior bilateral surgical oophorectomy 
Age ≥ 56 years: 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 who had 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 who have medical menopause on LHRH agonist (on stable dose 
≥ 1 year) with amenorrhea ≥ 1 year since last menses and serum estradiol levels in the 
postmenopausal range (< 20 pg/mL) irrespective of FSH/LH levels for Phase Ia; 
medical menopause is defined as ovarian suppression by any medical cause including 
treatment with LHRH agonist, radiation, or surgery causing inhibition of pituitary 
gonadotropin secretion, irrespective of FSH/LH levels. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2  
• 
Resolution of all acute toxic effects of prior therapy or surgical procedures to baseline or 
Grade ≤ 1 (except alopecia or other toxicities not considered to be a safety risk for the 
patient) 
• 
Adequate organ function as defined by the following criteria: 
Absolute neutrophil count (ANC) ≥ 1500/μL  
Platelets ≥ 100,000/μL 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 times 
the upper limit of normal (ULN) or AST and ALT ≤ 5 × ULN if liver function 
abnormalities are due to underlying malignancy or liver metastasis 
Total serum bilirubin ≤ 1.5 × ULN regardless of liver involvement secondary to tumor.  
Inclusion of patients with increased serum indirect bilirubin (≤ 3 × ULN) due to Gilbert’s 
syndrome is permitted. 
Serum creatinine ≤ 1.5 × ULN  
QTc ≤ 460 msec 
• 
Signed and dated informed consent document indicating that the subject has been informed 
of all the pertinent aspects of the trial prior to enrollment 


 
GDC-0810—Genentech, Inc. 
33/Protocol GO29642, Version 9 
• 
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures 
• 
For women of childbearing potential (including patients with menopause induced by LHRH 
agonists):  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the 
treatment period and for at least 90 days after the last dose of LHRH agonist or 28 days 
after the last dose of GDC-0810 and palbociclib (whichever is latest) 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and 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. 
 
Phase Ia Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Untreated or symptomatic CNS metastases. 
Note:  Patients with treated and asymptomatic CNS metastases that are 
radiographically stable within 12 weeks prior to enrollment will be allowed, provided 
long-term use of corticosteroids has been discontinued within 4 weeks prior to 
enrollment. 
• 
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. 
• 
More than two prior chemotherapies in the advanced/metastatic setting (prior adjuvant 
chemotherapy is allowed so long as it occurred ≥ 12 months prior to enrollment) 
• 
Current treatment with any systemic anti-cancer therapies for advanced disease or any 
systemic experimental treatment on another clinical trial 
• 
Diagnosis of any secondary malignancy within 2 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ 
• 
Any of the following within 12 months prior to enrollment:  myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of Grade ≥ 2, atrial fibrillation of any 
grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, or 
cerebrovascular accident including transient ischemic attack  
• 
Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or upper 
gastrointestinal surgery including gastric resection 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol 
abuse, or cirrhosis 
• 
Major surgery within 4 weeks prior to enrollment 
• 
Radiation therapy within 2 weeks prior to enrollment 
• 
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the subject inappropriate for entry into this study 
 


 
GDC-0810—Genentech, Inc. 
34/Protocol GO29642, Version 9 
Phase IIa Inclusion Criteria 
• 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of either locally recurrent disease not amenable to resection or radiation therapy 
with curative intent, or metastatic disease, both progressing after at least 6 months of 
endocrine therapy with an aromatase inhibitor for ER+  breast cancer 
• 
ER-positive tumor (staining in ≥ 1% cells by IHC as per local laboratory testing)  
• 
HER2-negative breast cancer as per local laboratory testing (IHC result of 0 or +1 for 
cellular membrane protein expression or a FISH result showing HER2/CEP17 ratio < 1.8 or 
an average of fewer than 4 copies of HER2 gene per nucleus for systems without an 
internal control probe) 
• 
Cohort A only:  
Confirmed ESR1 mutations of the LBD (as determined in a Clinical Laboratory 
Improvement Amendments [CLIA]-certified laboratory) and consent to provide an 
archival tumor sample for retrospective confirmation (LBD further defined as the region 
between ER-α amino acids 302 to 595) and 
Presence of evaluable disease as per RECIST Version 1 further defined as follows: 
Measurable disease, or evaluable bone disease⎯that is, bone lesions that are 
lytic or mixed (lytic + sclerotic) in the absence of measurable lesion.  Note: 
previously irradiated lesions are deemed measurable only if progression is 
documented at the site after completion of radiation.   
• 
For patients with soft tissue or visceral metastases that are safely accessible, paired 
pre- and on-treatment tumor biopsies are required.  
Cohort A1 only:  No prior fulvestrant allowed; at least 2 months must have elapsed 
from the use of tamoxifen (if applicable)  
Cohort A2 only:  Prior fulvestrant allowed 
 
• 
Cohort B only: Disease progression following ≤ 1 prior treatment with an AI in the 
advanced/metastatic setting (prior adjuvant treatment with an AI is allowed): 
Patients must have relapsed ≥ 12 months from completion of adjuvant treatment or 
progressed following ≥ 6 months of treatment in the advanced/metastatic setting. 
Measurable disease, or evaluable bone disease⎯that is, bone lesions that are lytic or 
mixed (lytic + sclerotic) in the absence of measurable lesion.  Note: previously 
irradiated lesions are deemed measurable only if progression is documented at the site 
after completion of radiation.   
Cohort B1 only:  No prior fulvestrant allowed 
Cohort B2 only:  Prior fulvestrant allowed 
 
• 
At least 2 weeks must have elapsed from the use of the most recent endocrine therapy 
(for Cohort A1, if most recent endocrine therapy is tamoxifen, see inclusion criterion above) 
• 
At least 3 weeks must have elapsed from the use of any chemotherapy 
• 
Females, 18 years of age or older 
• 
Postmenopausal status defined as:  
Prior bilateral surgical oophorectomy 
Age ≥ 56 years: 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 FSH levels (> 40 mIU/mL) in the postmenopausal range 
Age < 56 years who had 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 


 
GDC-0810—Genentech, Inc. 
35/Protocol GO29642, Version 9 
Age < 56 years who have medical menopause, such as LHRH agonist (on stable dose 
≥ 1 year) with amenorrhea ≥ 1 year since last menses and serum estradiol levels in the 
postmenopausal range (< 20 pg/mL) irrespective of FSH/LH levels.  Cause of medical 
menopause should be discussed with the Medical Monitor. 
• 
ECOG performance status 0 or 1  
• 
Resolution of all acute toxic effects of prior therapy or surgical procedures to baseline or 
Grade ≤ 1 (except alopecia or other toxicities not considered to be a safety risk for the 
patient) 
• 
Adequate organ function as defined by the following criteria: 
Absolute neutrophil count (ANC) ≥ 1500/ L  
Platelets ≥ 100,000/ L 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 
≤ 3 × ULN, or AST and ALT ≤ 5 × ULN if liver function abnormalities are due to 
underlying malignancy or liver metastasis 
Total serum bilirubin ≤ 1.5 × ULN regardless of liver involvement secondary to tumor. 
Inclusion of patients with increased serum indirect bilirubin (≤ 3 × ULN) due to Gilbert’s 
syndrome is permitted 
Serum creatinine ≤ 1.5 × ULN  
QTc ≤ 460 msec 
• 
Signed and dated informed consent document indicating that the subject has been informed 
of all the pertinent aspects of the trial prior to enrollment 
• 
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures 
• 
For women of childbearing potential (including patients with menopause induced by LHRH 
agonists):  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the 
treatment period and for at least 90 days after the last dose of LHRH agonist or 28 days 
after the last dose of GDC-0810 and palbociclib (whichever is latest). 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation and copper intrauterine devices. 
• 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and 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. 
 
Phase IIa Exclusion Criteria 
• 
Untreated or symptomatic CNS metastases. 
Note:  Patients with treated and asymptomatic CNS metastases that are 
radiographically stable within 12 weeks prior to enrollment will be allowed, provided 
long-term use of corticosteroids have been discontinued within 4 weeks prior to 
enrollment 
• 
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.   


 
GDC-0810—Genentech, Inc. 
36/Protocol GO29642, Version 9 
• 
Prior treatments: 
 
 
• 
Current treatment with any systemic anti-cancer therapies for advanced disease  
• 
Diagnosis of any secondary malignancy within 2 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ 
• 
Any of the following within 12 months prior to enrollment: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of Grade ≥ 2, atrial fibrillation of any 
grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, or 
cerebrovascular accident including transient ischemic attack  
• 
Active inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis), any active 
bowel inflammation (including diverticulitis), chronic diarrhea, short bowel syndrome,  or 
history of upper gastrointestinal surgery including gastric resection 
• 
Known human immunodeficiency virus infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., Hepatitis B or Hepatitis C virus), current alcohol 
abuse, or cirrhosis 
• 
Major surgery within 4 weeks prior to enrollment 
• 
Radiation therapy within 2 weeks prior to enrollment 
• 
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the Investigator, would make the subject inappropriate for entry into this study 
 
Phase Ib Inclusion Criteria 
• 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of either locally recurrent disease not amenable to resection or radiation therapy 
with curative intent, or metastatic disease 
• 
Documented sensitivity to prior hormonal therapy (Relapsed after 24 mo of adjuvant 
endocrine therapy or had a clinical benefit from prior endocrine therapy in the context of 
advanced disease) 


 
GDC-0810—Genentech, Inc. 
37/Protocol GO29642, Version 9 
• 
ER-positive tumor (staining in ≥ 1% cells by immunohistochemistry [IHC] as per local 
laboratory testing)  
• 
HER2-negative breast cancer as per local laboratory testing (IHC result of 0 or +1 for 
cellular membrane protein expression or a FISH result showing HER2/CEP17 ratio < 1.8 or 
an average of fewer than 4 copies of HER2 gene per nucleus for systems without an 
internal control probe)  
• 
At least 2 weeks must have elapsed from the use of any other anti-cancer hormonal therapy 
excluding LHRH agonist for patients enrolled in Cohorts C3, D1 and D2  
• 
At least 3 weeks must have elapsed from the use of any chemotherapy 
• 
Females, 18 years of age or older 
• 
Postmenopausal status defined as:  
Prior bilateral surgical oophorectomy 
Age ≥ 56 years: 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 who had 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 who have medical menopause on LHRH agonist (on stable dose 
≥ 1 year) with amenorrhea ≥ 1 year since last menses and serum estradiol levels in the 
postmenopausal range (< 20 pg/mL) irrespective of FSH/LH levels; medical 
menopause is defined as ovarian suppression by any medical cause including 
treatment with LHRH agonist, radiation, or surgery causing inhibition of pituitary 
gonadotropin secretion, irrespective of FSH/LH levels. 
Age < 56 years who have medical menopause on LHRH agonist (on stable dose 
≥ 1 month) for Phase Ib Cohorts D1, D2, and C3 
• 
Eastern Cooperative Oncology Group (ECOG) performance status < 2  
• 
Resolution of all acute toxic effects of prior therapy or surgical procedures to baseline or 
Grade ≤ 1 (except alopecia or other toxicities not considered to be a safety risk for the 
patient) 
• 
Adequate organ function as defined by the following criteria: 
Absolute neutrophil count (ANC) ≥ 1500/μL  
Platelets ≥ 100,000/μL 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 times 
the upper limit of normal (ULN) or AST and ALT ≤ 5 × ULN if liver function 
abnormalities are due to underlying malignancy or liver metastasis 
Total serum bilirubin ≤ 1.5 × ULN regardless of liver involvement secondary to tumor.  
Inclusion of patients with increased serum indirect bilirubin (≤ 3 × ULN) due to Gilbert’s 
syndrome is permitted. 
Serum creatinine ≤ 1.5 × ULN  
QTc ≤ 460 msec 
• 
Signed and dated informed consent document indicating that the subject (or legally 
acceptable representative) has been informed of all the pertinent aspects of the trial prior to 
enrollment 
• 
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures 


 
GDC-0810—Genentech, Inc. 
38/Protocol GO29642, Version 9 
• 
For women of childbearing potential (including patients with menopause induced by LHRH 
agonists):  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the 
treatment period and for at least 90 days after the last dose of LHRH agonist or 28 days 
after the last dose of GDC-0810 and palbociclib (whichever is latest) 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and 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. 
• 
Additional inclusion criteria for Cohorts C0, C1, C2, and C3 (palbociclib combination 
cohorts):  No prior treatment with CDK4/6 inhibitor 
 
Phase Ib Exclusion Criteria 
• 
Untreated or symptomatic CNS metastases. 
Note:  Patients with treated and asymptomatic CNS metastases that are 
radiographically stable within 12 weeks prior to enrollment will be allowed, provided 
long-term use of corticosteroids haves been discontinued within 4 weeks prior to 
enrollment. 
• 
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. 
• 
More than two prior chemotherapies including  adjuvant chemotherapy  
• 
Current treatment with any systemic anti-cancer therapies for advanced disease or any 
systemic experimental treatment on another clinical trial 
• 
Diagnosis of any secondary malignancy within 2 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ 
• 
Any of the following within 12 months prior to enrollment:  myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of Grade ≥ 2, atrial fibrillation of any 
grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, or 
cerebrovascular accident including transient ischemic attack  
• 
Active inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis), any active 
bowel inflammation (including diverticulitis), chronic diarrhea, short bowel syndrome, or 
history of upper gastrointestinal surgery including gastric resection 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol 
abuse, or cirrhosis 
• 
Major surgery within 4 weeks prior to enrollment 
• 
Radiation therapy within 2 weeks prior to enrollment 
• 
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the subject inappropriate for entry into this study 
• 
Pregnancy, lactation, or breastfeeding  


 
GDC-0810—Genentech, Inc. 
39/Protocol GO29642, Version 9 
• 
Additional exclusion criteria for patients in Cohorts C0, C1, C2 or C3 (palbociclib 
combination cohorts)  
History of venous thromboembolic event requiring therapeutic anticoagulation 
Vaginal bleeding within 2 months prior to enrollment 
 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
GDC-0810 drug supply is exhausted, or when Sponsor decides to stop the study. 
Length of Study 
Study duration will be from April 2013 to when GDC-0810 drug supply is exhausted, or when 
Sponsor decides to stop the study. 
Investigational Medicinal Products 
The research staff at each participating site will provide detailed instructions and training for the 
handling of the study drug (GDC-0810) and study treatment (palbociclib) and their 
administration to each patient at the beginning of her study participation. 
All patients should take the full prescribed dose of GDC-0810 by mouth at approximately the 
same time each day and within 30 minutes after eating a meal.  GDC-0810 tablets should be 
swallowed whole and tablets should not be cut or crushed. 
Evening dosing may be initiated to alleviate gastrointestinal symptoms from GDC-0810.  Please 
note that morning dosing the day before PK evaluation days is required to allow accurate 
assessment of PK trough levels of study drug. 
If a dose is missed, patients should just take the next scheduled GDC-0810 dose, without 
compensating for the missed dose. 
Palbociclib (Phase Ib Cohorts C0 and C1):  Refer to palbociclib package insert for details on 
the formulation and storage of palbociclib.  Palbociclib will be supplied by the Sponsor.   
Phase Ia 
During Phase Ia, the full prescribed dose of GDC-0810 should be taken by mouth in the 
morning, after fasting overnight, at approximately the same time each day; food should not be 
eaten for at least 1 hour after taking GDC-0810.  The dosing regimen may be changed if the PK 
and safety data from the dose escalation suggest that a discontinuous regimen or another 
dosing frequency (e.g., BID), with or without a fasting requirement, may be preferable for the 
Phase IIa portion of the study. 
PK Week Lead-In:  In Phase Ia, patients enrolled in the dose escalation cohorts will receive a 
single oral dose of GDC-0810 in the clinic on Day −7 and will return to the clinic for the next 
2 consecutive days for PK sample collection.  The time of dose administration will be called 
“0” (zero) hour.  If a patient vomits after receiving GDC-0810, this should be recorded in the 
patient’s Case Report Form (CRF) but the dose should not be repeated. 
In Phase Ib and Phase IIa, there will be no Day − 7 to Day 0 PK lead-in period. 
Continuous Dosing:  Phase Ia GDC-0810 will be given continuously beginning on Cycle 1 
Day 1 in 28-day cycles.  During Cycle 1 of the dose escalation, patients will return to the clinic 
on a weekly basis (Days 8, 15, and 22) for safety evaluation and collection of predose PK 
samples.  On those days, treatment will be administered in the clinic. 
Similarly, on Day 1 of every subsequent new cycle of dosing beginning with Cycle 2, study drug 
will be administered in the clinic following all the assessments as indicated in the Schedule of 
Activities.   
All other doses of GDC-0810 will be administered on an outpatient basis.  It is anticipated that 
some patients may occasionally forget to take a dose of GDC-0810.  In those cases, patients 
should just take the next scheduled dose, without compensating for the missed dose. 
 
Phase IIa 
The full bed dose of GDC-0810 should be taken by mouth at approximately the same time each 
day and within 30 minutes after eating a meal. 


 
GDC-0810—Genentech, Inc. 
40/Protocol GO29642, Version 9 
Phase Ib 
Palbociclib administration (if applicable):  Palbociclib should be taken with food at the same time 
each day.  The capsule should be swallowed whole.  The capsules should not be chewed, 
crushed, or opened.  If a dose is missed, patients should just take the next scheduled 
palbociclib dose, without compensating for the missed dose. 
LHRH administration (if applicable):  LHRH agonists should be administered monthly by site 
staff. 
Continuous Dosing:  In Phase Ib, GDC-0810 will be given continuously beginning on Cycle 1 
Day 1 in 28-day cycles.  During Cycle 1 of the dose escalation, patients will return to the clinic 
on a weekly basis (Days 8, 15, and 22) for safety evaluation and collection of predose PK 
samples.  On those days, treatment will be administered in the clinic.  Study treatments, 
palbociclib will be given on Days 1−21 of each cycle and LHRH agonist will be given on Day 1 
of each cycle.  Evening dosing may be initiated to alleviate gastrointestinal symptoms from 
GDC-0810.  However, on Day 28 of Cycles 1, 2, and 3, the dose of GDC-0810 should be taken 
in the morning to allow trough PK sample collections on Cycle 2 Day 1, Cycle 3 Day 1, and 
Cycle 4 Day 1. 
Similarly, on Day 1 of every subsequent new cycle of dosing beginning with Cycle 2, study 
treatment will be administered in the clinic following all the assessments as indicated in the 
Schedule of Activities. 
All other doses of GDC-0810 or palbociclib will be administered on an outpatient basis. It is 
anticipated that some patients may occasionally forget to take a dose of GDC-0810 or 
palbociclib.  In those cases, patients should just take the next scheduled dose, without 
compensating for the missed dose. 
Non-Investigational Medicinal Products 
Luteinizing Hormone Releasing Hormone Agonist (LHRH) (Phase Ib Cohort D1):  Choice 
of LHRH agonist will be an institutional choice approved for use in breast cancer.  Refer to 
LHRH agonist package insert for details on the formulation and storage of LHRH agonist.  
If patient becomes intolerant to current LHRH agonist, then patient may switch to another 
approved LHRH agonist during trial.  LHRH agonists will be prescribed by the study sites and 
cost of the study treatment will be reimbursed by the Sponsor for the duration of the study.  
Statistical Methods 
Primary Analysis 
Phase Ia and Phase Ib 
For safety analyses, the analysis population will include all enrolled patients who receive at 
least one dose of study medication. 
Study treatment discontinuation and reasons for patient discontinuations from the study will be 
described and summarized.  Study drug administration data will be listed and any dose 
modifications will be flagged. 
Phase IIa 
Disease assessments (CT scan of the chest, abdomen, and pelvis, plus a bone scan) will be 
performed at screening and every 8 weeks from Cycle 1 Day 1 thereafter, regardless of 
treatment delays resulting from toxicity.  Radiographic confirmation of objective tumor response 
or disease progression will be based on RECIST v1.1. 
Determination of Sample Size 
Phase Ia 
The number of patients to be enrolled in Phase Ia will depend upon the observed safety and 
PK/PD profile, which will determine the number of dose escalations. 


 
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Phase IIa 
At the RP2D, a total of approximately 100 patients have been enrolled to further assess the 
safety, tolerability, preliminary evidence of anti-tumor activity, and exploratory PD markers of 
response of GDC-0810 in 3 distinct patient populations (Cohorts A1 and A2 will be combined for 
analysis purposes). 
Phase Ib 
Approximately 5 patients have been enrolled in the Phase Ib dose escalation cohorts 
(Cohorts C0 and C1).  No additional patients will be enrolled. 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
21/7 
21/7 = Days 1−21 of 28-day cycle (no dosing holiday) 
28/7 
28/0 = Days 1−28 of 28-day cycle (no dosing holiday); 
AE 
adverse event 
AI 
aromatase inhibitor 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
BID 
bis en die (twice daily) 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CRF 
case report form 
CSF 
colony stimulating factors 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DLT 
dose-limiting toxicity 
eCRF 
electronic Case Report Form 
ECOG 
Eastern Cooperative Oncology Group 
ER 
estrogen receptor 
ESR1 
ER-α 
FDA 
U.S. Food and Drug Administration 
FES-PET 
fluoroestradiol positron emitting tomography 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GIST 
gastrointestinal stromal tumor 
HER2 
human epidermal growth factor 2 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IC50 
50% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
 


 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IV 
intravenous 
LBD 
ligand-binding domain 
LHRH 
luteinizing hormone-releasing hormone 
LPLV 
last patient last visit 
mBC 
metastatic breast cancer 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
objective response rate  
PD 
pharmacodynamic 
PET 
positron emitting tomography 
PGx 
pharmacogenomic 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit 
alpha 
PK 
pharmacokinetic 
PO 
by mounth 
QD 
once daily 
Q4W 
every 4 weeks 
QTc 
corrected QT interval 
Rb 
retinoblastoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase II dose 
SAE 
serious adverse event 
SERD 
selective estrogen receptor down-regulator 
SHBG 
sex hormone-binding globulin 
SOC 
system organ class 
Tmax 
time of maximal plasma concentration 
ULN 
upper limit of normal 
VTE 
venous thromboembolism 
 


 
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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 the 
therapeutic approach in 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 and therefore require further treatment for optimal disease 
control.  As such, there is a need for the development of 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 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-/third-line hormonal treatment after progression on prior hormonal 
therapy (Di Leo et al. 2010; Baselga et al. 2011).  Importantly, there is growing evidence 
that in the endocrine resistant state, 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 ER-α 
(ESR1) affecting the ligand-binding domain (LBD) of the ER.  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 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). 
Background on GDC-0810 
The term "study drug" will be used throughout the protocol to refer to GDC-0810.  
GDC-0810 is a novel, potent ER-α antagonist that was being developed for use as a 
single agent or in combination with other anti-cancer therapies as treatment for ER+ 
advanced breast cancer.  The development of GDC-0810 has been halted as a result of a 
Sponsor decision to evaluate strategic options for this molecule.  The decision to halt 
the development of GDC-0810 is not due to any safety concerns.  No further patients 
will be enrolled into GDC-0810 studies.   


 
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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 
bioavailability in all nonclinical species tested, unlike fulvestrant, which has a steroidal 
structure and exhibits poor bioavailability. 
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.  
1.1 
GDC-0810 SINGLE AGENT CLINICAL SAFETY SUMMARY 
As of 1 October 2014, enrollment in the Phase I dose-escalation portion of the study was 
completed with 41 patients enrolled at doses from 100 mg to 800 mg. 
As of 15 April 2016, one of 6 patients had experienced a dose-limiting toxicity (DLT) of 
Grade 3 diarrhea in the 800-mg once daily (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 pharmacokinetic (PK) profile of GDC-0810.   
As of 15 April 2016, adverse events of any grade related to study drug occurring at 
> 20% frequency in the Phase Ia 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. 


 
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As of 9 September 2016, 107 patients have been enrolled in the combined Phase Ib 
Cohort D1 and Phase IIa dose-expansion portion 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 600 mg of GDC-0810 in combination with a 
luteinizing hormone-releasing hormone (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 Phase Ia experience with GI toxicities when GDC-0810 was 
administered under fasting or non-fasting conditions.  Safety data for the Phase IIa study 
remain preliminary with the median treatment duration being 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 potential risks of GDC-0810, regardless of relatedness, 
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 successfully 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. 
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. 


 
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1.2 
CLINICAL PK SUMMARY 
The clinical pharmacokinetics of GDC-0810 is under investigation in the ongoing clinical 
Phase Ia/IIa Study GO29642.  Preliminary PK information from this study is summarized 
below. 
• 
GDC-0810 was rapidly absorbed with peak concentrations achieved at 1−3 hours 
after dosing. 
• 
The mean terminal half-life was approximately 8 hours, and mean apparent oral 
clearance was 8 L/hour after a single dose of GDC-0810 at 600 mg under the 
non-fasted condition.  Consistent with the half-life, minimal drug accumulation was 
observed following multiple dosing. 
• 
GDC-0810 exposure in the fasted state increased with dose across the entire dose 
range tested (100−800 mg). 
• 
In the Phase Ia portion of the study, at 600 mg QD, mean ± SD steady state AUC0-6 
and Cmax for GDC-0810 was 41.1 ± 27.5 μg • hour/mL and 11.8 ± 6.61 μg/mL, 
respectively, under the fasted state (n=6), and 74.9 ± 30.1 μg • hour/mL and 
25 ± 8.35 μg/mL, respectively, under the nonfasted state (n=5). 
• 
In the Phase IIa portion of the study, at the RP2D of 600 mg QD under the fed 
state, mean ± SD steady state AUC0-6 and Cmax for GDC-0810 was 
39.5 ± 22.5 μg • hour/mL (n=40) and 14.3 ± 7.3 μg/mL (n=42), respectively. 
 
Based on pharmacodynamic (PD), clinical tolerability, and preliminary PK data collected 
to date, once-daily administration of 600 mg under fed conditions (within 30 minutes 
after eating a meal) was selected as the single-agent RP2D for GDC-0810.  See the 
GDC-0810 Investigator Brochure for further details. 
2. 
BACKGROUND ON CYCLIN-DEPENDENT KINASES AND 
PALBOCICLIB (IBRANCE) 
Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression.  The 
cyclin D-CDK4/6 pathway is involved in promoting the transition from G1 phase to 
S phase (Musgrove et al. 2011). 
CDK4 and CDK6 initiate the phosphorylation of retinoblastoma (Rb) protein, resulting in 
activation of E2F transcription factors.  E2Fs initiate the S phase gene expression 
program, including the expression of both cyclin E and CDK2, resulting in further Rb 
phosphorylation and ultimately S phase entry (Malumbres et al. 2009). 
Some cancer types disrupt cell cycle progression through loss of RB1 function, making 
them refractory to the effects of CDK4/6 inhibition (Aarts et al. 2013).  In contrast, ER+ 
breast cancers drive progression through overexpression of cyclin D.  Overexpressed 
cyclin D1 is a common downstream effector of many of the oncogenic drivers of ER+ 
breast cancer (Finn et al. 2009). 


 
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Palbociclib is a highly selective oral inhibitor of CDK4 and CDK6 at low nanomolar 
concentrations, with 50% inhibitory concentration (IC50) values of 11 nM and 16 nM 
respectively, that has no inhibitory activity against a panel of 36 additional protein 
kinases (including CDK1, CDK2 and CDK5) (Fry et al. 2004).  It is a reversible, non-ATP 
competitive inhibitor, which blocks phosphorylation of Rb at serine 780 and serine 795.  
Palbociclib is anti-proliferative with G1 phase cell arrest in vitro (Turner et al. 2015) and 
in vivo with activity occurring only in RB1 wild-type cancer models (Fry et al. 2004).  
2.1 
NONCLINICAL OVERVIEW OF PALBOCICLIB 
Palbociclib is anti-proliferative, inhibits cellular DNA syntheses by preventing S phase 
entry, and specifically causes G1 cell cycle arrest in Rb-positive cells.  In Rb-positive 
cancer cell lines including breast, colon, and lung carcinomas, palbociclib inhibited 
thymidine incorporation into DNA.  These effects of palbociclib were not observed in 
Rb-deficient cell lines such as MDA-MB-468 human breast carcinomas (Fry et al. 2004). 
In vitro, palbociclib reduced cellular proliferation of ER+ breast cancer cell lines by 
blocking progression from G1 to S phase of the cell cycle.  Treatment of breast cancer 
cell lines with the combination of palbociclib and tamoxifen was synergistic in vitro with 
more than additive effects on growth arrest compared to treatment with each drug alone 
(Finn et al. 2009). 
Bazedoxifene, a selective estrogen modulator, in combination with palbociclib is 
efficacious in an ESR1 mutant (Y537S) PDX model (Wardell et al. 2015).  Furthermore, 
AZD9496, an oral selective estrogen receptor down-regulator (SERD) in Phase I 
development, demonstrated tumor regressions in combination with palbociclib in vivo 
(De Savi et al. 2015). 
2.2 
CLINICAL OVERVIEW OF PALBOCICLIB 
Palbociclib is being evaluated in many cancer types including breast, ovarian, 
gastrointestinal stromal tumors (GIST), liposarcomas, acute leukemias, and mantle cell 
lymphomas.  
The DLT of palbociclib is reversible myelosuppression, specifically reversible 
neutropenia (Gr 1−2:  33−54%; Gr 3−4:  20−50%).  Other hematological toxicities include 
thrombocytopenia (Gr 1−2:  7−58%; Gr 3−4:  0−17%) and anemia (Gr 1−2:  20−64%; 
Gr 3−4:  2−17%).  Phase I and II clinical trials demonstrate that palbociclib is a 
well-tolerated agent with mild to moderate fatigue (10−34%), nausea (24−30%), and 
diarrhea (1−30%) as the most commonly reported non-hematological adverse reactions 
(Schwartz et al. 2011; Flaherty et al. 2012; Dickson et al. 2013; Vaughn et al. 2015).  
Grade 3 and Grade 4 febrile neutropenia occurred in one of 30 patients (3%) in the two 
single-agent Phase II studies, respectively (Dickson et al. 2013; Vaughn et al. 2015). 
The PALOMA-1 Phase II study randomized women with advanced ER+ human 
epidermal growth factor 2 (HER2−) breast cancer who had not received any systemic 


 
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treatment for their advanced disease to receive either letrozole 2.5 mg QD alone or with 
palbociclib 125 mg QD administered daily for 21 days followed by a seven day off-period 
(21/7).  The most common adverse events reported for the palbociclib plus letrozole 
group were neutropenia (74%), leukopenia (43%), fatigue (40%), anemia (35%), and 
nausea (25%).  Grade 3 treatment-related adverse events (AEs) reported in ≥ 20% of 
patients were neutropenia (48%) and leukopenia (19%).  There were no cases of febrile 
neutropenia reported.  The most frequently reported Grade 4 adverse events were 
neutropenia (6%), pulmonary embolism (5%), and fatigue (2%).  The results showed 
substantial efficacy with the palbociclib and letrozole combination by significant 
improvement in median progression-free survival of 20 months (95% CI:  13.8, 
27.5 months) compared to letrozole alone (10.2 months; 95% CI:  5.7, 12.6 months) 
(Finn et al. 2009).  Palbociclib received accelerated approval from the United States 
Food and Drug Administration (FDA) in 2015. 
In the randomized Phase III study (PALOMA-3), pre- and postmenopausal women with 
ER+ (HER2)-breast cancer that relapsed or progressed on endocrine therapy received 
palbociclib in combination with fulvestrant or placebo and fulvestrant.  The median 
progression-free survival was 9.2 months (95% CI:  7.5 months, not estimable) with 
palbociclib and fulvestrant, and 3.8 months (95% CI: 3.5, 5.5 months) with placebo and 
fulvestrant.  Hematological adverse events were more common in the fulvestrant plus 
palbociclib arm compared with the fulvestrant plus placebo arm, including neutropenia 
(81% vs. 3%), leucopenia (50% vs. 4%), anaemia (28% vs. 11%), and 
thrombocytopenia (21% vs. 0%).  Anaemia and thrombocytopenia were predominantly 
Grade 1 to 2 in the palbociclib arm.  Neutropenia (Grade ≥ 3 was 65%) and leucopenia 
(Grade ≥ 3 was 28%) were predominantly a higher grade in the palbociclib arm.  
Whereas infections were more common in the palbociclib arm than the placebo arm 
(42% vs 30%), these were predominantly Grade 1 to 2 in severity with only 2% of 
patients in the palbociclib arm experiencing infections of Grade ≥ 3 compared with 3% 
in the placebo arm.  Febrile neutropenia was rare in both arms at 1% each (all events 
were Grade ≥ 3 in each arm with no Grade 5 events in either arm).  Common 
non-hematological events for the palbociclib and placebo arms, respectively, included 
fatigue (39% vs. 28%), nausea (32% vs. 28%), headache (24% vs. 19%), diarrhea (21% 
vs. 19%), and vomiting (17% vs. 15%) (Cristofanilli et al. 2016).  
Thromboembolic events have been reported in patients receiving palbociclib.  In the 
PALOMA-3 study of palbociclib in combination with fulvestrant, pulmonary embolism 
was reported in three patients receiving palbociclib (0.9%) compared with no patients 
receiving placebo (Cristofanilli et al. 2016).  In the PALOMA-1 study of palbociclib in 
combination with letrozole, pulmonary embolism was reported in 5% of patients 
compared with no cases in the letrozole alone arm (Finn et al. 2016). 


 
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2.3 
BACKGROUND ON OVARIAN ABLATION AND LHRH AGONIST 
Peri- and premenopausal women comprise approximately 20% of patients with 
metastatic breast cancer and constitute a group with high unmet need of additional 
therapy options.  Ovarian ablation methods for peri- and premenopausal women include 
surgical oophorectomy, ovarian irradiation, and treatment with LHRH agonists; the latter 
initially stimulate the production of estrogen in a non-pulsatile/non-physiological manner, 
causing disruption of the endogenous hormonal feedback systems, which results in the 
down-regulation of estrogen production.  LHRH agonists have been combined with 
endocrine therapies without significantly affecting their respective safety profiles in 
adjuvant and metastatic settings, as demonstrated in studies such as such as 
SOFT/TEXT (LHRH agonist combined with exemestane or tamoxifen) and PALOMA-3 
(LHRH agonist combined with fulvestrant), respectively (Pagani et al. 2014; Turner et al. 
2015).  Studies are ongoing to evaluate the selective ER degrader fulvestrant in 
combination with medical ovarian suppression in premenopausal women with metastatic 
breast cancer (Samsung Medical Center 2011; Hospital Affiliated to Military Medical 
Science 2014).  
3. 
STUDY RATIONALE FOR GDC-0810 AS A SINGLE AGENT AND 
RISK BENEFIT ASSESSMENT 
GDC-0810 is a small-molecule therapeutic agent that competes with estrogens for 
binding to the ER with low nanomolar potency.  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 to fulvestrant at 
clinically relevant exposures.  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 bioavailability in all nonclinical species 
tested, unlike fulvestrant, which has a steroidal structure and exhibits poor 
bioavailability. 
As of 15 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 (fluoroestradiol positron emitting tomography) 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 metastatic breast cancer (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 


 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 since the data cut at 
GDC-0810 doses of 300 mg BID and 400 mg twice daily (BID). 
At 600 mg by mouth (PO) daily under nonfasting conditions, GDC-0810 was well 
tolerated.  The associated adverse events were largely Grade 1, without need for any 
dose holds, dose reductions or permanent study drug discontinuations.  Diarrhea was 
the most frequently reported adverse event, occurring in all 6 patients at the 600-mg QD 
nonfasting dose level (5 patients with Grade 1 and 1 patient with Grade 2 diarrhea), with 
2 patients receiving loperamide, and 4 patients not requiring any anti-diarrheal agents.  
The RP2D chosen for this study is 600 mg PO QD under fed conditions (within 
30 minutes after a meal).  Based on the nonclinical findings and preliminary clinical 
findings, the following additional potential safety risks have been highlighted:  
uterotrophic effects (i.e., endometrial thickening and polyps), VTE effects 
(e.g., pulmonary embolism, deep vein thrombosis), kidney dysfunction (animal models 
only), phototoxicity (in-vitro model only), and drug-drug interaction with CYP2C9 
substrates (in-vitro model only). 
Specific eligibility criteria designed to minimize risk of GI toxicity and other potential risks 
are included in Section 7, and robust safety monitoring and risk mitigation strategies for 
all expected or potential safety risks are described in Section 10.4.  The implementation 
of appropriate dose-modification and treatment guidelines, appropriate choice of 
inclusion/exclusion criteria, real-time safety monitoring and assessments, and periodic 
assessment of aggregate safety data and risk/benefit ratio combine to form the 
monitoring and risk mitigation system. 
In summary, the GDC-0810 safety profile remains acceptable and clinical benefit has 
been observed in patients with refractory ER+ (HER2−) breast cancer.  
4. 
STUDY RATIONALE FOR GDC-0810 IN COMBINATION WITH 
PALBOCICLIB AND/OR LHRH AGONISTS AND RISK BENEFIT 
ASSESSMENT  
Palbociclib is an orally active selective inhibitor of CDK4/6.  The Phase II PALOMA-1 
and Phase III PALOMA-3 studies demonstrated the superiority of combining palbociclib 
with anti-hormonal therapy (letrozole or fulvestrant, respectively) over single agent 
therapy in first-line and second-line ER+ (HER2−) mBC (Finn et al. 2015; 
Turner et al. 2015).  
In two ER+ patient−derived xenograft tumor models (HCI-011 and HCI-005, 
respectively), the combination of GDC-0810 with palbociclib resulted in increased tumor 
growth inhibition compared with either single agent alone (Figure 1).  In clinical trials, the 
toxicities for palbociclib and GDC-0810 are predominantly non-overlapping.  Potential 
overlapping toxicities include fatigue, nausea, and diarrhea, which are amenable to 
monitoring, manageable, and reversible.  VTE events (including pulmonary embolism) 




 
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Vehicle ( − ) =  no estrogen supplementation;  Vehicle ( + ) = 1 mg estrogen supplementation 
 
5. 
STUDY RATIONALE FOR GDC-0810 IN COMBINATION WITH 
LHRH AGONIST AND RISK BENEFIT ASSESSMENT  
Peri- and premenopausal women, including young women diagnosed with breast cancer 
before the age of 40, have generally worse prognosis than postmenopausal women 
(Narod et al. 2012).  Peri- and premenopausal women with ER+ (HER2−) breast cancer 
need more effective endocrine therapy options. 
LHRH agonists have been combined with endocrine therapies without significantly 
affecting their safety profiles in adjuvant and metastatic settings for peri- and 
premenopausal women (Pagani et al. 2014; Turner et al. 2015).  Peri- and 
premenopausal women are rendered postmenopausal with the LHRH agonists and are 
able to benefit from endocrine therapies for postmenopausal women.  For example, 
approximately 20% of PALOMA-3 patients were pre- or perimenopausal and 
demonstrated similar benefit to the overall population (Turner et al. 2015).  
5.1 
CLINICAL DOSE SELECTION OF PALBOCICLIB 
In Cohorts C1 and C2, palbociclib 125 mg will be administered orally on Days 1−21 of a 
28-day schedule (Ibrance® [palbociclib] Prescribing Information).  


 
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5.2 
CLINICAL DOSE SELECTION OF LHRH AGONIST  
Enrollment in this study has been discontinued; therefore, no further patients will be 
enrolled.  
In Cohorts D1, D2, and Cohort C3 (in up to 6 patients who will receive GDC-0810, 
palbociclib and LHRH agonist) LHRH agonist will be administered as a monthly injection 
on a 28-day schedule.  The LHRH agonist will be the physician’s choice of an approved 
LHRH agonist administered according to its respective prescribing information.  Dose of 
LHRH agonist used for study should not deviate from the product’s labeled dosage.  
If patient becomes intolerant to current LHRH agonist, then patient may switch to 
another approved LHRH agonist during trial. 
Peri- and premenopausal women are able to benefit from endocrine therapies for 
postmenopausal women with the addition of LHRH agonists, which render them 
postmenopausal but do not have significant additional toxicities (Pagani et al. 2014; 
Turner et al. 2015).  After recommended Phase II dosages of GDC-0810 and palbociclib 
have been determined from dose escalation cohorts (C1 and C2) and combination of 
GDC-0810 and LHRH agonists has been shown to be safe (cohort D1), up to 6 pre- and 
peri-menopausal patients in Cohort C3 will receive LHRH agonist with the RP2D of 
GDC-0810 in combination with palbociclib.  This will enable development of more 
treatment options for peri- and premenopausal women with breast cancer. 
6. 
STUDY OBJECTIVES  
6.1 
PRIMARY OBJECTIVES 
6.1.1 
Phase Ia 
• 
To determine the MTD and/or RP2D and assess the safety of single agent 
GDC-0810 in postmenopausal women with locally advanced or metastatic ER+ 
(HER2−) breast cancer 
 
6.1.2 
Phase IIa 
• 
To determine the anti-tumor activity of single agent GDC-0810 in postmenopausal 
women with locally advanced or metastatic ER+ (HER2−) breast cancer 
 
6.1.3 
Phase Ib 
• 
To determine the RP2D and assess the safety and tolerability of concomitant 
administration of GDC-0810 with palbociclib and/or LHRH agonist in women with 
locally advanced or metastatic ER+ (HER2−) breast cancer 
 
6.2 
SECONDARY OBJECTIVES 
Phase Ia 
• 
To evaluate the pharmacokinetics of GDC-0810 single agent and its glucuronide 
metabolites following single and multiple dose treatments. 
 


 
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Phase IIa 
• 
To evaluate the safety of GDC-0810 single agent when administered at the RP2Ds 
in women with locally advanced or metastatic ER+ (HER2−) breast cancer 
• 
To evaluate the effect of GDC-0810 single agent on ventricular repolarization in 
postmenopausal women participating in the Phase IIa portion of the study 
 
Phase Ib 
• 
To evaluate the pharmacokinetics of GDC-0810 in combination with palbociclib 
and/or an LHRH agonist. 
• 
To evaluate the pharmacokinetics of palbociclib and/or an LHRH agonist in 
combination with GDC-0810  
 
6.2.1 
Exploratory Objectives 
• 
To perform exploratory evaluation of biomarkers of PD response with 
[18F]-fluoroestradiol (FES)-PET in Phase Ia and Phase IIa  
• 
To perform exploratory evaluation of ER target genes  
• 
To perform exploratory evaluation of mechanisms of resistance to GDC-0810 
 
7. 
STUDY DESIGN 
This is a multi-institution Phase Ia/Ib/IIa open-label, dose-finding, safety, PK, and 
proof-of-concept study of GDC-0810 as a single agent and in combination with 
palbociclib and/or LHRH agonist. 
The study is divided into three phases:  Phase Ia, Phase Ib, and Phase IIa (see Table 1 
and Table 2).  The Phase Ib palbociclib combination cohorts will be conducted in the 
U.S. only and the LHRH agonists combination cohorts will be conducted in the U.S. and 
South Korea.  The Phase Ia and IIa part of the study (single agent GDC-0810 cohorts) 
will be conducted in Spain, Netherlands South Korea and the U.S. 
Enrollment in Study GO29642 has been discontinued; therefore, no patients will be 
enrolled in the Phase Ib Cohorts C2, C3, and D2.  Any patient currently enrolled in 
Phase Ia, Ib Cohort C1, Ib Cohort D1, or IIa experiencing clinical benefit may continue 
to receive GDC-0810 as a single agent or combination with LHRH agonist or 
palbociclib until disease progression, unmanageable toxicity, patient withdrawal of 
consent, GDC-0810 drug supply has been exhausted, or the Sponsor terminates the 
study. 


 
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Table 1 
Single Agent Cohorts (Phase Ia and IIa) 
Phase 
Stage 
Dose and Schedule 
Cohorts 
Ia 
Dose Escalation 
GDC-0810 (28/0) 
1−9 
IIa 
Dose Expansion 
GDC-0810 (28/0) at RP2D 
A1, A2, B1, B2 
28/0 = Days 1−28 of 28-day cycle (no dosing holiday); RP2D = recommended Phase II dose. 
 
Table 2 
Combination Cohorts (Phase Ib) 
Phase 
Stage 
Dose and Schedule 
Cohorts 
Ib 
Dose Escalation 
400 mg GDC-0810 (28/0) + 100 mg Palbociclib (21/7) 
C0b 
Ib 
Dose Escalation 
400 mg GDC-0810 (28/0) + 125 mg Palbociclib (21/7) 
C1 
Ib 
Dose Escalation 
600 mg GDC-0810 (28/0) + 125 mg Palbociclib (21/7) 
C2 
Ib 
Dose Expansion 
GDC-0810 (28/0) at RP3D + 125 mg Palbociclib (21/7) 
C3a 
Ib 
Safety Run-in 
≤ 600 mg GDC-0810 (28/0) + LHRH agonist (Q4W) 
D1 
Ib 
Dose Expansion 
≤ 600 mg GDC-0810 (28/0) + LHRH agonist (Q4W) 
D2 
28/0 = Days 1−28 of 28-day cycle (no dosing holiday); 21/7 = Days 1−21 of 28-day cycle (no 
dosing holiday); LHRH = luteinizing hormone releasing hormone; Q4W = every 4 weeks. 
a Up to 6 peri- or premenopausal women may be enrolled in Cohort C3 to receive a combination 
of GDC-0810 (28/0), LHRH (Q4W), and palbociclib (21/7). 
b Potential de-escalation cohort 
These doses are guidelines only; actual dose escalations or reductions (including different 
regimens, e.g. 2 weeks on/2 weeks off schedule for palbociclib) may differ and will be 
determined jointly by Sponsor and study investigators during meetings at which all available 
safety and PK data will be reviewed prior to dose escalation decisions. 
 
7.1 
PHASE IA 
Phase Ia consists of dose escalation in postmenopausal women with locally advanced or 
metastatic ER+ (HER2−) breast cancer and enrollment into dose escalation cohorts has 
been completed.  
During Phase Ia, GDC-0810 single agent was administered orally to postmenopausal 
women with locally advanced or metastatic ER+ (HER2−) breast cancer on a continuous 
daily dosing regimen with a Day −7 lead-in period for single dose PK evaluation prior to 
the start of daily treatment.  The incidence of DLTs will be evaluated from Day −7 
through the first cycle (28 days) of treatment (35 days total).  Depending on safety and 
tolerability, patients will be assigned sequentially to escalating doses of GDC-0810 using 
standard 3 + 3 design.   
The starting dose will be 100 mg once daily.  Dosing will be based on flat milligram 
increments without adjustments for body size.  It is anticipated that dose levels will span 
the anticipated pharmacologically active dose range and be within the safety margin 


 
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indicated by nonclinical toxicology studies.  The dosing regimen may be changed if the 
PK and safety data suggest that a discontinuous regimen or another dosing frequency 
(e.g., BID), with or without a fasting requirement, may be preferable for the Phase IIa 
portion of the study. 
 
7.2 
PHASE IIA 
Expansion cohorts consisting of a total of 100 postmenopausal women with locally 
advanced or metastatic ER+ (HER2−) breast cancer previously treated with an AI will be 
treated at the RP2D to further characterize the safety, PK, PD, and anti-tumor activity of 
GDC-0810 as follows:  
• 
Cohort A:  30 patients who have confirmed ESR1 mutation of the LBD, further 
divided into 2 subsets: 
Cohort A1:  20 patients who had no prior treatment with fulvestrant.  FES-PET 
will be obtained for PD analysis only in Cohort A1. 
Cohort A2:  10 patients where prior treatment with fulvestrant is allowed 
• 
Cohort B:  70 patients who have progressed following ≤ 1 prior therapy with an AI in 
the advanced/metastatic setting, further divided into 2 subsets: 
Cohort B1:  50 patients who had no prior treatment with fulvestrant 
Cohort B2:  20 patients where prior treatment with fulvestrant is allowed 
(Figure 2) 
 
During the Phase Ib and Phase IIa portion of the study, there will be no PK week lead-in 
period (i.e., all eligible patients will start continuous daily dosing treatment on Cycle 1 
Day 1). 
The effect of GDC-0810 on ventricular repolarization will be evaluated in all patients 
enrolled in the Phase IIa portion of the study. 
After enrollment is complete in Cohorts A2, B1, and B2 of the Phase IIa portion of the 
study, further enrollment in Cohort A1 may be discontinued.  Enrollment in the Phase IIa 
portion of the study is complete. 
All patients will be treated until disease progression, unacceptable toxicity, or patient 
withdrawal of consent. 


 
GDC-0810—Genentech, Inc. 
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Figure 2 Phase IIa Schema  
 
 
7.3 
PHASE IB 
Enrollment in Study GO29642 has been discontinued; therefore, no patients will be 
enrolled in the Phase Ib Cohorts C2, C3, and D2.   
In Cohorts C1, C2, and C3 of the Phase Ib study (dose escalation and expansion), 
GDC-0810 will be administered orally on Days 1−28 of a 28-day schedule and 125 mg 
palbociclib will be administered on Days 1−21 of a 28-day schedule to women with 
locally advanced or metastatic ER+ (HER2−) breast cancer (Figure 3).  In Cohorts C1 
and C2 (dose escalation), patients will be assigned sequentially to escalating doses of 
GDC-0810 using standard 3 + 3 design.  If the MTD is exceeded at dose level C1 (or the 
dose level is deemed intolerable in the absence of dose limiting toxicities), de-escalation 
to dose level C0 may occur.  Palbociclib dose de-escalation below 75 mg/day is not 
allowed, but the schedule may be changed in consultation with the Medical Monitor for 
example to 75 mg/day 2 weeks on followed by 2 weeks off (2/2 schedule).  The starting 
dose of GDC-0810 will be 400 mg daily, one dose level below the single agent RP2D 
(Table 2).   


 
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Figure 3 Cohorts C1, C2, and C3 (Dose Escalation and Expansion) Dosing 
Schema  
 
In Cohort C3, up to 6 pre- or perimenopausal women may be enrolled to receive a 
combination of GDC-0810 (28/0), LHRH every 4 weeks (Q4W), and palbociclib (21/7).  
In Phase Ib Cohort D1 (safety run-in cohort) and Cohort D2 (dose expansion), 
GDC-0810 will be administered orally on Days 1−28 of a 28-day schedule and an LHRH 
agonist administered monthly (Figure 4).  The GDC-810 dose for Cohort D1 will be 
600 mg daily.  There will be no dose escalation of either study drug or study drug 
treatment.  No patients will be enrolled in Cohort D2. 
Figure 4 Cohort D1 (Safety Run-In and Expansion) Dosing Schema 
 
DLT = dose-limiting toxicity; LHRH = luteinizing hormone releasing hormone. 
 
For Cohorts, C0, C1, C2 and D1, the incidence of DLTs will be evaluated from Days 1 
to 28 of Cycle 1.   
8. 
PATIENT SELECTION 
This study can only fulfill its objectives if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is 
considered appropriate.  All relevant medical and non-medical conditions should be 
taken into consideration when deciding whether this protocol is suitable for a particular 
patient.  No waivers or exceptions will be granted for eligibility criteria deviations. 


 
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8.1 
PHASE IA 
8.1.1 
Phase Ia Inclusion Criteria 
• 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of either locally recurrent disease not amenable to resection or radiation 
therapy with curative intent, or metastatic disease, both progressing after at least 
6 months of endocrine therapy for ER+ breast cancer 
• 
ER-positive tumor (staining in ≥ 1% cells by immunohistochemistry [IHC] as per local 
laboratory testing)  
• 
HER2-negative breast cancer as per local laboratory testing (IHC result of 0 or +1 
for cellular membrane protein expression or a fluorescence in situ hybridization 
[FISH] result showing HER2/CEP17 ratio < 1.8 or an average of fewer than 4 copies 
of HER2 gene per nucleus for systems without an internal control probe)  
• 
At least 2 months must have elapsed from the use of tamoxifen  
• 
At least 6 months must have elapsed from the use of fulvestrant 
• 
At least 2 weeks must have elapsed from the use of any other anti-cancer hormonal 
therapy  
• 
At least 3 weeks must have elapsed from the use of any chemotherapy 
• 
Females, 18 years of age or older 
• 
Postmenopausal status defined as:  
Prior bilateral surgical oophorectomy 
Age ≥ 56 years: 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 who had 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 who have medical menopause on LHRH agonist (on stable 
dose ≥ 1 year) with amenorrhea ≥ 1 year since last menses and serum estradiol 
levels in the postmenopausal range (< 20 pg/mL) irrespective of FSH/LH levels 
for Phase Ia; medical menopause is defined as ovarian suppression by any 
medical cause including treatment with LHRH agonist, radiation, or surgery 
causing inhibition of pituitary gonadotropin secretion, irrespective of FSH/LH 
levels. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2  
• 
Resolution of all acute toxic effects of prior therapy or surgical procedures to 
baseline or Grade ≤ 1 (except alopecia or other toxicities not considered to be a 
safety risk for the patient) 


 
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• 
Adequate organ function as defined by the following criteria: 
Absolute neutrophil count (ANC) ≥ 1500/μL  
Platelets ≥ 100,000/μL 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 
≤ 3 times the upper limit of normal (ULN) or AST and ALT ≤ 5 × ULN if liver 
function abnormalities are due to underlying malignancy or liver metastasis 
Total serum bilirubin ≤ 1.5 × ULN regardless of liver involvement secondary to 
tumor.  Inclusion of patients with increased serum indirect bilirubin (≤ 3 × ULN) 
due to Gilbert’s syndrome is permitted. 
Serum creatinine ≤ 1.5 × ULN  
QTc ≤ 460 msec 
• 
Signed and dated informed consent document indicating that the subject has been 
informed of all the pertinent aspects of the trial prior to enrollment 
• 
Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests, and other trial procedures 
• 
For women of childbearing potential (including patients with menopause induced by 
LHRH agonists):  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use non-hormonal contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 90 days after the last 
dose of LHRH agonist or 28 days after the last dose of GDC-0810 and palbociclib 
(whichever is latest) 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of 
< 1% per year include bilateral tubal ligation and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and 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. 
 
8.1.2 
Phase Ia Exclusion Criteria 
• 
Untreated or symptomatic CNS metastases.    
Note:  Patients with treated and asymptomatic CNS metastases that are 
radiographically stable within 12 weeks prior to enrollment will be allowed, 
provided long-term use of corticosteroids has been discontinued within 4 weeks 
prior to enrollment. 


 
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• 
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. 
• 
More than two prior chemotherapies in the advanced/metastatic setting (prior 
adjuvant chemotherapy is allowed so long as it occurred ≥ 12 months prior to 
enrollment) 
• 
Current treatment with any systemic anti-cancer therapies for advanced disease or 
any systemic experimental treatment on another clinical trial 
• 
Diagnosis of any secondary malignancy within 2 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ 
• 
Any of the following within 12 months prior to enrollment:  myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of Grade ≥ 2, atrial fibrillation 
of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart 
failure, or cerebrovascular accident including transient ischemic attack  
• 
Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or 
upper gastrointestinal surgery including gastric resection 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh Class 
B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), 
current alcohol abuse, or cirrhosis 
• 
Major surgery within 4 weeks prior to enrollment 
• 
Radiation therapy within 2 weeks prior to enrollment 
• 
Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study 
 
8.2 
PHASE IIa 
8.2.1 
Phase IIa Inclusion Criteria 
• 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of either locally recurrent disease not amenable to resection or radiation 
therapy with curative intent, or metastatic disease, both progressing after at least 
6 months of endocrine therapy with an aromatase inhibitor for ER+  breast cancer 
• 
ER-positive tumor (staining in ≥ 1% cells by IHC as per local laboratory testing)  
• 
HER2-negative breast cancer as per local laboratory testing (IHC result of 0 or +1 
for cellular membrane protein expression or a FISH result showing HER2/CEP17 
ratio < 1.8 or an average of fewer than 4 copies of HER2 gene per nucleus for 
systems without an internal control probe) 


 
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• 
Cohort A only:  
Confirmed ESR1 mutations of the LBD (as determined in a Clinical Laboratory 
Improvement Amendments [CLIA]-certified laboratory) and consent to provide 
an archival tumor sample for retrospective confirmation (LBD further defined as 
the region between ER-α amino acids 302 to 595) and 
Presence of evaluable disease as per RECIST Version 1 further defined as 
follows: 
Measurable disease, or evaluable bone disease⎯that is, bone lesions that 
are lytic or mixed (lytic + sclerotic) in the absence of measurable lesion.  
Note: previously irradiated lesions are deemed measurable only if 
progression is documented at the site after completion of radiation.   
• 
For patients with soft tissue or visceral metastases that are safely accessible, paired 
pre- and on-treatment tumor biopsies are required.  
Cohort A1 only:  No prior fulvestrant allowed; at least 2 months must have 
elapsed from the use of tamoxifen (if applicable)  
Cohort A2 only:  Prior fulvestrant allowed 
 
• 
Cohort B only: Disease progression following ≤ 1 prior treatment with an AI in the 
advanced/metastatic setting (prior adjuvant treatment with an AI is allowed): 
Patients must have relapsed ≥ 12 months from completion of adjuvant treatment 
or progressed following ≥ 6 months of treatment in the advanced/metastatic 
setting. 
Measurable disease, or evaluable bone disease⎯that is, bone lesions that are 
lytic or mixed (lytic + sclerotic) in the absence of measurable lesion.  
Note: previously irradiated lesions are deemed measurable only if progression 
is documented at the site after completion of radiation.   
Cohort B1 only:  No prior fulvestrant allowed 
Cohort B2 only:  Prior fulvestrant allowed 
 
• 
At least 2 weeks must have elapsed from the use of the most recent endocrine 
therapy (for Cohort A1, if most recent endocrine therapy is tamoxifen, see inclusion 
criterion above) 
• 
At least 3 weeks must have elapsed from the use of any chemotherapy 
• 
Females, 18 years of age or older 
• 
Postmenopausal status defined as:  
Prior bilateral surgical oophorectomy 
Age ≥ 56 years: 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 FSH levels (> 40 mIU/mL) in the postmenopausal range 


 
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Age < 56 years who had 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 who have medical menopause, such as LHRH agonist (on 
stable dose ≥ 1 year) with amenorrhea ≥ 1 year since last menses and serum 
estradiol levels in the postmenopausal range (< 20 pg/mL) irrespective of 
FSH/LH levels.  Cause of medical menopause should be discussed with the 
Medical Monitor. 
• 
ECOG performance status 0 or 1  
• 
Resolution of all acute toxic effects of prior therapy or surgical procedures to 
baseline or Grade ≤ 1 (except alopecia or other toxicities not considered to be a 
safety risk for the patient) 
• 
Adequate organ function as defined by the following criteria: 
Absolute neutrophil count (ANC) ≥ 1500/μL  
Platelets ≥ 100,000/μL 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 
≤ 3 × ULN, or AST and ALT ≤ 5 × ULN if liver function abnormalities are due to 
underlying malignancy or liver metastasis 
Total serum bilirubin ≤ 1.5 × ULN regardless of liver involvement secondary to 
tumor. Inclusion of patients with increased serum indirect bilirubin (≤ 3 × ULN) 
due to Gilbert’s syndrome is permitted 
Serum creatinine ≤ 1.5 × ULN  
QTc ≤ 460 msec 
• 
Signed and dated informed consent document indicating that the subject has been 
informed of all the pertinent aspects of the trial prior to enrollment 
• 
Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests, and other trial procedures 
• 
For women of childbearing potential (including patients with menopause induced by 
LHRH agonists):  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use non-hormonal contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 90 days after the last 
dose of LHRH agonist or 28 days after the last dose of GDC-0810 and palbociclib 
(whichever is latest). 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of 
< 1% per year include bilateral tubal ligation and copper intrauterine devices. 


 
GDC-0810—Genentech, Inc. 
65/Protocol GO29642, Version 9 
• 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and 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. 
 
8.2.2 
Phase IIa Exclusion Criteria 
• 
Untreated or symptomatic CNS metastases. 
Note:  Patients with treated and asymptomatic CNS metastases that are 
radiographically stable within 12 weeks prior to enrollment will be allowed, 
provided long-term use of corticosteroids have been discontinued within 
4 weeks prior to enrollment 
• 
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.   
• 
Prior treatments: 
 
 
• 
Current treatment with any systemic anti-cancer therapies for advanced disease  
• 
Diagnosis of any secondary malignancy within 2 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ 


 
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• 
Any of the following within 12 months prior to enrollment: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of Grade ≥ 2, atrial fibrillation 
of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart 
failure, or cerebrovascular accident including transient ischemic attack  
• 
Active inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis), any 
active bowel inflammation (including diverticulitis), chronic diarrhea, short bowel 
syndrome,  or history of upper gastrointestinal surgery including gastric resection 
• 
Known human immunodeficiency virus infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh 
Class B or C, including active viral or other hepatitis (e.g., Hepatitis B or Hepatitis C 
virus), current alcohol abuse, or cirrhosis 
• 
Major surgery within 4 weeks prior to enrollment 
• 
Radiation therapy within 2 weeks prior to enrollment 
• 
Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator, would make the subject 
inappropriate for entry into this study 
 
8.3 
PHASE IB 
8.3.1 
Phase Ib Inclusion Criteria 
• 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of either locally recurrent disease not amenable to resection or radiation 
therapy with curative intent, or metastatic disease 
• 
Documented sensitivity to prior hormonal therapy (relapsed after 24 months of 
adjuvant endocrine therapy or had a clinical benefit from prior endocrine therapy in 
the context of advanced disease) 
• 
ER-positive tumor (staining in ≥ 1% cells by immunohistochemistry [IHC] as per local 
laboratory testing)  
• 
HER2-negative breast cancer as per local laboratory testing (IHC result of 0 or +1 
for cellular membrane protein expression or a FISH result showing HER2/CEP17 
ratio < 1.8 or an average of fewer than 4 copies of HER2 gene per nucleus for 
systems without an internal control probe)  
• 
At least 2 weeks must have elapsed from the use of any other anti-cancer hormonal 
therapy excluding LHRH agonist for patients enrolled in Cohorts C3, D1 and D2  
• 
At least 3 weeks must have elapsed from the use of any chemotherapy 
• 
Females, 18 years of age or older 
• 
Postmenopausal status defined as:  
Prior bilateral surgical oophorectomy 
Age ≥ 56 years: natural amenorrhea with ≥ 1 year since last menses 


 
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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 who had 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 who have medical menopause on LHRH agonist (on stable 
dose ≥ 1 year) with amenorrhea ≥ 1 year since last menses and serum estradiol 
levels in the postmenopausal range (< 20 pg/mL) irrespective of FSH/LH levels; 
medical menopause is defined as ovarian suppression by any medical cause 
including treatment with LHRH agonist, radiation, or surgery causing inhibition 
of pituitary gonadotropin secretion, irrespective of FSH/LH levels. 
Age < 56 years who have medical menopause on LHRH agonist (on stable 
dose ≥ 1 month) for Phase Ib Cohorts D1, D2, and C3 
• 
Eastern Cooperative Oncology Group (ECOG) performance status < 2  
• 
Resolution of all acute toxic effects of prior therapy or surgical procedures to 
baseline or Grade ≤ 1 (except alopecia or other toxicities not considered to be a 
safety risk for the patient) 
• 
Adequate organ function as defined by the following criteria: 
Absolute neutrophil count (ANC) ≥ 1500/μL  
Platelets ≥ 100,000/μL 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 
≤ 3 times the upper limit of normal (ULN) or AST and ALT ≤ 5 × ULN if liver 
function abnormalities are due to underlying malignancy or liver metastasis 
Total serum bilirubin ≤ 1.5 × ULN regardless of liver involvement secondary to 
tumor.  Inclusion of patients with increased serum indirect bilirubin (≤ 3 × ULN) 
due to Gilbert’s syndrome is permitted. 
Serum creatinine ≤ 1.5 × ULN  
QTc ≤ 460 msec 
• 
Signed and dated informed consent document indicating that the subject (or legally 
acceptable representative) has been informed of all the pertinent aspects of the trial 
prior to enrollment 
• 
Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests, and other trial procedures 
• 
For women of childbearing potential (including patients with menopause induced by 
LHRH agonists):  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use non-hormonal contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 90 days after the last 
dose of LHRH agonist or 28 days after the last dose of GDC-0810 and palbociclib 
(whichever is latest) 


 
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A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of 
< 1% per year include bilateral tubal ligation and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and 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. 
• 
Additional inclusion criteria for Cohorts C0, C1, C2, and C3 (palbociclib combination 
cohorts):  No prior treatment with CDK4/6 inhibitor  
 
8.3.2 
Phase Ib Exclusion Criteria 
• 
Untreated or symptomatic CNS metastases. 
Note:  Patients with treated and asymptomatic CNS metastases that are 
radiographically stable within 12 weeks prior to enrollment will be allowed, 
provided long-term use of corticosteroids haves been discontinued within 
4 weeks prior to enrollment. 
• 
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. 
• 
More than two prior chemotherapies including prior adjuvant chemotherapy  
• 
Current treatment with any systemic anti-cancer therapies for advanced disease or 
any systemic experimental treatment on another clinical trial 
• 
Diagnosis of any secondary malignancy within 2 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ 
• 
Any of the following within 12 months prior to enrollment:  myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of Grade ≥ 2, atrial fibrillation 
of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart 
failure, or cerebrovascular accident including transient ischemic attack  
• 
Active inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis), any 
active bowel inflammation (including diverticulitis), chronic diarrhea, short bowel 
syndrome, or history of upper gastrointestinal surgery including gastric resection 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh 
Class B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C 
virus), current alcohol abuse, or cirrhosis 
• 
Major surgery within 4 weeks prior to enrollment 
• 
Radiation therapy within 2 weeks prior to enrollment 


 
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• 
Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study 
• 
Pregnancy, lactation, or breastfeeding  
• 
Additional exclusion criteria for patients in Cohorts C0, C1, C2 or C3 (palbociclib 
combination cohorts)  
History of venous thromboembolic event requiring therapeutic anticoagulation 
Vaginal bleeding within 2 months prior to enrollment 
 
9. 
STUDY DRUG  
The term "study drug" will be used to refer GDC-0810. 
9.1 
GDC-0810  
9.1.1 
Description and Composition of the Drug Substance 
Chemical Name:  (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-N-methylhexan-1-aminium 
(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate 
Code Name:  GDC-0810 N-Methyl-D-Glucamine (NMG) Salt 
Molecular Formula:  C33H37ClFN3O7 (C26H20ClFN2O2 • C7H17NO5) 
Molecular Weight:  642.11 Daltons (neutral form 446.90 Daltons) 
Appearance:  White to yellow to tan crystalline solid 
 
9.1.2 
Study Drug Product 
GDC-0810 will be provided in two different strengths:  50 mg (8 mm white round tablet 
containing 50 mg GDC-0810 free acid) and 200 mg (19 mm × 8 mm white caplet 
containing 200 mg GDC-0810 free acid).  Inactive ingredients include microcrystalline 
cellulose (Avicel PH101), sodium laurel sulfate, sodium bicarbonate, sodium 
carboxymethylcellulose (Croscarmellose Sodium), fumed silica (Cab-O-Sil), and 
magnesium stearate.   
9.1.3 
Packaging and Labeling 
GDC-0810 will be supplied as 50 or 200 mg tablets (depending on total dose levels) 
packaged in 30-ct, 100 cc HDPE bottles with child-resistant closures and tamper-proof 
heat induction seals.   
Each bottle of study drug will be labeled with the required regulatory agency warning 
statement, lot number, the Sponsor’s name, and directions for patient use and storage. 


 
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10. 
STUDY TREATMENTS 
The term "study treatment" will be used to refer to palbociclib and/or LHRH agonist. 
Palbociclib (Cohorts C0 and C1) 
Refer to palbociclib package insert for details on the formulation and storage of 
palbociclib.  Palbociclib will be supplied by the Sponsor.  The Sponsor does not intend to 
provide other study interventions to patients after the conclusion of the study or any 
earlier withdrawal. 
Luteinizing Hormone Releasing Hormone Agonist (LHRH) (Cohort D1)  
Choice of LHRH agonist will be an institutional choice approved for use in breast cancer.  
Refer to LHRH agonist package insert for details on the formulation and storage of 
LHRH agonist.  If patient becomes intolerant to current LHRH agonist, then patient may 
switch to another approved LHRH agonist during trial.  LHRH agonists will be prescribed 
by the study sites and cost of study treatment will be reimbursed by the Sponsor for the 
duration of the study.  The Sponsor does not intend to provide other study interventions 
to patients after the conclusion of the study or any earlier withdrawal. 
10.1 
TREATMENT DOSE ASSIGNMENT 
10.1.1 
Phase Ia 
Standard 3 + 3 design will be followed for dose-escalation in Phase Ia.  The starting dose 
in Phase Ia of GDC-0810 single agent (Cohorts 1−9) will be 100 mg per day, followed by 
dose escalation to 200 mg (dose level 2), and by 200 mg increments thereafter 
(Table 3).  
In Phase Ia, a minimum of 3 evaluable patients will be entered at each dose level.  
If 1 out of the first 3 patients enrolled at any given dose level experiences a DLT, 
3 additional patients will be assigned to that dose level.  If ≤ 1 patient in 6 experiences a 
DLT, dose escalation will proceed. 
In Phase Ia if ≥ 2 patients at any given dose level experience a DLT, dose escalation will 
stop and the MTD may be defined as either the previous dose level or upon further 
evaluation of an intermediate lower dose level (e.g., by 100 mg decrement).   
If no DLTs are observed, the RP2D will be based on the overall safety and PK/PD profile 
of GDC-0810 single agent (Phase Ia), and not necessarily the MTD.  The decision to 
dose escalate or dose reduce will be made during dose escalation data review 
teleconferences held between the Sponsor and the investigators.   
If only 3 patients have been treated at a dose level under consideration as the MTD 
and/or RP2D, a minimum of 3 additional patients will be treated at that dose level to 
confirm the MTD and/or RP2D.   




 
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In Cohort C1 of Phase Ib, if ≥ 2 patients at any given dose level experience a DLT, dose 
escalation will stop and the MTD may be defined as either the previous dose level or 
upon further evaluation of an intermediate lower dose level.   
In addition to any DLTs, other available relevant demographic, adverse event, 
laboratory, dose administration, PK, and PD data will be reviewed prior to all dose 
escalation decisions.  
If no DLTs are observed, the RP2D will be based on the overall safety and PK/PD profile 
of GDC-0810 and palbociclib, and not necessarily the MTD.  The decision to escalate or 
reduce the dose will be made during dose-escalation data review teleconferences held 
between the Sponsor and the investigators. 
If only 3 patients have been treated at a dose level under consideration as the MTD 
and/or RP2D, a minimum of 3 additional patients will be treated at that dose level to 
confirm the MTD and/or RP2D.   
Patients enrolled in Cohort C1 of Phase Ib will continue treatment at their assigned dose 
level for at least 2 cycles and observed for cumulative toxicity.  After 2 cycles, they may 
then be treated at the next higher dose level provided it has been shown to be safe 
(passed the DLT evaluation period) in a previously treated cohort at the discretion of the 
investigator and in agreement with the patient.  
10.1.3.2 
Cohort D1  
Study GO29642 enrollment in Phase Ib has been discontinued.  No patient will be 
enrolled in Cohort D2. 
Cohort D1 of the Phase Ib study is a safety run-in of 6 patients.  
The dose of GDC-0810 in Phase Ib Cohort D1 safety run-in will be 600 mg per day.  
Dose escalation is not planned for either drug in Cohort D1.  However, the dose of 
GDC-0810 in Cohort D2 may be reduced on the basis of joint review by Sponsor and 
study investigators of available safety and tolerability data. 
In Phase Ib Cohort D1, if 2 or more patients at the combination dose level experience a 
DLT, evaluation of a lower dose level of GDC-0810 may be initiated. 
In addition to any DLTs, other available relevant demographic, adverse event, 
laboratory, dose administration, PK, and PD data will be reviewed. 
If no DLTs are observed, the RP2D will be based on the overall safety and PK/PD profile 
of and LHRH agonist and not necessarily the MTD.  The decision to reduce the dose of 
GDC-0810 will be made during data review teleconferences held between the Sponsor 
and the investigators. 


 
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10.2 
DLT DEFINITION 
For DLT evaluation, toxicity will be graded according to the National Cancer Institute 
Common Toxicity Criteria for Adverse Events (NCI CTCAE; Version 4.0) (Appendix 7).   
10.2.1 
Phase Ia 
For Phase Ia, the DLT evaluation period will start from the first dose of GDC-0810 
(Day −7) through the first cycle (28 days) of treatment for a total of 35 days.  
For Phase Ia, patients who miss 7 or more doses of GDC-0810 during the DLT 
evaluation period due to reasons other than a DLT will be replaced.   
In addition, patients who are discontinued from the study prior to completing the DLT 
evaluation period, due to reasons other than a DLT (e.g., disease progression, consent 
withdrawn), will also be replaced. 
DLT Definitions 
For Phase Ia, DLTs will be defined as any of the following adverse events that are 
deemed by the investigator or the Sponsor to be related to study drug (toxicities will be 
attributed to single agent GDC-0810 unless they are clearly related to disease 
progression or can clearly be attributed to a cause other than GDC-0810 administration):  
• 
Any grade ≥ 3 non-hematologic toxicity (excluding alopecia)  
• 
Any grade ≥ 3 hematologic toxicity of > 7 days’ duration 
• 
Any grade toxicity that leads to study drug interruption of > 7 days’ duration 
 
10.2.2 
Phase IIa 
DLT definitions are not applicable for the Phase IIa dose expansion portion of the study. 
10.2.3 
Phase Ib 
No patients will be enrolled in Phase Ib Cohorts C0 and C2. 
For Phase Ib Cohorts C0, C1, and D1, the DLT evaluation period will start from Day 1 
through Day 28 of Cycle 1.  
For Phase Ib, patients who miss ≥ 7 doses of GDC-0810 or ≥ 5 doses of palbociclib 
(in Cohort C0 or C1) during the DLT evaluation period due to reasons other than a DLT 
will be replaced.   


 
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Phase Ib Cohorts C0 and C1 DLT Definitions 
DLT definitions reflect the known and expected toxicities of GDC-0810 administered 
alone and palbociclib administered alone or in combination with other endocrine 
therapies.  A DLT is defined as one of the following toxicities occurring during the DLT 
assessment window and considered by the investigator to be related to GDC-0810 or 
palbociclib. 
• 
Any Grade ≥ 3 non-hematologic, non-hepatic toxicity with the exception of: 
Alopecia of any grade; 
Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤ 2 within 24 hours 
with maximal medical therapy 
Grade 3 fatigue, unless the fatigue has increased by at least two grades from 
baseline 
• 
Any grade non-hematologic toxicity that leads to study drug or study drug treatment 
interruption of > 7 days’ duration 
• 
Grade ≥ 3 elevation of serum hepatic transaminase (ALT or AST) lasting > 7 days 
For patients with Grade ≤ 2 hepatic transaminase levels at baseline as a result 
of liver metastases, only a transaminase level ≥ 10 × ULN lasting for > 7 days will 
be considered a DLT. 
• 
Grade ≥ 3 elevation of serum bilirubin  
• 
Any case of potential drug-induced liver injury that includes an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s Law as recommended in the U.S. FDA Guidance “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation,” July 2009: 
The finding of an elevated ALT or AST (> 3 times 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.  Therefore, investigators must report as an 
adverse event the occurrence of either of the following: 
Treatment-emergent ALT or AST > 3 times baseline value in combination with 
clinical jaundice 
Treatment-emergent ALT or AST > 3 times baseline value in combination with 
total bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Grade 4 febrile neutropenia of any duration 
• 
Grade 4 neutropenia ≥ 10 days 
• 
Grade 3 thrombocytopenia associated with clinically significant bleeding 
• 
Grade 4 thrombocytopenia associated with:  
≥ 10 days duration 
Active bleeding 
Requirement for platelet transfusion 


 
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• 
Grade 4 anemia 
Note:  In the event of a Grade 4 neutropenia, thrombocytopenia, or anemia, a 
complete blood count (CBC) must be performed at least on Day 5 after the 
onset of the event.  If the absolute neutrophil count, platelet count, or 
hemoglobin has not recovered to ≤ Grade 3, CBC should be rechecked again on 
or before Day 10.  In order to define DLT, patients should not be prophylactically 
prescribed growth factor support prior to commencement of therapy (GDC-0810 
and palbociclib). 
• 
Grade 3 laboratory abnormalities that are asymptomatic and considered by the 
investigator not to be clinically significant will not be considered a DLT. 
 
Phase Ib Cohort D1 Dose Safety Run-in DLT Definitions 
DLT definitions reflect the known and expected toxicities of GDC-0810 and LHRH 
agonists.  A DLT is defined as one of the following toxicities occurring during the DLT 
assessment window and considered by the investigator to be related to GDC-0810 or 
LHRH agonists: 
• 
Any Grade ≥ 3 non-hematologic, non-hepatic toxicity with the exception of: 
Alopecia of any grade 
Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤ 2 within 24 hours 
with maximal medical therapy 
Grade 3 fatigue, unless the fatigue has increased by at least two grades from 
baseline 
Grade 3 premature menopause or Grade 3 hot flashes that resolve to Grade 2 
with optimal medical management within 7 days 
Grade 3 laboratory abnormalities that are asymptomatic and considered by the 
investigator not to be clinically significant will not be considered a DLT. 
• 
Any Grade ≥ 3 hematologic toxicity of more than 7 days’ duration 
• 
Any grade toxicity that leads to study drug or study drug treatment interruption of 
more than 7 days duration 
• 
Grade ≥ 3 elevation of serum hepatic transaminase (ALT or AST) lasting > 7 days 
For patients with Grade ≤ 2 hepatic transaminase levels at baseline as a result 
of liver metastases, only a transaminase level ≥ 10 × ULN lasting for ≥ 7 days 
will be considered a DLT. 
• 
Grade ≥ 3 elevation of serum bilirubin 


 
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• 
Any case of potential drug-induced liver injury that includes an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s Law as recommended in the U.S. FDA Guidance “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation,” July 2009: 
The finding of an elevated ALT or AST (> 3 times 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.  Therefore, investigators must report as an 
adverse event the occurrence of either of the following: 
Treatment-emergent ALT or AST > 3 times baseline value in combination with 
clinical jaundice 
Treatment-emergent ALT or AST > 3 times baseline value in combination with 
total bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
 
10.3 
STUDY DRUG AND STUDY TREATMENT ADMINISTRATION 
The research staff at each participating site will provide detailed instructions and training 
for the handling of the study drug (GDC-0810) and study treatment (palbociclib and 
LHRH agonist) and their administration to each patient at the beginning of her study 
participation.  
All patients should take the full prescribed dose of GDC-0810 by mouth at approximately 
the same time each day and within 30 minutes after eating a meal.  GDC-0810 tablets 
should be swallowed whole and tablets should not be cut or crushed. 
Evening dosing may be initiated to alleviate gastrointestinal symptoms from GDC-0810.  
Please note that morning dosing the day before PK evaluation days is required to allow 
accurate assessment of PK trough levels of study drug (see Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4). 
If a dose is missed, patients should just take the next scheduled GDC-0810 dose, 
without compensating for the missed dose. 
10.3.1 
Phase Ia  
During Phase Ia, the full prescribed dose of GDC-0810 should be taken by mouth in the 
morning, after fasting overnight, at approximately the same time each day; food should 
not be eaten for at least 1 hour after taking GDC-0810.  The dosing regimen may be 
changed if the PK and safety data from the dose escalation suggest that a discontinuous 
regimen or another dosing frequency (e.g., BID), with or without a fasting requirement, 
may be preferable for the Phase IIa portion of the study.  
PK Week Lead-In 
In Phase Ia, patients enrolled in the dose escalation cohorts will receive a single oral 
dose of GDC-0810 in the clinic on Day −7 and will return to the clinic for the next 
2 consecutive days for PK sample collection.  The time of dose administration will be 


 
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called “0” (zero) hour.  If a patient vomits after receiving GDC-0810, this should be 
recorded in the patient’s Case Report Form (CRF) but the dose should not be repeated. 
In Phase Ib and Phase IIa, there will be no Day − 7 to Day 0 PK lead-in period.  
Continuous Dosing 
In Phase Ia GDC-0810 will be given continuously beginning on Cycle 1 Day 1 in 28-day 
cycles.  During Cycle 1 of the dose escalation, patients will return to the clinic on a 
weekly basis (Days 8, 15, and 22) for safety evaluation and collection of predose PK 
samples.  On those days, treatment will be administered in the clinic. 
Similarly, on Day 1 of every subsequent new cycle of dosing beginning with Cycle 2, 
study drug will be administered in the clinic following all the assessments as indicated in 
the Schedule of Activities.   
All other doses of GDC-0810 will be administered on an outpatient basis.  It is 
anticipated that some patients may occasionally forget to take a dose of GDC-0810.  
In those cases, patients should just take the next scheduled dose, without compensating 
for the missed dose. 
10.3.2 
Phase IIa 
The full prescribed dose of GDC-0810 should be taken by mouth at approximately the 
same time each day and within 30 minutes after eating a meal.   
10.3.3 
Phase Ib  
Palbociclib administration (if applicable):  Palbociclib should be taken with food at the 
same time each day.  The capsule should be swallowed whole.  The capsules should 
not be chewed, crushed, or opened.  If a dose is missed, patients should just take the 
next scheduled palbociclib dose, without compensating for the missed dose. 
LHRH administration (if applicable):  LHRH agonists should be administered monthly by 
site staff.  
Continuous Dosing 
In Phase Ib, GDC-0810 will be given continuously beginning on Cycle 1 Day 1 in 28-day 
cycles.  During Cycle 1 of the dose escalation, patients will return to the clinic on a 
weekly basis (Days 8, 15, and 22) for safety evaluation and collection of predose PK 
samples.  On those days, treatment will be administered in the clinic.  Study treatments, 
palbociclib will be given on Days 1−21 of each cycle and LHRH agonist will be given on 
Day 1 of each cycle.  Evening dosing (within 30 minutes after dinner or within 
30 minutes of the consistently largest meal of the day) may be initiated to alleviate 
gastrointestinal symptoms from GDC-0810.  However, on Day 28 of Cycles 1, 2, and 3, 
the dose of GDC-0810 should be taken in the morning to allow trough PK sample 
collections on Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1. 


 
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Similarly, on Day 1 of every subsequent new cycle of dosing beginning with Cycle 2, 
study treatment will be administered in the clinic following all the assessments as 
indicated in the Schedule of Activities.   
All other doses of GDC-0810 or palbociclib will be administered on an outpatient basis.  
It is anticipated that some patients may occasionally forget to take a dose of GDC-0810 
or palbociclib.  In those cases, patients should just take the next scheduled dose, without 
compensating for the missed dose. 
Palbociclib and GDC-0810 do not have to be taken together; however, each drug should 
be taken at a consistent time each day. 
10.4 
DOSE MODIFICATIONS 
Patients who have had treatment interruptions due to reasons other than DLTs may 
restart daily dosing at the same dose at the discretion of the investigator when the 
toxicity has resolved to Grade ≤ 1 or baseline; however, any patients whose treatment is 
interrupted for an adverse event that is related to study drug and who do not restart 
treatment within 28 days will be withdrawn from study treatment. 
For patients experiencing a DLT, treatment should be held until the severity of the 
toxicity decreases to Grade ≤ 1 or baseline.  If they are deriving clinical benefit, patients 
may be restarted on study drug at the next lower dose level that has been tested in a 
previous cohort, at the discretion of the investigator and in consultation with the Sponsor.  
For Phase Ia and Phase IIa, no more than 2 dose reductions of GDC-0810 will be 
allowed.   
For Phase Ib Cohort C1 a maximum of two dose reductions of GDC-0810 and 
palbociclib will be allowed.  No dose reductions are planned for the LHRH agonists 
(Cohort D1).  GDC-0810 dose reductions should be managed without changing regimen, 
for example, patients in Phase Ia who were being treated on a BID regimen will dose 
reduce to the next lower GDC-0810 dose level but still administered as BID.  Similarly, 
Phase Ia patients who were being treated without a fasting requirement will dose reduce 
to the next lower dose level but still administered without a fasting requirement. 
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. 
10.4.1 
Dose Modifications for Phase Ia, Ib Cohort D, and IIa 
During the Phase Ia dose escalation DLT evaluation period, dose modifications will not 
be permitted; however, dose interruptions can be instituted for patient safety purposes.  
In Cycle 1, any interruption > 7 days due to an adverse event assessed as related to 
GDC-0810 will meet the criteria for DLT. 


 
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After the DLT evaluation period is concluded and/or during the Phase IIa portion of the 
study, dose interruptions and/or reductions to the next lower dose level will be permitted 
as needed, provided that study discontinuation criteria have not been met 
(e.g., documented disease progression or unacceptable toxicity). 
In Cohort D, no dose modification of the LHRH agonist will be permitted.  However, the 
dose of GDC-0810 may be reduced in Cohort D1 or D2 on the basis of joint review by 
Sponsor and study investigators of available safety and tolerability data observed during 
the DLT assessment window. 
GDC-0810 must be held in the presence of the following toxicities potentially attributed 
to the study drug: 
• 
Decrease in post-treatment glomerular filtration rate (GFR) of more than 25% as 
compared to baseline 
• 
Any other Grade ≥ 3 adverse events potentially attributed to the study drug 
 
GDC-0810 dose reductions may occur in increments of 200 mg.  Therefore, the possible 
GDC-0810 doses permitted in Phase IIa are 600 mg, 400 mg, and 200 mg.  Because no 
more than two dose reductions are permitted, patients should discontinue GDC-0810 if 
they experience adverse events at 200 mg of GDC-0810 requiring dose reduction. 
Adverse events should be managed as shown in Table 4.


 
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Table 4 
Dose Modification and Management Guidelines 
Toxicity 
Dose Modification and Management Guidelines 
Gastrointestinal Toxicities:  
General 
• Patients should be closely monitored for gastrointestinal (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). 
AESI = adverse event of special interest 
 


 
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Table 4 
Dose Modification and Management Guidelines (cont.) 
Toxicity 
Dose Modification and Management Guidelines 
Diarrhea (cont.): 
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).  
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 of GDC-0810. 
• Upon resolution, consider starting loperamide 2 mg 1−2 times daily as secondary prophylaxis (i.e., use 
of loperamide to prevent further diarrhea).  
AESI = adverse event of special interest 
 


 
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Table 4 
Dose Modification and Management Guidelines (cont.) 
Toxicity 
Dose Modification and Management Guidelines 
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.  
Venous Thromboembolic Events (including Pulmonary Embolism): 
General 
• Patients should be advised to seek immediate medical attention if they become aware of any symptoms 
of pulmonary embolism (PE) or deep vein thrombosis (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 inferior vena cava (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.  
AESI = adverse event of special interest 


 
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Table 4 
Dose Modification and Management Guidelines (cont.) 
Toxicity 
Dose Modification and Management Guidelines 
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.  
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 
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 should be 
consulted.  
• Patients experiencing hepatic enzyme elevation should be treated and managed per standard of care.  
Grade ≥ 3 
• Hold study drug until resolution to baseline or below upper limit of normal (ULN).  
AESI = adverse event of special interest. 


 
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10.4.2 
Dose Modifications for Phase Ib Cohort C1 
During the dose escalation DLT evaluation period, dose modifications will not be 
permitted; however, dose interruptions can be instituted for patient safety purposes.  
In Phase Ib Cohort C1, any grade non-hematologic toxicity assessed as related to 
GDC-0810 and/or palbociclib that leads to study drug interruption of > 7 days’ duration 
will meet the criteria for DLT.  Patients who miss ≥ 7 doses of GDC-0810 or ≥ 5 doses of 
palbociclib during the DLT evaluation period due to reasons other than a DLT will be 
replaced.   
After the DLT evaluation period is concluded, dose interruptions and/or reductions to the 
next lower dose level will be permitted as needed, provided that study discontinuation 
criteria have not been met (e.g., documented disease progression or unacceptable 
toxicity).  Dose modification guidelines for treatment-related non-hematologic and 
hematologic toxicities are shown in Table 5 and Table 6, respectively. 
GDC-0810 dose reductions may occur in decrements of 200 mg.  Therefore, the 
possible GDC-0810 doses permitted in Phase Ib Cohorts C1 and C2 are 600 mg, 
400 mg, and 200 mg.  Because no more than two dose reductions are permitted, 
patients should discontinue GDC-0810 if they experience adverse events at 200 mg of 
GDC-0810 requiring dose reduction. 
Palbociclib dose reductions may occur in decrements of 25 mg.  Therefore, the possible 
palbociclib doses permitted in Phase Ib Cohorts C1, C2 and C3 are 125 mg, 100 mg, 
and 75 mg.  Palbociclib dose de-escalation below 75 mg/day is not allowed, but in 
consultation with the sponsor, the schedule may be changed for example to 75 mg/day 
2 weeks on followed by 2 weeks off (2/2 schedule). 
Both GDC-0810 and palbociclib must be held in the presence of the following toxicities 
potentially attributed to the study drug: 
• 
Decrease in post-treatment GFR of more than 25% as compared to baseline 
• 
Any other Grade ≥ 3 non-hematologic adverse events potentially attributed to the 
study drug. 


 
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Table 5 
Dose Modification Guidelines for Treatment-Related Non-Hematologic Toxicities 
Toxicity 
Palbociclib and/or GDC-0810 Dose Modification 
Gastrointestinal Toxicities:  
General 
• Patients should be closely monitored for gastrointestinal (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.  
Diarrhea: 
 
General and Grade 1 
• See Section 10.4.1.  
• If diarrhea does not resolve after 14 days and GDC-0810 has already been held, consider withholding 
palbociclib.  
• If palbociclib hold was required, consider starting loperamide 2 mg 1−2 times daily as secondary 
prophylaxis (i.e., use of loperamide to prevent further diarrhea).  
Grade 2 diarrhea 
• See Section 10.4.1. 
• If diarrhea persists for more than 7 days after GDC-0810 is held, consider withholding palbociclib until 
symptoms resolve to Grade ≤ 1.  
• If palbociclib hold was required, consider starting loperamide 2 mg 1−2 times daily as secondary 
prophylaxis (i.e., use of loperamide to prevent further diarrhea) upon restart.  
Grade ≥ 3 diarrhea  
• Manage with adequate anti-diarrheal agents (e.g., loperamide) and maximum supportive care according to 
local standards and practices.  
• Closely monitor for resolution. 
• Withhold GDC-0810 and palbociclib until symptoms resolve to Grade ≤ 1.  
• At resolution of first occurrence, reduce the dose of GDC-0810 by one dose level on improvement to 
Grade ≤ 1.  Consider reducing palbociclib by one dose level.  
• At resolution of second occurrence, reduce dose of GDC-0810 by one dose level on improvement to 
Grade ≤ 1.  Consider reducing palbociclib by one dose level. 
• On third occurrence, discontinue GDC-0810 
• At any occurrence of Grade 4 diarrhea, consider discontinuation of GDC-0810.  
• Upon resolution, 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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Table 5 
Dose Modification Guidelines for Treatment-Related Non-Hematologic Toxicities (cont.)  
Toxicity 
Palbociclib and/or GDC-0810 Dose Modification 
Nausea and or Vomiting: 
 
General and Grade 1 
See Section 10.4.1.   
Grade ≥ 2 nausea or vomiting 
• If persistent despite maximal medical therapy, withhold GDC-0810 until recovery to Grade ≤ 1.  If no 
improvement is noted in palbociclib combination patient, consider additionally withholding palbociclib 
until recovery to Grade ≤ 1.  
Grade ≥ 3 nausea or vomiting 
• Manage with anti-emetics and supportive care.  
• Withhold GDC-0810 and/or palbociclib until symptoms resolve to Grade ≤ 1.  
• On resolution of first occurrence, reduce dose of GDC-0810 by one dose level when treatment resumes and 
consider reducing dose of palbociclib.  
• On resolution of second occurrence, reduce dose of GDC-0810 and/or palbociclib by one dose level when 
treatment resumes.  
Venous thromboembolic events (including pulmonary embolism): 
General and Grade 1−2 
See Section 10.4.1. 
Grade ≥ 3 venous 
thromboembolic events 
(including pulmonary 
embolism) 
• Withhold GDC-0810 and palbociclib until patient is stable and consult with Sponsor before resuming 
treatment.  
Vaginal hemorrhage: 
 
General and Grade 1 
See Section 10.4.1.  
Grade ≥ 2 vaginal hemorrhage 
• Withhold GDC-0810 and palbociclib until Grade ≤ 1 and consult with Sponsor before resuming treatment.  
Grade ≥ 3 non-hematologic 
toxicity 
• Withhold GDC-0810 and/or palbociclib until symptoms resolve to Grade ≤ 1 or Grade ≤ 2 (after discussion 
with Medical Monitor).  
• If repeated toxicity is seen in the next cycle or if recovery from Grade 3 is delayed beyond 7 days discuss 
with Medical Monitor.  
 


 
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Table 5 
Dose Modification Guidelines for Treatment-Related Non-Hematologic Toxicities (cont.)  
Toxicity 
Palbociclib and/or GDC-0810 Dose Modification 
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 should be consulted.  
• Patients experiencing hepatic enzyme elevation should be treated and managed per standard of care.  
Grade ≥ 3 
• Hold study drug until resolution to baseline or below upper limit of normal (ULN).  


 
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Table 6 
Dose Modification Guidelines for Hematologic Toxicities 
Toxicity 
Palbociclib 
GDC-0810 
Neutropenia or 
thrombocytopenia Grade ≤ 2 
No dose modification required. 
No dose modification 
required. 
Uncomplicated Grade 3 
neutropenia 
Withhold palbociclib until recovery to Grade ≤ 2 (≥ 1000/mm3).  No dose adjustment 
is required unless recovery of neutrophil count is delayeda,b, in which case reduce 
by one dose level. 
No dose modification 
required. 
Uncomplicated Grade 4 
neutropenia (ANC 
< 500/mm3) 
Withhold palbociclib until recovery to Grade ≤ 2 (≥ 1000/mm3).  Resume at next 
lower dose.  Reduce by two dose levelsc if neutrophil recovery is delayeda or in 
case of recurrent Grade 4 event. 
No dose modification 
required. 
Grade ≥ 3 neutropenia 
associated with infection or 
fever 
Withhold palbociclib until neutrophil count recovery to Grade ≤ 2 (≥ 1000/mm3) and 
afebrile and infection is clinically improving. 
Resume palbociclib at next lower dose.  Reduce by two dose levelsc if neutrophil 
recovery is delayeda. 
In case of Grade 4 febrile neutropenia, discuss with Medical Monitor prior to 
resuming palbociclib. 
No dose modification 
required. 
Uncomplicated Grade ≥ 3 
thrombocytopenia (platelet 
count < 50,000/mm3) 
Withhold palbociclib until recovery to Grade ≤ 2 (≥ 50,000/mm3).  Resume at next 
lower dose.  Reduce by two dose levelsc if platelet count recovery is delayeda or in 
case of recurrent Grade 4 event. 
No dose modification 
required. 
ANC = absolute neutrophil count. 
a If recovery of neutrophils to ≥ 1000/mm3 or platelet count to ≥ 50,000/mm3 takes > 2 weeks (including dose holding due to toxicity, the scheduled 
week off treatment, or > 7 days of cycle delay). 
b If uncomplicated Grade 3 neutropenia recurs in 2 consecutive cycles, after recovery as per retreatment criteria (ANC ≥ 1000/mm3 and no fever), 
treatment may restart at the next lower dose level at investigator’s discretion. 
c If no further dose reduction is possible (i.e, patient is already receiving 75 mg/day according to the 3/1 schedule), consider changing the 
schedule to 75 mg/day, 2 weeks on/2 weeks off, or discontinue palbociclib and continue with GDC-0810 alone. 


 
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Table 6 
Dose Modification Guidelines for Hematologic Toxicities (cont.) 
Toxicity 
Palbociclib 
GDC-0810 
Grade ≥ 3 thrombocytopenia 
(platelet count<50,000/mm3) 
associated with bleeding 
Withhold palbociclib until platelet count recovery to Grade ≤ 2 (≥ 50,000/mm3) and 
clinically stable. 
Resume palbociclib at next lower dose.  Reduce by two dose levelsc if platelet 
count recovery is delayeda.  In case of recurrent Grade 3 event following a 
previous delayed recovery of platelet count, discuss with Medical Monitor. 
In case of Grade 4 thrombocytopenia associated with bleeding, discuss with 
Medical Monitor prior to resuming palbociclib. 
No dose modification 
required. 
Grade 3 anaemia 
Withhold palbociclib until recovery to Grade ≤ 2 (≥ 8.0 g/dL).  No dose 
adjustment is required unless recovery of hemoglobin is delayed a, in which case 
reduce by one dose level. 
No dose modification 
required. 
Grade 4 anaemia 
Withhold palbociclib until recovery to Grade ≤ 2 (≥ 8.0 g/dL).  Resume at next 
lower dose.  Reduce by two dose levels c if hemoglobin recovery is delayed a or in 
case of recurrent Grade 4 event. 
No dose modification 
required. 
ANC = absolute neutrophil count. 
a If recovery of neutrophils to ≥ 1000/mm3 or , platelet count to ≥ 50,000/mm3, or hemoglobin to ≥ 8.0 g/dL takes > 2 weeks (including dose holding 
due to toxicity, the scheduled week off treatment, or > 7 days of cycle delay). 
b If uncomplicated Grade 3 neutropenia recurs in 2 consecutive cycles, after recovery as per retreatment criteria (ANC ≥ 1000/mm3 and no fever), 
treatment may restart at the next lower dose level at investigator’s discretion. 
c If no further dose reduction is possible (i.e, patient is already receiving 75 mg/day according to the 3/1 schedule), consider changing the 
schedule to 75 mg/day, 2 weeks on/2 weeks off, or discontinue palbociclib and continue with GDC-0810 alone. 
 


 
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10.4.3 
Concomitant Medications and Treatments 
Concomitant therapy includes any medications (prescription drugs or over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days before screening through the study completion visit.  
All concomitant medications administered to the patient will be reported from 7 days 
before screening through 4 weeks following receipt of the last dose of study drug.  
The drug name, its route of administration, as well as its start and stop dates will be 
recorded. 
Any new anti-cancer therapies initiated within the safety follow-up visit (including 
drug name and date of initiation) will be recorded as well.   
Use of Colony Stimulating Factors 
Primary prophylactic use of colony stimulating factors (CSF) is not permitted, but they 
may be used to treat treatment-emergent neutropenia as per current American Society 
of Clinical Oncology (ASCO) guidelines (Smith et al. 2006).  If neutropenic complications 
are observed in a cycle in which primary prophylaxis with CSFs was not received, 
secondary prophylaxis may be given at the discretion of the investigator but only if dose 
reduction or delay are not considered a reasonable alternative. 
10.4.3.1 
Drug Interactions of GDC-0810 
Nonclinical studies have shown that the major metabolic pathway of GDC-0810 was via 
glucuronidation by multiple UDP-glucuronosyltransferase (UGT) isoforms.  GDC-0810 
was shown to inhibit human CYP enzymes in vitro, especially CYP2B6 and CYP2C 
enzymes; therefore, drug-drug interactions with co-administered CYP2B6 and CYP2C 
substrates cannot be excluded and should be avoided.  Note that many of these 
medications are metabolized by multiple CYP enzymes, thus attenuating the potential for 
drug-drug interactions to some extent.  If there is clinical need for a particular CYP2B6 
and CYP2C substrate drug, dose adjustments and/or use of alternative medications are 
recommended.  A list of sensitive in vivo CYP2B6 and CYP2C substrates and substrates 
with narrow therapeutic range can be found in Appendix 8a.  GDC-0810 was also shown 
to inhibit human transporters in vitro, including OATP1B1/1B3.  A drug-drug interaction 
study with pravastatin as the OATP1B1/1B3 substrate has been initiated to evaluate the 
potential risk.  The preliminary PK results showed no significant drug-drug interaction 
between GDC-0810 and pravastatin. 
10.4.3.2 
Drug Interactions of Palbociclib 
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme 
SULT2A1. In vivo, palbociclib is a time-dependent inhibitor of CYP3A. 


 
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10.4.3.3 
Agents that may increase palbociclib plasma concentrations  
Effect of CYP3A inhibitors 
Co-administration of a strong CYP3A inhibitor (itraconazole) increased the plasma 
exposure of palbociclib in healthy subjects by 87%.  Avoid concomitant use of strong 
CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, verapamil, and voriconazole).  Avoid grapefruit or grapefruit juice during 
palbociclib treatment (Ibrance® Prescribing Information).  If co-administration of 
palbociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of 
palbociclib.  A list of strong CYP3A inhibitors can be found in Appendix 8b. 
10.4.3.4 
Agents that may decrease palbociclib plasma concentrations  
Effect of CYP3A inducers  
Co-administration of a strong CYP3A inducer (rifampin) decreased the plasma exposure 
of palbociclib in healthy subjects by 85% (Ibrance® Prescribing Information).  Avoid 
concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine 
and St. John’s Wort).  Co-administration of moderate CYP3A inducers may also 
decrease the plasma exposure of palbociclib.  Avoid concomitant use of moderate 
CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin).  A list of 
strong and moderate CYP3A inducers can be found in Appendix 8c.  
10.4.3.5 
Drugs that may have their plasma concentrations altered by 
palbociclib  
Co-administration of midazolam with multiple doses of palbociclib increased the 
midazolam plasma exposure by 61%, in healthy subjects, compared with administration 
of midazolam alone.  The dose of the sensitive CYP3A substrates with a narrow 
therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be 
reduced as may increase their exposure (Ibrance® Prescribing Information).  A list of 
sensitive in vivo CYP3A substrates and CYP3A substrates with narrow therapeutic 
range can be found in Appendix 8a. 
10.4.3.6 
Drug Interactions of LHRH Agonists 
Leuprolide acetate  
No pharmacokinetic-based drug-drug interaction studies have been conducted; 
however, drug interactions are not expected to occur. 
Goserelin acetate  
No formal drug-drug interaction studies have been performed.  No confirmed interactions 
have been reported between goserelin acetate (Zoladex®) and other drugs. 
Triptorelin pamoate 
No drug-drug interaction studies involving triptorelin have been conducted. 


 
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Drug-Drug Interactions with GDC-0810 and Palbociclib 
Glucuronidation is the major metabolic pathway of GDC-0810.  GDC-0810 is a weak 
inhibitor of CYP3A.  Palbociclib is primarily metabolized by CYP3A and SULT2A1 and 
shown as a weak time-dependent inhibitor of CYP3A.  In general, on the basis of data 
on GDC-0810 and palbociclib, the risk for drug interactions is low. 
Drug-Drug Interactions with GDC-0810 and LHRH Agonists 
No pharmacokinetic-based drug-drug interaction studies have been conducted with 
LHRH agonists.  However, because LHRH agonists are peptides that are primarily 
degraded by peptidase and not by cytochrome P-450 enzymes and glucuronidation, the 
risk for drug interactions is low. 
Prohibited Therapies 
No other hormonal therapy, chemotherapy, immunotherapy, or experimental anti-cancer 
medications will be permitted while the patient is in the study.   
Other Therapies 
Symptomatic anti-emetics, anti-diarrheal therapy, as well as other palliative and 
supportive care for disease- or treatment-related symptoms may be administered at the 
investigator’s discretion.  All concomitant medication and/or therapies should be 
documented in the patient’s CRF.  In certain instances, focal radiation therapy for 
palliation of bone disease-related symptoms might be allowable after discussion with the 
Sponsor; however, the need for radiation therapy will generally be considered indicative 
of progressive disease.  Bone-sparing agents (e.g., bisphosphonates, denosumab) for 
palliation of bone metastases or for the treatment of osteoporosis/osteopenia are 
allowed in the study.  In general, it is recommended to stop GDC-0810 and/or palbociclib 
treatment at least 7 days prior to surgical procedures.  Postoperatively, the decision to 
reinitiate GDC-0810 and/or palbociclib treatment should be based upon a clinical 
assessment of satisfactory wound healing and recovery from surgery. 
Lifestyle Guidelines 
Patients should take precautionary measures regarding sun exposure, with daily 
sunscreen use and wearing protective clothing, sunglasses, and hats when outdoors. 
Dietary Restrictions 
Patients enrolled in Cohort C1 who are receiving GDC-0810 concurrently with palbociclib 
should avoid grapefruit and grapefruit juice due to the CYP3A inhibition.  
10.5 
STUDY DRUG ACCOUNTABILITY 
The Sponsor (or designee) will ship GDC-0810 to the investigational sites.  The initial 
study drug shipment will be shipped after site activation (i.e., all required regulatory 
documentation has been received by the Sponsor and a contract has been executed).  
Study drug treatments, palbociclib and LHRH agonist will be prescribed by the study 
sites and cost of study treatment will be reimbursed by the Sponsor.   


 
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An accurate and current accounting of the dispensing and return of all applicable study 
drug (i.e. GDC-0810 and study drug treatment) for each patient will be maintained on an 
ongoing basis by a member of the study site staff.  The number of study drug dispensed 
and returned by the patient will be recorded on the accountability log.  The study monitor 
will verify these documents throughout the course of the study. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug.  If destruction at the site is authorized, the investigator must ensure 
that all investigational product is destroyed in compliance with the applicable 
environmental regulations, institutional policy, and any other special instructions 
provided by the Sponsor.  Drug destruction must be adequately documented. 
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 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 postmenopausal women 
with ER+ advanced breast cancer. 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for postmenopausal women with ER+ advanced breast cancer. 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country. 
 
Genentech does not intend to provide other study interventions to patients after the 
conclusion of the study or any earlier withdrawal. 
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  


 
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10.6 
MEASURES OF TREATMENT COMPLIANCE 
At each clinic visit starting with Cycle 2, patients will be asked to return any remaining 
applicable study drug GDC-0810 and/or study drug treatment (i.e. palbociclib) from the 
previous dosing cycle as well as all used and unused study drug containers.   
In the dose escalation portion of the study, patients should also bring their study drug 
containers to the weekly visits in Cycle 1 in order to verify treatment compliance for the 
DLT evaluation period. 
Treatment compliance will be defined as the number of tablets or capsules taken divided 
by the expected number of tablets and reported as percentage.  In case of dose 
reductions, the expected number of tablets or capsules should reflect the new dose 
level.   
Tablets or capsules that are not returned will be considered to have been taken, unless 
otherwise specified in the patient’s CRF. 
11. 
STUDY PROCEDURES AND GUIDELINES 
Schedule of Activities representing the required testing procedures to be performed 
during the study are diagrammed in Appendix 1 (Phase Ia), Appendix 2 (Phase IIa), 
Appendix 3 (Phase Ib Cohort C1), and Appendix 4 (Phase Ib Cohort D1). 
Prior to conducting any study-related activities, written informed consent and any other 
authorizations must be signed and dated by the patient. 
Every effort should be made to ensure that the protocol-required tests and procedures 
are completed as described.  However, it is anticipated that from time to time there may 
be circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In those cases, the investigator should take all steps necessary to 
ensure the safety and wellbeing of the patient.  When a protocol-required test cannot be 
performed, the investigator will document the reason for this and any corrective and 
preventive actions which he/she has taken to ensure that normal processes are adhered 
to as soon as possible.  The Sponsor study team should be informed of these incidents 
in a timely fashion. 
11.1 
CLINICAL ASSESSMENTS 
11.1.1 
Demographics  
Demographic information (e.g., date of birth and race) will be recorded at screening. 
11.1.2 
Medical History  
Relevant medical history includes clinically significant diseases; smoking history, use of 
alcohol and drugs of abuse, history of current disease, surgeries, other pertinent clinical 
conditions, and information regarding underlying diseases will be recorded at screening.  


 
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All medications used by the patient within 7 days before the screening visit 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) will be recorded at screening. 
11.1.3 
Physical Examination 
A complete physical examination will be performed by either the investigator or a 
sub-investigator at screening.  Qualified staff (e.g., nurses or physician assistants) may 
complete the abbreviated physical exam at all other visits.  New abnormal physical exam 
findings must be documented and followed by a physician or other qualified staff at the 
next scheduled visit.  
The physical examination should include, but is not limited to, general appearance, skin, 
neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, back, lymph nodes, 
extremities, and nervous system, as well as examination of known and suspected sites 
of disease.  Height will be recorded at screening only.  
11.1.4 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed at screening 
and at every clinic visit. 
11.1.5 
Performance Status 
The ECOG performance status scale will be assessed at screening and at every clinic 
visit (Appendix 6). 
11.1.6 
Adverse Events 
Assessment of adverse events will include type, incidence, severity (graded by the 
NCI CTCAE, Version 4.0, Appendix 7), timing, seriousness, and relatedness.  Adverse 
events will be assessed at every clinic visit. 
11.1.7 
Concomitant Medications and Treatments 
All concomitant medication and concurrent therapies will be documented at screening 
and at every clinic visit.  The indication for administration and dates of medication will be 
captured. 
11.1.8 
Tumor Assessments 
Disease assessments will be performed at screening, per institutional guidelines, and 
as clinically indicated.  
Imaging studies will include a CT scan of the chest, abdomen, and pelvis, plus a bone 
scan.  At screening, a CT/MRI brain should be obtained if clinically indicated to rule out 
newly diagnosed, untreated brain metastasis.  
Radiographic confirmation of objective tumor response or disease progression will be 
based on RECIST v1.1 (Eisenhauer et al. 2009).   


 
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The same method of assessment and the same technique should be used at screening 
and during follow up.  Intravenous (IV) contrast is required when not medically 
contraindicated.  Patients who have a contraindication to IV contrast may have MRI 
exams of the abdomen and pelvis performed in lieu of CTs and a non-contrast CT of the 
chest.  Tumor evaluation by PET scan or by ultrasound may not substitute for CT or MRI 
scans.  However, a CT for tumor assessment may be acquired on a PET/CT scanner if it 
is of full diagnostic quality and includes IV contrast.  
11.1.9 
Endometrial Thickness Assessments (if applicable) 
To assess for any potential effect of study treatment on the uterus, transvaginal 
ultrasound scans will be performed to monitor endometrial thickness at screening, the 
study drug discontinuation visit, and as clinically indicated.  Transvaginal ultrasounds 
are not required for patients who have had a hysterectomy.  
11.2 
CLINICAL LABORATORY MEASUREMENTS  
Blood and urine will be obtained as clinically indicated (except creatinine and liver 
function tests) and analyzed at a local or central laboratory for hematology, blood 
chemistry profile, and urinalysis, respectively.  Liver function test and creatinine will be 
collected at least monthly and as clinically indicated.  Appendix 5 lists all of the specific 
tests that will be performed.  
Investigators may have additional local laboratory tests performed for the purpose of 
planning treatment administration, dose modification, or following adverse events. 
11.3 
ELECTROCARDIOGRAM (ECG) 
11.3.1 
Phase Ia 
Standard single 12-lead ECGs (with a 10-second rhythm strip) will be collected at 
screening and at Cycle 2 Day 1 at the 2-hour post-dose timepoint (prior to the respective 
PK sample collection).  ECGs should be collected after the patient has rested quietly and 
is awake in a fully supine (or semi-recumbent, if supine is not tolerated) position for 
5 to 10 minutes and prior to any blood draw collection. 
11.3.2 
Phase IIa 
During Phase IIa, all patients will participate in the evaluation of the effect of GDC-0810 
on ventricular repolarization.  Triplicate 12-lead ECGs (with a 10-second rhythm strip) 
will be collected approximately 2 minutes apart at screening, at Cycle 2 Day 1 predose, 
and at 1, 2, 3, 4, and 6 hours following dosing.  
After each set of ECGs on Cycle 2 Day 1, blood samples to assess PK will be collected 
(see Section 11.4.2). 
ECGs will be recorded and evaluated at the clinical study (local) site for the purposes of 
real-time cardiac safety monitoring for individual patients and will be subsequently 


 
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analyzed at a designated central facility for the purposes of assessing the effects of 
GDC-0810 on the QTc and other cardiac intervals.  For real-time safety monitoring of 
patients, only one ECG printout per timepoint (of the triplicate samples) will need to be 
reviewed by the investigator.  For the purposes of central analysis, triplicate ECGs will 
be obtained in a rigorous and standardized fashion and transmitted digitally to the 
central reading facility for review and interpretation by specialized cardiac readers. 
11.3.3 
Phase Ib 
Standard single 12-lead ECGs (with a 10-second rhythm strip) will be collected at 
screening, Cycle 1 Day 1 (prior to first dose), Cycle 2 Day 1 (prior to the respective PK 
sample collection), and at the end of treatment.  ECGs should be collected after the 
patient has rested quietly and is awake in a fully supine (or semi-recumbent, if supine is 
not tolerated) position for 5 to 10 minutes and prior to any blood draw collection. 
11.4 
PHARMACOKINETIC MEASUREMENTS 
11.4.1 
Phase Ia 
Blood samples for full PK profile analysis of GDC-0810 (and its acyl-glucuronide and 
N-glucuronide metabolites) will be collected on Day −7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 
6, 8, 24 (Day −6), and 48 (Day −5) hours postdose.  A second set will be collected on 
Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose 
(Cycle 2 Day 2, prior to the next dose). 
11.4.2 
Phase IIa 
Blood samples for determining trough PK (predose) concentrations of GDC-0810 will be 
collected in Cycles 1, 2, 3 and 4.   
Additionally, on Cycle 2 Day 1, PK samples will also be collected predose and at 1, 2, 3, 
4, 6 hours following dosing.  If PK sampling times coincide with ECG collection times, 
the ECGs have to be assessed prior to PK blood collection. 
11.4.3 
Phase Ib 
For Cohort C1, on Cycle 1 Day 1 and Cycle 1 Day 8, PK samples will be collected 
predose and at 1, 2, 3, 4, and 6 hours following dosing to measure the concentrations of 
GDC-0810 and palbociclib.  Additionally, blood samples for determining trough 
PK (predose) concentrations of GDC-0810 and palbociclib will be collected on Day 1 in 
Cycles 2, 3, 4, and at end of treatment. 
For Cohort D1, on Cycle 1 Day 1 and Cycle 2 Day 1, PK samples will be collected 
predose and at 1, 2, 3, 4, and 6 hours following dosing to measure the concentrations of 
GDC-0810 and LHRH agonists.  If PK sampling times coincide with ECG collection 
times, the ECGs have to be assessed prior to PK blood collection.  Additionally, blood 
samples for determining trough PK (pre-dose) concentrations of GDC-0810 and LHRH 
agonists will be collected on Day 1 in Cycles 3, 4, and at end of treatment. 


 
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See the Laboratory Manual for collection and processing procedures.   
11.5 
CORRELATIVE STUDIES 
11.5.1 
FES-PET 
Imaging with FES-PET will be performed to quantify ER expression in the tumor and to 
assess for PD response to GDC-0810 therapy.  While FES uptake can vary between 
patients, in general, the FES uptake is fairly consistent across lesions at a given 
timepoint, and the average uptake provides a reasonable summary of ER expression for 
an individual patient (Kurland et al. 2011).  Factors that can affect standardized uptake 
value, such as sex hormone-binding globulin (SHBG), will be adjusted as per standard 
protocol (Peterson et al. 2011).  In addition, a washout period for patients previously 
treated with tamoxifen (at least 2 months), fulvestrant (at least 6 months), or other 
hormonal therapy (at least 2 weeks) will be required due to the long half-life of each drug 
and its potential to interfere with FES uptake.  FES-PET studies will be performed as 
hybrid PET/CT imaging for attenuation correction and lesion localization.  FES-PET scan 
is not required for patients enrolled in Phase Ib. 
11.5.1.1 
Phase Ia 
During dose escalation, pre- and post-treatment functional ER imaging with 
FES-PET/CT scans will be performed starting at dose level 2 (200 mg) at screening 
(baseline) and at 4 weeks of treatment (Cycle 2 Day 3), as per Table 7: 
 
Table 7 
Pre- and Post-Treatment Functional ER Imaging with FES-PET/CT 
Schedule (Phase Ia) 
Cycle 2  
Day 1 
PK sampling day at 0 (predose) to 8 hours postdose as per protocol 
Section 11.4.1 
Cycle 2  
Day 2 
No GDC-0810 dose prior to clinic visit 
24-hr PK sample 
Take GDC-0810 dose in the evening that day (please see below 
instructions for fasting before and after) 
Cycle 2  
Day 3 
FES-PET scan during the period between ≥ 18 and ≤ 24 hours post 
the evening dose on C2D2 
No GDC-0810 dose on this day 
Cycle 2  
Day 4 
Resume daily dosing of GDC-0810 in the morning as per protocol 
Section 10.3.1 
Cycle 2  
Day 8  
(± 1 day) 
Optional biopsy as per protocol Section 11.5.2.1 below 
Cycle 3  
(~same day as 
CT/MRI scans) 
FES-PET scan during the period between ≥ 2 and ≤ 12 hours post the 
morning dose 
Only necessary if Cycle 2 Day 3 scan shows incomplete 
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In addition, if feasible, a FES-PET/CT scan should also be performed at the time when 
disease progression is suspected (especially if disease progression occurs prior to 
Cycle 3). 
11.5.2 
Tumor Biopsies 
Pre- and post-treatment tumor biopsies from the same (whenever feasible) soft tissue or 
visceral metastatic lesion will be collected to evaluate the histology of the tumor versus 
stroma, to assess for ER degradation and PR protein levels (via IHC), PR 
downregulation, proliferative index (Ki67), and ER target gene modulation studies.  
Tumor biopsies will also be used for DNA and /or RNA extraction to enable next 
generation sequencing (NGS) and/ or whole genome sequencing (WGS) for exploratory 
research on biomarkers (including, but not limited to, cancer-related genes and 
biomarkers associated with common molecular pathways). 
 
 
 
 
 
 
 
 
11.5.2.1 
Phase Ia  
Optional tumor biopsies will be collected predose and after 4 weeks of treatment 
(Cycle 2 Day 8 ± 1 day, during the period between ≥ 2 and ≤ 12 hours postdose).  This 
schedule will allow the patient to have resumed daily morning dosing of GDC-0810 for at 
least 3 days since the FES-PET/CT scan was performed. 
11.5.2.2 
Phase IIa 
All Cohort A patients with safely accessible soft tissue and/or visceral metastases will be 
required to have tumor biopsies.  Optional tumor biopsies will be collected for Cohort B 
patients with safely accessible soft tissue and/or visceral metastases.  Biopsies should 
be performed predose, at Cycle 3 (Day 8 ± 1 day for patients in Cohort A1), and if 
feasible, at the time when disease progression is suspected (especially if disease 
progression occurs prior to Cycle 3).  Biopsies should be collected during the period 
between ≥ 2 and ≤ 12 hours postdose. 
11.5.2.3 
Phase Ib 
Tumor biopsies are mandatory for patients in Phase Ib with safely accessible soft tissue 
and/or visceral metastases.  Biopsies should be obtained predose and after 2 weeks of 
treatment (Cycle 1 Day 15 ± 1 day, during the period between ≥ 2 and ≤ 12 hours 
postdose) and at the time of disease progression. 


 
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11.5.2.4 
Archival Tissue Collection  
Archival paraffin-embedded tissue may be collected to evaluate the histology of the 
tumor in all Phases of this study (Ia, Ib, IIa) for DNA and /or RNA extraction to enable 
next generation sequencing (NGS) for exploratory research on non-inherited biomarkers 
(including, but not limited to, cancer-related genes and biomarkers associated with 
common molecular pathways).  If fresh tumor tissue biopsy cannot be obtained at 
screening, every reasonable effort should be made to obtain the most recent archival 
tissue sample.  Tumor blocks are preferred, but in the event that local regulations 
prevent the shipment of tumor blocks, 15−20 unstained, serially cut slides are requested.  
Minimum tissue requirements are further described in the laboratory manual.  
Cytological, fine-needle aspiration, and decalcified bone biopsy samples are not 
acceptable.  Tissue blocks from archival biopsies will be returned to the archival facility 
from which they were originally received. 
11.5.3 
Circulating Tumor DNA Analyses 
In Phase Ia and IIa, additional blood samples will be collected at screening and at the 
time of study discontinuation for analysis of circulating tumor DNA (ctDNA).  During 
Phase IIa, ctDNA will also be collected at Cycle 3. 
In Phase Ib, additional blood samples will be collected at screening, Cycle 3, Cycle 5, 
and at the time of study discontinuation for analysis of ctDNA.   
Recent nonclinical and clinical data suggest that mutations in ER-α and 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) are 
associated with endocrine resistant breast cancer.  To gain insights into potential causal 
relationships between GDC-0810’s clinical activity and resistance mechanisms, 
mutational status of both of these genes will be monitored in ctDNA isolated from plasma 
using next generation sequencing and other molecular technologies.  
11.5.4 
Pharmacogenomic (PGx) Evaluations 
It is established that genetic variants of drug-metabolizing enzymes and transporters can 
affect the PK of drugs, affecting 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 higher risk for adverse effects associated with the use of standard 
doses of irinotecan (O’Dwyer et al. 2006).  Similarly, it has recently been shown that 
patients with genetic polymorphisms in the gene that encodes cytidine deaminase have 
decreased clearance of gemcitabine and an increased incidence of neutropenia when 
they received platinum containing drugs or fluorouracil concurrently 
(Sugiyama et al. 2007). 
For potential PGx analysis of genes that may affect the PK and safety of GDC-0810, a 
mandatory blood sample for DNA isolation will be collected from all patients in Phase IIa 
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12. 
SAFETY ASSESSMENTS 
12.1 
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 12.3. 
12.1.1 
Adverse Events 
According to the International Conference on Harmonisation (ICH) guideline for Good 
Clinical Practice (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 
Section 12.3 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
12.1.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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 12.2.5.10)  


 
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• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 12.2.3); 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 12.3 for 
reporting instructions). 
12.1.3 
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, irrespective of severity or regulatory 
seriousness (i.e., no more than 24 hours after learning of the event; see Section 12.3 for 
reporting instructions).  Adverse events of special interest for this study include the 
following: 
General Drug Development Adverse Events 
• 
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 12.3) 
• 
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. 
 
Adverse Events of Interest 
• 
DLTs occurring during the DLT assessment window 
• 
Grade ≥ 2 vomiting/diarrhea  


 
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• 
Grade ≥ 3 nausea 
• 
Grade ≥ 2 thromboembolic events (including pulmonary embolism) 
• 
Grade ≥ 2 vaginal or uterine hemorrhage 
• 
Grade ≥3 elevation of ALT or AST 
 
Adverse Events of Special Interest for Patients Assigned to Receive GDC-0810 in 
Combination with Palbociclib 
• 
Grade 4 neutropenia, thrombocytopenia, or anemia 
• 
Any grade febrile neutropenia 
 
12.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 12.1.1 
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 12.3.2). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 12.1.2 for seriousness criteria), severity 
(see Section 12.2.3), and causality (see Section 12.2.4).   
12.2.1 
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 12.3.2 for instructions for reporting serious adverse events). 
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 12.3.2). 
12.2.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 


 
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12.2.3 
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 9  will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 9 
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 12.3.2 for reporting instructions), per the definition of serious 
adverse event in Section 12.1.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 12.3.2 for 
reporting instructions), per the definition of serious adverse event in Section 12.1.2. 
 
12.2.4 
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 10): 
• 
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 


 
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• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 10 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). 
 
12.2.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
12.2.5.1 
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. 
12.2.5.2 
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 


 
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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 gastrointestinal 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. 
12.2.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 12.3.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
12.2.5.4 
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 
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• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
• 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating 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 12.2.5.3 for 
details on recording persistent adverse events). 
12.2.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
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. 


 
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• 
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 12.2.5.3 for 
details on recording persistent adverse events). 
 
12.2.5.6 
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 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 12.2.5.4) 
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 12.3.2). 
12.2.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 12.2.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 12.3.2).  
This includes death attributed to progression of breast cancer. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death"). 
If the death is attributed to progression of cancer, “breast cancer progression" should be 
recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 12.5.  


 
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12.2.5.8 
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"). 
12.2.5.9 
Lack of Efficacy or Worsening of Breast Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST criteria.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
12.2.5.10 
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 12.1.2), 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 
• 
Hospitalization solely for coordination of care, including hospice arrangements 
• 
Hospitalization due solely to progression of underlying disease 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 


 
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
12.2.5.11 
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 12.1.2). 
12.2.5.12 
Adverse Events in Individuals Not Enrolled in the Study 
If an adverse event inadvertently occurs in an individual not enrolled in the study 
(e.g., during administration of study drug), the Adverse Event Form provided to 
investigators should be completed and submitted to the Sponsor or its designee, either 
by faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators. 
12.3 
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 12.1.2 for further details) 
• 
Non-serious adverse events of special interest (see Section 12.1.3 for further 
details) 
• 
Pregnancies (see Section 12.3.3 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 


 
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• 
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). 
12.3.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
Medical Monitors: 
, M.D., Ph.D.  
Telephone Nos.: 
 (
 office) 
 
 (mobile) 
Email: 
 
 
Alternate Medical Monitor contact information will be provided in the study manual. 
12.3.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
12.3.2.1 
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 using the fax number or email address provided to 
investigators (see Section 12.3.2.2). 
12.3.2.2 
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.   
For the Phase Ia portion of the study, 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 using the 
fax number or email address provided below.  
For the Phase Ib/IIa portion of the study, 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), either by faxing or by scanning and emailing the form using 
the contact information below: 
Phase Ia/Ib/IIa study:  
Serious adverse events and adverse events of special interest should be reported to 
PPD using the contact information below. 
North America:  
Phone: 1.800.201.8725  
Fax: 1.888.488.9697  
Email:  rtpsafety@ppdi.com 
 
EMEA and Asia Pacific:  
Phone: 44.1223.374.240  
Fax: 44.1223.374.102 
Email:  EMEAASIA SafetyCentral.SM@ppdi.com 
 
For patients in Phase Ib/IIa, 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 12.3.2. 
12.3.3 
Reporting Requirements for Pregnancies 
12.3.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential 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.   
A Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy either by faxing or by scanning and emailing to the contacts listed in 
Section 12.3.2.2.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 


 
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12.3.3.2 
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 12.1.2).  Any abortion should be reported in the same 
fashion (as the Sponsor considers abortions to be medically significant). 
12.4 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
12.4.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
12.4.2 
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. 
12.5 
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. 


 
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12.6 
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 for the Investigational Medicinal Product (IMP) 
including GDC-0810 and palbociclib using the following reference documents: 
• 
GDC-0810 Investigator's Brochure 
• 
Ibrance® US Package Insert 
 
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. 
13. 
PATIENT END OF TREATMENT 
A patient may be discontinued from study treatment at any time if the patient, the 
Investigator, or the Sponsor feels that it is not in the patient’s best interest to continue on 
study.  The following is a list of possible reasons for early discontinuation of study 
treatment:  
• 
Disease progression (unless there is reasonable evidence of clinical benefit to justify 
continuation on the protocol⎯to be discussed with the Sponsor)  
• 
Any other adverse event that cannot be adequately managed with dose 
modifications, including dose interruption for up to 28 days 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Patient is not compliant with study procedures 
• 
Lost to follow-up 
• 
Patient withdrawal of consent  
• 
Sponsor request for early termination of study 
 
Patients will be followed for at least 28 calendar days after the last dose of study drug.  
If a patient is withdrawn from treatment due to an adverse event, the patient will be 
followed until the adverse event has resolved or stabilized as per Section 12.4. 


 
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End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) 
occurs, GDC-0810 drug supply is exhausted, or when Sponsor decides to stop the 
study. 
14. 
PROTOCOL VIOLATIONS 
A protocol violation occurs when the patient or Investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, patient safety, and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Dose modifications (e.g., wrong treatment or incorrect dose) that are not within the 
protocol specifications 
• 
Use of a prohibited concomitant medication 
• 
Any other deviation that presents significant risk or safety concerns to the patient 
 
Failure to comply with GCP guidelines will also result in a protocol violation.  The 
Sponsor, in consultation with the Investigator, will determine if a protocol violation should 
result in withdrawal of a patient. 
When a protocol violation occurs, it will be discussed with the Investigator and 
appropriate forms detailing the violation will be generated.  This form will be signed by 
representatives from the Sponsor.  A copy of the form will be filed in the site’s regulatory 
binder and in the Sponsor’s files. 
15. 
STATISTICAL METHODS AND CONSIDERATIONS 
The objective of the Phase Ia/Ib dose escalation is to determine the MTD and/or RP2D 
of GDC-0810, either as single agent or in combination.   
If the safety and PK profile seen in Phase Ia is deemed to be favorable, the Phase Ia will 
be followed by Phase IIa and Phase Ib, where different cohorts of patients will be 
enrolled to further assess safety, tolerability, preliminary evidence of anti-tumor activity, 
and exploratory PD markers of response. 
15.1 
PLANNED ANALYSES 
Planned analyses include the analyses of safety, PK, anti-tumor activity, and data from 
the 18FES-PET imaging correlative studies. 
Due to the exploratory nature of this study, no confirmatory inferential analyses are 
planned, and no imputation for missing data will be done.  Descriptive statistics (such as 
means, medians, standard deviations, and ranges for continuous data and percentages 
for categorical data) will be used to summarize patient characteristics, treatment 


 
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administration/compliance, safety parameters, pharmacokinetic parameters, anti-tumor 
activity endpoints, and exploratory biomarkers.  Data will also be displayed graphically, 
where appropriate.  Baseline values will be defined as the closest measurement prior to 
the first dose of study drug, typically those collected during screening.  Change from 
baseline will be defined as (post-baseline value − baseline value).  Data will be 
summarized by phase/stage and dose cohorts. 
15.2 
DETERMINATION OF SAMPLE SIZE 
15.2.1 
Phase Ia 
The number of patients to be enrolled in Phase Ia will depend upon the observed safety 
and PK/PD profile, which will determine the number of dose escalations. 
The operating characteristics of the dose escalation rules are shown in Table 11 below, 
which provides the probability of escalation to the next higher dose for each underlying 
true DLT rate.  For example, for a toxicity that occurs in 5% of subjects, there is a 
greater than 95% probability of escalating.  Conversely, for a common toxicity that 
occurs with a rate of 70%, the probability of escalating is < 5%. 
Table 11 Probability of Escalation to the Next Dose 
True Underlying 
DLT Rate 
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
Escalating the 
Dose 
97% 
91% 
71% 
49% 
31% 
17% 
8% 
3% 
1% 
0.1% 
 
Table 12 shows the probability of failing to observe toxicity in a sample size of 3 or 
6 patients given various true underlying toxicity rates.  For example, with 6 patients, the 
probability of failing to observe toxicity occurring at least 40% of the time is less than 5%. 
Table 12 Probability of Failing to Observe Toxicity 
True Underlying 
DLT Rate 
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
Failing to Observe 
Toxicity, N = 3 
86% 
73% 
51% 
34% 
22% 
13% 
6.4% 
2.7% 
0.8% 
0.01%
Probability of 
Failing to Observe 
Toxicity, N = 6  
74% 
53% 
26% 
12% 
4.7% 
1.6% 
0.41% <0.1% <0.1%
<0.1%
 


 
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15.2.2 
Phase IIa 
At the RP2D, a total of approximately 100 patients have been enrolled to further assess 
the safety, tolerability, preliminary evidence of anti-tumor activity, and exploratory 
PD markers of response of GDC-0810 in 3 distinct patient populations (Cohorts A1 and 
A2 will be combined for analysis purposes). 
A total of 100 patients in Phase IIa will provide a more robust safety profile as well as 
sample size for preliminary assessment of anti-tumor activity based on clinical benefit 
rate (CBR) (see Table 13), defined as the percentage of patients achieving confirmed 
RECIST v1.1 defined complete response, partial response, and/or stable disease 
≥ 24 weeks.   
In Cohort A, because the presence of ESR1 mutations are associated with poor 
prognosis, an objective response rate (ORR), defined as the percentage of patients 
achieving confirmed complete and/or partial responses of at least 15% (5 out of 
30 patients) would be considered of more clinical interest than CBR to warrant further 
development of GDC-0810 in this mutant patient population.   
In Cohort B1, the desired observed CBR is 50%, based on historical CBRs of 46% 
(Di Leo et al. 2010) and 48% (Bachelot et al. 2012) for patients with ER+/HER2− 
advanced breast cancer after prior treatment with aromatase inhibitors. 
In Cohort B2, the desired observed CBR is 20%, based on historical CBRs ranging from 
18% to 26% for patients with ER+/HER2− advanced breast cancer after prior treatment 
with fulvestrant (Baselga et al. 2011; Yardley et al. 2013). 
Table 13 Two-Sided Confidence Intervals for Phase IIa Cohorts 
Cohort 
Sample 
Size 
Assumed 
Observed 
Effect 
Confidence Level 
Two-sided CI 
A 
N = 30 
15% ORR 
80% 
(8.34%, 28.74%) 
B1 
N = 50 
50% CBR 
80% 
(40.09%, 59.91%) 
B2 
N = 20 
20% CBR 
80% 
(9.02%, 36.07%) 
 
15.2.3 
Phase Ib 
Approximately 5 patients have been enrolled in the Phase Ib dose escalation cohorts 
(Cohorts C0 and C1).  No additional patients will be enrolled. 
Because the dose escalation portion of Phase Ib follows the same dose escalation rules 
as the Phase Ia, the probability of escalation from dose level C1 to dose level C2 is also 
shown in Table 11.  Similarly, the probability of failing to observe toxicity in dose 


 
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escalation cohorts (Cohorts C0 and C1) and safety run-in cohort (Cohort D1) is shown in 
Table 14. 
Approximately 4 patients have been enrolled at the RP2D of GDC-0810 and palbociclib, 
and approximately 6 patients have been enrolled at 600 mg of GDC-0810 and an LHRH 
agonist.  With 10 patients, there is a 80% probability of observing an adverse event with 
a true underlying probability of 15%. 
Table 14 Probability of Safety-Signal Detection with 10 Patients 
True Underlying 
Probability of an AE (%) 
Probability of Observing at 
Least 1 AE in 10 Patients (%)
5 
40 
10 
65 
15 
80 
20 
89 
 
15.3 
SAFETY ANALYSES 
For safety analyses, the analysis population will include all enrolled patients who receive 
at least one dose of study medication. 
Study treatment discontinuation and reasons for patient discontinuations from the study 
will be described and summarized.  Study drug administration data will be listed and any 
dose modifications will be flagged. 
15.3.1 
Adverse Events 
Adverse events will be graded according to the NCI CTCAE v4.0 and coded to preferred 
term and system organ class (SOC).  
All adverse events reported during the adverse event reporting period will be considered 
as treatment-emergent adverse events.  Incidence rates will be summarized with 
frequency and percentage by MedDRA SOC and preferred term, with all patients treated 
as the denominator, unless otherwise specified.  In addition, adverse event incidence 
rates will also be summarized by severity and relationship to study drug.  
Treatment-related adverse events are those judged by the Investigator to be at least 
possibly related to the study drug.  Patients with multiple occurrences of events will only 
be counted once at the maximum severity attributed to study drug for each preferred 
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15.3.2 
Clinical Laboratory Results 
Normal ranges will be used to identify values that are outside the normal ranges and 
abnormal laboratory results will be graded according to the NCI CTCAE v4.0.  
A shift summary of baseline grade by maximum post-baseline CTCAE grade will be 
presented, as appropriate.  For each laboratory parameter, the baseline laboratory value 
will be defined as the last laboratory value collected on or prior to the date of the first 
dose of study drug. 
Patients who develop toxicities of Grade ≥ 3 will be summarized.  Laboratory test results 
not having CTCAE grade will also be summarized.  Parameters that have criteria 
available for both low and high values (e.g., hypercalcaemia vs. hypocalcaemia) will be 
summarized for both criteria.  Patients will only be counted once for each criterion. 
15.3.3 
Vital Signs 
Each vital sign (temperature, blood pressure [systolic and diastolic], respiration rate, and 
heart rate) will be summarized and presented by study visit.  Patients with clinically 
significant abnormalities in vital signs as compared to baseline will be listed. 
15.3.4 
Concomitant Medications/Treatments 
All medications and/or treatments received during the protocol treatment period will be 
considered as concomitant medications and/or concomitant treatments and will be 
coded by medical dictionary; patients who received concomitant medications and/or 
treatments will be listed. 
15.3.5 
Endometrial Thickness 
Endometrial thickness changes during study as compared to baseline will be 
summarized and presented by study visit.   
15.3.6 
Ventricular Repolarization 
Standard ECG intervals RR and QT will be determined for each ECG recording.  
Corrected QT intervals (QTc) will be determined using Fridericia's formula.  Changes in 
ECG intervals from baseline will be calculated.  Baseline is defined as either the single 
ECG measurement (Phase I) or the mean of the triplicate ECG measurements (Phase II) 
collected during screening.  Standard evaluation procedures will be employed in the 
reading of the ECGs. 
Tables to be prepared include analysis of time-matched mean differences between 
baseline and postdose assessments, and analysis of maximum change from baseline for 
each patient. 


 
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In addition, patient’s QTc (Fridericia) will be categorized based on ICH E14 guidance.  
Tables will present the number and percentage of patients meeting or exceeding the 
following categories: 
QTc interval prolongation 
Absolute values > 450 to ≤ 480 msec 
Absolute values > 480 to ≤ 500 msec 
Absolute values > 500 msec 
 
QTc interval change from baseline 
Increase from baseline > 30 to ≤ 60 msec 
Increase from baseline > 60 msec 
 
15.4 
PHARMACOKINETIC ANALYSES 
For PK analyses, the analysis population will consist of the subset of treated patients 
who have at least one PK sample collected. 
During the Phase Ia portion of the study, full plasma PK profiles will be obtained for 
GDC-0810 and its glucuronide metabolites, and analyzed using non-compartmental 
methods for all patients in the dose escalation portion of the study.   
In the Phase IIa portion of the study, full plasma PK profiles will be obtained for 
GDC-0810 and analyzed using non-compartmental methods. 
In the Phase Ib portion of the study, full plasma PK profiles will be obtained for 
GDC-0810 and palbociclib and/or LHRH agonists and analyzed using 
non-compartmental methods.  
In addition, in the Phase Ia/IIa/Ib, blood samples for determination of the steady-state 
trough concentrations (predose) of GDC-0810 will be obtained from all patients. 
15.5 
ANTI-TUMOR ACTIVITY 
Objective response and clinical benefit rates will be derived according to RECIST v1.1 
and summarized by dose level and cohort.  Progression-free survival will be listed for all 
patients in Phase IIa, when appropriate. 
Objective response is defined as a complete response or partial response, as 
determined by investigator assessment and confirmed by repeat assessment ≥ 4 weeks 
after initial documentation.  Patients with missing baseline or no response assessments 
will be classified as non-responders. 
CBR is defined as the percentage of patients achieving confirmed RECIST v1.1−defined 
complete response, partial response, and/or stable disease ≥ 24 weeks.   


 
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Progression-free survival is defined as the time from the first day of study treatment with 
GDC-0810 in the Phase IIa until documented disease progression or death, whichever 
occurs first.  For patients who do not have documented progressive disease or death 
before the end of the study or who are lost to follow-up, progression-free survival will be 
censored at the day of the last tumor assessment. 
15.6 
EXPLORATORY STUDIES 
18FES-PET imaging correlative studies will be performed at baseline and after treatment 
to assess ER occupancy and establish correlations with anti-tumor activity and other 
tumor biopsy−based biomarkers of response. 
Archival and biopsy tissues will be analyzed to assess correlation of efficacy with 
molecular markers related to the mechanism of action of GDC-0810 and include 
alterations in DNA mutational status, RNA expression levels, DNA copy number. and 
protein expression. 
Matched biopsies pre- and on-treatment of safely accessible metastatic sites will be 
collected to assess for downstream indicators of ER target gene modulation, ER and PR 
protein levels, and Ki67 (tumor cell proliferation).  These biomarkers will be measured at 
baseline and on- treatment to explore the association between changes in the tumor 
biomarkers as a PD readout of drug activity and objective response rate.  Post-
progression biopsies, whenever feasible and safely accessible, will be collected to 
assess for markers correlating to drug resistance. 
Circulating tumor DNA will be analyzed for mutational status of, but not limited to, ER-α 
and PIK3CA to gain insights into potential causal relationships between GDC-0810’s 
clinical activity and resistance mechanisms to endocrine therapy. 
16. 
DATA COLLECTION, RETENTION, AND MONITORING 
16.1 
DATA COLLECTION INSTRUMENTS 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each patient treated with 
the study drug.  
Study personnel at each site will enter data from source documents corresponding to a 
patient’s visit into the protocol-specific electronic Case Report Form (eCRF) when the 
information corresponding to that visit is available.  Patients will not be identified by 
name in the study database or on any study documents to be collected by the Sponsor 
(or designee) but will be identified by a site number, patient number, and initials. 
If a correction is required for an eCRF, the time and date stamps will track the person 
entering or updating eCRF data and will create an electronic audit trail.   


 
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The Investigator is responsible for reviewing all information collected on patients enrolled 
in this study for completeness and accuracy.  A copy of the eCRF will remain at the 
Investigator’s site at the completion of the study. 
16.2 
DATA MANAGEMENT PROCEDURES 
The data will be entered into a validated database.  The Sponsor-designated data 
management group will be responsible for data processing, in accordance with 
procedural documentation.  Database lock will occur once quality assurance procedures 
have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
16.3 
DATA QUALITY CONTROL AND REPORTING 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis.  
Queries are entered, tracked, and resolved through the EDC system directly.  The study 
database will be updated in accordance with the resolved queries.  All changes to the 
study database will be documented. 
16.4 
ARCHIVAL OF DATA 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim and final reports), data for 
analysis are locked and cleaned per established procedures. 
An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient scans throughout the trial.  The review facility will retain 
copies of scans for centralized assessments of FES-PET and tumor assessment scans.  
16.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL 
RECORDS 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
Investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, e.g., CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, telephone calls, and reports).  The 
records should be retained by the Investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever is longer, but at a minimum, all study 


 
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documentation must be retained for 2 years after the last marketing application approval 
in an ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of GDC-0810. 
If the Investigator becomes unable for any reason to continue to retain study records for 
the required period (e.g., retirement, relocation), the Sponsor should be prospectively 
notified.  The study records must be transferred to a designee acceptable to the 
Sponsor, such as another investigator, another institution, or to the Sponsor itself.  
The Investigator must obtain the Sponsor’s written permission before disposing of any 
records, even if retention requirements have been met. 
16.6 
MONITORING 
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).  By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation. 
16.7 
PATIENT 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. 
17. 
ADMINISTRATIVE, ETHICAL, REGULATORY 
CONSIDERATIONS 
Clinical Practice 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. 


 
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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 
(E.U.) or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
17.1 
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). 
17.2 
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. 
17.3 
INSTITUTIONAL REVIEW BOARDS OR ETHICS COMMITTEE 
The protocol, Investigator’s Brochure, the consent forms, any information to be given to 
the patient (including patient recruitment materials), and relevant supporting information 
must be submitted to the IRB/EC by the Investigator for review and approval before the 
study is initiated.  The IRB’s/EC’s unconditional approval statement will be transmitted 
by the Investigator to the Sponsor or designee prior to the shipment of study supplies to 
the site.  This approval must refer to the study by exact protocol title and number and 
should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB, and written verification that the 
modification was submitted and subsequently approved should be obtained.   
Investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all serious adverse events, whereas others require notification only about 


 
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events that are serious, assessed to be related to study treatment, and are 
unexpected.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 regulatory requirements and 
with the policies and procedures established by their IRB and archived in the site’s 
Study File.  
Finally, the Investigator will keep the IRB/EC informed as to the progress of the study, 
revisions to documents originally submitted for review, annual updates, and/or request 
for re-approvals, and when the study has been completed.  
17.3.1 
Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability 
and Accountability Act (HIPAA, if applicable), and local regulations. 
The Sponsor’s Sample Informed Consent Form (ICF) will be provided to each site.  
Sponsor or its designee must review and approve any proposed deviations from the 
Sample ICF or any alternate consent forms proposed by the site before IRB submission.  
Patients must be re-consented to the most current version of the Consent forms during 
their participation in the study.  The final IRB-approved Consent Forms must be provided 
to Sponsor for regulatory purposes. 
The Consent Forms must be signed by the patient before her participation in the study.  
The case history for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.  A copy of each 
signed Consent Form must be provided to the patient.  If applicable, it will be provided in 
a certified translation of the local language. 
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB-approved Informed Consent Form must be provided to Sponsor for 
regulatory purposes. 


 
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17.4 
REPORTING OF SAFETY ISSUES AND SERIOUS BREACHES 
OF THE PROTOCOL OR ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority in any area of the world or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, the Sponsor should be informed immediately.   
In addition, the Investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate 
hazard and of any serious breaches of this protocol or of ICH GCP that the Investigator 
becomes aware of. 
17.5 
SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority 
decision, change in opinion of the IRB, drug safety problems, or at the discretion of the 
Sponsor.  In addition, the Sponsor retains the right to discontinue development of 
GDC-0810 at any time. 
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator.  After notification, the Investigator must notify the respective IRB and 
contact all participating subjects and the hospital pharmacy (if applicable) within a 
4-week time period.  As directed by the Sponsor, all study materials must be collected 
and all CRFs completed to the greatest extent possible. 
17.6 
PUBLICATIONS  
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 


 
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proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 


 
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18. 
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Appendix 1 Schedule of Activities: Phase Ia  (cont.) 
 
Footnotes 
1. Cycle 2+:  To be performed per institutional guidelines and/or as clinically indicated except for ECOG, physical examination, vital signs, creatinine, 
liver function tests, adverse events, concomitant medication, and study drug compliance should be monitored at each cycle. 
2. End of Treatment:  These assessments do not need to be completed if they have been performed within 1 week of study withdrawal (within 4 weeks for 
imaging studies and 3 months for the transvaginal ultrasound).  
3. Safety Follow-Up: Patients should be evaluated for safety up to 28 days after the last dose of study treatment.  Physical examination (including ECOG and 
vitals), hematology, and blood chemistry should be performed as clinically indicated. Adverse events should be followed until all serious or study drug-related 
toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.   
4. Medical/Oncological History:  Includes oncologic history, demographics, history of other disease processes (active or resolved) and concomitant illnesses.  
5. Physical Examination:  Examination of major body systems, including known and suspected sites of disease.  Height should be collected at Screening. 
6. CT/MRI of the brain: To be performed as needed to rule out the presence of untreated CNS metastases. 
7. Samples for hematology, blood chemistry (except creatinine and liver function tests), and urinalysis will be performed per institutional guidelines 
and as clinically indicated,  Circulating tumor DNA will be analyzed by a specialty laboratory.  Creatinine and liver function tests should be monitored at 
each cycle.  ctDNA will be collected at screening and end of study visit. 
8. Trough PK Sample:  Samples should be obtained predose on the specified days (patient should not take the study drug at home).  Additionally, if 
clinically feasible, samples should be obtained at the time of any serious and/or unusual adverse events that may be causally related to study drug. 
9. GDC-0810 Dosing: GDC-0810 will be orally self-administered, except on clinic days, when they will take their daily dose at the clinic, prior to any study 
assessment.  One cycle consists of 28 days. 
10. ECG:  Single 12-lead ECGs will be collected at Screening and at Cycle 2 Day 1 (at the 2-hour postdose timepoint) to assess the QTc interval. If there is 
QTc interval prolongation (Grade > 1), the ECG should be over read by a cardiologist at the site for confirmation. 
11. 24-Hour PK Assessment:  Samples will be drawn relative to time of dose at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose. 
 
Screening 
PK Week 
Lead-In 
Cycle 1 
Cycle 2+ [1] 
Protocol Activities  
≤ 28 days 
of 1
st dose 
Day -7 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 1 day) 
Day 22 
(± 1 day) 
Labs 
CT/MRI scans  
End of 
Treatment 
[1] 
Safety 
Follow-Up 
(+ 2 days) 
[2] 
Transvaginal Ultrasound [17] 
X 
 
 
 
 
 
X 
X 
 
Study Drug Compliance [18] 
 
 
 
X 
X 
X 
X 
X 
 
Study assessments may be delayed or moved ahead of the window specified to accommodate holidays, vacations, and unforeseen delays. 


 
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Appendix 1 Schedule of Activities: Phase Ia  (cont.) 
 
12. Day -7 PK Assessment: Samples will be drawn relative to time of dose at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours postdose. 
13. Tumor Imaging: CT scans of the chest, abdomen and pelvis and a bone scan will be performed to assess disease status at Screening, and per 
institutional guidelines and as clinically indicated. 
14. FES-PET/CT scans: Functional ER imaging will be performed at Screening and at Cycle 2 Day 3 (between ≥ 18 and ≤ 24 hours post- evening dose from 
the previous day) starting at Dose Level 2 (200 mg).  If needed, a third scan will be performed at Cycle 3 (same day as the tumor evaluation scans, between 
≥ 2 and ≤ 12 hours postdose).  If low FES uptake is observed at Screening, the investigator will determine whether the post-treatment scans are warranted.  
Blood samples for analysis of drug levels (PK), E2, and SHBG should be collected prior to each PET scan performed. 
15. Tumor Biopsies (optional): Pre- and post-treatment biopsies from the same (whenever feasible) soft tissue or visceral metastatic lesion will be collected 
at Screening and Cycle 2 Day 8, between ≥ 2 and ≤ 12 hours postdose. 
16. Adverse Events and Concomitant Medications/Treatments:  Patients must be followed for adverse events and associated concomitant medications and 
treatments on a monthly basis, from the first day of study treatment until at least 28 days after the last dose of study treatment, or until all serious or study 
drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.   
17. Transvaginal Ultrasound (if applicable):  Assessment of endometrial thickness will be performed at Screening, at the end of treatment (if treated for at 
least 2 cycles), and as clinically indicated.  Any abnormal bleeding should be evaluated with a complete gynecological workup. 
18. Study Drug Compliance:  GDC-0810 bottle(s) including any unused capsules should be brought to each clinic visit for drug accountability.  
 






 
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Appendix 2 Schedule of Activities: Phase IIa  (cont.) 
 
9. GDC-0810 Dosing: GDC-0810 will be orally self-administered within 30 minutes after eating a meal (unless specified otherwise).  One cycle consists of 
28 days. 
10. ECG:  Triplicate 12-lead ECGs will be collected approximately 2 minutes apart at Screening, on Cycle 2 Day 1 predose and at 1, 2, 3, 4, and 6 hours 
following dosing to assess the QTc interval.   For real-time safety monitoring of patients, only one ECG printout per timepoint (of the triplicate -matched PK 
samples) will need to be reviewed by the investigator.  For the purposes of central analysis, triplicate ECGs will be obtained in a rigorous and standardized 
fashion and transmitted digitally to the central reading facility for review and interpretation by specialized cardiac readers. For real-time safety monitoring of 
patients, only one ECG printout per timepoint (of the triplicate -matched PK samples) will need to be reviewed by the investigator.  For the purposes of central 
analysis, triplicate ECGs will be obtained in a rigorous and standardized fashion and transmitted digitally to the central reading facility for review and 
interpretation by specialized cardiac readers. 
11. PK Sample:  PK samples will also be collected predose and at 1, 2, 3, 4, and 6 hours following dosing at Cycle 2 Day 1.  If PK sampling times coincide 
with ECG collection times, the ECGs have to be assessed prior to PK blood collection. 
12. Tumor Imaging: CT scans of the chest, abdomen and pelvis and a bone scan will be performed to assess disease status at Screening and per 
institutional guidelines and as clinically indicated. 
13. FES-PET/CT scans: Functional ER imaging will be performed in all Cohort A1 patients at Screening, at Cycle 3 (per Section 11.5.1.2).  If low FES uptake 
is observed at Screening, the investigator will determine whether the post-treatment scan(s) are warranted. Blood samples for analysis of E2 and SHBG should 
be collected prior to each PET scan performed. 
14. Tumor Biopsies: All Cohort A patients with safely accessible soft tissue and/or visceral metastases will have tumor biopsies performed at Screening, at 
Cycle 2 (Day 8 for patients in Cohort A1), and if feasible, at the time when disease progression is suspected (especially if disease progression occurs prior to 
Cycle 3).  Biopsies should be collected during the period between ≥ 2 and ≤ 12 hours postdose.  Tumor Biopsies are optional but strongly encouraged for 
Cohort B patients with safely accessible soft tissue and/or visceral metastases. 
15. Archival paraffin-embedded tissue may be collected to evaluate the histology of the tumor. If fresh tumor tissue biopsy cannot be obtained at screening, 
every reasonable effort should be made to obtain the most recent archival tissue sample.  Tumor blocks are preferred, but in the event that local regulations 
prevent the shipment of tumor blocks, 15-20 unstained, serially cut slides are requested.  Minimum tissue requirements are further described in the laboratory 
manual.  Cytological, fine-needle aspiration, and decalcified bone biopsy samples are not acceptable. 
16. Adverse Events and Concomitant Medications/Treatments:  Patients must be followed for adverse events and associated concomitant medications 
and treatments on a monthly basis, from the first day of study treatment until at least 28 days after the last dose of study treatment, or until all serious or study 
drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.   
17. Transvaginal Ultrasound (if applicable): Assessment of endometrial thickness will be performed at Screening, at the end of treatment (if treated for at 
least 2 cycles), and as clinically indicated.  Any abnormal bleeding should be evaluated with a complete gynecological workup. 
18. Study Drug Compliance:  GDC-0810 bottle(s) including any unused capsules should be brought to each clinic visit for drug accountability.  






 
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Appendix 3 Schedule of Activities: Phase Ib Cohorts C0 and C1 (Dose Escalation)  (cont.)  
4. Medical/Oncological History:  Includes oncologic history, demographics, history of other disease processes (active or resolved) and concomitant illnesses.  
5. Physical Examination:  Examination of major body systems, including known and suspected sites of disease.  Height should be collected at Screening. 
6. CT/MRI of the brain: To be performed as needed to rule out the presence of untreated CNS metastases. 
7. Serum pregnancy test (for patients on LHRH agonists) must be performed and documented as negative within 14 days prior to Cycle 1, Day 1. 
8. A pharmacogenomic sample will be collection prior to Cycle 1 Day 1.  The pharmacogenomic analysis of genes that may affect the PK of GDC-0810 and 
circulating tumor DNA will be analyzed at specialty laboratories. 
9. Samples for hematology, blood chemistry (except creatinine and liver function tests), and urinalysis will be performed per institutional guidelines 
and as clinically indicated,  Circulating tumor DNA will be collected at screening C3, C5, and at progression and analyzed by a specialty laboratory.  At Cycle 
2 Day 15 collection of a complete blood count is required only.  Creatinine and liver function tests should be monitored at each cycle.   
10. Trough PK Sample:  Samples should be obtained predose on the specified days (patient should not take the study drug at home).  Additionally, if 
clinically feasible, samples should be obtained at the time of any serious and/or unusual adverse events that may be causally related to study drug. 
11. GDC-0810 Dosing: GDC-0810 will be orally self-administered within 30 minutes after eating a meal (unless specified otherwise), except on clinic days, 
when the daily dose will be taken at the clinic, prior to any study assessment.  One cycle consists of 28 days. 
12. Palbociclib Dosing: Palbociclib will be orally self-administered on Days 1-21 of each cycle, except on clinic days, when the daily dose will be taken at the 
clinic, prior to any study assessment.  One cycle consists of 28 days. 
13. ECG:  Single ECGs will be collected at Screening, Cycle 1 Day 1 (prior to first dose), Cycle 2 Day 1 and end of treatment visits.  At other study visits they 
should be recorded as clinically indicated.  If there is QTc interval prolongation (Grade > 1), the ECG should be over read by a cardiologist at the site for 
confirmation. 
14. PK Assessment:  Samples will be drawn relative to time of dose at 0 (predose), 1, 2, 3, 4, 6 hours , post-dose at Cycle 1 Day 1 and Cycle 1 Day 8. 
15. Tumor Imaging: CT scans of the chest, abdomen and pelvis and a bone scan will be performed to assess disease status at Screening and per 
institutional guidelines and as clinically indicated.  
16. Tumor Biopsies : Pre-, on- treatment and post-progression biopsies from the same (whenever feasible) soft tissue or visceral metastatic lesion that is 
safely accessible will be collected at Screening,  Cycle1 Day 15, between ≥ 2 and ≤ 12 hours post-dose, and at the time of progression.   


 
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Appendix 3 Schedule of Activities: Phase Ib Cohorts C0 and C1 (Dose Escalation)  (cont.)  
17. Archival paraffin-embedded tissue may be collected to evaluate the histology of the tumor. If fresh tumor tissue biopsy cannot be obtained at screening, 
every reasonable effort should be made to obtain the most recent archival tissue sample.  Tumor blocks are preferred, but in the event that local regulations 
prevent the shipment of tumor blocks, 15-20 unstained, serially cut slides are requested.  Minimum tissue requirements are further described in the laboratory 
manual.  Cytological, fine-needle aspiration, and decalcified bone biopsy samples are not acceptable. 
18. Adverse Events and Concomitant Medications/Treatments:  Patients must be followed for adverse events and associated concomitant medications and 
treatments at each clinic visit on a monthly basis, from the first day of study treatment until at least 28 days after the last dose of study treatment, or until all 
serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.    
19. Transvaginal Ultrasound (if applicable): Assessment of endometrial thickness will be performed at Screening, at the end of treatment (if treated for at 
least 2 cycles), and as clinically indicated.  Any abnormal bleeding should be evaluated with a complete gynecological workup. 
20. Study Drug Compliance:  GDC-0810 and palbociclib bottle(s) including any unused capsules should be brought to each clinic visit for drug accountability. 
21. LHRH agonist (if applicable):  Treatment with LHRH agonist as per local practice for all women who are pre- or peri-menopausal at study entry.  Patients 
must have commenced treatment with LHRH agonist at least 4 weeks prior to study entry. It is recommended to administer the LHRH agonist (given every 
28 days) on-site. If LHRH agonist is administered at home by the patient, a patient diary will be implemented. 






 
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Appendix 4 Schedule of Activities: Phase Ib Cohort D1 (Safety Run-In)  (cont.)  
5. Physical Examination:  Examination of major body systems, including known and suspected sites of disease.  Height should be collected at Screening. 
6. Serum pregnancy test (for patients on LHRH agonists) must be performed and documented as negative within 14 days prior to Cycle 1, Day 1. 
7. A pharmacogenomic sample will be collection prior to Cycle 1 Day 1.  The pharmacogenomic analysis of genes that may affect the PK of GDC-0810 and 
circulating tumor DNA will be analyzed at specialty laboratories. 
8. CT/MRI of the brain: To be performed as needed to rule out the presence of untreated CNS metastases. 
9. Samples for hematology, blood chemistry (except creatinine and liver function tests), and urinalysis will be performed per institutional guidelines 
and as clinically indicated,  Circulating tumor DNA will be collected at screening C3, C5, and at disease progression and will be analyzed by a specialty 
laboratory.  Creatinine and liver function tests should be monitored at each cycle. 
10. Trough PK Sample:  Plasma samples should be obtained pre-dose on the specified days (patient should not take the study drug at home).  Additionally, 
if clinically feasible, samples should be obtained at the time of any serious and/or unusual adverse events that may be causally related to study drug. 
11. GDC-0810 Dosing: GDC-0810 will be orally self-administered within 30 minutes after eating a meal (unless specified otherwise). One cycle consists of 
28 days. 
12. LHRH agonist Dosing: Treatment with LHRH agonist as per local practice for all women who are pre- or peri-menopausal at study. Patients must have 
commenced treatment with LHRH agonist at least 4 weeks prior to study entry. It is recommended to administer the LHRH agonist (given every 28 days) on-
site. If LHRH agonist is administered at home by the patient, a patient diary will be implemented. 
13. ECG:  Single ECGs will be collected at Screening, Cycle 1 Day 1 (prior to first dose), Cycle 2 Day 1 and end of treatment visits.  At other study visits they 
should be recorded as clinically indicated.  If there is QTc interval prolongation (Grade > 1), the ECG should be over read by a cardiologist at the site for 
confirmation. 
14. PK Sample:  PK samples will also be collected pre-dose and at 1, 2, 3, 4, and 6 hours following dosing at Cycle 1 Day 1 and Cycle 2 Day 1. If PK 
sampling times coincide with ECG collection times, the ECGs have to be assessed prior to PK blood collection. 
15. Tumor Imaging: CT scans of the chest, abdomen and pelvis and a bone scan will be performed to assess disease status at Screening and per 
institutional guidelines and as clinically indicated.  
16. Tumor Biopsies: Patients with safely accessible soft tissue and/or visceral metastases will have tumor biopsies performed at Screening, at Cycle 1 Day 15 
and if feasible, at the time when disease progression is suspected (especially if disease progression occurs prior to Cycle 3).  Biopsies should be collected 
during the period between ≥ 2 and ≤ 12 hours post-dose.  


 
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Appendix 4 Schedule of Activities: Phase Ib Cohort D1 (Safety Run-In)  (cont.)  
17. Archival Tissue Sample: Archival paraffin-embedded tissue may be collected to evaluate the histology of the tumor. If fresh tumor tissue biopsy cannot be 
obtained at screening, every reasonable effort should be made to obtain the most recent archival tissue sample.  Tumor blocks are preferred, but in the event 
that local regulations prevent the shipment of tumor blocks, 15-20 unstained, serially cut slides are requested.  Minimum tissue requirements are further 
described in the laboratory manual.  Cytological, fine-needle aspiration, and decalcified bone biopsy samples are not acceptable. 
18. Adverse Events and Concomitant Medications/Treatments:  Patients must be followed for adverse events and associated concomitant medications 
and treatments on a monthly basis, from the first day of study treatment until at least 28 days after the last dose of study treatment, or until all serious or study 
drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.   
19. Transvaginal Ultrasound (if applicable): Assessment of endometrial thickness will be performed at Screening, at the end of treatment (if treated for at 
least 2 cycles), and as clinically indicated.  Any abnormal bleeding should be evaluated with a complete gynecological workup. 
20. Study Drug Compliance:  GDC-0810 bottle(s) including any unused capsules should be brought to each clinic visit for drug accountability.  




 
GDC-0810—Genentech, Inc. 
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Appendix 6 ECOG Performance Status  
0 
Fully active, able to carry on all pre-disease activities 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 house work or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 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. 
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Appendix 7 National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE)  
The NCI CTCE (Version 4.0) may be reviewed online at the following NCI website: 
http://ctep.cancer.gov/reporting/ctc.html 


 
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Appendix 8 Restricted Medications or Treatments  
a. The following drugs are sensitive substrates or substrates of CYPs 2B6, 2C8, 
2C9, 2C19 and 3A with a narrow 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  
CYP3A 
Alfentanil, aprepitant, 
budesonide, buspirone, 
conivaptan, darifenacin, 
darunavir, dasatinib, 
dronedarone, eletriptan, 
eplerenone, everolimus, 
felodipine, indinavir, 
fluticasone, lopinavir, 
lovastatin, lurasidone, 
maraviroc, midazolam, 
nisoldipine, quetiapine, 
saquinavir, sildenafil, 
simvastatin, sirolimus, 
tolvaptan, tipranavir, 
triazolam, ticagrelor, 
vardenafil 
Alfentanil, astemizole, 
cisapride, cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine 
 
b. The following drugs are strong inhibitors of CYP3A. It is strongly recommended 
to avoid concomitant use of strong CYP3A inhibitors with IBRANCE (palbociclib) 
and to avoid grapefruit or grapefruit juice during IBRANCE treatment. If 
coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, 
reduce the dose of IBRANCE.  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. 


 
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Appendix 8 Restricted Medications or Treatments  (cont.) 
CYP Enzymes 
Strong Inhibitors 
CYP3A 
Boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole 
c. The following drugs are strong and moderate inducers of CYP3A. It is strongly 
recommended to avoid concomitant use of strong and moderate inducers of 
CYP3A with IBRANCE (palbociclib). 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 
Strong Inducers 
Moderate Inducers 
CYP3A 
Avasimibe, carbamazepine, 
phenytoin, rifampin, St. John’s 
wort 
Bosentan, efavirenz, 
etravirine, modafinil, nafcillin