A Phase III, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Inavolisib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche

Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of Inavolisib Plus Palbociclib and 
Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in 
Patients With PIK3CA-Mutant, Hormone Receptor-Positive, HER2-
Negative, Locally Advanced or Metastatic Breast Cancer 
NCT Number: 
NCT04191499 
Document Date: 
Protocol Version 8: 08-March-2023 

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Inavolisib—F. Hoffmann-La Roche Ltd 
Protocol WO41554, Version 8 
PROTOCOL 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY EVALUATING 
THE EFFICACY AND SAFETY OF INAVOLISIB 
PLUS PALBOCICLIB AND FULVESTRANT VERSUS 
PLACEBO PLUS PALBOCICLIB AND 
FULVESTRANT IN PATIENTS WITH 
PIK3CA-MUTANT, HORMONE 
RECEPTORPOSITIVE, HER2-NEGATIVE 
LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER 
PROTOCOL NUMBER: WO41554 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2019-002455-42 
IND NUMBER: 
130909 
NCT NUMBER 
NCT04191499 
TEST PRODUCT: 
Inavolisib (RO7113755, GDC-0077) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 
 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
2/Protocol WO41554, Version 8 
PROTOCOL HISTORY 
 
Protocol 
Associated Country and Region 
Protocols 
Version 
Date Final 
Country and 
Region 
Version 
Date Final 
8 
See electronic date stamp on the 
final page of this document. 
 
 
 
7 
21 October 2022 
 
 
 
6 
12 August 2022 
 
 
 
4 
3 November 2020 
Canada 
5 
21 May 
2021 
 
 
VHP 
3 
4 August 
2020 
2 
16 October 2019 
VHP 
2 
16 October 
2019 
1 
12 August 2019 
VHP 
1 
12 August 
2019 
VHP    Voluntary Harmonization Procedure. 
 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
3/Protocol WO41554, Version 8 
PROTOCOL AMENDMENT, VERSION 8: 
RATIONALE 
Protocol WO41554 Version 8 has been amended to redefine the study sample size due 
to the unanticipated slow enrollment experienced during the pandemic and is intended to 
minimize the risk of Last Patient In (LPI) occurring after the number of planned events 
for the primary PFS analysis is reached.  Substantive changes to the protocol, along with 
a rationale for each change, are summarized below. 
 
The total planned enrollment of 400 participants has been reduced to 320 to 
minimize the risk of LPI occurring after the number of planned events for the primary 
PFS analysis is reached. (Sections 3.1.1, 4.1, 6.1) 
 
The number of progression free survival events to trigger primary study readout has 
been reduced from 227 to 194, resulting in a change in the power of PFS from 90% 
to 85%, which is considered adequate for the primary endpoint (Sections 6, and 
6.1). 
 
An interim and a final OS analysis were added to preserve the integrity of this key 
secondary study endpoint (Sections 6.4.2, 6.4.2.1, 6.9.1, 6.9.1.1). 
 
Non-investigational medicinal products were clarified (Section 4.3.3). 
 
Additional minor changes and clarifications have been made to improve clarity and 
consistency. Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol. 
 
 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
4/Protocol WO41554, Version 8 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
PROTOCOL SYNOPSIS .................................................................................... 14 
1. 
BACKGROUND ............................................................................ 31 
1.1 
Background on Hormone Receptor-Positive, HER2-
Negative Advanced or Metastatic Breast Cancer .................... 31 
1.2 
Background on the PI3K/AKT/mTOR Pathway and Breast 
Cancer ..................................................................................... 33 
1.3 
Background on inavolisib ......................................................... 35 
1.3.1 
Nonclinical Data for Inavolisib .................................................. 36 
1.3.2 
Clinical Data for Inavolisib ....................................................... 37 
1.4 
Background on Palbociclib....................................................... 39 
1.4.1 
Clinical Pharmacokinetics of Palbociclib .................................. 40 
1.5 
Background on Fulvestrant ...................................................... 41 
1.5.1 
Clinical Pharmacokinetics of Fulvestrant ................................. 41 
1.6 
Study Rationale and BenefitRisk Assessment ....................... 42 
1.6.1 
COVID-19 ................................................................................ 45 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 46 
2.1 
Efficacy Objectives .................................................................. 46 
2.1.1 
Primary Efficacy Objective ....................................................... 46 
2.1.2 
Secondary Efficacy Objective .................................................. 46 
2.1.3 
Exploratory Efficacy Objective ................................................. 47 
2.2 
Safety Objectives ..................................................................... 47 
2.3 
Pharmacokinetic Objectives..................................................... 48 
2.4 
Biomarker Objective ................................................................ 48 
2.5 
Health Status Utility Objective .................................................. 49 
3. 
STUDY DESIGN ........................................................................... 49 
3.1 
Description of the Study ........................................................... 49 
3.1.1 
Overview of Study Design........................................................ 49 
3.1.2 
Independent Data Monitoring Committee ................................ 55 
3.1.3 
Blinded Independent Central Imaging Review ......................... 55 
3.2 
End of Study and Length of Study ........................................... 55 

 
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5/Protocol WO41554, Version 8 
3.3 
Rationale for Study Design ...................................................... 55 
3.3.1 
Rationale for Inavolisib, Palbociclib, and Fulvestrant Doses 
and Schedules ......................................................................... 55 
3.3.2 
Rationale for Patient Population .............................................. 56 
3.3.3 
Rationale for Exclusion of Diabetic Patients ............................ 56 
3.3.4 
Rationale for Control Group ..................................................... 57 
3.3.5 
Rationale for Double-Blind Design ........................................... 58 
3.3.6 
Rationale for Biomarker Assessments ..................................... 58 
3.3.6.1 
Rationale for Using Circulating Tumor DNA for Examining 
PIK3CA Mutation Status .......................................................... 58 
3.3.6.2 
Rationale for the Collection of Tissue Samples ....................... 58 
3.3.7 
Rationale for Primary Endpoint of Investigator-Assessed 
Progression-Free Survival ....................................................... 59 
3.3.8 
Rationale for Clinical Outcome Assessments .......................... 59 
3.3.9 
Rationale for Pharmacokinetic Sample Collection ................... 60 
3.3.9.1 
Rationale for Intense Pharmacokinetic Sample Collection 
in Chinese Patients .................................................................. 61 
4. 
MATERIALS AND METHODS ...................................................... 61 
4.1 
Patients .................................................................................... 61 
4.1.1 
Inclusion Criteria ...................................................................... 61 
4.1.2 
Exclusion Criteria ..................................................................... 65 
4.2 
Method of Treatment Assignment and Blinding ....................... 68 
4.2.1 
Treatment Assignment ............................................................. 68 
4.2.2 
Blinding .................................................................................... 68 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 69 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 69 
4.3.1.1 
Inavolisib and Placebo ............................................................. 69 
4.3.1.2 
Palbociclib................................................................................ 69 
4.3.1.3 
Fulvestrant ............................................................................... 70 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 70 
4.3.2.1 
Inavolisib and Placebo ............................................................. 71 
4.3.2.2 
Palbociclib................................................................................ 71 
4.3.2.3 
Fulvestrant ............................................................................... 71 

 
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6/Protocol WO41554, Version 8 
4.3.2.4 
Extended Cycle in the Event of a Palbociclib Hold due to 
an Adverse Event .................................................................... 72 
4.3.3 
Non-Investigational Medicinal Products ................................... 72 
4.3.3.1 
LHRH Agonists ........................................................................ 72 
4.3.3.2 
Dexamethasone Mouth Rinse .................................................. 72 
4.3.3.3 
Metformin ................................................................................. 73 
4.3.4 
Investigational Medicinal Product Accountability ..................... 73 
4.3.5 
Continued Access to Inavolisib ................................................ 73 
4.4 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions .............................................................................. 74 
4.4.1 
Permitted Therapy ................................................................... 74 
4.4.2 
Cautionary Therapy ................................................................. 75 
4.4.2.1 
Medications Given with Precaution due to Effects Related 
to CYP Enzymes ...................................................................... 75 
4.4.2.2 
Herbal Therapies ..................................................................... 75 
4.4.3 
Prohibited Therapy .................................................................. 76 
4.4.4 
Prohibited Food ....................................................................... 78 
4.4.5 
Additional Restrictions ............................................................. 78 
4.5 
Study Assessments ................................................................. 78 
4.5.1 
Informed Consent Forms and Screening Log .......................... 79 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 79 
4.5.3 
Physical Examinations ............................................................. 79 
4.5.4 
Vital Signs ................................................................................ 80 
4.5.5 
Tumor and Response Evaluations ........................................... 80 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ............ 82 
4.5.7 
Ophthalmologic Examinations ................................................. 86 
4.5.8 
Electrocardiograms .................................................................. 87 
4.5.9 
Clinical Outcome Assessments ............................................... 87 
4.5.9.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 88 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments ....... 89 
4.5.10 
Blood Samples for Whole Genome Sequencing (Patients 
at Participating Sites) ............................................................... 90 
4.5.11 
Optional Tumor Biopsies ......................................................... 91 

 
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7/Protocol WO41554, Version 8 
4.5.12 
Optional Samples for Research Biosample Repository ........... 92 
4.5.12.1 
Overview of the Research Biosample Repository .................... 92 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 92 
4.5.12.3 
Sample Collection .................................................................... 93 
4.5.12.4 
Confidentiality .......................................................................... 93 
4.5.12.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 94 
4.5.12.6 
Withdrawal from the Research Biosample Repository ............. 94 
4.5.12.7 
Monitoring and Oversight ......................................................... 95 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 95 
4.6.1 
Study Treatment Discontinuation ............................................. 95 
4.6.2 
Patient Discontinuation from the Study .................................... 96 
4.6.3 
Study Discontinuation .............................................................. 96 
4.6.4 
Site Discontinuation ................................................................. 96 
5. 
ASSESSMENT OF SAFETY ......................................................... 97 
5.1 
Safety Plan .............................................................................. 97 
5.1.1 
Identified and Potential Risks Associated with Inavolisib ......... 97 
5.1.1.1 
Hyperglycemia ......................................................................... 98 
5.1.1.2 
Stomatitis and Oral Mucositis .................................................. 98 
5.1.1.3 
Potential Gastrointestinal Toxicities ......................................... 99 
5.1.1.4 
Potential Skin Disorders .......................................................... 99 
5.1.1.5 
Potential Lung Inflammation/Pneumonitis ................................ 99 
5.1.1.6 
Potential Immunosuppressant Effects ................................... 100 
5.1.1.7 
Potential Reproductive Effects ............................................... 100 
5.1.1.8 
Potential Ocular Toxicities ..................................................... 100 
5.1.1.9 
DrugDrug Interactions .......................................................... 101 
5.1.2 
Management of Patients Who Experience Adverse Events ... 101 
5.1.2.1 
Dose Modifications of Inavolisib/Placebo ............................... 101 
5.1.2.2 
Management of Hyperglycemia ............................................. 102 
5.1.2.3 
Management of Stomatitis/Oral Mucositis ............................. 107 
5.1.2.4 
Management of Rash ............................................................ 109 
5.1.2.5 
Management of Diarrhea ....................................................... 110 

 
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8/Protocol WO41554, Version 8 
5.1.2.6 
Management of Inflammatory Colitis ..................................... 111 
5.1.2.7 
Management of Pneumonitis ................................................. 112 
5.1.2.8 
Management of Other Clinically Significant Adverse Events . 113 
5.1.2.9 
Safety Monitoring for Fulvestrant ........................................... 113 
5.1.2.10 
General Guidance of Dose Modifications or Delays for 
Fulvestrant ............................................................................. 114 
5.1.2.11 
Safety Monitoring for Palbociclib ............................................ 114 
5.2 
Safety Parameters and Definitions ........................................ 116 
5.2.1 
Adverse Events ...................................................................... 117 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 117 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 118 
5.2.4 
Selected Adverse Events to Monitor ...................................... 119 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 119 
5.3.1 
Adverse Event Reporting Period ............................................ 119 
5.3.2 
Eliciting Adverse Event Information ....................................... 120 
5.3.3 
Assessment of Severity of Adverse Events ........................... 120 
5.3.4 
Assessment of Causality of Adverse Events.......................... 121 
5.3.5 
Procedures for Recording Adverse Events ............................ 121 
5.3.5.1 
Diagnosis versus Signs and Symptoms ................................. 122 
5.3.5.2 
Adverse Events That Are Secondary to Other Events ........... 122 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 122 
5.3.5.4 
Abnormal Laboratory Values ................................................. 123 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 124 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 124 
5.3.5.7 
Deaths ................................................................................... 125 
5.3.5.8 
Preexisting Medical Conditions .............................................. 125 
5.3.5.9 
Lack of Efficacy or Worsening of Breast Cancer .................... 125 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 126 
5.3.5.11 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 126 
5.3.5.12 
Patient-Reported Outcome Data ............................................ 128 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
9/Protocol WO41554, Version 8 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 128 
5.4.1 
Emergency Medical Contacts ................................................ 129 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 130 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 130 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 130 
5.4.3 
Reporting Requirements for Pregnancies .............................. 130 
5.4.3.1 
Pregnancies in Female Patients ............................................ 130 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 131 
5.4.3.3 
Abortions................................................................................ 131 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 131 
5.5 
Follow-Up of Patients after Adverse Events........................... 132 
5.5.1 
Investigator Follow-Up ........................................................... 132 
5.5.2 
Sponsor Follow-Up ................................................................ 132 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 132 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 132 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 133 
6.1 
Determination of Sample Size ............................................... 134 
6.2 
Summaries of Conduct of Study ............................................ 134 
6.3 
Summaries of Treatment Group Comparability ...................... 134 
6.4 
Efficacy Analyses ................................................................... 134 
6.4.1 
Primary Efficacy Endpoint ...................................................... 135 
6.4.2 
Secondary Efficacy Endpoints ............................................... 136 
6.4.2.1 
Overall Survival ...................................................................... 136 
6.4.2.2 
Objective Response Rate ...................................................... 136 
6.4.2.3 
Best Overall Response Rate.................................................. 137 
6.4.2.4 
Clinical Benefit Rate .............................................................. 137 
6.4.2.5 
Duration of Objective Response ............................................ 137 
6.4.2.6 
Patient- Reported Outcomes (TTD of Pain, PF, RF, and 
GHS/QoL) .............................................................................. 137 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 138 

 
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10/Protocol WO41554, Version 8 
6.4.3.1 
Exploratory Clinical Outcomes ............................................... 138 
6.4.3.2 
Exploratory Patient Reported-Outcome Analyses.................. 138 
6.5 
Safety Analyses ..................................................................... 139 
6.5.1 
Exploratory Analyses of PRO-CTCAE Data .......................... 140 
6.6 
Pharmacokinetic Analyses ..................................................... 140 
6.7 
Exploratory Biomarker Analyses ............................................ 141 
6.8 
Health Status Utility Analyses ................................................ 141 
6.9 
Interim Analysis ..................................................................... 141 
6.9.1 
Planned Interim Analysis ....................................................... 141 
6.9.1.1 
Alpha-Spending Function for OS Analysis ........................... 141 
6.10 
Data Quality Assurance ......................................................... 142 
6.11 
Electronic Case Report Forms ............................................... 142 
6.12 
Electronic Patient Reported Outcome Data ........................... 143 
6.13 
Source Data Documentation .................................................. 143 
6.14 
Use of Computerized Systems .............................................. 144 
6.15 
Retention of Records ............................................................. 144 
7. 
ETHICAL CONSIDERATIONS .................................................... 144 
7.1 
Compliance with Laws and Regulations ................................ 144 
7.2 
Informed Consent .................................................................. 145 
7.3 
Institutional Review Board or Ethics Committee .................... 146 
7.4 
Confidentiality ........................................................................ 146 
7.5 
Financial Disclosure ............................................................... 147 
8. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 147 
8.1 
Study Documentation ............................................................ 147 
8.2 
Protocol Deviations ................................................................ 147 
8.3 
Site Inspections ..................................................................... 148 
8.4 
Management of Study Quality ................................................ 148 
8.5 
Administrative Structure ......................................................... 148 
8.6 
Dissemination of Data and Protection of Trade Secrets ........ 148 
8.7 
Protocol Amendments ........................................................... 149 
9. 
REFERENCES............................................................................ 150 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
11/Protocol WO41554, Version 8 
 
 
LIST OF TABLES 
Table 1 
Overall Dose Modification Guidelines for Inavolisib-Related 
Adverse Events ......................................................................... 102 
Table 2 
Management of Hyperglycemia ................................................ 104 
Table 3 
Additional Management Guidelines for Patients at High Risk 
of Hyperglycemia ...................................................................... 107 
Table 4 
Management of Stomatitis/Oral Mucositis ................................. 108 
Table 5 
Management of Rash ................................................................ 109 
Table 6 
Management of Diarrhea .......................................................... 110 
Table 7 
Management of Inflammatory Colitis ......................................... 111 
Table 8 
Management of Pneumonitis .................................................... 112 
Table 9 
Inavolisib/Placebo Dose Delay and Modification Guidelines 
for Other Clinically Significant Adverse Events Attributed to 
Inavolisib ................................................................................... 113 
Table 10 
Palbociclib Dose Modification and Management:  
Hematologic Toxicities .............................................................. 115 
Table 11 
Palbociclib Dose Modification and Management:  
Non-Hematologic Toxicities ...................................................... 116 
Table 12 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 120 
Table 13 
Causal Attribution Guidance ..................................................... 121 
Table 14 
Stopping Boundaries for Efficacy at the Interim or Final OS 
Analysis .................................................................................... 142 
 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Periods ........................................................ 51 
Figure 2 
Study Schema ............................................................................. 54 
Figure 3 
Dosing Schedule for Inavolisib, Palbociclib, and Fulvestrant ...... 71 
 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
12/Protocol WO41554, Version 8 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ............................................................... 158 
Appendix 2 
 Schedule of Pharmacokinetic Sampling ................................... 171 
Appendix 3 
 Schedule of Intense Pharmacokinetic Sampling in Chinese 
Patients ..................................................................................... 172 
Appendix 4 
 European Organisation for Research and Treatment of 
Cancer Quality of Life–Core 30 Questionnaire (EORTC 
QLQ-C30) ................................................................................. 173 
Appendix 5 
 European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire, Breast Cancer Module 
(EORTC QLQ-BR23) ................................................................ 175 
Appendix 6 
 Brief Pain Inventory-Short Form “Worst Pain” Item .................. 177 
Appendix 7 
 National Cancer Institute Patient-Reported Outcomes 
Common Terminology Criteria for Adverse Events (NCI 
PRO-CTCAE) Items .................................................................. 178 
Appendix 8 
 European Quality of Life 5-Dimension, 5-Level (EQ-5D-5L) 
Questionnaire ............................................................................ 180 
Appendix 9 
 Eastern Cooperative Oncology Group Performance Status ..... 183 
Appendix 10 
 FoundationOne Liquid CDx Assay Coverage of PIK3CA ....... 184 
Appendix 11 
 Response Evaluation Criteria in Solid Tumors (RECIST):   
Modified Excerpt from Original Publication ............................... 185 
Appendix 12 
 American Joint Committee on Cancer TNM Classification of 
Malignant Tumors ..................................................................... 197 
 
 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
13/Protocol WO41554, Version 8 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY EVALUATING 
THE EFFICACY AND SAFETY OF INAVOLISIB 
PLUS PALBOCICLIB AND FULVESTRANT VERSUS 
PLACEBO PLUS PALBOCICLIB AND 
FULVESTRANT IN PATIENTS WITH 
PIK3CA-MUTANT, HORMONE 
RECEPTORPOSITIVE, HER2-NEGATIVE 
LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER 
PROTOCOL NUMBER: WO41554 
VERSION NUMBER: 
8 
TEST PRODUCT: 
Inavolisib (RO7113755, GDC-0077) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study monitor. 
 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
14/Protocol WO41554, Version 8 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY EVALUATING THE EFFICACY 
AND SAFETY OF INAVOLISIB PLUS PALBOCICLIB AND 
FULVESTRANT VERSUS PLACEBO PLUS PALBOCICLIB AND 
FULVESTRANT IN PATIENTS WITH PIK3CA-MUTANT, 
HORMONE RECEPTORPOSITIVE, HER2-NEGATIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER 
PROTOCOL NUMBER: 
WO41554 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2019-002455-42 
IND NUMBER: 
130909 
NCT NUMBER 
NCT04191499 
TEST PRODUCT: 
Inavolisib (RO7113755, GDC-0077) 
PHASE: 
III 
INDICATION: 
Breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics of inavolisib (also known as 
“GDC-0077”) in combination with palbociclib and fulvestrant compared with placebo plus 
palbociclib and fulvestrant in patients with PIK3CA-mutant, hormone receptor (HR)-positive, 
human epidermal growth factor 2 (HER2)-negative locally advanced or metastatic breast cancer 
whose disease progressed during treatment or within 12 months of completing adjuvant 
endocrine therapy and who have not received prior systemic therapy for locally advanced or 
metastatic disease.  Specific objectives and corresponding endpoints for the study are outlined 
below. 
Throughout this protocol, "study drug" refers to any of the individual agents assigned to patients 
as part of this study (i.e., inavolisib, placebo, palbociclib, or fulvestrant), while "study treatment" 
refers to the combination of agents assigned to patients as part of this study (i.e., inavolisib plus 
palbociclib and fulvestrant, or placebo plus palbociclib and fulvestrant). 
Efficacy Objectives 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis 
of the following endpoint: 
 
Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression or death from any cause (whichever occurs first), as 
determined by the investigator according to Response Evaluation Criteria in Solid 
Tumors (RECIST), Version 1.1. 

 
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Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis 
of the following endpoints: 
 
Objective response rate, defined as the proportion of patients with a complete 
response (CR) and/or partial response (PR) on at least two consecutive 
occasions   4 weeks apart, as determined by the investigator according to RECIST v1.1 
 
Best overall response rate, defined as the proportion of patients with a CR or PR, as 
determined by the investigator according to RECIST v1.1 
 
Duration of response, defined as the time from the first occurrence of a CR or PR to the first 
occurrence of disease progression or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1 
 
Clinical benefit rate, defined as the proportion of patients with a CR, PR, and/or stable 
disease for at least 24 weeks, as determined by the investigator according to RECIST v1.1 
 
Overall survival (OS), defined as the time from randomization to death from any cause 
 
Time to deterioration (TTD) in pain, defined as the time from randomization to the first 
documentation of a   2-point increase from baseline on the “worst pain” item from the 
Brief Pain InventoryShort Form (BPI-SF) 
 
TTD in Physical Function, defined as the time from randomization to the first documentation 
of a  10-point decrease from baseline in the European Organisation for Research and 
Treatment of Cancer Quality of LifeCore 30 Questionnaire (EORTC QLQ-C30) Physical 
Function scale (items 15) 
 
TTD in Role Function, defined as the time from randomization to the first documentation of 
a  10-point decrease from baseline in the EORTC QLQ-C30 Role Function scale (items 
6 and 7) 
 
TTD in global health status (GHS)/health-related quality of life (HRQoL), defined as the time 
from randomization to the first documentation of a   10-point decrease from baseline in the 
EORTC QLQ-30 GHS/HRQoL scale (items 29 and 30) 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis 
of the following endpoints: 
 
Time to end of next-line treatment (proxy for time to second objective disease 
progression [PFS2]), defined as the time from randomization to end or discontinuation of 
next-line treatment, or death from any cause (whichever occurs first) 
 
Time to first skeletal-related event (SRE), defined as the time from randomization to the first 
occurrence of an SRE 
A SRE is a pathologic fracture, radiation therapy to bone, cancer-related surgery to 
bone, or spinal cord compression. 
 
Mean and mean change-from-baseline scores in all functions (Physical, Role, Cognitive, 
Emotional, and Social), GHS/HRQoL, and disease- or treatment-related symptom scores, 
as measured by the scales of the EORTC QLQ-C30 and EORTC QLQBreast Cancer 
Module 23 Questionnaire (EORTC QLQ-BR23) 
Safety Objectives 
The safety objective for this study is to evaluate the safety of inavolisib plus palbociclib and 
fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis of the following 
endpoints: 
 
Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 5.0 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 

 
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 
Change from baseline in ECG parameters 
 
The exploratory safety objective for this study is to evaluate the tolerability of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant from the 
patient's perspective, on the basis of the following endpoints: 
 
Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptomatic treatment toxicities (i.e., diarrhea, nausea, vomiting, 
decreased appetite, fatigue, mouth sores, and rash symptoms) as assessed through use of 
the NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) instrument, as well as an additional item regarding the overall bother 
experienced due to side effects of treatment 
 
Change from baseline in symptomatic treatment toxicities, as assessed through use of the 
PRO-CTCAE and the additional bother item 
Pharmacokinetic Objectives 
The PK objective for this study is to characterize the pharmacokinetics of inavolisib, palbociclib, 
and fulvestrant, when administered in combination in this population, on the basis of the 
following endpoints: 
 
Plasma concentration of inavolisib at specified timepoints 
 
Plasma concentration of palbociclib at specified timepoints 
 
Plasma concentration of fulvestrant at specified timepoints 
 
The exploratory PK objective is to evaluate potential relationships between the plasma 
exposure of inavolisib, palbociclib, and fulvestrant and efficacy and safety outcomes from this 
study. 
The China-specific pharmacokinetic objective is to characterize the pharmacokinetics of 
inavolisib in all patients enrolled in China. 
Biomarker Objective 
The exploratory biomarker objective for this study are to identify and/or evaluate biomarkers that 
are associated with response and disease control with the study treatments, are early 
surrogates of efficacy of the study treatments, are associated with progression to a more severe 
disease state (i.e., prognostic biomarkers), are associated with innate or acquired resistance to 
the study treatments, are associated with susceptibility to developing adverse events or can 
lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), can provide 
evidence of activity of the study treatments (i.e., pharmacodynamic biomarkers), can increase 
the knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoint: 
 
Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, or other biomarker endpoints 
Health Status Utility Objective 
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with inavolisib plus palbociclib and fulvestrant compared with placebo 
plus palbociclib and fulvestrant on the basis of the following endpoint: 
 
Health utility and visual analog score of the European Quality of Life 5-Dimension, 5 Level 
(EQ-5D-5L) questionnaire 
Study Design 
Description of Study 
Study WO41554 is a Phase III, randomized, double-blind, placebo-controlled, multicenter, 
global study designed to compare the efficacy, as measured by PFS, and the safety of the 
triplet combination of inavolisib plus palbociclib and fulvestrant versus placebo plus palbociclib 
and fulvestrant in patients with PIK3CA-mutant, HR-positive, HER2-negative locally advanced 
or metastatic breast cancer whose disease progressed during treatment or within 12 months of 
completing adjuvant endocrine therapy and who have not received prior systemic therapy for 
locally advanced or metastatic disease.  Approximately 320 patients will be enrolled at 
approximately 200 global investigative sites. 

 
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Patients will be randomized to one of the following treatment arms in a 1:1 ratio: 
Inavolisib plus palbociclib and fulvestrant 
 
Inavolisib:  9-mg tablet taken orally once a day (PO QD) on Days 128 of each 28-day 
cycle, beginning on Day 1 of Cycle 1 
 
Palbociclib:  125-mg capsule or tablet taken PO QD on Days 121 of each 28-day cycle, 
beginning on Day 1 of Cycle 1 
 
Fulvestrant:  500 mg administered by intramuscular (IM) injection on Days 1 and 15 of 
Cycle 1 and then on Day 1 of each subsequent 28-day cycle, or approximately every 
4 weeks. 
Placebo plus palbociclib and fulvestrant 
 
Placebo:  tablet taken PO QD on Days 128 of each 28-day cycle, beginning on Day 1 of 
Cycle 1 
 
Palbociclib:  125-mg capsule or tablet taken PO QD on Days 121 of each 28-day cycle, 
beginning on Day 1 of Cycle 1 
 
Fulvestrant:  500 mg administered by IM injection on Days 1 and 15 of Cycle 1 and then on 
Day 1 of each subsequent 28-day cycle, or approximately every 4 weeks. 
The study consists of a screening period of up to 28 days, a treatment period, a post-treatment 
follow-up period (which includes a “30-day safety follow-up” for all patients and, when 
applicable, a “post-treatment hyperglycemia follow-up,” and/or a “post-treatment tumor 
assessment follow-up with patient-reported outcome [PRO] collection”), and a survival follow-up 
period. 
Patients may be prescreened for PIK3CA-mutation status through central testing of circulating 
tumor DNA by participating in a separate prescreening consent.  Patients may be re-screened 
only in cases of study-required assessments falling out of the screening window; all other 
screen failures are exclusionary. 
Study treatment may continue until unequivocal disease progression as determined by the 
investigator, unacceptable toxicity, patient withdrawal of consent, or study termination. 
Following study treatment discontinuation, patients will be followed for safety for 30 days after 
final study treatment (30-day safety follow-up, including a 30-day follow-up visit), or until the 
initiation of another anti-cancer therapy, whichever occurs first. 
Patients on anti-hyperglycemic agents for the treatment of hyperglycemia during the study 
treatment period and those patients with events of hyperglycemia ongoing at the end of the 
30-day safety follow-up, will undergo additional safety follow-up assessments (“post-treatment 
hyperglycemia follow-up”) monthly until resolution of their fasting glucose to baseline levels, 
complete down-titration of their anti-hyperglycemic medications, or up to approximately 
3 months after the final dose of study treatment, even if the patient initiates another anti-cancer 
therapy subsequent to study treatment discontinuation. 
In addition, patients who discontinue active study treatment for reasons other than progression 
of disease or death will continue to have tumor assessments performed every 8 weeks 
(  7 days) for the first 2 years from randomization and every 12 weeks (  7 days) thereafter, 
and complete PRO assessments at those timepoints (“post-treatment tumor assessment 
follow-up with PRO collection”), until documented disease progression or the initiation of 
another anti-cancer therapy, whichever occurs first. 
All patients will subsequently move onto the survival follow-up period until death, patient 
withdrawal of consent, loss to follow-up, or study termination. 
Study patients must have measurable disease per RECIST v1.1.  Patients with evaluable 
(non-measurable) bone-only disease are not eligible; disease that is limited to bone but that 
has lytic or mixed lytic/blastic lesions and at least one measurable soft-tissue component (per 
RECIST v1.1) may be eligible.  Locally advanced disease must not be amenable to resection or 
other local therapy with curative intent. 
Patients may enroll based on eligible PIK3CA mutation results from testing performed by a 
central investigational testing site or a site local test.  Local testing of blood or tumor tissue must 
be performed using a Sponsor-approved polymerase chain reaction (PCR)-based or 
next-generation sequencing (NGS) assay at a Clinical Laboratory Improvement 

 
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Amendments (CLIA)- or equivalently-certified laboratory.  Patients without available local test 
results for PIK3CA mutation status must submit a blood sample to determine whether an eligible 
PIK3CA mutation is present.  Samples will be evaluated by the NGS-based FoundationOne 
Liquid CDx (F1LCDx) assay, unless not implemented in specific localities.  In this case, 
samples will be submitted to an alternative, Sponsor-designated central testing laboratory.  
Regardless of the testing strategy to determine a patient’s tumor PIK3CA mutation status, all 
patients must provide both blood and tumor tissue for evaluation by a central investigational 
testing site.  Demographic data will be collected on all patients who undergo screening, 
including those who screen fail. 
Patients will be closely monitored for adverse events throughout the study treatment, and for 
30 days after the final dose of study treatment or until initiation of another anti-cancer therapy, 
whichever occurs first.  Adverse events will be graded according to NCI CTCAE v5.0.  Patients 
who, at the 30-day safety follow-up visit, are still on anti-hyperglycemic agents for the treatment 
of hyperglycemia during the study treatment, and those patients with events of hyperglycemia 
ongoing at the 30-day safety follow-up visit, will go on to the post-treatment hyperglycemia 
follow-up (as defined above). 
Tumor assessments will be performed to assess for response every 8 weeks (  7 days) during 
the first 2 years of study treatment and every 12 weeks (  7 days) thereafter.  Patients who 
discontinue active study treatment for any reason other than unequivocal disease progression 
or death will follow the same tumor assessment schedule during the “post-treatment tumor 
assessment follow-up with PRO collection” period. 
After study treatment discontinuation, all patients will be followed for survival and all subsequent 
anti-cancer therapies.  These data will be collected via telephone calls and/or clinic visits 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study 
termination by the Sponsor, whichever occurs first. 
To evaluate the PK properties of GDC-0077, palbociclib, and fulvestrant administered in this 
triplet combination, blood samples will be taken at various timepoints before and after dosing. 
Patient-reported outcome instruments will be completed by patients to evaluate the treatment 
impact from the patient's perspective as specified in the schedule of activities.  The 
EORTC QLQ-C30 will assess disease and treatment-related symptoms often experienced by 
patients with locally advanced or metastatic cancer including fatigue, pain, depression/anxiety, 
and any limitations in function.  The EORTC QLQ-BR23 will provide additional assessment on 
some treatment-related symptoms and symptoms that may occur with advanced disease.  The 
“worst pain” item from the BPI-SF will be used to evaluate an increase in pain severity.  
Additionally, the PRO-CTCAE will be used to assess the impact of treatment-related symptoms, 
with the goal being to demonstrate benefit of treatment without adverse impact on patients’ 
HRQoL.  The EQ-5D-5L will be used to assess health status. 
Mobile Nursing (MN) is only available at sites which have separately approved the use of the 
MN vendor; MN may not be conducted independently of the Sponsor-selected MN vendor.  At 
applicable sites, study treatment may be administered and specified study assessments may be 
performed by a trained mobile nurse at the patient's home, if the patient has provided written 
informed consent to participate in MN visits. 
Number of Patients 
Approximately 320 patients with PIK3CA-mutant, HR-positive, HER2-negative locally advanced 
or metastatic breast cancer will be enrolled in this study. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Women or men   18 years of age at time of signing Informed Consent Form 

 
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 
If female, patients must meet at least one of the following definitions: 
Postmenopausal, as defined by at least one of the following criteria: 
Age    60 years 
Age    60 years and 12 months of amenorrhea plus follicle-stimulating hormone and 
plasma or serum estradiol levels within postmenopausal range by local laboratory 
assessment in the absence of oral contraceptive pills, hormone replacement therapy, 
or gonadotropin-releasing hormone agonist or antagonist 
Documented bilateral oophorectomy (  14 days prior to first treatment on Day 1 of 
Cycle 1 and recovery to baseline) 
Premenopausal or perimenopausal (i.e., not meeting the criteria for postmenopausal) and 
meeting the following criterion: 
Treatment with luteinizing hormonereleasing hormone (LHRH) agonist therapy 
(e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and 
continuing for the duration of study treatment 
 
If male, recommendation of treatment with LHRH agonist therapy (e.g., goserelin or 
leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the 
duration of study treatment 
 
Histologically or cytologically confirmed adenocarcinoma of the breast that is locally 
advanced or metastatic and is not amenable to surgical or radiation therapy with curative 
intent 
 
Documented estrogen receptor-positive and/or progesterone receptorpositive tumor 
according to American Society of Clinical Oncology/College of American 
Pathologists (ASCO/CAP) guidelines, defined as   1% of tumor cells stained positive based 
on the most recent tumor biopsy and assessed locally 
 
Documented HER2-negative tumor according to ASCO/CAP guidelines, defined as a 
HER2 immunohistochemistry (IHC) score of 0 or 1  , or an IHC score of 2   accompanied 
by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the 
absence of HER2 gene amplification, or a HER2/CEP17 ratio of   2.0 based on the most 
recent tumor biopsy and assessed locally 
 
Confirmation of biomarker eligibility:  valid results from either central testing of blood or local 
testing of blood or tumor tissue documenting PIK3CA-mutant tumor status 
Eligible PIK3CA mutations are defined as follows: 
H1047D/I/L/N/P/Q/R/T/Y 
G1049A/C/D/R/S 
E545A/D/G/K/L/Q/R/V 
E453A/D/G/K/Q/V 
E542A/D/G/K/Q/R/V 
K111N/R/E 
Q546E/H/K/L/P/R 
G106A/D/R/S/V 
N345D/H/I/K/S/T/Y 
G118D 
C420R 
R88Q 
M1043I/T/V 
 
 
The central test for identification of eligible PIK3CA mutations is the F1LCDx assay 
performed at Foundation Medicine, Inc.  In localities where this is not available, 
samples will be submitted to an alternative, Sponsor-designated central testing 
laboratory. 
All patients are required to submit a freshly collected pre-treatment blood sample, 
whether patients are enrolled by local or central test results. 
Local tests of blood or tumor tissue may only be performed using a Sponsor 
pre-approved PCR- or NGSbased assay at a CLIAcertified or equivalent laboratory.  
The full laboratory report of the PIK3CA mutation result must be available and 
submitted for confirmation. 

 
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Local test results reported from blood should be from a blood specimen 
representative of patient’s metastatic disease state, collected after conclusion of 
patient’s most recent anti-cancer therapy. 
Local test results reported from tumor tissue should be from the patient’s 
metastatic disease state whenever possible. 
 
Consent to provide fresh (preferred) or archival tumor tissue specimen.  It is preferred that 
the specimen be from the most recently collected and available tumor tissue, and whenever 
possible, from a metastatic site of disease.  See the laboratory manual for specimen 
requirements. 
 
Patients must have progressed during adjuvant endocrine treatment or within 12 months of 
completing adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen. 
If a cyclin-dependent kinase (CDK 4/6) inhibitor was included as part of neoadjuvant or 
adjuvant therapy, progression event must be   12 months since completion of 
CDK4/6 inhibitor portion of neoadjuvant or adjuvant therapy. 
 
Measurable disease per RECIST v1.1 
Patients with evaluable bone-only disease are not eligible; disease that is limited to 
bone but has lytic or mixed lytic/blastic lesions and at least one measurable 
soft-tissue component per RECIST v1.1 may be eligible. 
 
Treatment with endocrine-based therapy (e.g., palbociclib and fulvestrant) is recommended 
at time of entry into the study, as per national or local treatment guidelines 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as defined below: 
Women must remain abstinent or use non-hormonal contraceptive methods with a failure 
rate of   1% per year during the treatment period and for at least 60 days after the final 
dose of study treatment.  Based on local prescribing information for fulvestrant, patients 
may be advised to use an effective means of contraception for up to 2 years after the final 
dose of fulvestrant.  Women must refrain from donating eggs during this same period. 
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 is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of non-hormonal contraceptive methods with a failure rate of   1% per year 
include bilateral tubal ligation, male sterilization, 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.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for at least 98 days 
after the final dose of study treatment to avoid exposing the embryo.  Based on local 
prescribing information for fulvestrant, patients may be advised to use an effective 
means of contraception for up to 2 years after the final dose of fulvestrant.  Men must 
refrain from donating sperm during this same period. 
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 

 
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are not acceptable methods of contraception.  If required per local guidelines or 
regulations, information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
 
Life expectancy of   6 months 
 
Adequate hematologic and organ function within 14 days prior to initiation of study 
treatment, defined by the following: 
Absolute neutrophil count   1500/L 
Hemoglobin   9 g/dL 
Platelet count   100,000/L 
Fasting glucose   126 mg/dL (  7.0 mmol/L) and HbA1c   6.0% (  42 mmol/mol) 
For patients with fasting glucose   100 mg/dL (  5.5 mmol/L) (i.e., threshold for 
pre-diabetes) at baseline, recommend lifestyle changes according to American 
Diabetes Association guidelines; that is, dietary advice (e.g., small frequent 
meals, low carbohydrate content, high fiber, balanced carbohydrate intake over 
the course of the day, three small meals and two small snacks rather than one 
large meal) and exercise.  Consultation with an endocrinologist or diabetologist is 
highly recommended. 
Total bilirubin   1.5  upper limit of normal (ULN) (  3  ULN if Gilbert’s disease) 
Serum albumin   2.5 g/dL (25 g/L) 
AST and ALT   2.5  ULN with the following exception: 
Patients with documented liver metastases may have AST and/or ALT  5.0  ULN 
Alkaline phosphatase (ALP)   2.5  ULN with the following exception: 
Patients with documented liver or bone metastases may have ALP   5.0  ULN 
Creatinine clearance   50 mL/min on the basis of the CockcroftGault glomerular 
filtration rate estimation 
 
INR  1.5  ULN and aPTT  1.5  ULN  
For patients requiring anticoagulation therapy with warfarin or similar agents (such 
as Vitamin K antagonists), a stable INR between 2 and 3 is required.  If 
anticoagulation is required for a prosthetic heart valve, then stable INR 
between 2.5 and 3.5 is permitted.  Consult the local prescribing information for 
fulvestrant. 
 
Ability, in the investigator’s judgment, and willingness to comply with all study-related 
procedures, including completion of patient-reported endpoints 
 
For patients enrolled in China:  current resident of mainland China and must be of Chinese 
ancestry. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Metaplastic breast cancer 
 
Any history of leptomeningeal disease or carcinomatous meningitis 
 
Any prior systemic therapy for metastatic breast cancer 
 
Prior treatment with fulvestrant or any selective estrogen-receptor degrader, with the 
exception of patients that have received fulvestrant or any selective estrogen-receptor 
degrader as part of neoadjuvant therapy only and with treatment duration of no longer than 
6 months 

 
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 
Prior treatment with any phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), or 
mammalian target of rapamycin (mTOR) inhibitor, or any agent whose mechanism of action 
is to inhibit the PI3K-AKT-mTOR pathway 
 
Appropriate for treatment with cytotoxic chemotherapy at time of entry into the study, as per 
national or local treatment guidelines (e.g., patients with visceral crisis) 
 
Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any 
history of Type 1 diabetes 
 
Inability or unwillingness to swallow pills or receive IM injections 
 
Malabsorption syndrome or other condition that would interfere with enteral absorption 
 
Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants 
or corticosteroids for symptomatic control).  Patients with a history of treated 
CNS metastases are eligible, provided they meet all of the following criteria: 
Measurable disease outside the CNS 
No ongoing requirement for corticosteroids as therapy for CNS metastases, with 
corticosteroids discontinued for  2 weeks prior to enrollment and no ongoing 
symptoms attributed to CNS metastases 
Radiographic demonstration of improvement upon the completion of CNS-directed 
therapy and no evidence of interim progression between the completion of 
CNS-directed therapy and the screening radiographic assessments 
Screening CNS radiographic assessments   4 weeks since completion of radiotherapy 
No history of intracranial hemorrhage or spinal cord hemorrhage 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures biweekly or more frequently 
Indwelling pleural or abdominal catheters may be allowed, provided the patient has 
adequately recovered from the procedure, is hemodynamically stable and 
symptomatically improved. 
 
Serious infection requiring intravenous (IV) antibiotics within 7 days prior to Day 1 of 
Cycle 1 
 
Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in 
the opinion of the investigator, would require medical or surgical intervention during the 
study period to prevent or treat vision loss that might result from that condition 
 
Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, 
scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or 
autoimmune-associated uveitis in either eye 
 
Requirement for daily supplemental oxygen 
 
Symptomatic active lung disease, including pneumonitis 
 
History of or active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) 
Patients currently receiving immunosuppressants for inflammatory bowel disease 
(e.g., sulfasalazines) are considered to have active disease and are thus ineligible. 
 
Any active bowel inflammation (including diverticulitis) 
 
Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab 
therapy 
Bisphosphonate and denosumab therapy for bone metastases or 
osteopenia/osteoporosis is allowed. 
 
Clinically significant and active liver disease, including severe liver impairment (Child-Pugh 
Class B/C), viral or other hepatitis, current alcohol abuse, or cirrhosis 

 
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 
Known HIV infection 
Sites should include an HIV test during screening, as allowed per local regulations. 
 
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, metabolic, or infectious disease) or any other diseases, active or uncontrolled 
pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug, that may affect the interpretation of the results, or that 
renders the patient at high risk from treatment complications 
 
Chemotherapy, radiotherapy, or any other anti-cancer therapy within 2 weeks before 
randomization 
 
Investigational drug(s) within 4 weeks before randomization 
 
Prior radiotherapy to   25% of bone marrow, or hematopoietic stem cell or bone marrow 
transplantation 
 
Unresolved toxicity from prior therapy, except for hot flashes, alopecia, and 
Grade  2 peripheral neuropathy 
 
History of other malignancy within 5 years prior to screening, except for cancers with very 
low risk of recurrence including, but not limited to, appropriately treated carcinoma in situ of 
the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer.  The Medical Monitor 
is available for consultation. 
 
History of or active clinically significant cardiovascular dysfunction, including the following: 
History of stroke or transient ischemic attack within 6 months prior to first dose of study 
treatment 
History of myocardial infarction within 6 months prior to first dose of study treatment 
New York Heart Association Class III or IV cardiac disease or congestive heart failure 
requiring medication 
Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring 
medication 
Coronary heart disease that is symptomatic or unstable angina 
Congenital long QT syndrome or QT interval corrected through use of Fridericia’s 
formula   470 ms demonstrated by at least two ECGs   30 minutes apart, or family 
history of sudden unexplained death or long QT syndrome 
 
Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, 
hypocalcemia) 
 
Chronic corticosteroid therapy of   10 mg of prednisone per day or an equivalent dose of 
other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease 
 
Allergy or hypersensitivity to components of the GDC-0077/placebo, palbociclib, or 
fulvestrant formulations  
 
Treatment with strong cytochrome P450 (CYP) 3A4 inducers or strong CYP3A4 inhibitors 
within 1 week or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study 
treatment 
 
Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or 
within 60 days after the final dose of study treatment (based on local prescribing information 
for fulvestrant, patients may be advised to use an effective means of contraception for up to 
2 years after the last dose of fulvestrant) 
Women of childbearing potential (including those who have had a tubal ligation) must 
have a negative serum pregnancy test result within 14 days prior to initiation of study 
treatment. 
 
Major surgical procedure, or significant traumatic injury, within 28 days prior to Day 1 of 
Cycle 1 or anticipation of the need for major surgery during the course of study treatment 
 
Minor surgical procedures   7 days prior to first dose of study treatment 

 
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Patients must have sufficiently recovered from surgery, including adequate wound 
healing. 
End of Study 
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later. 
In addition, the Sponsor may decide to terminate the study at any time. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years. 
Investigational Medicinal Products 
Test Products (Investigational Drug) 
The investigational medicinal products for this study are inavolisib or its placebo, palbociclib, 
and fulvestrant.  Inavolisib 9-mg tablet is taken PO QD on Days 128 of each 28-day cycle, 
beginning on Day 1 of Cycle 1.  Placebo tablet is taken PO QD on Days 128 of each 28-day 
cycle, beginning on Day 1 of Cycle 1.  Palbociclib 125-mg capsule or tablet is taken PO QD on 
Days 121 of each 28-day cycle, beginning on Day 1 of Cycle 1.  Fulvestrant 500 mg is 
administered by IM injection on Days 1 and 15 of Cycle 1 and then on Day 1 of each 
subsequent 28-day cycle, or approximately every 4 weeks. 
Non-Investigational Medicinal Products 
LHRH Agonists 
Luteinizing hormonereleasing hormone agonists are required beginning at least 2 weeks prior 
to initiation of study treatment for pre-/peri-menopausal women.  For male patients, 
LHRH agonist therapy beginning at least 2 weeks prior to initiation of study is recommended.  
Acceptable agents include goserelin or leuprolide; triptorelin is also acceptable.  Patients 
already on one of these three agents may remain on the same agent without switching.  Every 
effort should be made to administer goserelin (given every 28 days) or alternative LHRH agonist 
as applicable on site at the time of fulvestrant administration in order to minimize the number of 
clinic visits.  Where allowed per local standards, patients receiving LHRH agonists should be 
monitored (via follicle-stimulating hormone and/or estradiol level, as per local standards) 
approximately every 3 months for appropriate hormonal suppression; in cases of inadequate 
suppression, alternative hormonal suppression methods (e.g., ovarian ablation, as per local 
standards) must be considered. 
Dexamethasone Mouth Rinse 
If locally available, a compounded alcohol-free mouthwash of dexamethasone (0.5 mg in 5 mL) 
is recommended for prophylaxis or treatment of stomatitis/mucositis.  As per the SWISH study 
(Rugo et al. 2017), patients may use 4 times daily for 8 weeks (10 mL swished for 2 minutes 
and spat) started concurrently with study treatment and/or used reactively with the first 
appearance of symptoms.  No food or drink should be consumed for at least 1 hour after 
swishing and spitting the mouthwash.  Additional mouthwash formulations (e.g., combinations of 
local anesthetic, antihistamine, corticosteroid, antacid, antifungal, and/or antibiotics) or topical 
corticosteroids (e.g., triamcinolone acetonide 0.05%0.5%, fluocinolone acetonide 
0.025%0.05%, clobetasol propionate 0.025%) may be implemented.  Diet should be modified 
(e.g., avoidance of spicy foods) and harsh mouthwashes (e.g., Listerine) should be avoided. 
Metformin 
Patients experiencing hyperglycemia may require anti-hyperglycemic medication.  The preferred 
first agent is metformin.  At the investigator’s discretion and where allowed by local regulations, 
prophylactic metformin may be initiated on Cycle 1, Day 1 for patients at high risk of 
hyperglycemia. 

 
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Statistical Methods 
Primary Analysis 
The primary efficacy objective for this study is to evaluate the efficacy of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis 
of the following endpoint: 
 
Progression free survival, defined as the time from randomization to the first occurrence of 
disease progression or death from any cause (whichever occurs first), according to RECIST 
v1.1 
Data for patients without the occurrence of disease progression or death will be censored at the 
time of the last tumor assessment (or at the time of randomization if no tumor assessment was 
performed after the baseline visit). 
The primary efficacy analysis population will consist of all randomized patients grouped 
according to their assigned treatment at randomization. 
The primary analysis of the study will test the equality of PFS distributions in the inavolisib plus 
palbociclib and fulvestrant and placebo plus palbociclib and fulvestrant arms, as follows: 
H0:  PFS inavolisib plus palbociclib and fulvestrant  PFS placebo plus palbociclib and 
fulvestrant  
versus  
H1:  PFS inavolisib plus palbociclib and fulvestrant ≠ PFS placebo plus palbociclib and 
fulvestrant 
The treatment arms will be compared using a two-sided stratified log-rank test.  The 
stratification factors that will be used are the same as those for randomization: 
 
Visceral disease (yes or no) 
 
Endocrine resistance  
(primary or secondary according to European Society for Medical Oncology Advanced 
Breast Cancer 4 guidelines [Cardoso et al. 2018])  
 
Geographic region (North American/Western Europe, Asia, or other) 
The results from the unstratified log-rank test also will be provided. 
Survival curves in each treatment arm will be estimated using Kaplan-Meier estimates.  The 
Kaplan-Meier estimates will provide a visual description of the survival curves and the difference 
across treatment arms.  In addition, the Kaplan-Meier approach will be used to estimate median 
PFS for each treatment arm.  The treatment effect will be quantified via a hazard ratio, 
computed from a stratified Cox proportional-hazards regression, including a 95% confidence 
interval. 
Sensitivity analyses will be conducted including only patients whose tumor PIK3CA mutation 
status has been confirmed centrally in blood and based on independent central review of 
response.  Further sensitivity analyses are defined in the Statistical Analysis Plan (SAP). 
Determination of Sample Size 
Estimates of the number of events required to demonstrate efficacy with regard to PFS are 
based on the following assumptions: 
 
Two-sided log-rank test at the 0.05 level of significance 
 
Eighty-five percent power to detect a hazard ratio for inavolisib plus palbociclib and 
fulvestrant versus placebo plus palbociclib and fulvestrant of 0.65, corresponding to an 
improvement in median PFS from 11 to 16.9 months 
 
Exponential distribution of PFS 
 
An annual dropout rate of 15% 
With these assumptions,194 PFS events are required to achieve 85% power for the primary 
analysis.  The 320 patients will be enrolled over approximately 43 months and the primary 
analysis is expected to occur approximately 50 months after the first patient randomized. 
The minimal detectable difference for the PFS hazard ratio is 0.754 (i.e., an improvement of 
11 to 14.6 months in median PFS). 

 
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Of the 320 patients, no more than 60 patients will be allowed to have a PIK3CA tumor mutation 
not confirmed by the central F1LCDx assay.  As such, at least 260 patients will have the 
presence of (one or more) PIK3CA mutation(s) confirmed by the central F1LCDx assay. 
Interim Analyses 
An independent Data Monitoring Committee will convene to review cumulative safety data 
approximately every 4 months. 
One interim analysis for futility will be conducted after approximately 75 PFS events (33% of 
information) are observed.  The futility boundary is non-binding.  The cutoff is expected to occur 
18 months after first patient enrolled and, hence, approximately 265 patients will have been 
enrolled when the decision is available. 
As an additional safety monitoring measure, an interim safety review will be performed after the 
enrollment of the first 25 patients and treatment for at least three cycles. 
One interim analysis will be performed for OS at the time of the primary endpoint analysis.

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABC 
Advanced Breast Cancer 
AE 
adverse event 
AESI 
adverse events of special interest 
AKT 
protein kinase B 
ALP 
alkaline phosphatase 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the concentration-time curve 
BICR 
blinded independent central review 
BOR 
best overall response rate 
BPI-SF 
Brief Pain Inventory-Short Form 
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CDK 
cyclin-dependent kinase 
CI 
confidence interval 
ctDNA 
circulating tumor DNA 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum concentration observed 
CNA 
copy number alteration 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drugdrug interaction 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC QLQ-BR23 
European Organisation for Research and Treatment of Cancer 
Quality of LifeBreast Cancer Module 23 Questionnaire 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality of LifeCore 30 Questionnaire 
EQ-5D-5L 
European Quality of Life 5-Dimension, 5 Level Questionnaire 

 
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Abbreviation 
Definition 
ESMO 
European Society for Medical Oncology 
ER 
estrogen receptor 
F1LCDx 
FoundationOne Liquid CDx 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
FMI 
Foundation Medicine, Inc. 
GHS 
global health status 
HbA1c 
glycosylated hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HER2 
human epidermal growth factor 2 
HR 
hormone receptor 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
iDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 
LHRH 
luteinizing hormonereleasing hormone 
MN 
mobile nursing 
MRI 
magnetic resonance imaging 
mTOR 
mammalian target of rapamycin 
NaF 
sodium fluoride 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NE 
not estimable 
NGS 
next-generation sequencing 
ORR 
overall response rate 
OS 
overall survival 
p110 
alpha isoform of PI3K 
pAKT 
phosphorylated form of protein kinase B 

 
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Abbreviation 
Definition 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PF 
physical functioning 
PFS 
progression-free survival 
PFS2 
second objective disease progression 
PI3K 
phosphatidylinositol 3-kinase 
PIK3CA 
phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit 
alpha isoform [gene name/acronym] 
PIP2 
phosphatidylinositol 4,5-bisphosphate 
PIP3 
phosphatidylinositol 3,4,5-bisphosphate 
PK 
pharmacokinetic 
PO 
orally 
PopPK 
population PK 
pPRAS40 
PRAS40 phosphorylated at Threonine 246 
PR 
partial response 
PRO 
patient-reported outcome 
pS6RP 
S6RP phosphorylated at Serine 235/236 
PTEN 
phosphatase and tensin homolog 
QD 
once a day 
QoL 
quality of life 
Rb 
retinoblastoma protein 
RBR 
Research Biosample Repository 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RF 
role functioning 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SGLT2 
sodium glucose co-transporter 2 
SmPC 
Summary of Product Characteristics 
SRE 
skeletal-related event 
TL 
target lesion 
TMB 
tumor mutational burden 
TTD 
time to deterioration 
ULN 
upper limit of normal 
USPI 
U.S. Package Insert 
VAS 
visual analog score 
WES 
whole exome sequencing 

 
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Abbreviation 
Definition 
WGS 
whole genome sequencing 
WT 
wild type 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HORMONE RECEPTOR-POSITIVE, HER2-
NEGATIVE ADVANCED OR METASTATIC BREAST CANCER 
Breast cancer is the most commonly diagnosed cancer in women, with an estimated 
global incidence of 2,088,849 new cases and 626,679 deaths reported in 2018 
(Bray et al. 2018).  Breast cancer in men is rare; in 2019   1% of new breast cancer 
diagnoses in the United States occurred in men (American Cancer Society 2019). 
Hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative 
breast cancer accounts for 60%70% of all breast cancers.  Current treatments for 
advanced or metastatic disease focus on prolonging life and improving or maintaining 
quality of life.  Preventing resistance to therapy and ultimately achieving a cure remain 
unmet needs in this disease setting. 
Standard-of-care treatment options for patients with de novo metastatic disease, or for 
whom disease recurs following surgery and adjuvant treatment, include endocrine 
therapy, endocrine and targeted therapy combinations, or chemotherapy (National 
Comprehensive Cancer Network [NCCN] 2019).  Chemotherapy is indicated in patients 
with symptomatic visceral disease or in patients with disease progression after multiple 
consecutive endocrine therapy regimens (NCCN 2019).  For most patients, endocrine 
therapy alone or in combination with a targeted therapy is the treatment of choice in the 
metastatic setting. 
Endocrine therapy options for the treatment of postmenopausal women with locally 
advanced or metastatic HR-positive breast cancer include nonsteroidal aromatase 
inhibitors (anastrozole, letrozole), steroidal aromatase inhibitors (exemestane), estrogen 
receptor (ER) downregulators (fulvestrant), and ER modulators (tamoxifen, toremifene).  
In premenopausal women, ovarian ablation or suppression is also generally 
recommended. 
Not all HR-positive breast cancers respond optimally to endocrine therapy.  Multiple 
mechanisms may lead to primary and/or secondary resistance to endocrine therapy in 
HR-positive breast cancer including upregulation of growth factor signaling pathways, 
such as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian 
target of rapamycin (mTOR) pathway (Johnston 2009; Musgrove and Sutherland 2009).  
The addition of targeted therapies to endocrine therapy may be able to overcome 
mechanisms of resistance to endocrine therapy. 
Recent data from Phase III studies have demonstrated significant improvements in 
progression-free survival (PFS) with the addition of targeted therapies to endocrine 
therapy, leading to new standard-of-care treatment options.  The BOLERO-2 trial 
demonstrated that the addition of an mTOR inhibitor, everolimus, to exemestane 
significantly improved PFS in postmenopausal patients with ER-positive advanced 

 
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breast cancer who had experienced recurrence or progression of disease while receiving 
previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting and/or 
for advanced disease (Baselga et al. 2012; Yardley et al. 2013). 
Cyclin-dependent kinases (CDKs) are key regulators of cell-cycle progression.  The 
cellular transition from G1 phase to S phase, commonly referred to as the restriction 
point, is controlled by the interaction of cyclin D and CDKs 4 and 6 (CDK4/6).  CDK4 and 
CDK6 phosphorylate the retinoblastoma (Rb) protein, leading to the activation of 
E2F transcription factors that initiate S phase gene expression, thereby promoting 
cell-cycle progression.  Amongst others, palbociclib is a CDK4/6 inhibitor that has been 
evaluated in combination with endocrine therapy in multiple clinical trials. 
Data from the Phase III PALOMA-2 study confirms the findings of the randomized 
Phase II study PALOMA-1 (Finn et al. 2015, 2016).  In PALOMA-2, 666 postmenopausal 
patients with HR-positive, HER2-negative advanced breast cancer who had received no 
prior treatment for advanced disease were randomized in a 2:1 ratio to the combination 
of palbociclib (125 mg orally [PO] once a day [QD] on Days 121 of 28-day cycles) and 
letrozole (2.5 mg PO QD on Days 128 of 28-day cycles) or to placebo and letrozole.  
The primary endpoint of investigator-assessed PFS in the intent-to-treat (ITT) population 
demonstrated a significant improvement in PFS from 14.5 months with placebo and 
letrozole to 24.8 months with palbociclib and letrozole (hazard ratio: 0.58).  Objective 
response rate (42% vs. 35%), clinical benefit rate (CBR; 85% vs. 70%), and median 
duration of response (DOR; 23 months vs. 17 months) all favored palbociclib and 
letrozole over placebo and letrozole.  In addition, significantly greater improvement in 
pain scores was observed in the palbociclib and letrozole arm (Rugo et al. 2018).  
Toxicity observed with palbociclib and letrozole was similar to other Phase II and III 
studies of palbociclib and endocrine therapy, with Grade 3 or 4 neutropenia occurring in 
66% of patients.  Dose interruptions, cycle delays, and   1 dose reduction were 
common, occurring in 70%, 68%, and 36% of patients treated with palbociclib and 
letrozole, respectively.  Permanent discontinuation for adverse events was 9.7% in the 
palbociclib and letrozole treatment arm, compared with 5.9% in the placebo and 
letrozole treatment arm. 
In the Phase III PALOMA-3 study, 521 patients with advanced HR-positive, 
HER2-negative breast cancer that had relapsed or progressed during prior endocrine 
therapy were randomized 2:1 to palbociclib and fulvestrant or to placebo and fulvestrant 
(Turner et al. 2015).  After a median follow-up of 8.9 months, ORR (19% vs. 9%), 
CBR (67% vs. 40%), and median PFS (9.5 months vs. 4.6 months) all favored 
palbociclib and fulvestrant over placebo and fulvestrant.  Significantly greater 
improvement from baseline in pain was observed in the palbociclib and fulvestrant arm 
(Harbeck et al. 2016).  Toxicity observed with palbociclib and fulvestrant was similar to 
other Phase II and III studies of palbociclib and endocrine therapy, with the following 
Grade 3 or 4 hematological adverse events:  neutropenia, 65%; anemia, 3%; and 
thrombocytopenia, 3%.  Febrile neutropenia occurred in 0.9% of patients.  Permanent 

 
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discontinuation for adverse events was 4% in the palbociclib and fulvestrant treatment 
arm compared with 2% in the placebo and fulvestrant treatment arm 
(Cristofanilli et al. 2016).  After a median follow-up of 44.8 months, median OS also 
favored palbociclib and fulvestrant over placebo and fulvestrant (34.9 months vs. 
28.0 months, stratified hazard ratio for death 0.81) (Turner et al. 2018). 
Thus, the addition of targeted therapy to endocrine therapy has demonstrated 
improvement in PFS, although with additional toxicity over endocrine therapy alone.  
Predictive biomarkers to identify patients most likely to derive the greatest benefit from 
the combination of endocrine and targeted therapies remain limited. 
Approximately 40% of patients with HR-positive breast cancer have tumors that harbor 
mutations in PIK3CA, the gene encoding the catalytic subunit of the alpha isoform of 
PI3K (p110).  These mutations result in upregulation of PI3K pathway activity 
(Saal et al. 2005; Stemke-Hale et al. 2008) and sensitize nonclinical models to inhibition 
with selective PI3K inhibitors (O’Brien et al. 2010; Schleifman et al. 2014).  A number of 
PI3K inhibitors are in clinical development for the treatment of HR-positive breast 
cancer, and one, alpelisib, has recently been approved in the United States in 
combination with fulvestrant for treatment of HR-positive, HER2-negative, 
PIK3CA-mutated advanced or metastatic breast cancer following progression on or after 
an endocrine-based regimen.   
The specificity of inavolisib (also known as GDC-0077) for the PI3K isoform, together 
with its unique mechanism of action that leads to specific degradation of mutant p110, 
should enable a broad therapeutic index as a single agent and in combination with 
standard-of-care endocrine and targeted therapies. 
Improved treatment options in HR-positive, HER2-negative breast cancer may decrease 
or eliminate the risk of late recurrences after adjuvant therapy, provide more tolerable 
effective treatment options, and ultimately achieve a cure for patients with advanced 
disease.  Maximizing therapeutic benefit, while minimizing treatment-related toxicities, is 
particularly important in HR-positive, HER2-negative breast cancer where treatment 
duration can be long. 
1.2 
BACKGROUND ON THE PI3K/AKT/MTOR PATHWAY AND 
BREAST CANCER 
Phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of 
rapamycin (mTOR) are major nodes in the PI3K/AKT/mTOR intracellular signaling 
pathway and are critical for cell-cycle modulation, cell growth, metabolism, motility, and 
survival (Cantrell 2001; Hanahan and Weinberg 2011; Vanhaesebroeck et al. 2012).  
The PI3K/AKT/mTOR pathway is generally activated following ligand-receptor tyrosine 
kinase interactions.  Under physiologic conditions, the main role of PI3K is to facilitate 
the metabolism of inositol phospholipids for intracellular signal transduction. 

 
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There are three classes of PI3K, with Class I being the most responsive to external 
stimuli.  Class I PI3Ks are composed of two subunits:  a p110 catalytic subunit and a 
regulatory adapter subunit, p85.  There are four isoforms of the p110 catalytic subunit of 
PI3K:  , , , and .  These four isoforms are the respective products of the genes 
PIK3CA, PIK3CB, PIK3CG, and PIK3CD.  PIK3CA and PIK3CB are expressed in all 
cells, while PIK3CD is primarily expressed in leukocytes and PIK3CG is expressed in 
multiple tissues, including pancreas, skeletal muscle, liver, and heart. 
Dysregulation of the PI3K/AKT/mTOR signaling pathway has been described in multiple 
solid tumor malignancies:  glioblastoma, colorectal, gastric, lung, endometrial, ovarian, 
prostate, and breast cancers (Gustin et al. 2008).  Pathway activation may occur through 
multiple mechanisms:  loss of the tumor suppressor phosphatase and tensin 
homolog (PTEN), amplification or somatic mutations in PIK3CA, mutations in AKT, 
mutations in the regulatory subunit p85, mutations and/or amplification of 
upstream-receptor tyrosine kinases, mutations in RAS, and loss of liver kinase B1, type 
II inositol polyphosphate-4-phosphatase, or tuberous sclerosis (Staal 1987; 
Cheng et al. 1992; Bellacosa et al. 1995; Li et al. 1997; Steck et al. 1997; 
Aoki et al. 1998).  Activating mutations in the PIK3CA gene are the most common 
genomic alterations and occur primarily in exons 9 and 20 (“hotspot” regions), which 
encode the helical and kinase domains of the PI3K protein (Bachman et al. 2004; 
Samuels et al. 2004). 
Up to 70% of breast cancers can have some form of molecular aberration of the 
PI3K/AKT/mTOR pathway (Cancer Genome Atlas Network 2012).  Hyperactivation of 
the PI3K/AKT/mTOR signaling pathway was proven to promote both de novo and 
acquired resistance to hormone therapy in ER-positive breast cancer cell lines and 
xenograft models (Sabnis et al. 2007), and simultaneous blocking of the 
PI3K/AKT/mTOR pathway with everolimus and the ER pathway with letrozole results in 
greater anti-tumor activity than either agent alone (Boulay et al. 2005).  In addition, 
evidence of baseline PI3K activation was found to be predictive of a poor prognosis after 
adjuvant endocrine therapy (Miller et al. 2010). 
These data provide support for the hypothesis that blocking PI3K/AKT/mTOR pathway 
signaling may have a therapeutic benefit in patients with ER-positive, HER2-negative 
breast cancer. 
In the clinical setting, results of the combination of exemestane and everolimus, an 
mTOR inhibitor, were reported in the BOLERO-2 trial (Baselga et al. 2012).  This study 
compared everolimus and exemestane with placebo and exemestane in 
724 postmenopausal patients with ER-positive advanced breast cancer who had 
experienced recurrence or progression of disease while receiving previous therapy with 
a nonsteroidal aromatase inhibitor in the adjuvant setting and/or for advanced disease.  
Median PFS in the everolimus group was 6.9 months compared with 2.8 months in the 
placebo group.  The hazard ratio for PFS by investigator assessment was 

 
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0.43 (95% confidence interval [CI]: 0.35 to 0.54; p   0.001).  The magnitude of the effect 
was even greater with central independent review: hazard 
ratio  0.36 (95% CI: 0.27 to 0.47; p  0.001). 
An important finding in studies with mTOR-targeting drugs such as everolimus is that 
these drugs produce a pharmacodynamic paradox:  while inhibiting mTOR, the 
administration of these drugs leads to an upregulation of the phosphorylated form of 
AKT (pAKT), resulting in feedback PI3K/AKT/mTOR pathway activation 
(Tabernero et al. 2008).  This finding suggests that alternative pharmacologic strategies 
to effectively shut down the pathway upstream of AKT should be pursued. 
One of these strategies is inhibiting the PI3K/AKT/mTOR pathway with agents that 
specifically target PI3K.  One such example is alpelisib, a molecule that primarily inhibits 
PI3K.  The recently reported SOLAR-1 trial (André et al. 2019) studied alpelisib in 
combination with fulvestrant in HR-positive, HER2-negative advanced or metastatic 
breast cancer.  Based on study results, the U.S. Food and Drug Administration (FDA) 
has approved the use of alpelisib in combination with fulvestrant for the treatment of 
HR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer 
following progression on or after an endocrine-based regimen.  In the cohort of 
341 patients with PIK3CA-mutated cancer, PFS at a median follow-up of 20 months was 
11.0 months (95% CI: 7.5 to 14.5 months) in the alpelisib plus fulvestrant group, as 
compared with 5.7 months (95% CI: 3.7 to 7.4 months) in the placebo plus fulvestrant 
group (hazard ratio  0.65; 95% CI: 0.50 to 0.85; p  0.001).  This provides clinical 
validation of the addition of PI3K inhibition to endocrine therapy in this disease space. 
This therapy is accompanied, however, by significant toxicities.  Among all patients in 
SOLAR-1 (n  571), the most frequent Grade 3 or 4 adverse events were 
hyperglycemia (36.6% in the alpelisib plus fulvestrant group vs. 0.7% in the placebo plus 
fulvestrant group) and rash (9.9% vs. 0.3%).  Grade 3 diarrhea occurred in 6.7% versus 
0.3% of patients.  Twenty-five percent of patients treated with alpelisib permanently 
discontinued treatment due to adverse events versus 4.2% in the placebo arm. 
1.3 
BACKGROUND ON INAVOLISIB 
Inavolisib (also known as “GDC-0077”) is a potent and selective inhibitor of the Class I 
PI3K isoform, with  300-fold less potent biochemical inhibition of other Class I PI3Ks, 
including the , , and  isoforms, and with increased potency in tumor cells bearing 
mutant p110 over cells bearing wild type (WT) p110.  Inavolisib exerts its activity by 
binding to the adenosine 5′-triphosphate binding site of p110, thereby inhibiting the 
phosphorylation of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) to 
phosphatidylinositol 3,4,5-trisphophate (PIP3).  Inhibiting the phosphorylation of PIP2 to 
PIP3 decreases downstream activation of pathway effectors including AKT and S6RP, 
resulting in decreased cellular proliferation, metabolism, and angiogenesis.  Nonclinical 
studies demonstrate that inavolisib specifically degrades mutant p110, inhibits 
proliferation and induces apoptosis in PIK3CA-mutant breast cancer cell lines, inhibits 

 
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tumor growth in human breast cancer xenograft models harboring PIK3CA mutations, 
and reduces downstream PI3K pathway markers, including pAKT, PRAS40 
phosphorylated at Threonine 246 (pPRAS40), and S6RP phosphorylated at 
Serine 235/236 (pS6RP). 
1.3.1 
Nonclinical Data for Inavolisib 
Results of in vitro combination studies indicate positive combination effects between 
inavolisib and endocrine therapies and between inavolisib and palbociclib.  In the 
PIK3CA-mutant, ER-positive breast cancer cell line, MCF-7, inavolisib alone caused 
growth inhibition.  Effects on growth were also observed with fulvestrant and palbociclib 
when administered as single agents.  Combined treatment of cells with inavolisib and 
fulvestrant caused dose-dependent inhibition of cell viability at lower concentrations 
compared with either inavolisib or fulvestrant alone.  In addition, treatment with inavolisib 
and palbociclib yielded similar in vitro combination effects with increased 
dose-dependent inhibition of cell viability compared with either inavolisib or palbociclib 
alone. 
In vivo anti-tumor activity of inavolisib was established using human tumor xenograft 
models that harbor hotspot mutations in PIK3CA.  Anti-tumor activity was evaluated as 
percentage of tumor growth inhibition relative to vehicle controls for inavolisib as a single 
agent or in combination with either chemotherapeutics or targeted agents.  These in vivo 
studies demonstrated that inavolisib has robust anti-tumor activity as a single agent and 
improved efficacy when administered in combination with marketed anti-cancer agents, 
including fulvestrant (endocrine therapy), palbociclib (CDK4/6 inhibitor), and paclitaxel 
(chemotherapy), in the MCF-7 human breast cancer xenograft model, which harbors the 
E545K hotspot mutation in PIK3CA.  PI3K pathway markers, including pAKT, pPRAS40, 
and pS6RP, were reduced for up to 8 hours in response to a single dose of inavolisib. 
The nonclinical safety of inavolisib has been assessed in a comprehensive battery of 
toxicology studies which include single-dose and repeat-dose general toxicology studies 
(QD PO dosing) of up to 3 months duration in rats and dogs; in vitro and in vivo genetic 
toxicology studies; in vitro phototoxicity study; in vitro and in vivo secondary 
pharmacology and safety pharmacology studies; and embryofetal development 
(Segment II) studies in rats. 
The dose limiting toxicities (DLTs) identified in nonclinical toxicology studies were 
consistent with the anticipated pharmacologic effects of PI3K inhibition, and included 
hyperglycemia and body weight loss in rats and dogs, and inflammation in dogs.  In 
addition, bone marrow hypocellularity, atrophy of glandular and reproductive tissues and 
eye lens degeneration were observed in the rats; and lymphoid depletion and swelling of 
the lens fibers in the eye were observed in the dogs.  Findings were generally 
dose-dependent and reversible, and/or considered to be clinically monitorable and/or 
manageable. 

 
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In vitro and in vivo safety pharmacology studies of inavolisib demonstrated a low risk for 
adverse cardiovascular, neurologic, and respiratory effects at clinically relevant 
exposures.  Inavolisib is considered to have no phototoxic potential.  
Inavolisib was not mutagenic in the bacterial mutagenesis assay.  Inavolisib showed in 
vitro clastogenicity at high concentrations in human peripheral blood lymphocytes; 
however, there was no evidence of inavolisib-induced clastogenicity, aneugenicity, or 
DNA damage in a subsequent in vivo micronucleus and alkaline comet study in rats up 
to maximum tolerated dose of 40 mg/kg (~15.8   of clinical exposure at 9 mg). 
Fetal malformations and variations observed in rats warrant the continued use of highly 
effective contraception in clinical trials.  Refer to the Inavolisib Investigator’s Brochure for 
more detailed information. 
1.3.2 
Clinical Data for Inavolisib  
In the Phase I Study GO39374, 157 patients with PIK3CA-mutant metastatic tumors 
were enrolled and treated (as of the clinical cutoff date of 20 March 2020):  156 patients 
with breast cancer and 1 patient with colorectal cancer.  These patients were enrolled 
into one of six arms: 
 
Arm A:  GDC-0077 single agent, dose escalation 
 
Arm B:  GDC-0077 (9 mg QD) plus palbociclib and letrozole, dose escalation and 
expansion 
 
Arm C:  GDC-0077 (9 mg QD) plus letrozole, dose escalation and expansion 
 
Arm D:  GDC-0077 (9 mg QD) plus fulvestrant, expansion  
 
Arms E and F:  GDC-0077 (9 mg QD) plus palbociclib and fulvestrant (Arm E) and 
with metformin for patients with obesity or pre-diabetes (Arm F), expansion 
 
Enrollment was ongoing in the expansion stage at the GDC-0077 9 mg QD dose level in 
Arms D, E, and F at the clinical cutoff date. 
In Arm A of GO39374, among 20 patients with measurable disease treated with 6-mg, 
9-mg, or 12-mg QD starting dose of GDC-0077 as a single agent, 5 patients (25%) 
achieved partial responses (PRs), while 9 patients (45%) achieved clinical benefit 
(defined as the percentage of patients achieving confirmed Response Evaluation Criteria 
in Solid Tumors [RECIST], Version 1.1 defined complete response [CR], PR, and/or 
stable disease [SD] [non-complete response/non-progressive disease for patients with 
non-measurable disease at baseline]  24 weeks).  Of these, all were at the 6-mg or 
9-mg QD starting dose, and 3 patients had received prior CDK4/6 inhibitor therapy.  
Patients in Arm A also had 18F-fluorodeoxyglucose-positron emission tomography scans 
at baseline and after 2 weeks of QD GDC-0077 dosing to evaluate changes in glucose 
metabolism as a marker of PI3K pathway modulation.  At 6 mg, 9 mg, and 12 mg, 
respectively, 4 of 7 patients (57%), 6 of 9 patients (67%), and 2 of 4 patients (50%) were 

 
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metabolic responders by STARCIST criteria (Bengtsson et al. 2015) with mean percent 
decreases in maximum standard uptake value of 25.3%, 43.4%, and 41.5%. 
In Arm B, among 33 patients with measurable disease treated with 3-mg, 6-mg, or 
9-mg QD starting dose of GDC-0077 in combination with palbociclib and letrozole, 
14 patients (42%) achieved PRs, and 1 patient (3%) achieved CR; in addition, 
26 patients (79%) achieved clinical benefit (defined as the percentage of patients 
achieving confirmed RECIST v1.1 defined CR, PR, and/or SD [non-complete 
response/non-progressive disease for patients with non-measurable disease at 
baseline]   24 weeks).  Of these, 30 patients were at the 6-mg or 9-mg QD starting dose, 
and 2 patients had received prior CDK4/6 inhibitor therapy. 
In Arm C, among 37 patients with measurable disease treated with 6-mg or 9-mg QD 
starting dose of GDC-0077 in combination with letrozole, 6 patients (16%) achieved 
PRs, while 13 patients (35%) achieved clinical benefit (defined as the percentage of 
patients achieving confirmed RECIST v1.1 defined CR, PR, and/or SD [non-complete 
response/non-progressive disease for patients with non-measurable disease at 
baseline]   24 weeks).  Of these, 30 patients were at the 9-mg QD starting dose, and 
4 patients had received prior CDK4/6 inhibitor therapy. 
In Arm D, among 39 patients with measurable disease treated with 9-mg QD starting 
dose of GDC-0077 in combination with fulvestrant, 6 patients (15%) achieved PRs, while 
16 patients (41%) achieved clinical benefit (defined as the percentage of patients 
achieving confirmed RECIST v1.1 defined CR, PR, and/or SD [non-complete 
response/non-progressive disease for patients with non-measurable disease at 
baseline]   24 weeks).  Of these, 4 patients had received prior CDK4/6 inhibitor therapy. 
In Arm E, among 13 patients treated with 9-mg QD starting dose of GDC-0077 in 
combination with palbociclib and fulvestrant, 5 patients (39%) achieved PRs, while 
8 patients (62%) achieved clinical benefit (defined as the percentage of patients 
achieving confirmed RECIST v1.1 defined CR, PR, and/or SD [non-complete 
response/non-progressive disease for patients with non-measurable disease at 
baseline]   24 weeks). 
In Arm F, among 15 patients treated with 9-mg QD starting dose of GDC-0077 in 
combination with palbociclib and fulvestrant and prophylactic metformin, two 
patients (13%) achieved PRs, while 9 patients (60%) achieved clinical benefit (defined 
as the percentage of patients achieving confirmed RECIST v1.1 defined CR, PR, and/or 
SD [non-complete response/non-progressive disease for patients with non-measurable 
disease at baseline]   24 weeks). 
Overall, adverse events occurring in  20% of patients, regardless of attribution, included 
diarrhea (63%), hyperglycemia (62%), nausea (52%), vomiting (32%), 
neutropenia (31%), decreased appetite (31%), fatigue (28%), stomatitis (26%), 

 
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anemia (25%), dysgeusia (25%), headache (25%), alopecia (22%), cough (22%), and 
constipation (20%).  Grade   3 adverse events occurring in  4 patients (2.5%), 
regardless of attribution, included hyperglycemia and neutropenia (23% each; 
neutropenia included terms of neutropenia and neutrophil count decreased), 
anemia (6%), AST increased, lymphopenia, fatigue, hypokalemia, and 
hypophosphatemia (5% each), leukopenia, and nausea (4% each), ALT increased, 
hypercalcemia, thrombocytopenia, and hyponatremia (3% each).  Hyperglycemia is 
anticipated with PI3K inhibition, and events were manageable with oral 
anti-hyperglycemic agents.  Diarrhea was mild (all events Grade 1 or 2).  Other 
PI3K-inhibition associated adverse events observed included grouped terms for 
stomatitis (45% all grades; 1% Grade  3) and rash (21% all grades; 1% Grade  3).  The 
stomatitis cases were responsive to oral dexamethasone rinses, and rash was generally 
mild.  No DLTs were observed at the 6‑mg or 9-mg dose levels with GDC-0077 as single 
agent or in combination with letrozole, or with palbociclib and letrozole in 
Study GO39374; however, DLTs of Grade 4 hyperglycemia and Grade 3 fatigue 
(1 patient each) were reported at the 12-mg dose level with GDC-0077 as a single 
agent.  As of the current clinical data cutoff (20 March 2020), 4 patients (3%; N  157) 
had discontinued study treatment due to an adverse event (Arm B:  related 
Grade 3 hyperglycemia; Arm F:  related Grade 2 panniculitis; Arm B:  unrelated 
Grade 3 cerebrovascular disorder; Arm D:  unrelated unexplained death). 
Refer to the GDC-0077 Investigator’s Brochure for details on nonclinical and clinical 
studies. 
1.4 
BACKGROUND ON PALBOCICLIB 
Palbociclib is an inhibitor of Cyclin Dependent Kinase 4 (CDK4) and CDK6 and is 
approved in combination with the aromatase inhibitor letrozole for the initial treatment of 
postmenopausal women or men (U.S.) with advanced or metastatic HR-positive, 
HER2-negative breast cancer.  Palbociclib is also approved in combination with 
fulvestrant for the treatment of women or men (U.S.) with advanced or metastatic 
HR-positive, HER2-negative breast cancer that has progressed after endocrine therapy.  
The approval in combination with fulvestrant was based on the Phase III 
PALOMA-3 study, which showed that in women with HR-positive, HER2-negative 
advanced or metastatic breast cancer who had disease progression following endocrine 
therapy treatment with the combination of palbociclib and fulvestrant demonstrated a 
median PFS of 9.2 months (95% CI: 7.5 to not estimable [NE]) versus 3.8 months 
(95% CI: 3.5 to 5.5) for those treated with placebo and fulvestrant (hazard ratio: 0.42; 
95% CI: 0.32 to 0.56; p   0.001) (Turner et al. 2015).  Updated PFS analysis data from 
the PALOMA-3 study demonstrated a median PFS of 11.2 months in the palbociclib arm 
versus 4.6 months in the placebo arm (hazard ratio: 0.497) (Cristofanilli et al. 2018). 
As reported in the palbociclib Summary of Product Characteristics (SmPC), the most 
common adverse events (  10%) associated with the use of palbociclib in combination 

 
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with fulvestrant include neutropenia, leukopenia, infections, fatigue, nausea, anemia, 
stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, 
and pyrexia. 
1.4.1 
Clinical Pharmacokinetics of Palbociclib 
The mean maximum concentration observed (Cmax) of palbociclib is generally observed 
between 6 to 12 hours (time to reach maximum concentration) following oral 
administration.  The mean absolute bioavailability of palbociclib after an oral 125-mg 
dose is 46%.  In the dosing range of 25 to 225 mg, the area under the 
concentration-time curve (AUC) and Cmax increased proportionally with dose in general.  
Steady state was achieved within 8 days following repeated once daily dosing.  The 
geometric mean apparent oral clearance of palbociclib was 63.1 L/hr (29% coefficient of 
variation), and the mean (  standard deviation) plasma elimination half-life was 29 (  5) 
hours in patients with advanced breast cancer. 
Palbociclib absorption and exposure were very low in approximately 13% of the 
population under the fasted condition.  Food intake increased palbociclib exposure in 
this small subset of the population, but it did not alter palbociclib exposure in the rest of 
the population to a clinically relevant extent.  Therefore, food intake reduced the 
inter-patient variability of palbociclib exposure, which supports administration of 
palbociclib with food. 
In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in 
humans.  Following oral administration of a single 125-mg dose of [14C]palbociclib to 
humans, the primary metabolic pathways for palbociclib involved oxidation and 
sulfonation, with acylation and glucuronidation contributing as minor pathways.  
Palbociclib was the major circulating drug-derived entity in plasma (23%).  The major 
circulating metabolite was a glucuronide conjugate of palbociclib, although it only 
represented 1.5% of the administered dose in the excreta.  Palbociclib was extensively 
metabolized, with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces 
and urine, respectively.  In feces, the sulfamic acid conjugate of palbociclib was the 
major drug-related component, accounting for 26% of the administered dose.  In vitro 
studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant 
SULT enzymes indicated that cytochrome P450 (CYP) 3A and SULT2A1 are mainly 
involved in the metabolism of palbociclib. 
For more information, refer to the local prescribing information for palbociclib 
(i.e., package insert or SmPC). 
Preliminary palbociclib PK data from 23 female patients with HR-positive, 
HER2-negative breast cancer were evaluated in Study GO39374 when administered 
together with GDC-0077 and letrozole and compared with the palbociclib FDA New Drug 
Application clinical pharmacology review.  These data indicate no effect of GDC-0077 on 
the pharmacokinetics of palbociclib and further indicate a low risk of GDC-0077 as a 

 
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perpetrator of CYP3A4-based drugdrug interaction (DDI).  In addition, the combination 
of palbociclib and letrozole had no effect on the dose-normalized exposure of 
GDC-0077, suggesting that palbociclib will not alter GDC-0077 exposure. 
1.5 
BACKGROUND ON FULVESTRANT 
Fulvestrant is an ER antagonist approved for the treatment of postmenopausal women 
with advanced HR-positive, HER2-negative breast cancer with or without prior 
anti-estrogen therapy.  Fulvestrant is also approved in combination with the CDK4/6 
inhibitor palbociclib for the treatment of advanced or metastatic HR-positive, 
HER2-negative breast cancer that has progressed after endocrine therapy. 
Fulvestrant binds to the ER, disrupting the signaling pathway, which leads to 
ER degradation.  The recommended dosage of fulvestrant is 500 mg given by 
intramuscular (IM) injection on Days 1, 15, and 29 of the first month, and then monthly 
thereafter.  This dosage of fulvestrant was confirmed in a randomized clinical study of 
250 mg versus 500 mg IM on a monthly basis (Di Leo et al. 2010).  Fulvestrant 500 mg 
given on a monthly basis provided superior clinical benefit compared with a 250-mg 
dose (PFS hazard ratio: 0.80; 95% CI: 0.68 to 0.94; p  0.006), but the 500-mg dose was 
accompanied by a higher rate of injection-site reactions (Di Leo et al. 2010).  This dose 
of fulvestrant has also shown a trend toward improvement in overall survival (OS) 
compared with the 250-mg fulvestrant dose (median duration of OS 25.1 months vs. 
22.8 months; hazard ratio  0.84 [95% CI: 0.69 to 1.03; p  0.091]).  The lower dose of 
fulvestrant (250 mg) is recommended in patients who have liver dysfunction 
(Child-Pugh Class B disease). 
The Phase III FALCON study investigated whether fulvestrant could improve PFS 
compared with anastrozole in postmenopausal patients with HR-positive locally 
advanced or metastatic breast cancer who had not received previous endocrine therapy 
(Robertson et al. 2016).  The median PFS was 16.6 months in the fulvestrant group 
versus 13.8 months in the anastrozole group (hazard ratio: 0.797, p  0.0486). 
As reported in the fulvestrant SmPC, common adverse events associated with the use of 
fulvestrant include hypersensitivity reactions, hot flushes, nausea, elevated hepatic 
enzymes (ALT, AST, alkaline phosphatase [ALP]), rash, joint and musculoskeletal pain, 
asthenia, injection-site reactions, urinary tract infections, reduced platelet count, 
anorexia, headache, venous thromboembolism, vomiting, diarrhea, elevated bilirubin, 
back pain, vaginal hemorrhage, peripheral neuropathy, and sciatica.  In randomized 
studies that compared fulvestrant with anastrozole, similar rates of common adverse 
events were reported, with the exception of injection-site pain. 
1.5.1 
Clinical Pharmacokinetics of Fulvestrant 
At the 500-mg monthly dosing regimen, the geometric mean (%CV) Cmax and AUC of 
fulvestrant at steady state were 28.0 ng/mL (27.9%) and 13,100 ng  hr/mL (23.4%), 
respectively.  Following a single IM injection of fulvestrant 250 mg, the apparent 

 
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clearance (mean   standard deviation) of fulvestrant was 690  226 mL/min with an 
apparent half-life of approximately 40 days.  The 14C-labeled studies with fulvestrant 
indicate that fulvestrant is rapidly cleared by the hepatobiliary route with excretion 
primarily via the feces (approximately 90%).  Less than 1% of fulvestrant was excreted 
unchanged in the urine (Faslodex U.S. Package Insert [USPI]). 
Fulvestrant has no known drug interactions.  It does not significantly inhibit or induce any 
of the major CYP isoenzymes in vitro.  Although it is partially metabolized by CYP3A4, 
co-administration of fulvestrant with either rifampicin (a potent CYP3A4 inducer) or 
ketoconazole (a potent CYP3A4 inhibitor) had no effect on its pharmacokinetics 
(Faslodex USPI). 
Preliminary fulvestrant pharmacokinetic (PK) data from 16 female patients with 
HR-positive, HER2-negative breast cancer were evaluated in Study GO39374.  Results 
suggest that the minimum concentration observed after several months of dosing is 
comparable to historical data suggesting no DDI with fulvestrant as a victim and 
GDC-0077 as a perpetrator (Faslodex USPI).  Furthermore, exposure of GDC-0077 in 
the presence of fulvestrant is similar to GDC-0077 single-agent exposure and suggests 
no DDI interaction with GDC-0077 as a victim. 
For more information, refer to the local prescribing information for fulvestrant 
(i.e., package insert or SmPC). 
1.6 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
HR-positive, HER2-negative breast cancer remains a disease with significant unmet 
need:  HR-positive tumors represent the most common form of breast cancer, yet 
despite adjuvant endocrine therapy, a significant proportion of patients (~30%) remain at 
risk of relapse.  With the development of metastatic disease and subsequent treatment 
with endocrine therapies, most patients develop resistance to endocrine therapy and the 
majority of all breast cancer deaths are due to HR-positive disease. 
There are multiple mechanisms of resistance to hormonal therapies in patients with 
HR-positive metastatic breast cancer:  estrogen-independent tumor growth; loss of 
ER expression; or activation of intracellular signaling pathways, 
including mitogen-activated protein kinase and PI3K (Acconcia et al. 2005; 
Björnström and Sjöberg 2005; Gutierrez et al. 2005; Johnston 2009; 
Osborne and Schiff 2011). 
The addition of targeted therapies (such as PI3K/mTOR inhibitors and 
CDK4/6 inhibitors) to endocrine therapy may overcome mechanisms of resistance to 
endocrine therapies, leading to significant clinical improvements in PFS.  Mechanisms of 
resistance to targeted therapies, such as everolimus and palbociclib, remain poorly 
understood but are likely multifactorial, including signaling pathway reactivation and 
alterations in cell-cycle components (Rb1 loss or cyclin E amplification). 

 
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The scientific rationale for combining PI3K pathway inhibition with endocrine therapy is 
supported by nonclinical and clinical data.  Activation of the PI3K pathway (via 
PIK3CA mutations, PTEN expression loss, or HER2 overexpression) has been 
demonstrated to promote resistance to anti-estrogen therapy and hormonal 
independence in ER-positive breast cancer models (Shou et al. 2004; 
Miller et al. 2009, 2010).  Proteomic and transcriptional profiling of human HR-positive 
tumors suggest that increased PI3K signaling is associated with lower ER levels, which 
has been correlated with resistance to endocrine therapy (Creighton et al. 2010; 
Miller et al. 2010).  Inhibition of the PI3K/mTOR pathway in nonclinical models has been 
shown to upregulate ER/progesterone receptor expression (Creighton et al. 2010) and 
enhance the anti-tumor effect of letrozole (Boulay et al. 2005).  Retrospective analyses 
of tumor samples from HR-positive patients who are treated with tamoxifen lend support 
to the nonclinical observations linking the PI3K pathway to endocrine resistance; 
patients with an activated PI3K pathway have been found to have decreased OS 
(Kirkegaard et al. 2005) and shorter relapse-free survival (Shoman et al. 2005). 
In the clinical setting, data from Phase II and III studies suggest that the combined 
inhibition of the PI3K/mTOR and estrogen-signaling pathways provides superior benefit 
when compared with single-agent endocrine therapies.  The addition of everolimus to 
tamoxifen in a Phase II study of patients with ER-positive breast cancer who received 
prior treatment with an aromatase inhibitor significantly improved CBR, time to 
progression, and OS compared with single-agent tamoxifen (Bachelot et al. 2012).  Data 
from the Phase III BOLERO-2 study demonstrated that the addition of everolimus to 
exemestane more than doubled PFS compared with single-agent exemestane in 
patients with ER-positive, HER2-negative metastatic breast cancer whose disease was 
refractory to prior treatment with letrozole or anastrozole (Baselga et al. 2012). 
Recent data have shown that the presence of PIK3CA mutations in breast cancers may 
confer a worse prognosis (Caldas, AACR, 2016).  PIK3CA mutations occur in 
approximately 40% of HR-positive, HER2-negative breast cancers (Saal et al. 2005; 
Stemke-Hale et al. 2008), and inhibition of PI3K has been clinically validated in 
HR-positive, HER2-negative metastatic breast cancer (André et al. 2019). 
Alpelisib is a selective inhibitor of the PI3K isoform.  Data from Phase I and Ib studies 
with alpelisib as a single agent and in combination with fulvestrant have demonstrated 
anti-tumor activity and a tolerable adverse event profile (Janku et al. 2014; 
Juric et al. 2014).  Recent data from the Phase Ib study of alpelisib in combination with 
letrozole provide further support for combining endocrine therapy and PI3K inhibition.  In 
ER-positive, HER2-negative metastatic breast cancer, confirmed PRs occurred in 
25% of patients with PIK3CA-mutant and 10% of patients with WT tumors; CBR with the 
combination was greater in patients with PIK3CA-mutant compared with WT tumors 
(44% vs. 20%).  The most common adverse events attributed to the study treatment 
included hyperglycemia, nausea, fatigue, diarrhea, and rash (Mayer et al. 2019).  On the 
basis of a subsequent Phase III study (SOLAR-1; André et al. 2019), alpelisib has 

 
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received approval from the U.S. FDA, in combination with fulvestrant, for the treatment 
of patients with HR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic 
breast cancer following progression on or after an endocrine-based regimen.  In the 
cohort of 341 patients with PIK3CA-mutated cancer, PFS at a median follow-up of 
20 months was 11.0 months (95% CI: 7.5 to 14.5 months) in the alpelisib plus fulvestrant 
group compared with 5.7 months (95% CI: 3.7 to 7.4 months) in the placebo plus 
fulvestrant group (hazard ratio  0.65; 95% CI: 0.50 to 0.85; p   0.001).  Among all 
patients in SOLAR-1, the most frequent Grade 3 or 4 adverse events were 
hyperglycemia (36.6% in the alpelisib plus fulvestrant group vs. 0.7% in the placebo plus 
fulvestrant group) and rash (9.9% vs. 0.3%).  Grade 3 diarrhea occurred in 6.7% versus 
0.3% of patients.  Twenty-five percent of patients treated with alpelisib permanently 
discontinued treatment due to adverse events versus 4.2% of patients in the placebo 
arm. 
Thus, combined inhibition of the PI3K/mTOR and estrogen-signaling pathways offers an 
effective therapeutic approach in patients with HR-positive, HER2-negative metastatic 
breast cancer. 
The scientific rationale for combining a PI3K pathway inhibitor with CDK4/6 inhibitor 
therapy is supported by nonclinical data, and these combinations together with 
endocrine therapy are being evaluated in clinical trials.  A combinatorial drug screen of 
PIK3CA-mutant cancers found that combined CDK4/6-PI3K inhibition synergistically 
reduced tumor cell viability (Vora et al. 2014).  PI3K inhibitor treatment of 
palbociclib-arrested cells results in cell death, although the combination of 
CDK4/6-PI3K inhibition was not able to re-sensitize cancer cell lines with acquired 
resistance to CDK4/6 inhibition.  Importantly, in vivo data demonstrate that the 
combination of CDK4/6 and PI3K inhibition can prevent or delay the time to 
CDK4/6 inhibitor resistance (Herrera-Abreu et al. 2016). 
Currently, aromatase inhibitors and tamoxifen are approved for use in the adjuvant and 
locally advanced or metastatic setting whereas fulvestrant is approved for use in the 
locally advanced or metastatic setting only.  Given its distinct mechanism of action, 
fulvestrant, in combination with palbociclib, represents an appropriate treatment option 
for patients who experience disease progression during or shortly after completing 
adjuvant endocrine therapy.  This combination is supported by data from the PALOMA-3 
clinical trial (Cristofanilli et al. 2016). 
Patients whose disease progressed during or within 12 months of completion of adjuvant 
endocrine therapy or whose disease progressed on or within 1 month of prior endocrine 
therapy for advanced or metastatic disease enrolled in PALOMA-3.  Patients with 
measurable or bone-only disease (limited to lytic or mixed lytic/blastic) were also eligible.  
Overall, patients who had received neoadjuvant or adjuvant therapy only but no prior 
systemic therapy for metastatic disease achieved a median PFS of 9.5 months 
(95% CI: 7.4 months to NE) with palbociclib and fulvestrant, comparable to patients who 

 
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had received at least one prior systemic therapy for metastatic breast cancer and 
achieved a median PFS of 9.9 months (95% CI: 9.2 to 11.2 months).  While the relative 
benefit of adding CDK4/6 inhibition to endocrine therapy is independent of 
PIK3CA mutation status, median PFS was shorter in patients with PIK3CA mutations 
detectable in circulating tumor DNA (ctDNA) versus patients with no PIK3CA mutations 
in ctDNA in the PALOMA-3 study regardless of treatment arm (5.8 months 
[95% CI: 5.3 to 9.5 months] vs. 9.2 months [95% CI: 7.5 to 10.8 months]) 
(Cristofanilli et al. 2016).  In addition, shorter survival has been observed in patients with 
PIK3CA mutations detectable in ctDNA (Turner et al. 2018). 
Improved treatment options for HR-positive, HER2-negative breast cancer may 
ultimately decrease or eliminate the risk of late recurrences after adjuvant therapy, 
provide more tolerable effective treatment options, and ultimately achieve a cure for 
patients with advanced or metastatic disease.  The anticipated or potential safety issues 
associated with administration of GDC-0077 as a single agent or in combination with 
palbociclib and/or endocrine therapy are expected to be clinically monitorable and 
manageable in patients.  The measures to avoid or minimize such toxicities in this trial 
are described in detail in Section 5.1. 
The specificity of inavolisib for the PI3K-isoform, together with its unique mechanism of 
action that leads to specific degradation of mutant p110, should enable a 
clinically-effective therapeutic index as a single agent and in combination with 
standard-of-care endocrine and targeted therapies.  On the basis of all nonclinical data 
available for inavolisib and clinical data from the Phase I/Ib study (GO39374) as reported 
in the inavolisib Investigator’s Brochure, the Sponsor has assessed the benefitrisk 
profile of inavolisib as a single agent and in combination with standard-of-care endocrine 
and targeted therapies to be appropriate for initiating this Phase III clinical study. 
1.6.1 
COVID-19 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with metastatic cancer, are considered a more vulnerable 
population, with the potential for more severe clinical outcomes from 
COVID-19.  However, it is unclear whether or how systemic cancer therapies such as 
chemotherapy or targeted therapy may affect the incidence or severity of COVID-19. 
Since immunosuppressant effects are a potential risk for inavolisib and 
myelosuppression, a possible consequence of immunosuppression may lead to an 
increased susceptibility to acute infections including COVID-19. 
At this time, there is insufficient evidence for causal association between inavolisib and 
an increased risk of severe outcomes from COVID-19. 
Pneumonitis is a potential risk for inavolisib and a few cases of Grade 12 pneumonitis 
have been observed upon treatment with inavolisib.  There may be a potential overlap in 

 
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clinical and radiological features for inavolisib induced pneumonitis and 
COVID-19related interstitial pneumonia.  Thus, investigators should use their clinical 
judgment when evaluating and managing patients with pulmonary symptoms. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of inavolisib in 
combination with palbociclib and fulvestrant compared with placebo plus palbociclib and 
fulvestrant in patients with PIK3CA-mutant, HR-positive, HER2-negative locally 
advanced or metastatic breast cancer whose disease progressed during treatment or 
within 12 months of completing adjuvant endocrine therapy and who have not received 
prior systemic therapy for locally advanced or metastatic disease.  Specific objectives 
and corresponding endpoints for the study are outlined below. 
Throughout this protocol, "study drug" refers to any of the individual agents assigned to 
patients as part of this study (i.e., inavolisib, placebo, palbociclib, or fulvestrant), while 
"study treatment" refers to the combination of agents assigned to patients as part of this 
study (i.e., inavolisib plus palbociclib and fulvestrant, or placebo plus palbociclib and 
fulvestrant). 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the 
basis of the following endpoint: 
 
PFS, defined as the time from randomization to the first occurrence of disease 
progression or death from any cause (whichever occurs first), as determined by the 
investigator according to RECIST v1.1 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of inavolisib 
plus palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant 
on the basis of the following endpoints: 
 
Objective response rate, defined as the proportion of patients with a CR and/or PR 
on at least two consecutive occasions  4 weeks apart, as determined by the 
investigator according to RECIST v1.1 
 
Best overall response rate (BOR), defined as the proportion of patients with a CR or 
PR, as determined by the investigator according to RECIST v1.1 
 
DOR, defined as the time from the first occurrence of a CR or PR to the first 
occurrence of disease progression or death from any cause (whichever occurs first), 
as determined by the investigator according to RECIST v1.1 
 
CBR, defined as the proportion of patients with a CR, PR, and/or SD for at least 
24 weeks, as determined by the investigator according to RECIST v1.1 

 
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 
OS, defined as the time from randomization to death from any cause 
 
Time to deterioration (TTD) in pain, defined as the time from randomization to the 
first documentation of a   2-point increase from baseline on the “worst pain” item 
from the Brief Pain InventoryShort Form (BPI-SF) 
 
TTD in Physical Function, defined as the time from randomization to the first 
documentation of a   10-point decrease from baseline in the European Organisation 
for Research and Treatment of Cancer Quality of LifeCore 30 Questionnaire 
(EORTC QLQ-C30) Physical Function scale (items 15) 
 
TTD in Role Function, defined as the time from randomization to the first 
documentation of a 10-point decrease from baseline in the EORTC QLQ-C30 Role 
Function scale (items 6 and 7) 
 
TTD in global health status (GHS)/health-related quality of life (HRQoL), defined as 
the time from randomization to the first documentation of a  10-point decrease from 
baseline in the EORTC QLQ-30 GHS/HRQoL scale (items 29 and 30) 
 
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of inavolisib 
plus palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant 
on the basis of the following endpoints: 
 
Time to end of next-line treatment (proxy for time to second objective disease 
progression [PFS2]), defined as the time from randomization to end or 
discontinuation of next-line treatment, or death from any cause (whichever occurs 
first) 
 
Time to first skeletal-related event (SRE), defined as the time from randomization to 
the first occurrence of an SRE   
A SRE is a pathologic fracture, radiation therapy to bone, cancer-related 
surgery to bone, or spinal cord compression. 
 
Mean and mean change-from-baseline scores in all functions (Physical, Role, 
Cognitive, Emotional, and Social), GHS/HRQoL, and disease- or treatment-related 
symptom scores, as measured by the scales of the EORTC QLQ-C30 and EORTC 
QLQBreast Cancer Module 23 Questionnaire (EORTC QLQ-BR23) 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of inavolisib plus palbociclib 
and fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis of 
the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), Version 5.0 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 

 
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 
Change from baseline in ECG parameters 
 
The exploratory safety objective for this study is to evaluate the tolerability of inavolisib 
plus palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant 
from the patient's perspective, on the basis of the following endpoints: 
 
Presence, frequency of occurrence, severity, and/or degree of interference with 
daily function of selected symptomatic treatment toxicities (i.e., diarrhea, nausea, 
vomiting, decreased appetite, fatigue, mouth sores, and rash symptoms) as 
assessed through use of the NCI Patient-Reported Outcomes Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) instrument, as well as an 
additional item regarding the overall bother experienced due to side effects of 
treatment 
 
Change from baseline in symptomatic treatment toxicities, as assessed through use 
of the PRO-CTCAE and the additional bother item 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The PK objective for this study is to characterize the pharmacokinetics of inavolisib, 
palbociclib, and fulvestrant, when administered in combination in this population, on the 
basis of the following endpoints: 
 
Plasma concentration of inavolisib at specified timepoints  
 
Plasma concentration of palbociclib at specified timepoints 
 
Plasma concentration of fulvestrant at specified timepoints 
 
The exploratory PK objective is to evaluate potential relationships between the plasma 
exposure of inavolisib, palbociclib, and fulvestrant and efficacy and safety outcomes 
from this study. 
The China-specific pharmacokinetic objective is to characterize the pharmacokinetics of 
inavolisib in all patients enrolled in China. 
2.4 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study are to identify and/or evaluate 
biomarkers that are associated with response and disease control with the study 
treatments, are early surrogates of efficacy of the study treatments, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated 
with innate or acquired resistance to the study treatments, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event 
monitoring or investigation (i.e., safety biomarkers), can provide evidence of activity of 
the study treatments (i.e., pharmacodynamic biomarkers), can increase the knowledge 
and understanding of disease biology and drug safety, on the basis of the following 
endpoint: 
 
Relationship between biomarkers in blood, plasma, and tumor tissue (listed in 
Section 4.5.6) and efficacy, safety, PK, or other biomarker endpoints 

 
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2.5 
HEALTH STATUS UTILITY OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with inavolisib plus palbociclib and fulvestrant compared 
with placebo plus palbociclib and fulvestrant on the basis of the following endpoint: 
 
Health utility and visual analog score (VAS) of the European Quality of Life 
5-Dimension, 5 Level (EQ-5D-5L) Questionnaire 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
Study WO41554 is a Phase III, randomized, double-blind, placebo-controlled, 
multicenter, global study designed to compare the efficacy, as measured by PFS, and 
the safety of the triplet combination of inavolisib plus palbociclib and fulvestrant versus 
placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutant, HR-positive, 
HER2-negative locally advanced or metastatic breast cancer whose disease progressed 
during treatment or within 12 months of completing adjuvant endocrine therapy and who 
have not received prior systemic therapy for locally advanced or metastatic disease. 
Approximately 320 patients will be enrolled at approximately 200 global investigative 
sites. 
Patients will be randomized to one of the following treatment arms in a 1:1 ratio 
(randomization will be stratified [see Section 4.2.1]): 
Inavolisib plus palbociclib and fulvestrant 
 
Inavolisib:  9-mg tablet taken PO QD on Days 128 of each 28-day cycle, 
beginning on Day 1 of Cycle 1 
 
Palbociclib:  125-mg capsule or tablet taken PO QD on Days 121 of each 
28-day cycle, beginning on Day 1 of Cycle 1 
 
Fulvestrant:  500 mg administered by IM injection on Days 1 and 15 of Cycle 1 
and then on Day 1 of each subsequent 28-day cycle, or approximately every 
4 weeks 
 
Placebo plus palbociclib and fulvestrant   
 
Placebo:  tablet taken PO QD on Days 128 of each 28-day cycle, beginning on 
Day 1 of Cycle 1  
 
Palbociclib:  125-mg capsule or tablet taken PO QD on Days 121 of each 
28-day cycle, beginning on Day 1 of Cycle 1  
 
Fulvestrant:  500 mg administered by IM injection on Days 1 and 15 of Cycle 1 
and then on Day 1 of each subsequent 28-day cycle, or approximately every 
4 weeks 
 

 
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The study consists of a screening period of up to 28 days, a treatment period, a 
post-treatment follow-up period (which includes a “30-day safety follow-up” for all 
patients and, when applicable, a “post-treatment hyperglycemia follow-up,” and/or a 
“post-treatment tumor assessment follow-up with PRO collection”), and a survival 
follow-up period, as shown in Figure 1 and Appendix 1. 
Patients may be prescreened for PIK3CA-mutation status through central testing of 
ctDNA by participating in a separate prescreening consent.  Patients may be 
re-screened only in cases of study-required assessments falling out of the screening 
window; all other screen failures are exclusionary. 
Study treatment may continue until unequivocal disease progression as determined by 
the investigator, unacceptable toxicity, patient withdrawal of consent, or study 
termination. 
Following study treatment discontinuation, patients will be followed for safety for 30 days 
after final study treatment (30-day safety follow-up, including a 30-day follow-up visit), or 
until the initiation of another anti-cancer therapy, whichever occurs first. 
Patients on anti-hyperglycemic agents for the treatment of hyperglycemia during the 
study treatment period and those patients with events of hyperglycemia ongoing at the 
end of the 30-day safety follow-up, will undergo additional safety follow-up assessments 
(“post-treatment hyperglycemia follow-up”) monthly until resolution of their fasting 
glucose to baseline levels, complete down-titration of their anti-hyperglycemic 
medications, or up to approximately 3 months after the final dose of study treatment, 
even if the patient initiates another anti-cancer therapy subsequent to study treatment 
discontinuation. 
In addition, patients who discontinue active study treatment for reasons other than 
progression of disease or death will continue to have tumor assessments performed 
every 8 weeks (  7 days) for the first 2 years from randomization and every 12 weeks 
(  7 days) thereafter, and complete PRO assessments at those timepoints 
(“post-treatment tumor assessment follow-up with PRO collection”), until documented 
disease progression or the initiation of another anti-cancer therapy, whichever occurs 
first. 
All patients will subsequently move onto the survival follow-up period until death, patient 
withdrawal of consent, loss to follow-up, or study termination.

 
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Figure 1 Schematic of Study Periods 
 
FU  follow up; PD  progressive disease; PRO  patient-reported outcome.

 
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Study patients must have measurable disease (per RECIST v1.1; see Appendix 9).  
Patients with evaluable (non-measurable) bone-only disease are not eligible; disease 
that is limited to bone but that has lytic or mixed lytic/blastic lesions and at least one 
measurable soft-tissue component (per RECIST v1.1) may be eligible.  Detailed 
eligibility information is listed in the inclusion and exclusion criteria in Sections 4.1.1 and 
4.1.2.  Locally advanced disease must not be amenable to resection or other local 
therapy with curative intent. 
Patients may enroll based on eligible PIK3CA mutation results from testing performed by 
a central investigational testing site or a site local test.  Local testing of blood or tumor 
tissue must be performed using a Sponsor-approved polymerase chain 
reaction (PCR)-based or next-generation sequencing (NGS) assay at a Clinical 
Laboratory Improvement Amendments (CLIA)- or equivalently-certified laboratory.  
Patients without available local test results for PIK3CA mutation status must submit a 
blood sample to determine whether an eligible PIK3CA mutation is present.  Samples 
will be evaluated by the NGS-based FoundationOne Liquid CDx (F1LCDx) assay, 
unless not implemented in specific localities.  In this case, samples will be submitted to 
an alternative, Sponsor-designated central testing laboratory.  Regardless of the testing 
strategy to determine a patient’s tumor PIK3CA mutation status, all patients must 
provide both blood and tumor tissue for evaluation by a central investigational testing 
site.  Demographic data will be collected on all patients who undergo screening, 
including those who screen fail. 
Patients will be closely monitored for adverse events throughout the study treatment, 
and for 30 days after the final dose of study treatment or until initiation of another 
anti-cancer therapy, whichever occurs first.  Adverse events will be graded according to 
NCI CTCAE v5.0.  Patients who, at the 30-day safety follow-up visit, are still on 
anti-hyperglycemic agents for the treatment of hyperglycemia during the study treatment, 
and those patients with events of hyperglycemia ongoing at the 30-day safety follow-up 
visit, will go on to the post-treatment hyperglycemia follow-up (as defined above). 
Tumor assessments will be performed to assess for response every 8 weeks (  7 days) 
during the first 2 years of study treatment and every 12 weeks (  7 days) thereafter.  
Patients who discontinue active study treatment for any reason other than unequivocal 
disease progression or death will follow the same tumor assessment schedule during the 
“post-treatment tumor assessment follow-up with PRO collection” period. 
After study treatment discontinuation, all patients will be followed for survival and all 
subsequent anti-cancer therapies.  These data will be collected via telephone calls 
and/or clinic visits approximately every 3 months until death, loss to follow-up, 
withdrawal of consent, or study termination by the Sponsor, whichever occurs first. 

 
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To evaluate the PK properties of inavolisib, palbociclib, and fulvestrant administered in 
this triplet combination, blood samples will be taken at various timepoints before and 
after dosing (Appendix 2). 
Patient reported outcome instruments will be completed by patients to evaluate the 
treatment impact from the patient's perspective as specified in the schedule of activities 
(Appendix 1).  The EORTC QLQ-C30 will assess disease and treatment-related 
symptoms often experienced by patients with locally advanced or metastatic cancer 
including fatigue, pain, depression/anxiety, and any limitations in function.  The 
EORTC QLQ-BR23 will provide additional assessment on some treatment-related 
symptoms and symptoms that may occur with advanced disease.  The “worst pain” item 
from the BPI-SF will be used to evaluate an increase in pain severity.  Additionally, the 
PRO-CTCAE will be used to assess the impact of treatment-related symptoms, with the 
goal being to demonstrate benefit of treatment without adverse impact on patients’ 
HRQoL.  The EQ-5D-5L will be used to assess health status.  
Figure 2 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.

 
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Figure 2 Study Schema 
 
AKT  protein kinase B; ctDNA  circulating tumor DNA; DOR  duration of response; HER2    HER2-negative; HR    hormone-receptor positive; 
IM  intramuscular; mTOR  mammalian target of rapamycin; ORR  overall response rate; OS  overall survival; PFS  progression-free survival; 
PI3K  phosphatidylinositol 3-kinase; PRO  patient-reported outcome; QD  once daily; SERD  selective estrogen-receptor degrader. 
a Fulvestrant is administered on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day cycle, or approximately every 4 weeks. 
b “Visceral” (Yes/No) refers to lung, liver, brain, pleural, and peritoneal involvement.  
c Primary endocrine therapy resistance is defined as relapse while on the first 2 years of adjuvant endocrine therapy.  Secondary endocrine 
therapy resistance is defined as relapse while on adjuvant endocrine therapy but after the first 2 years or relapse within 12 months of completing 
adjuvant endocrine therapy (4th ESO–European Society for Medical Oncology [ESMO] International Consensus Guidelines for Advanced Breast 
Cancer [ABC4], Cardoso et al. 2018). 
d Region is stratified by site location:  i) North America/Western Europe, ii) Asia/Pacific, iii) Other.

 
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3.1.2 
Independent Data Monitoring Committee 
An external independent Data Monitoring Committee (iDMC) will be formed to evaluate 
safety data from the first patient randomized until the time of the primary analysis of PFS 
and to conduct the interim analysis (see Section 6.9).  The iDMC will monitor 
accumulating patient safety data approximately every 4 months during the course of the 
study.  The iDMC will include qualified personnel, all independent of the Sponsor, who 
are committed to preservation of the trial integrity and reaching valid conclusions as 
described in the iDMC guidance.  The primary responsibilities of the iDMC will be to 
thoroughly review the available cumulative safety data and to make recommendations 
regarding modification of the conduct of study, enrollment hold, performance of 
additional interim safety analyses, changes to the inclusion/exclusion criteria or safety 
evaluation, or termination of the study if there is evidence of undue risk to the study 
participants. 
The analyses will be conducted by an independent Data Coordinating Center and 
reviewed by the iDMC.  Interactions between the iDMC and Sponsor will be carried out 
as specified in the iDMC Charter. 
3.1.3 
Blinded Independent Central Imaging Review 
To facilitate a blinded independent central review (BICR) for PFS, all radiological data 
(e.g., computed tomography [CT] scan, magnetic resonance imaging [MRI], bone scan) 
and photographs for skin lesions obtained at baseline, during the treatment period, at the 
time of disease progression, and at the time of study treatment discontinuation (if not the 
same as disease progression) should be sent to a central imaging vendor (contracted by 
the Sponsor) within 2 weeks of imaging to enable retrospective BICR.  Additional details 
about tumor assessment collections and readings will be outlined in a separate charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.   
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Inavolisib, Palbociclib, and Fulvestrant Doses 
and Schedules 
This study will evaluate inavolisib (9-mg PO QD) or placebo equivalent in combination 
with palbociclib (125-mg capsule or tablet dose taken PO QD on Days 121 of each 
28-day cycle, beginning on Day 1 of Cycle 1) and fulvestrant (500-mg administered by 

 
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IM injection on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day 
cycle, or approximately every 4 weeks). 
The palbociclib dose of 125-mg PO QD on Days 121 of each 28-day cycle and the 
fulvestrant dose of 500-mg IM on Days 1 and 15 of Cycle 1, and then on Day 1 of each 
subsequent 28-day cycle, or approximately every 4 weeks, represent the dosage 
approved for the treatment of adult patients with HR-positive, HER2-negative locally 
advanced or metastatic breast cancer with disease progression following endocrine 
therapy. 
In the Phase I study GO39374, median dose intensity for GDC-0077 (inavolisib) was 
similar as a single agent and in combination with letrozole, with fulvestrant, or with 
palbociclib and letrozole (range:  97%99%).  No DLTs were observed at the 6-mg or 
9-mg dose levels with GDC-0077 as single agent or in combination with letrozole, or with 
palbociclib and letrozole.  Based on the available data from Study GO39374, the 9-mg 
PO QD GDC-0077 (inavolisib) dose, in combination with the full-approved doses of 
palbociclib and fulvestrant, was selected as the recommended Phase II/III dose and 
schedule to maximize efficacy while ensuring tolerability.  Please refer to the Inavolisib 
Investigator’s Brochure for additional information. 
3.3.2 
Rationale for Patient Population 
The population described by the eligibility criteria reflects patients for whom the 
combination of palbociclib and fulvestrant represents an appropriate standard-of-care 
therapy.  The requirement for disease progression during or within 12 months of 
completion of adjuvant endocrine therapy identifies patients who have become resistant 
to endocrine therapy and would be an appropriate population for treatment with the 
combination of palbociclib and fulvestrant.  Patients with PIK3CA-mutant, HR-positive, 
HER2-negative locally advanced or metastatic breast cancer who have shown evidence 
of endocrine resistance are expected to have clinical benefit from the addition of a 
PI3K inhibitor.  The requirement for patients to have tumors with confirmed mutations in 
PIK3CA is based on the mechanism of action for inavolisib as a selective p110 inhibitor 
and mutant p110 degrader, and that inhibition of PI3K has been clinically validated in 
PIK3CA-mutant, HR-positive, HER2-negative metastatic breast cancer 
(André et al. 2019).  The inclusion criterion of Eastern Cooperative Oncology 
Group (ECOG) Performance Status of 01 (Appendix 9) has been selected to test a 
more homogeneous patient population and to mitigate potential additional toxicities 
incurred by the addition of inavolisib to palbociclib and fulvestrant treatment. 
3.3.3 
Rationale for Exclusion of Diabetic Patients 
Patients with Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring systemic 
treatment are excluded from this study, and enrollment is further restricted for patients at 
risk for diabetes based on fasting glucose levels (  126 mg/dL [  7.0 mmol/L]) and 
glycosylated hemoglobin (HbA1c) (  6.0% [  42 mmol/mol]). 

 
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As inhibition of the PI3K/AKT/mTOR pathway disrupts the insulin-signaling pathway, 
glucose uptake and glycogen synthesis are frequently disrupted with treatments that 
suppress key pathway nodes, including PI3K (Saltiel and Kahm 2001).  Additionally, 
PI3K has a major role in maintaining glucose homeostasis (Engelman et al. 2006; 
Foukas et al. 2006; Luo et al. 2006).  As a result, inhibition of the PI3K/AKT/mTOR 
pathway can lead to the loss of glucose regulation, manifested in patients as 
hyperglycemia.  A meta-analysis of the incidence and severity of hyperglycemia in 
clinical trials targeting the PI3K/AKT/mTOR pathway (Geuna et al. 2015) illustrated the 
prevalence of severe (Grade  3) hyperglycemia with inhibitors targeting mTOR, AKT, or 
PI3K.  Clinical experience with PI3K-inhibition has shown that hyperglycemia is 
generally early onset (within the first 12 weeks of PI3K-inhibitor treatment) and is 
manageable with oral anti-hyperglycemic medications (e.g., metformin), sometimes 
accompanied with brief treatment interruption.  What is not well understood is the 
benefitrisk for patients predisposed to hyperglycemia prior to initiation of PI3K-inhibitor 
therapy, including patients with Type 1 or 2 diabetes.  To date, the Sponsor has 
collected limited clinical data on the treatment of patients with diabetes with inavolisib, 
and thus such patients will be excluded from the Phase III study until more clinical 
information has been collected and analyzed in contemporaneous studies. 
3.3.4 
Rationale for Control Group 
Treatment for HR-positive, HER2-negative, locally advanced or metastatic breast cancer 
usually consists of multiple rounds of endocrine therapy alone or in combination with 
CDK4/6 or mTOR inhibitionif these agents have not been utilized beforefollowed by 
cytotoxic chemotherapy when all endocrine therapy options have been exhausted or 
when symptomatic or rapid disease progression warrants use of cytotoxic 
chemotherapy.  Fulvestrant has been approved in the United States and European 
Union for the treatment of HR-positive advanced or metastatic breast cancer in 
postmenopausal women with disease progression following prior anti-estrogen therapy 
(Howell et al. 2002; Osborne et al. 2002; Di Leo et al. 2010).  Fulvestrant is an 
ER antagonist and an effective treatment for postmenopausal patients with HR-positive 
breast cancer that is relatively well tolerated.  The combination of an ER antagonist such 
as fulvestrant and a CDK4/6 inhibitor such as palbociclib has become standard-of-care 
in this target patient population, and thus is appropriate for the placebo-controlled arm of 
this study. 
The anti-tumor activity of combined inhibition of cell-cycle checkpoint inhibition 
(palbociclib) and ER signaling (fulvestrant) may be further synergized by the addition of 
a PI3K/AKT/mTOR pathway inhibitor in patients whose tumors exhibit dysregulation of 
this pathway.  Nonclinical data supported by Phase I/Ib (Study GO39374) clinical data 
indicate that the anti-PI3K activity of inavolisib in combination with palbociclib and 
fulvestrant confers additional tumor growth inhibition and efficacy beyond the 
combination of palbociclib and fulvestrant.  Therefore, it is expected that the triplet 

 
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combination of inavolisib plus palbociclib and fulvestrant is likely to confer improved 
efficacy in the proposed patient population. 
3.3.5 
Rationale for Double-Blind Design 
A double-blind, placebo-controlled design was chosen for this study to reduce the 
potential for bias by patients and investigators that would be related to knowledge of the 
treatment assignment.  For patients, the design is anticipated to minimize dropout and 
increase compliance; for investigators, the design facilitates objectivity in outcome 
assessments.  This design is especially important when investigator-assessed PFS is 
the primary endpoint. 
3.3.6 
Rationale for Biomarker Assessments 
HR-positive, HER2-negative breast cancer is a heterogeneous disease, and PIK3CA 
mutation status has been shown to vary among patients (Cancer Genome Atlas, 2012; 
Curtis et al. 2012).  In addition to PIK3CA mutation status, samples will be assessed for 
additional biomarkers in an effort to identify factors that may correlate with the safety and 
efficacy of treatment with inavolisib and/or palbociclib and fulvestrant. 
3.3.6.1 
Rationale for Using Circulating Tumor DNA for Examining 
PIK3CA Mutation Status  
Mutations in PIK3CA occur at a frequency of approximately 40% in HR-positive, 
HER2-negative breast cancer and have been shown to be associated with response to 
PI3K inhibitors (O’Brien et al. 2010; Schleifman et al. 2014; André et al. 2019).  There is 
increasing evidence that ctDNA obtained from blood specimens of patients with cancer 
is representative of the DNA and mutational status of tumor cells (Diehl et al. 2008; 
Maheswaran et al. 2008).  Currently available assays (e.g., droplet-digital PCR, NGS) 
can detect the major PIK3CA mutations (and other cancer-related gene alterations) in 
plasma, and results from this analysis correlate with mutation results from tumor tissue 
specimens (Clark et al., 2018).  Previous studies suggest that the acquisition of PIK3CA 
mutations is an early event in breast cancer (Miron et al. 2010) and that detection of 
PIK3CA mutations between plasma-derived ctDNA and tumor tissue specimens is 
largely concordant (Kodahl et al. 2018).  For these reasons, the use of ctDNA to identify 
patients with PIK3CA-mutant tumors through NGS is an appropriate minimally invasive 
method for determining patients’ biomarker eligibility for this study.  NGS may also be 
performed on blood and/or plasma samples collected at various times during study 
treatment and at the time of disease progression to understand potential changes in 
PIK3CA mutation frequency and investigate potential mechanisms of response and 
resistance to the study treatment. 
3.3.6.2 
Rationale for the Collection of Tissue Samples 
To better understand the role of alterations detected in tumor tissue and to support 
future diagnostic development, a fresh or archival tumor tissue sample from metastatic 
disease or from a primary breast tumor collected prior to the start of study treatment will 

 
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be profiled for mutations in hundreds of cancer-related genes, including PIK3CA, using 
NGS. 
This approach offers the opportunity to perform molecular subtyping that may inform 
breast cancer biology and response to inavolisib or other PI3K/AKT/mTOR pathway 
inhibitors, to endocrine therapy, or to CDK4/6 inhibition.  Furthermore, sequencing of 
cancer-related genes may identify de novo mechanisms of resistance to the study 
treatment. 
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
Next-generation sequencing analysis may also be performed on tumor tissue samples 
collected during study treatment or at the time of disease progression from patients who 
provide optional consent. 
3.3.7 
Rationale for Primary Endpoint of Investigator-Assessed 
Progression-Free Survival 
Investigator-assessed PFS is regarded as a clinically relevant measure of treatment 
benefit and an approvable endpoint in the setting of HR-positive, HER2-negative locally 
advanced or metastatic breast cancer.  For example, in the PALOMA-3 study, 
investigator-assessed median PFS for palbociclib plus fulvestrant and placebo plus 
fulvestrant arms were 9.5 months (95% CI: 9.2 to 11.0 months) and 4.6 months 
(95% CI: 3.5 to 5.6 months), respectively.  The associated PFS hazard ratio was 
0.46 (95% CI: 0.36 to 0.59) (Cristofanilli et al. 2016).  These results led to the approval of 
the combination of palbociclib and fulvestrant. 
The randomized, double-blind, placebo-controlled study design is intended to limit the 
risk of investigator bias in the assessment of treatment impact.  In addition, a BICR of 
tumor assessment data will be performed to support the primary endpoint of 
investigator‑assessed PFS. 
3.3.8 
Rationale for Clinical Outcome Assessments 
As metastatic breast cancer is not curable with currently approved and available 
therapies, the primary focus for patients is on living as long as possible and delaying the 
progression of cancer while maintaining their quality of life and the ability to carry out 
daily activities (Cardoso et al. 2012).  Research indicates that a higher proportion of 
patients who are HR‑positive have bone metastases compared with other subtypes, 

 
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which is often associated with pain (Irvin et al. 2011; Wood et al. 2016); thus, 
disease-related pain may be an important variable to assess during treatment.  Limited 
data are available characterizing the clinical presentation of disease in this population; 
however, it is hypothesized that progression of disease would be associated with an 
increase in pain symptoms.  Examining and measuring patients’ disease-related pain 
and interference with functioning is important to capture.  Additionally, cancer 
treatments, particularly combination therapies, can produce significant symptomatic 
adverse events.  Recent research has shown that clinicians may underreport the 
incidence and severity of symptoms experienced by patients receiving treatment for 
cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; Basch 2010; 
Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014).  Collecting tolerability 
information directly from patients can provide a better understanding of treatment 
characteristics and their effects. 
These issues will be assessed using validated PRO assessments in patients enrolled in 
the study.  The EORTC QLQ-C30 will be administered to patients to assess disease and 
treatment-related symptoms, functioning, and GHS/HRQoL (see Section 4.5.9 and 
Appendix 4).  The EORTC QLQ-BR23 will provide an additional assessment of some 
treatment-related symptoms and symptoms that may occur with advanced disease 
(Section 4.5.9 and Appendix 5).  The “worst pain” item from the BPI-SF (Section 4.5.9 
and Appendix 6) will be used to gain further insight into increase in pain severity.  In 
order to evaluate the tolerability of inavolisib plus palbociclib and fulvestrant, patients will 
be asked to report on their experience related to diarrhea, nausea, vomiting, decreased 
appetite, fatigue, mouth sores, and rash selected from the validated PRO-CTCAE item 
bank, as well as an additional item regarding bother due to side effects of treatment (see 
Section 4.5.9 and Appendix 7).  These symptoms were identified as being salient to 
patients' experience with inavolisib, palbociclib, and fulvestrant on the basis of 
preliminary safety data for inavolisib and published safety data for palbociclib and 
fulvestrant (see Section 1.4 and 1.5).  The EQ-5D-5L (see Section 4.5.9 and 
Appendix 8) will also be collected and utilized to derive health states for use in economic 
models and thus the results will not be reported in the Clinical Study Report. 
3.3.9 
Rationale for Pharmacokinetic Sample Collection 
A sparse sampling strategy will be applied in this study.  Samples for PK 
characterization of inavolisib, palbociclib, and fulvestrant will be collected as outlined in 
Appendix 2.  Samples will be collected on Day 8 of Cycle 1 and Day 15 of both Cycle 1 
and Cycle 2 to determine steady-state pharmacokinetics for inavolisib and palbociclib.  
The sampling schedule is designed to enable estimation of inavolisib key PK parameters 
using population PK methodology in individual patients.  In addition, the PK of inavolisib, 
palbociclib, and fulvestrant from this study will be compared with PK data from previous 
studies for each agent when administered alone to evaluate whether exposures are 
altered when administered in combination or in this patient population. 

 
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3.3.9.1 
Rationale for Intense Pharmacokinetic Sample Collection in 
Chinese Patients 
Intensive PK samples will be collected from approximately 30-40 patients enrolled in 
China in this study to characterize inavolisib PK in Chinese patients.  The 
PK parameters of inavolisib in these patients will be compared with those in 
non-Chinese patients from Arm E of the Phase I study (GO39374). The schedule of 
intense PK sampling in Chinese patients is provided in Appendix 3. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 320 patients with PIK3CA-mutant, HR-positive, HER2-negative locally 
advanced or metastatic breast cancer will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Women or men  18 years of age at time of signing Informed Consent Form 
 
If female, patients must meet at least one of the following definitions: 
Postmenopausal, as defined by at least one of the following criteria: 
– 
Age  60 years 
– 
Age  60 years and 12 months of amenorrhea plus follicle-stimulating 
hormone and plasma or serum estradiol levels within postmenopausal 
range by local laboratory assessment in the absence of oral contraceptive 
pills, hormone replacement therapy, or gonadotropin-releasing hormone 
agonist or antagonist 
– 
Documented bilateral oophorectomy ( 14 days prior to first treatment on 
Day 1 of Cycle 1 and recovery to baseline) 
Premenopausal or perimenopausal (i.e., not meeting the criteria for 
postmenopausal) and meeting the following criterion: 
– 
Treatment with luteinizing hormonereleasing hormone (LHRH) agonist 
therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to 
Day 1 of Cycle 1 and continuing for the duration of study treatment  
If male, recommendation of treatment with LHRH agonist therapy (e.g., goserelin or 
leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for 
the duration of study treatment 
 
Histologically or cytologically confirmed adenocarcinoma of the breast that is locally 
advanced or metastatic and is not amenable to surgical or radiation therapy with 
curative intent 
 
Documented ER–positive and/or progesterone receptorpositive tumor according to 
American Society of Clinical Oncology/College of American Pathologists 

 
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(ASCO/CAP) guidelines, defined as   1% of tumor cells stained positive based on 
the most recent tumor biopsy and assessed locally 
 
Documented HER2-negative tumor according to ASCO/CAP guidelines, defined as 
a HER2 immunohistochemistry (IHC) score of 0 or 1  , or an IHC score of 
2   accompanied by a negative fluorescence, chromogenic, or silver in situ 
hybridization test indicating the absence of HER2 gene amplification, or a 
HER2/CEP17 ratio of  2.0 based on the most recent tumor biopsy and assessed 
locally 
 
Confirmation of biomarker eligibility:  valid results from either central testing of blood 
or local testing of blood or tumor tissue documenting PIK3CA-mutant tumor status 
Eligible PIK3CA mutations are defined as follows: 
H1047D/I/L/N/P/Q/R/T/Y 
G1049A/C/D/R/S 
E545A/D/G/K/L/Q/R/V 
E453A/D/G/K/Q/V 
E542A/D/G/K/Q/R/V 
K111N/R/E 
Q546E/H/K/L/P/R 
G106A/D/R/S/V 
N345D/H/I/K/S/T/Y 
G118D 
C420R 
R88Q 
M1043I/T/V 
 
 
The central test for identification of eligible PIK3CA mutations is the 
F1LCDx assay performed at Foundation Medicine, Inc. (FMI).  In localities 
where this is not available, samples will be submitted to an alternative, 
Sponsor-designated central testing laboratory. 
All patients are required to submit a freshly collected pre-treatment blood 
sample, whether patients are enrolled by local or central test results. 
Local tests of blood or tumor tissue may only be performed using a Sponsor 
pre-approved PCR- or NGSbased assay at a CLIAcertified or equivalent 
laboratory.  The full laboratory report of the PIK3CA mutation result must be 
available and submitted for confirmation. 
Local test results reported from blood should be from a blood specimen 
representative of patient’s metastatic disease state, collected after 
conclusion of patient’s most recent anti-cancer therapy. 
Local test results reported from tumor tissue should be from the patient’s 
metastatic disease state whenever possible. 
 
Consent to provide fresh (preferred) or archival tumor tissue specimen.  It is 
preferred that the specimen be from the most recently collected and available tumor 
tissue, and whenever possible, from a metastatic site of disease.  See the laboratory 
manual for specimen requirements. 
 
Patients must have progressed during adjuvant endocrine treatment or within 
12 months of completing adjuvant endocrine therapy with an aromatase inhibitor or 
tamoxifen.  

 
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If a CDK4/6 inhibitor was included as part of neoadjuvant or adjuvant therapy, 
progression event must be  12 months since completion of CDK4/6 inhibitor 
portion of neoadjuvant or adjuvant therapy. 
 
Measurable disease per RECIST v1.1 
Patients with evaluable bone-only disease are not eligible; disease that is 
limited to bone but has lytic or mixed lytic/blastic lesions and at least one 
measurable soft-tissue component per RECIST v1.1 may be eligible. 
 
Treatment with endocrine-based therapy (e.g., palbociclib and fulvestrant) is 
recommended at time of entry into the study, as per national or local treatment 
guidelines 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from 
donating eggs, as defined below: 
Women must remain abstinent or use non-hormonal contraceptive methods with a 
failure rate of   1% per year during the treatment period and for at least 60 days 
after the final dose of study treatment.  Based on local prescribing information for 
fulvestrant, patients may be advised to use an effective means of contraception for 
up to 2 years after the final dose of fulvestrant.  Women must refrain from donating 
eggs during this same period. 
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 is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of non-hormonal contraceptive methods with a failure rate 
of   1% per year include bilateral tubal ligation, male sterilization, 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.  If 
required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for at 
least 98 days after the final dose of study treatment to avoid exposing the 
embryo.  Based on local prescribing information for fulvestrant, patients may be 
advised to use an effective means of contraception for up to 2 years after the 

 
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final dose of fulvestrant.  Men must refrain from donating sperm during this 
same period. 
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.  
If required per local guidelines or regulations, information about the reliability of 
abstinence will be described in the local Informed Consent Form. 
 
ECOG Performance Status of 0 or 1 
 
Life expectancy of  6 months 
 
Adequate hematologic and organ function within 14 days prior to initiation of study 
treatment, defined by the following: 
– 
Absolute neutrophil count  1500/L 
– 
Hemoglobin  9 g/dL 
– 
Platelet count  100,000/L 
– 
Fasting glucose  126 mg/dL ( 7.0 mmol/L) and HbA1c  6.0% ( 42 mmol/mol) 
For patients with fasting glucose   100 mg/dL ( 5.5 mmol/L) (i.e., threshold 
for pre-diabetes) at baseline, recommend lifestyle changes according to 
American Diabetes Association guidelines; that is, dietary advice 
(e.g., small frequent meals, low carbohydrate content, high fiber, balanced 
carbohydrate intake over the course of the day, three small meals and two 
small snacks rather than one large meal) and exercise.  Consultation with 
an endocrinologist or diabetologist is highly recommended. 
– 
Total bilirubin  1.5  upper limit of normal (ULN) ( 3  ULN if Gilbert’s disease)  
– 
Serum albumin  2.5 g/dL (25 g/L) 
– 
AST and ALT  2.5  ULN with the following exception: 
Patients with documented liver metastases:  AST and ALT  5.0  ULN 
– 
ALP  2.5  ULN with the following exception: 
Patients with documented liver or bone metastases:  ALP  5.0  ULN 
– 
Creatinine clearance  50 mL/min on the basis of the CockcroftGault 
glomerular filtration rate estimation  
 
– 
INR  1.5  ULN and aPTT  1.5  ULN 
For patients requiring anticoagulation therapy with warfarin or similar 
agents (such as Vitamin K antagonists), a stable INR between 2 and 3 
is required.  If anticoagulation is required for a prosthetic heart valve, 
then stable INR between 2.5 and 3.5 is permitted.  Consult the local 
prescribing information for fulvestrant.  

 
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 
Ability, in the investigator’s judgment, and willingness to comply with all 
study-related procedures, including completion of patient-reported endpoints 
 
For patients enrolled in China:  current resident of mainland China and must be of 
Chinese ancestry. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Metaplastic breast cancer  
 
Any history of leptomeningeal disease or carcinomatous meningitis 
 
Any prior systemic therapy for metastatic breast cancer 
 
Prior treatment with fulvestrant or any selective estrogen-receptor degrader, with the 
exception of patients that have received fulvestrant or any selective 
estrogen-receptor degrader as part of neoadjuvant therapy only and with treatment 
duration of no longer than 6 months 
 
Prior treatment with any PI3K, AKT, or mTOR inhibitor, or any agent whose 
mechanism of action is to inhibit the PI3K-AKT-mTOR pathway 
 
Appropriate for treatment with cytotoxic chemotherapy at time of entry into the 
study, as per national or local treatment guidelines (e.g., patients with visceral crisis) 
 
Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or 
any history of Type 1 diabetes 
 
Inability or unwillingness to swallow pills or receive IM injections 
 
Malabsorption syndrome or other condition that would interfere with 
enteral absorption 
 
Known and untreated, or active CNS metastases (progressing or requiring 
anticonvulsants or corticosteroids for symptomatic control).  Patients with a history 
of treated CNS metastases are eligible, provided they meet all of the following 
criteria: 
– 
Measurable disease outside the CNS 
– 
No ongoing requirement for corticosteroids as therapy for CNS metastases, 
with corticosteroids discontinued for  2 weeks prior to enrollment and no 
ongoing symptoms attributed to CNS metastases 
– 
Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic 
assessments 
– 
Screening CNS radiographic assessments  4 weeks since completion of 
radiotherapy 
– 
No history of intracranial hemorrhage or spinal cord hemorrhage 

 
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 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures biweekly or more frequently 
Indwelling pleural or abdominal catheters may be allowed, provided the patient 
has adequately recovered from the procedure, is hemodynamically stable and 
symptomatically improved. 
 
Serious infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1 
 
Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) 
that, in the opinion of the investigator, would require medical or surgical intervention 
during the study period to prevent or treat vision loss that might result from that 
condition 
 
Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, 
scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or 
autoimmune-associated uveitis in either eye 
 
Requirement for daily supplemental oxygen 
 
Symptomatic active lung disease, including pneumonitis 
 
History of or active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative 
colitis) 
Patients currently receiving immunosuppressants for inflammatory bowel 
disease (e.g., sulfasalazines) are considered to have active disease and are 
thus ineligible. 
 
Any active bowel inflammation (including diverticulitis) 
 
Symptomatic hypercalcemia requiring continued use of bisphosphonate or 
denosumab therapy 
Bisphosphonate and denosumab therapy for bone metastases or 
osteopenia/osteoporosis is allowed. 
 
Clinically significant and active liver disease, including severe liver impairment 
(Child-Pugh Class B/C), viral or other hepatitis, current alcohol abuse, or cirrhosis  
 
Known HIV infection 
Sites should include an HIV test during screening, as allowed per local 
regulations.  
 
Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, metabolic, or infectious disease) or any other diseases, 
active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, that may 
affect the interpretation of the results, or that renders the patient at high risk from 
treatment complications 
 
Chemotherapy, radiotherapy, or any other anti-cancer therapy within 2 weeks before 
randomization 

 
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 
Investigational drug(s) within 4 weeks before randomization 
 
Prior radiotherapy to  25% of bone marrow, or hematopoietic stem cell or bone 
marrow transplantation 
 
Unresolved toxicity from prior therapy, except for hot flashes, alopecia, and 
Grade  2 peripheral neuropathy 
 
History of other malignancy within 5 years prior to screening, except for cancers with 
very low risk of recurrence including, but not limited to, appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine 
cancer.  The Medical Monitor is available for consultation. 
 
History of or active clinically significant cardiovascular dysfunction, including the 
following: 
– 
History of stroke or transient ischemic attack within 6 months prior to first dose 
of study treatment 
– 
History of myocardial infarction within 6 months prior to first dose of study 
treatment 
– 
New York Heart Association Class III or IV cardiac disease or congestive heart 
failure requiring medication 
– 
Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring 
medication 
– 
Coronary heart disease that is symptomatic or unstable angina 
– 
Congenital long QT syndrome or QT interval corrected through use of 
Fridericia’s formula  470 ms demonstrated by at least two ECGs  30 minutes 
apart, or family history of sudden unexplained death or long QT syndrome 
 
Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, 
hypocalcemia) 
 
Chronic corticosteroid therapy of  10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease 
 
Allergy or hypersensitivity to components of the inavolisib/placebo, palbociclib, or 
fulvestrant formulations 
 
Treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors within 1 week 
or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study 
treatment (see Section 4.4.3 for examples) 
 
Pregnant, lactating, or breastfeeding, or intending to become pregnant during the 
study or within 60 days after the final dose of study treatment (based on local 
prescribing information for fulvestrant, patients may be advised to use an effective 
means of contraception for up to 2 years after the last dose of fulvestrant) 
Women of childbearing potential (including those who have had a tubal ligation) 
must have a negative serum pregnancy test result within 14 days prior to 
initiation of study treatment. 

 
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 
Major surgical procedure, or significant traumatic injury, within 28 days prior to 
Day 1 of Cycle 1 or anticipation of the need for major surgery during the course of 
study treatment 
 
Minor surgical procedures  7 days prior to first dose of study treatment 
Patients must have sufficiently recovered from surgery, including adequate 
wound healing. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1 
Treatment Assignment 
This is a randomized, double-blind study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS). 
Patients will be randomly assigned to one of two treatment arms:  inavolisib plus 
palbociclib and fulvestrant or placebo plus palbociclib and fulvestrant.  Randomization 
will occur in a 1:1 ratio using a permuted-block randomization method to ensure a 
balanced assignment to each treatment arm 
Randomization will be stratified according to the following factors: 
 
Visceral disease (yes or no) 
 
Endocrine resistance (primary or secondary according to European Society for 
Medical Oncology Advanced Breast Cancer 4 (ESMO ABC4) guidelines 
[Cardoso et al. 2018]) 
 
Geographic region (North America/Western Europe, Asia, other) 
 
4.2.2 
Blinding 
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial.  These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and iDMC members. 
While inavolisib PK samples must be collected from patients assigned to the comparator 
arm to maintain the blinding of treatment assignment, inavolisib PK assay results for 
these patients are generally not needed for the safe conduct or proper interpretation of 
the study data since those patients are expected to receive placebo and not inavolisib.  
Laboratories responsible for performing study drug PK assays will be unblinded to 
patient treatment assignments to identify appropriate samples for analysis.  PK samples 
from patients assigned to the comparator arm will not be analyzed for inavolisib PK 
concentration except by request (e.g., to evaluate a possible error in dosing). 

 
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To optimize timelines for delivery of PK-related analyses, unblinded PK data may be 
released to selected clinical pharmacology personnel at the clinical cutoff date, prior to 
study unblinding. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are inavolisib or its placebo, 
palbociclib, and fulvestrant.  LHRH agonists, dexamethasone mouth rinse, and 
metformin are considered non-investigational medicinal products (NIMPs). 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Inavolisib and Placebo 
Inavolisib and its matched placebo will be supplied by the Sponsor as an 
immediate-release tablet formulation (3-mg and 9-mg).  The 3-mg tablet is a greyish 
orange to brownish orange, round film-coated tablet and the 9-mg tablet is a greyish 
orange to brownish orange, oval film-coated tablet.  The 3-mg and 9-mg tablets should 
be stored at or below 86°F (30°C) and protected from light.  For information on the 
formulation and handling of inavolisib/placebo, see the pharmacy manual and/or the 
Inavolisib Investigator's Brochure. 
4.3.1.2 
Palbociclib 
Palbociclib will be supplied by the Sponsor as hard gelatin capsules or immediate 
release, film-coated tablets containing 125 mg, 100 mg, and 75 mg palbociclib.  For 

 
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additional information on the formulation, packaging, and handling of palbociclib, refer to 
the palbociclib package insert or SmPC. 
4.3.1.3 
Fulvestrant 
Fulvestrant will be supplied by the Sponsor per country-specific requirements.  For 
countries in which the Sponsor is supplying fulvestrant, it will be supplied in sterile, 
single-patient, prefilled syringes containing 50 mg/mL fulvestrant, as a 5-mL injection.  
For details regarding storage of fulvestrant, refer to the fulvestrant package insert or 
SmPC. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1 and illustrated in Figure 3. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Mobile Nursing (MN) is only available at sites which have separately approved the use of 
the MN vendor; MN may not be conducted independently of the Sponsor‑selected MN 
vendor.  At applicable sites, study treatment may be administered by a trained mobile 
nurse at the patient's home, if the patient has provided written informed consent to 
participate in MN visits. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.3.5.11. 
Guidelines for study treatment interruption, dosage modification, or discontinuation for 
patients who experience adverse events are provided in Sections 5.1–5.3. 
It is recommended that patients keep a daily medication diary to assist them with 
compliance.  Inavolisib/placebo tablets are to be taken daily; palbociclib capsules or 
tablets are taken 21 days on, 7 days off.  Patients should return daily dosing diaries at 
each clinic visit as a conversation aid to inform site staff regarding dosing compliance.  
Note:  dosing eCRFs should be completed using the prioritization of:  i) site pharmacy 
drug accountability logs (IMP disbursed minus IMP returned), ii) clinic visit patient 
interview notes, and lastly iii) patient daily dosing diary. 

 
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Figure 3 Dosing Schedule for Inavolisib, Palbociclib, and Fulvestrant 
 
 
4.3.2.1 
Inavolisib and Placebo 
Inavolisib/placebo will be administered orally QD on Days 128 of each 28-day cycle at 
a starting dose of 9 mg.  Inavolisib/placebo will be administered in the clinic on Day 1 of 
Cycle 1, and on each subsequent cycle visit; it will be taken at home on all non-clinic 
visit days.  Inavolisib/placebo should be taken at approximately the same time each day 
without regard to the timing of administration of food.  If a dose is missed (not taken 
within 9 hours after the scheduled dosing time), the patient should resume dosing with 
the next scheduled dose.  Missed or vomited doses will not be made up.  For additional 
details, see Appendix 1. 
4.3.2.2 
Palbociclib 
Palbociclib will be administered orally QD on Days 121 of each 28-day cycle (21 days 
on; 7 days off) at a starting dose of 125 mg.  Palbociclib will be administered in the clinic 
on Day 1 of Cycle 1, and on each subsequent cycle visit; it will be taken at home on all 
non-clinic visit days.  Palbociclib should be taken at approximately the same time each 
day, and should be taken with food to reduce the inter-patient variability of palbociclib 
exposure.  If a dose is missed (not taken within 9 hours after the scheduled dosing time), 
the patient should resume dosing with the next scheduled dose.  Missed or vomited 
doses will not be made up.  Refer to the local prescribing information for more details 
(Ibrance USPI and SmPC). 
4.3.2.3 
Fulvestrant 
Fulvestrant 500 mg will be administered in the clinic as two IM injections of 250 mg each 
on Days 1 and 15 of Cycle 1.  For subsequent cycles, patients will receive fulvestrant 
500 mg (two IM injections of 250 mg each) in the clinic on Day 1 of each cycle, or 
approximately every 4 weeks.  Refer to the local prescribing information for more details.  
It is recommended that fulvestrant be administered prior to the oral medications, 
inavolisib/placebo and palbociclib, during all clinic visits. 

 
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The fulvestrant dose level cannot be modified.  In general, the investigator may consider 
continuing fulvestrant if the adverse event observed is thought to not be 
fulvestrant-related.  See Sections 5.1.2.9 and 5.1.2.10 for guidelines for treatment 
interruption or discontinuation of fulvestrant. 
4.3.2.4 
Extended Cycle in the Event of a Palbociclib Hold due to an 
Adverse Event 
In the event palbociclib administration is held due to an adverse event on Day 1 of a 
given cycle, the palbociclib dosing cycle should not begin until the patient is able to 
resume administration, which will correspond to a delayed Day 1 visit.  All subsequent 
visits in that cycle will be based on the delayed Day 1 visit.  As such, the cycle will be 
extended past 28 days.  If appropriate, inavolisib/placebo administration may be 
continued daily, and fulvestrant administration may be continued approximately every 
4 weeks, independently from the start of the palbociclib dosing cycle. 
4.3.3 
Non-Investigational Medicinal Products 
4.3.3.1 
LHRH Agonists 
LHRH agonists are required beginning at least 2 weeks prior to initiation of study 
treatment for pre-/peri-menopausal women.  For male patients, LHRH agonist therapy 
beginning at least 2 weeks prior to initiation of study is recommended.  Acceptable 
agents include goserelin or leuprolide; triptorelin is also acceptable.  Patients already on 
one of these three agents may remain on the same agent without switching.  Every effort 
should be made to administer goserelin (given every 28 days) or alternative 
LHRH agonist as applicable on site at the time of fulvestrant administration in order to 
minimize the number of clinic visits.  Where allowed per local standards, patients 
receiving LHRH agonists should be monitored (via follicle-stimulating hormone and/or 
estradiol level, as per local standards) approximately every 3 months for appropriate 
hormonal suppression; in cases of inadequate suppression, alternative hormonal 
suppression methods (e.g., ovarian ablation, as per local standards) must be 
considered. 
4.3.3.2 
Dexamethasone Mouth Rinse 
If locally available, a compounded alcohol-free mouthwash of dexamethasone (0.5 mg in 
5 mL) is recommended for prophylaxis or treatment of stomatitis/mucositis.  As per the 
SWISH study (Rugo et al. 2017), patients may use 4 times daily for 8 weeks (10 mL 
swished for 2 minutes and spat) started concurrently with study treatment and/or used 
reactively with the first appearance of symptoms.  No food or drink should be consumed 
for at least 1 hour after swishing and spitting the mouthwash.  Additional mouthwash 
formulations (e.g., combinations of local anesthetic, antihistamine, corticosteroid, 
antacid, antifungal, and/or antibiotics) or topical corticosteroids (e.g., triamcinolone 
acetonide 0.05%0.5%, fluocinolone acetonide 0.025%0.05%, clobetasol 
propionate 0.025%) may be implemented.  Diet should be modified (e.g., avoidance of 
spicy foods) and harsh mouthwashes (e.g., Listerine) should be avoided. 

 
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4.3.3.3 
Metformin 
Patients experiencing hyperglycemia may require anti-hyperglycemic medication.  The 
preferred first agent is metformin (see Section 5.1.2.2).  At the investigator’s discretion 
and where allowed by local regulations, prophylactic metformin may be initiated on 
Cycle 1, Day 1 for patients at high risk of hyperglycemia. 
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study will be provided by the Sponsor where 
required by local regulations; local procurement of palbociclib and fulvestrant will be 
reimbursed in all other countries.  The study site will acknowledge receipt of IMPs 
supplied by the Sponsor using the IxRS to confirm the shipment condition and content.  
Any damaged shipments will be replaced.  The investigator or designee must confirm 
that appropriate temperature conditions have been maintained during transit, either by 
time monitoring (shipment arrival date and time) or temperature monitoring, for all IMPs 
received and that any discrepancies have been reported and resolved before use of the 
IMPs.  All IMPs must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with 
access limited to the investigator and authorized staff. 
Sponsor-supplied IMPs will either be disposed of at the study site according to the study 
site's institutional standard operating procedure or be returned to the Sponsor with the 
appropriate documentation.  The site's method of destroying Sponsor-supplied IMPs 
must be agreed to by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log; this includes all IMPs 
allocated to MN for delivery to and/or administration to enrolled patients utilizing home 
visits. 
4.3.5 
Continued Access to Inavolisib 
The Sponsor will offer continued access to Roche IMP (inavolisib) 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 Roche IMP (inavolisib) after completing the study if all 
of the following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 

 
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A patient will not be eligible to receive Roche IMP (inavolisib) after completing the study 
if any of the following conditions are met: 
 
The Roche IMP 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 Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for HR  /HER2   breast cancer 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
HR/HER2– breast cancer 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study treatment through to the study treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience toxicities 
should be treated symptomatically as clinically indicated. 
Please also refer to the palbociclib local prescribing information regarding permitted 
therapies and recommended dose adjustments for concomitant medications. 
Patients treated with anti-seizure medications or Vitamin K antagonist anticoagulation 
therapy (e.g., warfarin or similar agents) should have levels monitored regularly. 
Anti-emetic and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study treatment.  At the discretion of the investigator, 
prophylactic anti-emetic and anti-diarrheal medication(s) may be used as per standard 
clinical practice before subsequent doses of study drug. 
To reduce the risk of stomatitis, dexamethasone 0.5 mg/5mL alcohol-free mouthwash 
(10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks), or alternative 

 
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mouthwash formulation (see Sections 5.1.1.2 and 5.1.2.3), may be started concurrently 
with study treatment.  No food or drink should be consumed for at least 1 hour after 
swishing and spitting the mouthwash (Rugo et al. 2017). 
Pain medications administered per standard clinical practice are acceptable while the 
patient is enrolled in the study and are to be recorded on the Analgesic Concomitant 
Medications eCRF. 
Bisphosphonate or denosumab therapy for bone metastases or osteopenia/osteoporosis 
is allowed. 
Multivitamins, calcium, and vitamins C, D, and E as supplements are allowed.  However, 
due to the potential for drug-supplement interactions, and variability among suppliers 
and batches, the use of other dietary supplements is cautioned.  The Sponsor’s clinical 
pharmacology experts are available for advice on any specific supplements.  
4.4.2 
Cautionary Therapy 
4.4.2.1 
Medications Given with Precaution due to Effects Related to 
CYP Enzymes 
Co-administration of midazolam (sensitive CYP3A4 substrate) with multiple doses of 
palbociclib increased the midazolam plasma exposure by 61% in healthy subjects 
compared with administration of midazolam alone.  Therefore, the dose of a sensitive 
CYP3A4 substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and 
tacrolimus) may need to be reduced, as palbociclib may increase its exposure 
(Ibrance USPI). 
The above list of CYP3A4 sensitive substrates with a narrow therapeutic index is not 
necessarily comprehensive.  Thus, the investigator should consult the prescribing 
information for any concomitant medication as well as the internet reference provided 
below when determining whether a certain medication is a sensitive CYP3A4 substrate 
with a narrow therapeutic index.  Palbociclib local prescribing information should also be 
checked for information on prohibited therapies and recommended dose adjustments for 
concomitant medications.  In addition, the investigator should contact the Medical 
Monitor if questions arise regarding medications not listed above.  
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is strongly discouraged because the 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown. 

 
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4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited during the study and for at least 
7 days prior to initiation of study treatment, unless otherwise specified below: 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment. 
 
Any concomitant therapy intended for the treatment of cancer (including, but not 
limited to, chemotherapy, hormonal therapy, immunotherapy, biologic therapy, 
radiotherapy, or herbal therapy) is prohibited for various time periods prior to starting 
study treatment, depending on the agent (see Section 4.1.2), and during study 
treatment, until disease progression is documented and the patient has discontinued 
study treatment. 
 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate, and selective ER modulators (e.g., raloxifene) are 
prohibited unless required to treat adverse events. 
 
Quinidine or other anti-arrhythmic agents 
 
Radiotherapy for unequivocal progressive disease is prohibited, with the exception 
of new brain metastases in the setting of systemic response as follows:  patients 
who have demonstrated control of their systemic disease (defined as having 
received clinical benefit [i.e., a PR, CR, or SD for  3 months]), but who have 
developed brain metastases that are treatable with radiation, will be allowed to 
continue to receive therapy with inavolisib/placebo, palbociclib, and fulvestrant in 
the study until they either experience systemic progression of their disease and/or 
further progression in the brain (based on investigator assessments).  Treatment 
with inavolisib and palbociclib should be held at least 24 hours in advance of 
palliative radiotherapy and until any effects or sequelae have resolved to Grade 1 or 
better.  Patients should not miss more than one cycle of study treatment due to 
radiation treatment and must meet eligibility requirements to continue in the study 
treatment (Section 4.1.1). 
Other local radiotherapy is not permitted with the following exception.  It is 
understood that there may be circumstances requiring local radiotherapy in which 
the investigator does not believe that the symptoms are a result of disease 
progression (e.g., impending fracture) and the radiation field does not encompass a 
target/non-target lesion.  In such cases, the patient should have a tumor 
assessment of the lesion(s) before they receive radiotherapy.  If a patient received 
radiation therapy and a target or non-target lesion was included in the field of 
radiation, the lesion(s) will become unevaluable for tumor response. 
Further reasons for avoiding local radiotherapy include the difficulty in distinguishing 
new symptomatic pain or worsening of lytic bone lesions from disease progression.  
Time-to-Deterioration in Pain is a secondary endpoint of this study and 
Time‑to‑First-Skeletal-related-Event is an exploratory endpoint; palliative 
radiotherapy may alter these results.  As such, palliative radiotherapy to bone in the 
absence of disease progression may be allowed after consultation with the Medical 
Monitor, however, such patients will be censored from the aforementioned 

 
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secondary and exploratory endpoints.  Few clinical data are available about 
potential toxicities of radiation and treatment with inavolisib.  Study treatment should 
be held ~24 hours prior to palliative radiotherapy and until any effects or sequelae 
have resolved to Grade  1.  Patients should not miss more than one cycle of study 
treatment due to radiation treatment and must meet eligibility requirements to 
continue in the study treatment (Section 4.1.1).  Previous clinical experience also 
suggests that new bone pain is frequently a symptom of disease progression.  Bone 
pain secondary to fulvestrant treatment may be treated with pain medications, 
nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids. 
 
Primary prophylactic use of hematopoietic growth factors (e.g., erythropoietins, 
granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage colony-
stimulating factor is not permitted, however, they may be used to treat treatment-
emergent neutropenia or anemia as indicated by the current ASCO guidelines or as 
secondary prophylaxis if dose reduction or delay is not considered a reasonable 
alternative. 
 
Strong CYP3A4 inhibitors, including, but not limited to, the following:  atazanavir, 
ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, troleandomycin, 
itraconazole, ketoconazole, voriconazole, posaconazole, conivaptan, diltiazem, 
nefazodone, mibefradil, and grapefruit juice or grapefruit supplements.  If 
co-administration of palbociclib with a strong CYP3A inhibitor cannot be avoided, 
reduce the dose of palbociclib as per palbociclib local prescribing information. 
 
Strong CYP3A4 inducers, including, but not limited to, the following:  rifampin, 
carbamazepine, phenytoin, oxcarbazepine, phenobarbital, nevirapine, hyperforin 
(St. John's Wort), and cyproterone 
 
The above lists of CYP3A4 concomitant medications are not necessarily comprehensive.  
Thus, the investigator should consult the prescribing information for any concomitant 
medication as well as the internet references provided below when determining whether 
a certain medication strongly inhibits or induces CYP3A4.  Palbociclib local prescribing 
information should also be referred to for information on prohibited therapies and 
recommended dose adjustments for concomitant medications.  In addition, the 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above. 
Drug Interactions Flockhart Table: 
https://drug-interactions.medicine.iu.edu/MainTable.aspx 
FDA Drug Interactions Table of Substrates, Inducers, and Inhibitors: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers  
 
Enrolled patients who subsequently require the use of any prohibited therapies must be 
discontinued from study treatment and followed for safety outcomes for 30 days after 

 
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their last dose of study treatment, or until they receive another anti-cancer therapy, 
whichever occurs first. 
4.4.4 
Prohibited Food 
Use of the following foods is prohibited as described below: 
Consumption of grapefruit, grapefruit juice, or Seville oranges (potent CYP3A4 enzyme 
inhibitors), is prohibited for at least 3 days prior to initiation of study treatment and during 
study treatment. 
4.4.5 
Additional Restrictions 
No food or fluids other than water will be allowed from 8 hours prior to each study visit 
until after study laboratory samples are obtained.  Once all scheduled study laboratory 
samples are collected, a snack or light meal is recommended as palbociclib capsules 
should be taken with food. 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient. 
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity at each clinic visit and prior to each in-clinic 
dose of study treatment; dosing will occur only if the clinical assessment and local 
laboratory test values are acceptable. 
At applicable sites, certain study activities/assessments may be performed by a mobile 
nurse at the patient's home in order to alleviate clinic site access restrictions during the 
COVID-19 pandemic, and to more generally improve access and convenience for 
patients participating in the study.  The Sponsor will select a healthcare company that 
will be responsible for providing MN services (MN vendor) for participating sites.  Mobile 
Nursing is only available at sites which have separately approved the use of the MN 
vendor; MN may not be conducted independently of the Sponsor-selected MN vendor.  
The MN vendor is responsible for ensuring that all mobile nurses are licensed, qualified, 
and in good standing, as per applicable regulations, and that appropriate background 
checks have been performed.  If the investigator at a participating site determines that 
MN services are appropriate for a patient and the patient provides signed informed 
consent to participate in MN visits, the MN network will initiate contact with the patient at 
the direction of the investigator’s site.  MN visits will be scheduled on specified visit days 
(Appendix 1), to allow relevant assessments to be performed by the mobile nurse.  The 
schedule of activities (see Appendix 1) specifies the assessments that may be 
performed by a mobile nurse; assessments that have not been indicated for MN in 
Appendix 1 must not be performed by the mobile nurse. 

 
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4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Prior to 
signing the main consent form for the study, patients may specifically allow for the 
collection and testing of blood to assess biomarker eligibility by signing the prescreening 
consent form.  The prescreening consent form also asks patients to submit available 
archival tumor tissue to enable diagnostic biomarker development.  Informed Consent 
Forms for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening and 
prescreening (if applicable) log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures; staging data should be as per AJCC 
TNM version 8, found in Appendix 12), reproductive status, and tobacco use will be 
recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity in accordance 
with the applicable laws (e.g., health authority requirements). 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
An assessment of the patient’s ECOG Performance Status (see Appendix 9) will be 
completed at screening and as specified in the schedule of activities (see Appendix 1). 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Particular attention should be given to symptoms 
related to adverse events of special interest (see Section 5.2.3).  Changes from baseline 
abnormalities should be recorded in patient notes.  As part of tumor assessment, 

 
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physical examinations should also include the evaluation of the presence and degree of 
enlarged lymph nodes, hepatomegaly, and splenomegaly.  New or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF. 
Limited, symptom-directed physical examinations and ECOG Performance Status 
assessment may be performed by a mobile nurse according to the schedule of activities 
(Appendix 1). 
4.5.4 
Vital Signs 
Vital signs will include measurements of height, weight, respiratory rate, pulse rate, 
blood oxygenation (pulse oximetry), systolic and diastolic blood pressure while the 
patient is in a seated position, and temperature.  Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent 
visits, record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF. 
Vital sign measurement may be performed by a mobile nurse according to the schedule 
of activities (Appendix 1). 
4.5.5 
Tumor and Response Evaluations 
Response will be assessed by the investigator on the basis of physical examinations, 
CT scans, and other imaging modalities as clinically indicated, which may include brain 
imaging (CT or MRI), MRI scans, and/or bone scan, using RECIST v1.1 criteria 
(Appendix 11).  The same radiographic procedure used to assess disease sites at 
screening should be used throughout the study (e.g., the same contrast protocol for 
CT scans).  Assessments should be performed by the same evaluator to ensure internal 
consistency across visits.  All known sites of disease must be documented at screening 
(within 28 days prior to Cycle 1, Day 1) and re-assessed at each subsequent tumor 
evaluation. 
At screening, diagnostic quality, contrast-enhanced CT scans of the chest, abdomen, 
and pelvis should be acquired.  If IV contrast is contra-indicated, MRI scans of the 
abdomen and pelvis should be acquired along with a non-contrast CT scan of the chest.  
For metformin-treated patients undergoing CT scans with contrast, metformin should be 
held as per institutional standard-of-care.  The same scan protocol should be followed at 
all subsequent tumor assessment timepoints, however, pelvic coverage may be 
considered optional if not clinically indicated and no pelvic disease is identified at 
baseline. 
At screening, CT scans of the neck or extremities should be acquired if clinically 
indicated.  At subsequent tumor assessment timepoints, scans should be acquired if 
disease was present at baseline or if clinically indicated. 

 
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At screening, bone scans or other institutional standard bone imaging should be 
acquired in all patients.  Bone scan, positron emission tomography (PET) scan, or plain 
films are not considered adequate imaging techniques to measure bone lesions; 
however, these techniques can be used to confirm the presence or disappearance of 
bone lesions.  The special considerations regarding the measurability of bone lesions 
are outlined in RECIST v1.1 (see Appendix 11).  At subsequent tumor assessment 
timepoints, bone scans should be acquired if bone disease cannot be assessed by 
another modality, e.g., CT, if complete response is identified in target disease in patients 
with known bone disease, or if clinically indicated.  If a bone scan cannot be performed 
during the course of the study due to, for example, a Technetium-99m shortage, 
alternative imaging options should be discussed with the Medical Monitor (e.g., sodium 
fluoride [NaF]). 
At screening, a CT or MRI scan of the brain is required to confirm no progression in 
patients with previously treated brain lesions; the scan must be within the screening 
window and 4 weeks after the completion of radiotherapy.  For all other patients, brain 
scans should be acquired if clinically indicated.  At subsequent tumor assessment 
timepoints, brain scans should be acquired if disease was present at baseline or if 
clinically indicated.  
A documented standard-of-care tumor assessment performed within 28 days prior to 
Cycle 1, Day 1 may be used for the screening assessment provided it meets the above 
requirements.  Tumor assessments should be performed on schedule (approximately 
every 8 weeks [ 7 days] for the first 2 years after randomization, and every 12 weeks 
[  7 days] thereafter) as described in Appendix 1, regardless of dose delay or early 
discontinuation, until disease progression.  Patients who discontinue study treatment for 
any reason other than disease progression or death will continue to undergo 
tumor-response evaluations until progressive disease or the initiation of another 
anti-cancer therapy, whichever occurs first.  At the investigator's discretion, scans may 
be repeated at any time if progressive disease is suspected. 
Patients who have demonstrated control of their systemic disease (defined as having 
received clinical benefit [i.e., a PR, CR, or SD for  3 months]), but who have developed 
brain metastases that are treatable with radiation, will be allowed to continue to receive 
study treatment until they either experience systemic progression of their disease and/or 
further progression in the brain (based on investigator assessments). 
To ensure a valid comparison of tumor data and uniformity in the assessment of tumor 
response during the study, the following procedures must be implemented at the study 
site: 
 
All lesions identified at baseline (target and non-target) are to be reassessed using 
the same method throughout the course of the study. 

 
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 
All radiologic data (CT scans, MRI scans, bone scans, etc.) obtained for all patients 
enrolled at the center should be reviewed by the local radiologist who, together with 
the investigator, will determine the local assessment of response and progression. 
 
All radiologic data and photographs for skin lesions obtained at baseline, during the 
treatment period, and the follow-up period must be sent to a central imaging vendor 
contracted by the Sponsor within 2 weeks of imaging for BICR.  Additional details 
regarding the BICR will be outlined in a separate charter. 
 
Tumor response and progression will be assessed and will be the basis for the 
efficacy analyses (along with survival information).  The main analysis of the trial will 
be based on the local radiology review results.  Objective responses will be 
confirmed by assessments performed  4 weeks after an initial documentation of 
response. 
 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis.  When noted, fasting samples should be collected after a minimum 8-hour 
fast. 
 
Hematology panel includes:  RBC count, hemoglobin, hematocrit, reticulocyte count, 
platelet count, WBC count with differential count (neutrophils, bands [optional], 
eosinophils, basophils, monocytes, lymphocytes, other cells; i.e., must be sufficient 
for the determination of ANCs, lymphocytes).  Reporting the differential as absolute 
counts is preferred, but percent is accepted. 
Fasting blood chemistry panel (serum or plasma) includes:  sodium, potassium, 
chloride, bicarbonate # (or total carbon dioxide if considered standard-of-care for the 
region), BUN or urea, creatinine, glucose *, total protein, albumin, phosphate, 
calcium, magnesium, AST/SGOT, ALT/SGPT, total and direct bilirubin, and ALP.  
Laboratory samples should be drawn within 24 hours (all Cycle 1 and Cycle 2 visits) 
or within 48 hours prior to study drug administration at the clinic; glucose * is 
strongly preferred on the day of each clinic visit.  Results for glucose, AST/SGOT, 
ALT/SGPT, bilirubin, and ALP should be reviewed prior to dosing. 
* Fasting glucose may also be obtained by glucometer (fingerstick); however, in 
the clinic these must also be confirmed with fasting blood glucose values. 
# For investigational sites in countries where bicarbonate (or carbon dioxide) is 
not collected as part of the standard blood chemistry panel, bicarbonate (or 
carbon dioxide) will not be measured. 
 
Fasting insulin 
 
Fasting lipid profile includes:  total cholesterol, high-density lipoprotein, low-density 
lipoprotein, and triglycerides 
 
Amylase and lipase 
 
HbA1c 
 
Serum fibrinogen and coagulation (INR, aPTT, and PT) 

 
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Patients requiring Vitamin K antagonist anticoagulation therapy with warfarin or 
similar agents should have INR and aPTT monitored as clinically necessary to 
ensure appropriate anticoagulation. 
 
Urinalysis (dipstick allowed) panel includes:  pH, specific gravity, glucose, protein, 
ketones, blood; and, if clinically indicated, microscopic examination including 
sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Serum or urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test (see Appendix 1). 
 
Samples for the following laboratory tests will be sent to a central laboratory or to the 
Sponsor for analysis: 
 
Plasma samples for PK analysis (see Section 6.6 and Appendix 2) 
Plasma samples collected during the study may be used for development of PK 
or biomarker assays, or endogenous substrate of drug metabolizing enzymes or 
drug transporters. 
 
Blood samples for biomarker NGS, except at sites in China 
 
Blood samples for whole genome sequencing (WGS) (unless prohibited by local 
regulatory authorities) (not applicable in China) 
Unless prohibited by the local regulatory authority, gene mutations will be 
assayed by WGS or other acceptable methodology such as multiplex PCR or 
allele-specific PCR.  Results may be correlated to study treatment or other 
clinical measures to better understand the impact of genetic variants on drug 
metabolism, exposure, adverse events, and/or response. 
 
Biomarker assays in blood/plasma 
Blood samples will be collected from all patients at screening to determine 
PIK3CA mutation status using the F1LCDx assay (see Appendix 10) or the 
alternative, Sponsor-designated central laboratory for that region. 
Plasma samples will be collected at pre-defined timepoints during study 
treatment (see Appendix 1) and at the time of disease progression for 
exploratory biomarker research. 
 
Pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue samples for 
central, retrospective PIK3CA mutation status determination as well as for other 
protocol-mandated exploratory biomarker assessments.  Testing may be performed 
on tumor tissue from all screened patients (both enrolled patients and those who 
screen-fail based on the central test).  Testing of patients’ pre-treatment tumor 
tissue samples for PIK3CA mutation status may be used to establish performance 
characteristics of assays for diagnostic development.  These additional data will 
have no impact in the study eligibility, and tumor tissue testing will be performed 
only after biomarker eligibility is established for each patient. 

 
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A representative FFPE block (preferred) or approximately 20 (25 preferred) 
slides containing unstained, freshly cut, serial tumor tissue sections will be 
required for enrollment eligibility purposes.  If fewer than 20 slides are available, 
the patient may still be eligible for the study following consultation with the 
Sponsor.   
Tumor tissue should be of good quality based on total and viable tumor content.  
The submitted specimen should preferably be from the same block used for any 
local PIK3CA mutation testing, if preexisting local test results will be reported to 
the Sponsor to determine eligible PIK3CA mutation status, and accompanied by 
the associated local pathology report.  Samples should contain a minimum of 
500 viable tumor cells that preserve cellular context and tissue architecture 
regardless of needle gauge or retrieval method.  Samples collected via 
resection, core-needle biopsy (three cores preferred, embedded in a single 
paraffin block), or excisional, incisional, punch or forceps biopsy types are 
acceptable.  Fine-needle aspiration (defined as samples that do not preserve 
tissue architecture and yield cell suspension and/or smears), brushing, cell 
pellets from pleural effusion, and lavage samples are not acceptable.  Tumor 
tissue from bone metastases is not acceptable.  A detailed description of tissue 
quality requirements and procedures for collection, handling, and shipping of 
the samples will be provided in a separate laboratory manual.  
 
Any patient, except those enrolled in China, may provide optional consent to submit 
tumor tissue collected during treatment and/or at the time of disease progression 
(see Appendix 1). 
Tissue submission guidelines for optional on-treatment and end-of-treatment 
biopsies should follow those for pre-treatment tumor biopsies, above.  Please 
also refer to the laboratory manual. 
Note:  It is preferred that a target lesion (TL) not be biopsied while in the study 
treatment; however, if there is no other viable lesion and a TL is biopsied, it 
must be treated in the same manner as a TL that has been included in a field of 
radiation (Section 4.4.3) and can no longer be eligible for tumor response.  
Such a TL must remain as a TL due to its inclusion at baseline and must 
subsequently be marked "Unable to Evaluate.”  As such, the Overall 
Assessments must also subsequently be "Unable to Evaluate" except in cases 
of PD or CR; PR and SD will no longer be possible for this patient. 
 
Exploratory biomarker research may include, but will not be limited to, analysis of:  gene 
and/or protein expression, soluble systemic chemokines and cytokines, the copy number 
and mutational landscape of cancer-related genes, gene expression signatures of 
mutations, etc. that are predictive of response to study treatment, are associated with 
disease progression, are associated with acquired resistance to study treatment, or that 
can increase the knowledge and understanding of breast disease biology and PI3K 
signaling.  These studies may involve extraction of DNA, cell-free DNA (a.k.a. ctDNA), or 
RNA.  Methodologies employed to complete these analyses may include, but will not be 
limited to, NGS, PCR, RNAseq, IHC, and proteomics-based approaches.  NGS methods 

 
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may include WGS or whole exome sequencing (WES) of blood samples, but only at 
participating sites (see Section 4.5.10). 
Next-generation sequencing may be performed by FMI or by the alternative, Sponsor-
designated central laboratory in localities where FMI is not available.  If performed by 
FMI, the investigator may obtain results through FMI’s web portal.  If allowed by local 
laws, the investigator may share and discuss the results with the patient, unless the 
patient chooses otherwise.  The FMI NGS report is generated for research purposes 
only and is not provided for the purpose of guiding future treatment decisions.  Results 
may not be available for samples that do not meet criteria for testing or for samples that 
fail the testing process. 
The investigator may obtain results through FMI’s web portal for the following: 
 
FMI testing performed on the blood sample submitted in screening for biomarker 
eligibility or for central confirmation of a local blood test result  
 
FMI testing performed on tissue submitted from patients at the time of disease 
progression 
 
For patients enrolling in localities without access to FMI, physicians may obtain a 
molecular testing result from the alternative, Sponsor-designated laboratory for the blood 
sample submitted in screening for biomarker eligibility or central confirmation. 
FoundationOne Liquid CDx is a qualitative, NGS-based in vitro diagnostic test that uses 
high throughput hybridization-based capture technology for the detection of base 
substitutions, insertion and deletion alterations (indels), copy number alterations (CNAs), 
and select gene rearrangements in more than 300 cancer-related genes, as well as 
genomic signatures including tumor mutational burden (TMB) using ctDNA isolated from 
blood plasma.  The assay has been launched in a CLIA- and CAP‑accredited laboratory. 
FoundationOne CDx is a qualitative, NGS-based in vitro diagnostic test that uses high 
throughput hybridization-based capture technology for the detection of base 
substitutions, insertion and deletion alterations (indels), CNAs, and select gene 
rearrangements in more than 300 cancer-related genes, as well as genomic signatures 
including microsatellite instability  and TMB using DNA isolated from FFPE tumor tissue 
specimens.  The assay has been launched in a CLIA- and CAP-accredited laboratory. 
Blood and urine sample collection may be performed by a mobile nurse in accordance 
with the schedule of activities (Appendix 1). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for leftover samples to be stored for optional 
exploratory research (see Section 4.5.12), biological samples will be destroyed no later 

 
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than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
Plasma samples collected for PK analysis will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed. 
 
Blood, plasma, and tissue samples collected for biomarker assessments and 
research will be destroyed no later than 15 years after the final Clinical Study Report 
has been completed.  Samples collected for biomarker assessments in China will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.  
 
Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
Institutional Review Board/Ethics Committee (IRB/EC)-approved Informed Consent 
Form and applicable laws (e.g., health authority requirements). 
 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled (e.g., screen failure), 
remaining archival tissue blocks will be returned to the site no later than 612 weeks 
after eligibility determination. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 7.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law, with the exception of the report from FMI, in the specific 
cases outlined above.  The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy in the study data publication. 
4.5.7 
Ophthalmologic Examinations 
Patients will undergo ophthalmic examinations at baseline during the screening period, 
at Cycle 6 ( 2 weeks) during the study treatment period, at study treatment 
discontinuation, and based on any ocular disturbances.  The ophthalmic examination 
should consist of a full ophthalmic exam with dilation and refraction with specific 
attention paid to lens examination and detailed documentation.  In addition, patients will 
be asked if they have experienced any significant visual changes, pain, or sensitivity to 
light at each clinic visit.  Any new eye-related symptoms including significant change in 

 
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vision, eye pain, or photophobia will be evaluated by an ophthalmologist.  All clinically 
significant findings should be reported as Adverse Events. 
4.5.8 
Electrocardiograms 
Triplicate 12-lead ECG recordings will be obtained at baseline to determine eligibility; 
otherwise, single 12-lead ECG recordings will be obtained at specified timepoints during 
study treatment, as outlined in the schedule of activities (see Appendix 1), and may be 
obtained at unscheduled timepoints as clinically indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at the site.  The following should be 
recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and QT interval corrected through use of Fridericia’s formula 
based on the machine readings of the individual ECG tracings.  Any morphologic 
waveform changes or other ECG abnormalities must be documented on the eCRF.   
Clinically significant abnormalities observed during screening will be recorded on the 
General Medical History and Baseline Conditions eCRF.  New or worsened clinically 
significant abnormalities observed during the Study Treatment period will be recorded on 
the Adverse Event eCRF. 
4.5.9 
Clinical Outcome Assessments  
Patient-reported outcome data will be collected to more fully characterize the clinical 
profile of inavolisib in combination with palbociclib and fulvestrant compared with 
placebo plus palbociclib and fulvestrant in patients enrolled in the study.  PRO data will 
be collected via electronic questionnaires at the clinic sites or patients’ home using the 
following instruments:  EORTC QLQ-C30, BR23, “worst pain” item from the BPI-SF, 
select items of the PRO-CTCAE, and the EQ-5D-5L.  The questionnaires, translated into 
the local language as appropriate, will be distributed by the site staff or via secure web 
portal and completed in their entirety by the patient at baseline (Cycle 1, Day 1) and as 
noted in the schedule of activities (see Appendix 1). 

 
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In the event that after completion of the PROs at the start of a treatment cycle it is 
determined that the dose of palbociclib should be delayed, the Day 1 PROs will not be 
re-administered when the patient returns to the clinic following the delay.  Additionally, 
the timing of subsequent PRO assessments (e.g., Day 15 during Cycles 2 and 3, and 
Day 1 of subsequent cycles after a delay) will be based on the actual Day 1 of the given 
cycle, when palbociclib was administered.  For example, PROs will be completed at the 
planned Cycle 2, Day 1 visit prior to the actual office visit.  In the event that the review of 
clinical laboratory results and adverse events (AEs) demonstrates that palbociclib should 
not be resumed at this visit (e.g., neutropenia), the actual Cycle 2, Day 1 visit will not 
occur until the patient is fit to resume palbociclib dosing.  Frequently, this may require a 
1-week delay.  If appropriate, inavolisib and fulvestrant dosing may continue.  PROs will 
not be repeated at the delayed Cycle 2, Day 1 visit when palbociclib dosing resumes.  
PROs will be administered at the new Cycle 2, Day 15, calculated from the resumption 
of palbociclib dosing. 
4.5.9.1 
Data Collection Methods for Clinical Outcome Assessments 
Patient-reported outcome instruments will be self-administered at the clinic at specified 
timepoints during the study (see schedule of activities in Appendix 1).  At the clinic, 
instruments will be administered before the patient receives any information on disease 
status, prior to the performance of study assessments, and prior to the administration of 
study treatment, unless otherwise specified.  In cases where laboratory assessments 
(e.g., blood draws) are performed at a different location from the one providing treatment 
or where they are performed on a different day from study treatment administration, 
laboratory assessments can be completed before the completion of PROs as long as 
results have not been discussed with the patient. 
Patient-reported outcome instruments, translated into the local language as appropriate, 
will be completed through use of an electronic device provided by the Sponsor or 
through a secured website.  The device and the secured website will be 
pre-programmed to enable the appropriate instruments to be administered in the correct 
order at each specified timepoint.  The electronic device/secured website and 
instructions for completing the instruments electronically will be provided by the site staff.  
In cases where the electronic device cannot be used (e.g., patient is unable to visit the 
site in person or elects MN visit), the instruments can be administered through a secured 
website.  The data will be transmitted to a centralized database maintained by the 
electronic device vendor.  The data will be available for access by appropriate study 
personnel. 
During clinic visits and visits conducted by a mobile nurse (Appendix 1), 
PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 

 
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 
Sites must administer the official version of each instrument that is included on the 
electronic device, as provided by the Sponsor.  Instruments must not be printed 
from the protocol and given to patients on paper. 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 1015 minutes at each visit specified in the schedule of activities 
(see Appendix 1).  
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
During the post-treatment follow-up period, patients may be contacted by site staff or a 
mobile nurse with a request to complete the PRO instruments at home through a 
website if they are not able to visit the site.  Patients should be given the following 
instructions for completing PRO instruments at home: 
 
Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
 
Patients should answer questions to the best of their ability; there are no right or 
wrong answers. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments 
EORTC QLQ-C30 
The EORTC QLQ-C30 (see Appendix 4) is a validated and reliable self-reported 
measure (Aaronson et al. 1993; Sprangers et al. 1996; Fitzsimmons et al. 1999).  
It consists of 30 questions that assess 5 aspects of patient functioning (physical, 
emotional, role, cognitive, and social), eight symptom scales (fatigue, nausea and 
vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), financial 
difficulties, and GHS/HRQoL with a recall period of the previous week. 
EORTC QLQ-BR23 
The EORTC QLQ-BR23 breast cancer module is meant for use among patients 
diagnosed with breast cancer (Sprangers et al. 1996).  The breast cancer module 
incorporates five multiple-item scales to assess systemic therapy side effects, arm 
symptoms, breast symptoms, body image, and sexual functioning.  In addition, single 
items assess sexual enjoyment, hair loss, and future perspective. 

 
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BPI-SF “Worst Pain” Item 
The BPI-SF is a widely used patient-reported outcome measure for assessing pain, and 
the “worst pain” item is frequently recommended for evaluating increases in the severity 
of pain (Cleeland 2009; Shi et al. 2009).  The item asks patients to rate their pain at its 
worst in the last week on a scale from 0 to 10. 
PRO-CTCAE 
The PRO-CTCAE (see Appendix 7) is an item bank reflecting 78 symptomatic adverse 
events rated according to their severity, interference with daily function, frequency, 
and/or occurrence.  The item bank was designed and validated as a repository of 
standalone items (Basch et al. 2014).  PRO-CTCAE will be completed per the schedule 
of activities (see Appendix 1), if available in the patient’s preferred language. 
Only adverse events that are patient self-reportable (Basch et al. 2014) were selected 
for assessment in this study.  Adverse events that rely on laboratory testing 
assessments (e.g., neutropenia, anemia) and that may frequently present as being 
primarily asymptomatic or with nonspecific signs and symptoms were disregarded.  
Adverse events that did not have an identifiable symptom equivalent in the PRO-CTCAE 
were also excluded.  Based on the above criteria, 7 symptomatic adverse events that 
have been associated with inavolisib, palbociclib, or fulvestrant treatment were selected 
from the PRO-CTCAE item bank:  diarrhea, nausea, vomiting, decreased appetite, 
fatigue, mouth sores, and rash symptoms.  An additional question providing an overall 
assessment of the burden of side effects will also be collected. 
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There 
are two components to the EQ-5D-5L:  a five-item health state profile that assesses 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a 
VAS that measures health state.  Published weighting systems allow for creation of a 
single composite score of the patient's health status.  The EQ-5D-5L takes 
approximately 3 minutes to complete.  The EQ-5D-5L will be collected to inform 
pharmacoeconomic modeling and will be included only descriptively in the Clinical Study 
Report. 
4.5.10 
Blood Samples for Whole Genome Sequencing (Patients at 
Participating Sites) 
At participating sites (where approved locally), blood samples will be collected for DNA 
extraction to enable WGS to identify variants that are predictive of response to study 
treatment, are associated with progression to a more severe disease state, are 
associated with acquired resistance to study treatment, are associated with susceptibility 
to developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 

 
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drug safety.  Research may aim to distinguish germline mutations from somatic 
mutations.  The samples may be sent to one or more laboratories for analysis.  WGS is 
not applicable in China. 
Collection and submission of blood samples for WGS is contingent upon the review and 
approval of the exploratory research by each site's IRB/EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WGS sampling, 
this section of the protocol (Section 4.5.10) will not be applicable at that site. 
Genomics are increasingly informing researchers’ understanding of disease 
pathobiology.  WGS provides a comprehensive characterization of the genome and, 
along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches, new methods for monitoring efficacy and 
safety, and/or new methods for predicting which patients are more likely to respond to a 
drug or develop adverse events.  Data will be analyzed in the context of this study but 
may also be explored in aggregate with data from other studies.  The availability of a 
larger dataset will assist in identification and characterization of important biomarkers 
and pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
See Section 4.5.6 for details on use of samples after patient withdrawal, confidentiality 
standards for data, and availability of data from biomarker analyses. 
4.5.11 
Optional Tumor Biopsies  
Consenting patients will undergo optional tumor biopsies after treatment initiation 
between Days 15 and 22 ( 1 day) of Cycle 1 and/or at disease progression and may 
undergo additional on-treatment biopsies at any other time at the investigator's discretion 
(if deemed clinically feasible by the investigator).  Participation in “consent for optional 
biopsy collection” is not available in China.  Samples collected via resection, core needle 
biopsy (three cores in the same block preferred), or excisional, incisional, punch, or 
forceps biopsy are preferred.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.   
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 

 
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not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF. 
Samples may be used for exploratory biomarker research as described in Section 4.5.6.  
See Section 4.5.6 for details on duration of sample storage, use of samples after patient 
withdrawal, confidentiality standards for data, and availability of data from biomarker 
analyses.  
4.5.12 
Optional Samples for Research Biosample Repository 
4.5.12.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
Sites in China are excluded from the “optional samples for research biosample 
repository” collection. 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the IRB/EC and, if 
applicable, an appropriate regulatory body.  If a site has not been granted approval for 
RBR sampling, this section of the protocol (Section 4.5.12) will not be applicable at that 
site. 

 
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4.5.12.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to inavolisib, cancer, 
diseases, or drug safety: 
 
Leftover blood, serum, plasma, and tumor tissue samples (with the exception of 
remaining archival tissue blocks, which will be returned to sites) and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides), including leftover blood and tumor 
tissue samples from medically indicated procedures performed at the investigator’s 
discretion during the course of the study  
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researchers’ understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Research Biosample Repository samples are to be stored until they are no longer 
needed or until they are exhausted.  However, the RBR storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements). 
4.5.12.4 
Confidentiality 
Research Biosample Repository samples and associated data will be labeled with a 
unique patient identification number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 

 
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be available in accordance with the effective Sponsor policy in the study data 
publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.12.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.12.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global.rcr-withdrawal@roche.com 
 

 
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A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.12.7 
Monitoring and Oversight 
Research Biosample Repository samples will be tracked in a manner consistent with 
Good Clinical Practice by a quality-controlled, auditable, and appropriately validated 
laboratory information management system, to ensure compliance with data 
confidentiality as well as adherence to authorized use of samples as specified in this 
protocol and in the Informed Consent Form.  Sponsor monitors and auditors will have 
direct access to appropriate parts of records relating to patient participation in the RBR 
for the purposes of verifying the data provided to the Sponsor.  The site will permit 
monitoring, audits, IRB/EC review, and health authority inspections by providing direct 
access to source data and documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if she or he continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Intolerable toxicity related to study treatment determined by the investigator to be 
unacceptable given the potential for treatment benefit and the severity of the event 
 
Unequivocal disease progression per investigator assessment according to 
RECIST v1.1 
 
Symptomatic deterioration attributed to disease progression 
 
Non-compliance with protocol-specified drug administration and follow-up tests 
 
Concomitant use of any other (non-protocol) systemic anti-cancer therapy  
 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced. 
All patients will return to the clinic for a safety follow-up visit 30 ( 7) days after the final 
dose of study treatment (see Appendix 1 for additional details). 
Discontinuation from final study treatment is not discontinuation from the study.  After 
treatment discontinuation, information on survival follow-up and new anti-cancer therapy 
will be collected via telephone calls, patient medical records, and/or clinic visits, 
approximately every 3 months until death, unless the patient withdraws consent or the 

 
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Sponsor terminates the study.  Patients that discontinue study treatment for reasons 
other than objective disease progression, withdrawal of consent, or death will continue to 
have tumor assessments performed every 8 weeks ( 7 days) for the first 2 years after 
randomization and then every 12 weeks ( 7 days) until documented disease 
progression or onset of new anti-cancer therapy, whichever occurs first. 
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.   
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent  
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Study termination or site closure 
 
Note that all patients are to be followed for survival following the discontinuation of study 
treatment, except in the cases noted above.   
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  Patients will not be followed for any reason after consent has 
been withdrawn.  Patients who withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records, published obituaries, etc.), in accordance with local regulations, to 
obtain information about survival status. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 

 
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 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Inavolisib is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on nonclinical and clinical experience with inavolisib in 
ongoing studies and clinical experience with other PI3K pathway inhibitors.  The 
anticipated important safety risks for inavolisib are outlined below.  Please refer to the 
Inavolisib Investigator's Brochure for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients potentially at higher risk 
for toxicities due to one or more components of study treatment.  Patients will undergo 
safety monitoring during the study, including assessment of the nature, frequency, and 
severity of adverse events, with severity graded according to NCI CTCAE v5.0.  Safety 
assessments will include interval history since the previous assessment, physical 
examinations, and specific laboratory studies.  All serious adverse events and adverse 
events of special interest (AESI) are to be reported in "real time" (within 24 hours of the 
event) via the electronic data capture (EDC) system.  In addition, guidelines for 
managing adverse events, including criteria for treatment interruption, dosage 
modification, and/or treatment discontinuation, are provided below. 
In addition to the Sponsor’s routine and real-time safety monitoring, an iDMC will be 
established that will operate according to a pre-specified iDMC charter (see 
Section 3.1.2).  As an additional safety monitoring measure, an interim safety review will 
be performed after the enrollment of the first 25 patients and treatment for at least 
three cycles. 
5.1.1 
Identified and Potential Risks Associated with Inavolisib 
On the basis of the established class effects of PI3K and mTOR inhibitors in patients 
with cancer, as well as nonclinical data and clinical experience from Study GO39374 
with inavolisib, hyperglycemia, stomatitis/oral mucositis, rash, diarrhea/colitis, and 
pneumonitis are safety concerns for inavolisib.  Given that these adverse events may 
require either dose interruptions and/or dose reductions or may have the potential to 
cause life-threatening conditions, close monitoring and a robust risk-mitigation strategy 
is warranted during the conduct of this Phase III study. 

 
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The combinations of inavolisib with palbociclib and letrozole and with palbociclib and 
fulvestrant are also being explored in Study GO39374.  Results to date have shown 
good tolerability, with no additional safety signals beyond those associated with 
PI3K inhibitor class-effects and expected toxicities associated with each of the 
combination partners, palbociclib and letrozole or fulvestrant.  Refer to the Inavolisib 
Investigator’s Brochure for details.   
5.1.1.1 
Hyperglycemia 
Effects on glucose and/or insulin metabolism are a known effect with PI3K inhibitors.  
Increased glucose was observed in rat and dog toxicology studies at all doses tested 
and appeared to be dose dependent.  Hyperglycemia has been reported in patients 
receiving inavolisib and is an identified risk of inavolisib.  Hence, diabetic patients and 
patients with elevated fasting glucose at baseline (fasting glucose  126 mg/dL 
[ 7.0 mmol/L] or HbA1c  6.0% [ 42 mmol/mol]) will be excluded from the study.  
Fasting glucose levels will be assessed at baseline, and fasting glucose levels will be 
monitored during the study, as outlined in Appendix 1.  Patients should be advised to 
report symptoms associated with hyperglycemia such as polydipsia, polyuria, 
polyphagia, blurry vision, or symptoms associated with acidosis such as rapid or shallow 
breathing, confusion, fatigue, headache, or drowsiness.   
The preferred first-line agent for the management of hyperglycemia is metformin; more 
detailed guidelines for study treatment dose modification, interruption or discontinuation 
(Table 1), and medical management for patients who experience hyperglycemia 
(Table 2) are provided in Section 5.1.2.2. 
5.1.1.2 
Stomatitis and Oral Mucositis 
Treatment-related stomatitis/oral mucositis has been reported with the use of inavolisib.  
Stomatitis has also been reported in  10% of patients receiving palbociclib.  Therefore, 
there is a concern for potential overlapping toxicity for the combination of inavolisib and 
palbociclib.  Patients should be advised to report symptoms immediately.  Intervention 
should begin at the earliest signs of oral mucosal inflammation.  If locally available, a 
compounded alcohol-free mouthwash of dexamethasone (0.5 mg in 5 mL) is 
recommended for prophylaxis or treatment of stomatitis/mucositis.  As per the SWISH 
study (Rugo et al. 2017), patients may use 4 times daily for 8 weeks (10 mL swished for 
2 minutes and spat) started concurrently with study treatment, and/or used reactively 
with the first appearance of symptoms.  Additional mouthwash formulations 
(e.g., combinations of local anesthetic, antihistamine, corticosteroid, antacid, antifungal, 
and/or antibiotics) or topical corticosteroids (e.g., triamcinolone acetonide 0.05%0.5%, 
fluocinolone acetonide 0.025%0.05%, clobetasol propionate 0.025%) may be 
implemented.  Patients should avoid alcohol, hydrogen peroxide, iodine, or 
thyme‑containing products, as they may exacerbate the condition.  They should also 
avoid harsh mouthwashes (e.g., Listerine).  Diet should be modified (e.g., avoidance of 
spicy foods).  Guidelines for managing stomatitis and oral mucositis are provided in 
Table 4. 

 
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5.1.1.3 
Potential Gastrointestinal Toxicities  
In the 4-week toxicology study of inavolisib in dogs, gastrointestinal inflammation was 
observed.  Thus, patients with inflammatory bowel disease, such as Crohn’s disease or 
ulcerative colitis, and active bowel inflammation (e.g., diverticulitis) will be excluded from 
this study.  Diarrhea, nausea and vomiting have also been reported in  10% of patients 
receiving palbociclib.  Therefore, there is a concern for potential overlapping toxicity for 
the combination of inavolisib and palbociclib.  Gastrointestinal effects will be closely 
monitored by interval history and physical examination (see Appendix 1).  Development 
of abdominal pain, nausea, vomiting, clinically significant changes in stool 
(e.g., diarrhea, bloody stools) may necessitate more frequent monitoring, and study drug 
may be held if symptoms are prohibitive for normal function.  Clinical evaluation for 
infectious (e.g., Clostridium difficile, enteric bacteria, and cytomegalovirus) or 
inflammatory (e.g., inflammatory colitis) etiologies for diarrhea should be conducted.  
Guidelines for managing gastrointestinal toxicities and inflammatory colitis are provided 
in Table 6 and Table 7, respectively. 
5.1.1.4 
Potential Skin Disorders  
Treatment-related rash has been reported for other PI3K inhibitors in clinical studies and 
is commonly manifested as a maculo-papular rash with or without pruritus.  Rash has 
also been reported in  10% of patients receiving palbociclib.  Therefore, there is a 
concern for potential overlapping toxicity for the combination of inavolisib and 
palbociclib.  Rash and other dermatologic events should be closely monitored and 
managed per standard-of-care.  Guidelines for management of rash, including dosage 
modification, are provided in Table 5. 
When applicable, ad-hoc photographs of toxicities of the skin or the mucous membranes 
(i.e., rash or mucositis) may be taken and submitted to the Sponsor to allow further 
evaluation.   
5.1.1.5 
Potential Lung Inflammation/Pneumonitis  
Lung inflammation was observed in the inavolisib 4-week dog study at the highest dose 
tested.  This finding was observed only at a dose level considered not tolerable in this 
species.  Interstitial lung inflammation/pneumonitis has been observed in clinical studies 
with other PI3K inhibitors.  Rare but severe lung inflammation has been reported with 
CDK4/6 inhibitors, including palbociclib, when taken in combination with endocrine 
therapy.  Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), any grade and 
Grade  3 events of interstitial lung disease (ILD)/pneumonitis were reported in 1.0% 
and 0.1% of patients treated with palbociclib, respectively.  Although no fatal cases were 
reported from these studies, additional cases of ILD/pneumonitis with fatalities have 
been observed in the post-marketing setting.  Therefore, there is a concern for potential 
overlapping toxicity for the combination of inavolisib and palbociclib.  Specific 
management guidelines and guidance for holding or discontinuing therapy for 
symptomatic and asymptomatic pneumonitis based on the severity of pneumonitis are 
provided in Table 8. 

 
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5.1.1.6 
Potential Immunosuppressant Effects  
Immunosuppression and increased risk of infections are known to be associated with 
marketed PI3K-mTOR pathway inhibitors.  Toxicology studies demonstrated decreases 
in reticulocytes, leukocytes, and absolute lymphocyte counts in animals treated with 
inavolisib.  Thus, patients who are immunocompromised as the result of HIV or receiving 
immunosuppressive therapies will be excluded from this study.  Patients will be 
monitored routinely for changes in circulating blood counts, including white cell 
differential, and should be monitored for fever and signs of infection.  
5.1.1.7 
Potential Reproductive Effects  
Potential adverse effects on male reproductive function, including focal inspissation of 
seminiferous tubule contents and multinucleated spermatids in the testis and epithelial 
degeneration/necrosis in the epididymis, were observed in one or more dogs in the 
4-week repeat-dose toxicity study.  Focal inspissation of seminiferous tubule contents 
persisted in one animal at the end of the 4-week recovery period. 
Patients should be notified of the possibility of reproductive sterility.  In the event of 
patient concern and in accordance with local standards, Principal Investigators may opt 
to refer male patients for consultation with a local sperm preservation facility (i.e., sperm 
bank).  Because of the unknown effects on human reproductive organs and gonadal 
cells, all male and female patients should use an effective means of contraception 
(e.g., abstinence, double-barrier method, surgical sterilization of partner) while taking 
inavolisib. 
5.1.1.8 
Potential Ocular Toxicities  
In the 4-week toxicology study in rats, lens degeneration was observed in the highest 
inavolisib dose group (10 mg/kg; 4 of 30 rats).  This finding was characterized by 
minimal-to-mild lens fiber swelling, separation of lens fibers and/or accumulation of 
subcapsular proteinaceous material.  It is unclear whether the lens finding was a direct 
effect of inavolisib or an indirect effect secondary to marked hyperglycemia in this dose 
group.  No inavolisib-related eye findings were observed in rats at lower doses.  In dogs, 
ocular-related findings included inflammation and lens fiber swelling.  In dogs 
administered 1.5/1.0 mg/kg inavolisib for 3 months, ocular inflammation was limited to 
focal, minimal neutrophilic infiltrates in the stroma of the corneal-limbal junction of the 
eye.  In the 4-week study in dogs, neutrophilic infiltration in limbus and sclera, mild 
endophthalmitis, and low-grade uveitis were observed in the highest dose group (treated 
with 5 mg/kg and reduced to 3 mg/kg), a dose that was not considered tolerable.  These 
findings were reversible and likely part of a systemic generalized inflammatory condition.  
In dogs administered  0.3 mg/kg inavolisib in the 3-month toxicity study, bilateral, 
reversible, very slight swelling of the fibers at the equatorial region of the lens was 
observed in one male and one female at 0.3 mg/kg, and one male and one female at 
1.5/1.0 mg/kg.  Although lens fiber swelling may be a result of changes in lens osmotic 
pressure associated with hyperglycemia present at 1.5/1.0 mg/kg in this study, since 
hyperglycemia was not observed in animals at 0.3 mg/kg, a direct inavolisib effect 

 
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cannot be ruled out.  The clinical relevance of these ocular findings to humans is 
unknown.  
Patients with any concurrent ocular or intraocular condition, such as cataract or diabetic 
retinopathy, that would require medical or surgical intervention during the study period to 
prevent or treat vision loss, will be excluded from the study.  In addition, patients with 
active uveitis or vitritis, history of uveitis, or active infectious process in the eye will also 
be excluded from the study.  Patients will undergo ophthalmic examinations at baseline 
during the screening period, at Cycle 6 during the study treatment period, at study 
treatment discontinuation, and based on any ocular disturbances.  The ophthalmic 
examination should consist of a full ophthalmic exam with dilation and refraction with 
specific attention paid to lens examination and detailed documentation.  During study 
treatment, hyperglycemia will be managed according to the guidelines in Table 2.  In 
addition, patients will be asked if they have experienced any significant visual changes, 
pain, or sensitivity to light at each clinic visit.  Any new eye-related symptoms including 
significant change in vision, eye pain, or photophobia will be evaluated by an 
ophthalmologist.  
5.1.1.9 
DrugDrug Interactions  
In vitro data suggest that inavolisib is metabolized by CYP3A4 and that there is a 
low‑to‑moderate potential for DDI with any medication that strongly inhibits or induces 
this enzyme.  In addition, in vitro data suggest that inavolisib is a substrate of the efflux 
transporter P-glycoprotein.  Palbociclib is extensively metabolized by CYP3A4.  Co-
administration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure 
of palbociclib in healthy subjects by 87%, and co-administration of a strong CYP3A 
inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 
85%.  Therefore, strong CYP3A4 inhibitors and inducers are prohibited in this study (see 
Section 4.4.3). 
5.1.2 
Management of Patients Who Experience Adverse Events 
5.1.2.1 
Dose Modifications of Inavolisib/Placebo  
The inavolisib/placebo dose reduction instructions provided in Table 1 are intended to 
serve as recommended guidelines to allow ongoing treatment for patients experiencing 
clinical benefit without signs or symptoms of progression while monitoring patient safety.  
These guidelines are intended to inform rather than supersede clinical judgment and the 
benefit-risk balance as assessed by the investigator in managing individual cases.  In 
addition to these guidelines, more conservative drug interruptions or dose reductions for 
the management of adverse events are permitted at the discretion of the investigator 
when deemed to be in the best interest of the patient.  In general, decisions on 
interruption of any of the study treatment components (inavolisib/placebo, palbociclib, 
fulvestrant) should be made independently of the others; that is, one study treatment 
component alone may be interrupted for adverse events associated with that medication 
without mandatory interruptions of the other study treatment components. 

 
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Dose modification for adverse events should be taken first with inavolisib rather than 
palbociclib unless clearly attributable to palbociclib alone based on known toxicity profile 
and the investigator’s assessment.  When an adverse event is clearly attributed to 
palbociclib, dose modification of palbociclib alone based on its known toxicity profile and 
the investigator’s assessment is allowed.  For toxicities attributed to the combination of 
inavolisib, palbociclib and fulvestrant, it is preferred to initially modify the dosage of 
one drug (i.e., inavolisib or palbociclib), then modifying the other drug (e.g., if inavolisib 
dose was reduced but toxicity persisted or recurred, then reduce the dose of palbociclib), 
depending upon the nature and severity of the toxicity.  Further dose de-escalation may 
be considered if the same toxicity arises.  
Table 1 
Overall Dose Modification Guidelines for Inavolisib-Related 
Adverse Events 
 
Inavolisib/placebo 
Starting dose 
9 mg QD 
First reduction 
6 mg QD 
Second reduction 
3 mg QD a 
QD  once daily. 
a If the patient continues to experience specified drug-related adverse events after the second 
dose reduction, inavolisib/placebo should be discontinued. 
 
The investigator may temporarily suspend inavolisib/placebo dosing due to an 
inavolisib-related toxicity or an unanticipated medical event not associated with study 
treatment toxicity or with disease progression.  Dose interruptions for any component of 
study treatment should not exceed one cycle (i.e., approximately 28 days); patients 
withheld from treatment beyond 28 continuous days are expected to be withdrawn from 
study treatment.  However, the Medical Monitor is available to advise extension for 
extenuating circumstances.  Depending on the nature and the severity of the 
inavolisib-related toxicity, the investigator may resume inavolisib/placebo dosing in the 
patient at the same dose or at one dose level lower (as detailed in Table 9).  Dose 
re-escalation of inavolisib/placebo is permitted only after a thorough benefit-risk 
evaluation by the investigator; the Medical Monitor is available for consultation as 
needed. 
5.1.2.2 
Management of Hyperglycemia 
The anti-hyperglycemic agent metformin should be used first-line for the management of 
sustained fasting glucose  160 mg/dL or  8.9 mmol/L or anytime fasting glucose is 
 250 mg/dL or  13.9 mmol/L.  Investigators should exercise caution in the dosing and 
management of patients receiving metformin in combination with inavolisib and must be 
vigilant for signs of renal impairment and metformin toxicity (see also Section 5.1.1.2).  
Patients administered metformin should be cautioned and monitored for signs of 
intolerance or toxicity, including lactic acidosis, which may occur in the setting of acute 

 
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worsening of renal function or cardiorespiratory illness or sepsis and can be 
life‑threatening.  The most frequently reported adverse events with metformin are 
nausea, vomiting, diarrhea, abdominal pain, and loss of appetite.  Metformin does not 
produce hypoglycemia, but it may occur with a missed meal, alcohol consumption, 
heavy exercise, or when it is taken with another type of diabetes medicine.   
In the event metformin is not tolerated or not sufficient, another anti-hyperglycemic 
medication(s) may be added to or used in place of metformin.  Preferred agents include 
sodium glucose co-transporter 2 (SGLT2) inhibitors, pioglitazone, and dipeptidyl 
peptidase-4 inhibitors, where available and considered appropriate by investigators.  If 
SGLT2 inhibitors are prescribed, ensure adequate hydration and monitor for vaginal 
yeast infections.  Patients administered pioglitazone should be monitored closely for 
signs of heart failure including fluid retention or edema.  Patients administered insulin or 
sulfonylureas should be treated with caution when these agents are used to manage 
hyperglycemia and inavolisib is subsequently interrupted or discontinued:  this can lead 
to rapid escalation of insulin levels and risk of hypoglycemia.  For each of these agents, 
refer to the local prescribing information for additional information. 
Patients at risk for developing hyperglycemia (e.g., pre-diabetes, body mass index 
greater than or equal to 30 kg/m2, hemoglobin A1c greater or equal to 5.7%, over 
45 years of age, family history of diabetes, history of gestational diabetes, and any other 
factor that may lead to increased risk of developing hyperglycemia, including certain 
ethnicities, inactive lifestyle, may initiate treatment with metformin on Day 1 of the study, 
where allowed by local regulations.  Table 2 describes management guidelines of 
hyperglycemia and Table 3 presents proactive mitigation recommendations for patients 
with risk factors for hyperglycemia.  In addition, any patient may be instructed to utilize a 
glucometer to monitor fasting glucose at home on a daily basis at the treating 
investigator’s discretion. 
 

 
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Table 2 
Management of Hyperglycemia 
Fasting Glucose 
Values 
Action to be Taken 
 ULN to 160 mg/dL 
(8.9 mmol/L) 
 Encourage patients to adopt a diabetic diet. 
 Consider consultation with endocrinologist or diabetologist. 
 Provide home glucose monitoring to high risk patients and educate to check fasting glucose at home. a 
 Consider oral anti-diabetic medications (e.g., metformin) for high risk patients. a 
 Recheck in 3 days and adjust medications as needed. b 
 Continue current dose level of inavolisib/placebo. 
 160 to 250 mg/dL 
( 8.913.9 mmol/L)  
 Interrupt inavolisib/placebo dose until hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L. f 
 Start or increase dose for an oral anti-diabetic medication (e.g., metformin, SGLT2 inhibitor). c 
 Recheck in 3 days and adjust or add anti-diabetic medications as needed. b 
 Encourage patients to adopt a diabetic diet. 
 Consider consultation with endocrinologist or diabetologist. 
 Initiate fasting home glucose monitoring. 
 Resume current dose level of inavolisib/placebo when hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L. 
 If fasting blood glucose persists  200250 mg/dL or  13.927.8 mmol/L for 7 days despite above interventions, 
discuss with the Medical Monitor. f 
 

 
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Table 2  
Management of Hyperglycemia (cont.) 
Fasting Glucose 
Values 
Action to be Taken 
 250 to 500 mg/dL 
( 13.927.8 mmol/L) 
 Interrupt inavolisib/placebo. 
 Manage hyperglycemia as per standard-of-care. c, d 
 Start or increase dose for an oral anti-diabetic medication (e.g., metformin, SGLT2 inhibitor). c 
 Recheck in 3 days and adjust or add anti-diabetic medications as needed. b 
 Encourage patients to adopt a diabetic diet. 
 Consider consultation with endocrinologist or diabetologist. 
 Initiate fasting home glucose monitoring. 
 If hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L within 7 days, may resume at current dose level of 
inavolisib/placebo. 
 If hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L in  8 days, reduce inavolisib/placebo dose by one dose level 
when treatment resumes. e 
 If hyperglycemia  250500 mg/dL or  13.927.8 mmol/L recurs within 30 days, reduce inavolisib/placebo dose by one 
dose level. e 
 500 mg/dL  
( 27.8 mmol/L) 
 Interrupt inavolisib/placebo. 
 Manage hyperglycemia as per standard-of-care. c, d 
 Assess for volume depletion and ketosis and administer appropriate intravenous or oral hydration. 
 Start or increase the dose for an oral anti-diabetic medication (e.g., metformin, SGLT2 inhibitor). c 
 Recheck in 3 days and adjust or add anti-diabetic medications as needed. b 
 Encourage patients to adopt a diabetic diet. 
 Consider consultation with endocrinologist or diabetologist. 
 Initiate fasting home glucose monitoring. 
 When hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L, reduce inavolisib/placebo dose by one dose level when 
treatment resumes. e 
 If hyperglycemia  500 mg/dL or  27.8 mmol/L recurs within 30 days, permanently discontinue inavolisib/placebo. 
 

 
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Table 2  
Management of Hyperglycemia (cont.) 
SGLT2  sodium glucose co-transporter 2;  ULN upper limit of normal. 
a High-risk factors for diabetes include pre-diabetes, overweight, obese, body mass index greater or equal to 30 kg/m2, hemoglobin A1c greater or 
equal to 5.7%, over 45 years of age, family history of diabetes, certain ethnicities, inactive lifestyle, and history of gestational diabetes.  
b Fasting glucose should be checked by finger stick or lab value (if patient has scheduled appointment) PRIOR to dosing.  Oral anti-diabetic 
medications should be titrated to the maximum allowed dosages to achieve control of blood glucose to  160 mg/dL or 8.9 mmol/L.  For 
example, metformin may be administered to a maximum dose allowed as per local prescribing information, given in divided doses, as tolerated.  
Please see local prescribing information of individual oral anti-diabetic agent for dosing guidelines.  
c There is a risk of hypoglycemia if insulin or sulfonylureas are used, particularly if these agents are started during periods of inavolisib exposure 
and doses are not adjusted appropriately during periods of treatment interruption, during which patients’ insulin sensitivity may increase rapidly.  
Short-term insulin is allowed to control blood glucose levels, but goal should be to maintain on oral agents once acute episode resolves.  
d It is recommended that the patient is reassessed within 24 hours and preferably the same day for assessments of hydration status and renal 
function. 
e A maximum of two dose reductions will be allowed.  
f If, in the investigator’s opinion, the benefit-risk assessment favors continued inavolisib dosing without interruption, inavolisib may be continued 
without interruption upon discussion with Medical Monitor once patients are managed on anti-diabetic agent(s) and fasting glucose  200 mg/dL 
[  11.1 mmol/L].  It is recommended that patients be instructed to utilize a glucometer to monitor fasting glucose and to call the clinic if fasting 
glucose  200 mg/dL [  11.1 mmol/L] prior to inavolisib dosing at home. 

 
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Table 3 
Additional Management Guidelines for Patients at High Risk of 
Hyperglycemia 
Patient Characteristics 
Guidelines 
 Hemoglobin A1c  5.7% to 
 6.4%  
 Pre-diabetes  
 Body mass index  30 kg/m2 
  45 years of age  
 Family history of diabetes 
 History of gestational diabetes 
 Any other factor that increases 
the risk of hyperglycemia (e.g., 
certain ethnicities such as 
African American, South Asian; 
sedentary lifestyle) 
 Patient may be instructed to utilize a glucometer to 
monitor fasting glucose at home on a daily basis at the 
treating investigator’s discretion. 
 Recommend moderate lifestyle changes such as: 
Dietary advice (e.g., small frequent meals, low 
carbohydrate content, high fiber, balanced 
carbohydrate intake over the course of the day, three 
small meals and two small snacks rather than one 
large meal, avoiding drinking sugar-sweetened 
beverages and switch to water whenever possible) 
Increase daily physical activity and exercise 
 Consultation with an endocrinologist or diabetologist is 
highly recommended. 
 Consider initiating prophylactic treatment with metformin 
(on Cycle 1 Day 1) in patients with more than one risk 
factor, where allowed by local regulations and at the 
investigator’s discretion. 
 
5.1.2.3 
Management of Stomatitis/Oral Mucositis 
For any grade stomatitis/mucosal inflammation, aggressive mouth care should be 
implemented early to help manage or prevent symptoms.  If locally available, a 
compounded alcohol-free mouthwash of dexamethasone (0.5 mg in 5 mL) is 
recommended for prophylaxis or treatment of stomatitis/mucositis.  As per the SWISH 
study (Rugo et al. 2017), patients may use 4 times daily for 8 weeks (10 mL swished for 
2 minutes and spat) started concurrently with study treatment, and/or used reactively 
with the first appearance of symptoms.  No food or drink should be consumed for at least 
1 hour after swishing and spitting the mouthwash.  Additional mouthwash formulations 
(e.g., combinations of local anesthetic, antihistamine, corticosteroid, antacid, antifungal, 
and/or antibiotics) or topical corticosteroids (e.g., triamcinolone acetonide 0.05%0.5%, 
fluocinolone acetonide 0.025%0.05%, clobetasol propionate 0.025%) may be 
implemented.  Patients should avoid alcohol, hydrogen peroxide, iodine, or 
thyme-containing products, as they may exacerbate the condition.  Diet should be 
modified (e.g., avoidance of spicy foods) and harsh mouthwashes (e.g., Listerine) should 
be avoided.  Table 4 describes management of stomatitis/oral mucositis. 

 
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Table 4 
Management of Stomatitis/Oral Mucositis 
Grade of stomatitis/oral 
mucositis 
Action to Be Taken 
Any Grade 
 
Intervene early. 
 
Initiate aggressive mouth care that includes dexamethasone 
(0.1 mg per mL) alcohol-free mouthwash.  If that is not 
available, consider other mouthwash formulations (e.g., 
combinations of local anesthetic, antihistamine, corticosteroid, 
antacid, antifungal and/or antibiotics). 
 
Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme-
containing products, as they may exacerbate the condition.  
Avoid harsh mouthwashes (e.g., Listerine®). 
 
Diet should be modified (e.g., avoidance of spicy foods). 
Grade 1:  Asymptomatic or 
mild symptoms; intervention 
not indicated 
 
Initiate management as above. 
 
Monitor symptoms and compliance with oral regimen. 
 
Re-evaluate within 4872 hours. 
Grade 2:  Moderate pain or 
ulcer that does not interfere 
with oral intake; modified 
diet indicated 
 
Interrupt inavolisib/placebo and manage as above until 
Grade  1. 
 
When stomatitis/oral mucositis improves to Grade  1, resume 
dosing at the same dose. 
 
For recurrent Grade 2 stomatitis or oral mucositis within 
30 days, reduce inavolisib/placebo dose by one dose level. 
Grade 3:  Severe pain; 
interfering with oral intake 
 
Interrupt inavolisib/placebo until Grade  1 and reduce 
inavolisib/placebo dose by one dose level when dosing is 
resumed. 
 
Interrupt palbociclib until recovery to Grade  2; then may 
resume palbociclib as per local prescribing information a (see 
Table 11 below). 
Grade 4:  Life-threatening 
consequences; urgent 
intervention indicated 
 
Permanently discontinue inavolisib/placebo. 
 
Manage palbociclib as per local prescribing information (see 
Table 11 below). 
a Consider whether event is due to inavolisib, palbociclib, or both.  Initial dose modification(s) 
should be made to the agent(s) contributing to event and if unknown, consider adjusting both.  
 

 
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5.1.2.4 
Management of Rash 
Patients with severe rash should also be monitored for associated signs and symptoms, 
such as fever and hypotension that may be suggestive of a systemic hypersensitivity 
reaction.  Permanently discontinue treatment for any rash with concurrent 
signs/symptoms strongly suggestive of a severe Type I hypersensitivity or 
anaphylactic/anaphylactoid reaction or with painful desquamation or mucosal 
involvement suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis or with 
other life-threatening complications.  Dermatological consultation is recommended.  
Guidelines for management of rash are provided in Table 5. 
Table 5 
Management of Rash 
Grade  
Action to Be Taken 
Grade 1 
 
Continue inavolisib/placebo dosing and monitor for changes in 
severity. 
 
Consider prescribing topical corticosteroids a and/or 
antihistamines. 
Grade 2 
 
Interrupt inavolisib/placebo treatment. 
 
Treat rash per standard-of-care, including topical and/or oral 
corticosteroids b and/or antihistamines. 
 
When rash resolves to Grade  1, resume inavolisib/placebo at 
the same dose or one dose level lower per investigator 
evaluation. 
 
If Grade 2 rash recurs within 30 days, reduce inavolisib/placebo 
by one dose level when treatment resumes. 
Grade 3 
 
Interrupt inavolisib/placebo treatment. 
 
Interrupt palbociclib treatment until recovery to Grade  2 and 
manage as per local prescribing information (see Table 11 
below).c 
 
Treat rash with topical and/or systemic corticosteroids (oral or 
IV) and antihistamines. 
 
If rash resolves to Grade  1 within 30 days, reduce 
inavolisib/placebo by one dose level when treatment resumes. 
 
If rash does not resolve to Grade  1 within 30 days, discontinue 
inavolisib/placebo. 
 
Refer to dermatologist for consultation and skin biopsy. 
IV  intravenous. 
a Suggested topical steroids include hydrocortisone 2.5% to face 2  daily, triamcinolone 0.1% 
or fluocinonide 0.1% cream to body 2  daily. 
b Suggested oral steroids include methylprednisolone dose pack or prednisone 60 mg daily 
followed by taper (e.g., 60 mg  2 days, 40 mg   2 days, 20 mg  2 days, etc.). 
c Consider whether event is due to inavolisib, palbociclib, or both.  Initial dose modification(s) 
should be made to the agent(s) contributing to event and if unknown, consider adjusting both.  
 

 
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5.1.2.5 
Management of Diarrhea 
Table 6 
Management of Diarrhea 
Grade  
Action to Be Taken 
Grade 1 
 
Adequate treatment with anti-diarrheals a and maximum 
supportive care. b 
Grade 2 
 
Adequate treatment with anti-diarrheals a and maximum 
supportive care. b 
 
Close monitoring. 
 
Interrupt inavolisib/placebo until recovery to Grade  1, then may 
resume at the same dose. 
 
If recurs within 30 days, reduce inavolisib/placebo by one dose 
level. 
Grade 3 
 
Interrupt inavolisib/placebo until recovery to Grade  1, then 
reduce by one dose level. 
 
Interrupt palbociclib treatment until Grade  2 and manage as 
per local prescribing information (see Table 11 below). c  
 
Manage as per Grade 2 diarrhea guidelines. 
 
If recurs within 30 days after initiation of the first dose reduction, 
reduce inavolisib/placebo by one dose level.  If recurs within 
30 days from the second dose reduction, permanently 
discontinue inavolisib/placebo. 
Grade 4 
 
Permanently discontinue inavolisib/placebo 
 
Manage palbociclib as per local prescribing information (see 
Table 11 below) 
a Initiate loperamide (Imodium®) dose with 4 mg, then 2 mg every loose stool up to 16 mg/day.  
May consider using combination of loperamide and Lomotil® (diphenoxylate and atropine) or 
codeine phosphate.  Monitor closely for dehydration or constipation.  May initiate second-line 
therapy (e.g., octreotide) if Grade  2 diarrhea persists after 48 hours of treatment with 
loperamide and/or Lomotil.  
b Supportive care:  initiate appropriate dietary modification, hydration therapy, and electrolyte 
supplements when clinically indicated.  Dietary modification includes:  stop all 
lactose-containing products and eat small meals; encourage adequate hydration with salt-
containing liquids such as broth or Gatorade®. 
c Consider whether event is due to inavolisib, palbociclib or both.  Initial dose modification(s) 
should be made to the agent(s) contributing to event and if unknown, consider adjusting both. 
 

 
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5.1.2.6 
Management of Inflammatory Colitis 
Table 7 
Management of Inflammatory Colitis 
Grade  
Action to Be Taken 
Grade 1 
 
Close monitoring and treat as appropriate. 
Grade 2 
 
If colitis-related symptoms do not improve to Grade  1 after 
48 hours of anti-diarrheals, start treatment with oral 
corticosteroid. a 
 
Interrupt inavolisib/placebo until recovery to Grade  1, then may 
resume at the same dose or one dose level lower per investigator 
evaluation. 
 
If recurs within 30 days, reduce inavolisib/placebo by one dose 
level. 
Grade 3 
 
Treat with high dose corticosteroids (IV solumedrol or PO 
prednisone). b 
 
Interrupt inavolisib/placebo until recovery to Grade  1, then 
reduce by one dose level. 
 
Hold palbociclib until recovery to Grade  1 and manage as per 
local prescribing information (see Table 11 below). 
 
Consider colonoscopy. 
 
If Grade 3 recurs, permanently discontinue inavolisib/placebo. 
Grade 4 
 
Permanently discontinue inavolisib/placebo. 
 
Manage palbociclib as per local prescribing information 
(see  Table 11 below). 
IV  intravenous; PO  by mouth; QD  once daily. 
a 2040 mg prednisone PO QD (starting dose).  
b For severe grades, may also consider IV solumedrol 1620 mg every 8 hours, or prednisone 
6080 mg PO QD equivalent to start. 
 

 
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5.1.2.7 
Management of Pneumonitis 
Table 8 
Management of Pneumonitis 
Grade 
Intervention 
Investigation 
Inavolisib and Palbociclib 
Dose Modification and 
Management 
Grade 
1 
 
No specific 
therapy 
required 
 
Chest CT scan. 
 
Repeat CT at least every 
8 weeks until return to 
baseline. 
 
Consider pulmonologist/ 
respirologist consult. 
 
Advise patient to promptly 
report new or worsening 
respiratory symptoms. 
 
No action. 
Grade 
2 
 
Prescribe 
corticosteroids 
if infectious 
etiology is ruled 
out. 
 
Taper as 
clinically 
indicated. 
 
Chest CT scan. 
 
Repeat CT at least every 
8 weeks until return to 
baseline. 
 
Consider PFTs. 
 
Obtain 
pulmonologist/respirologist 
consult. 
 
Hold inavolisib/placebo and 
palbociclib as long as 
corticosteroids are being 
given. When pneumonitis 
improves to Grade  1 and 
upon completion of any 
corticosteroid treatment, 
resume inavolisib/placebo 
and palbociclib dosing at the 
same dose or one dose level 
lower per investigator 
evaluation.  For recurrent 
Grade 2 event, resume 
inavolisib/placebo and 
palbociclib dosing at one 
dose level lower. 
Grade 
3 
 
Prescribe 
corticosteroids 
if infectious 
etiology is ruled 
out. 
 
Taper as 
clinically 
indicated. 
 
Chest CT scan. 
 
Repeat CT at least every 
8 weeks until return to 
baseline. 
 
Consider PFTs and 
bronchoscopy. 
 
Obtain pulmonologist/ 
respirologist consult. 
 
Hold inavolisib/placebo as 
long as corticosteroids are 
being given.  When 
pneumonitis improves to 
Grade  1 and upon 
completion of any 
corticosteroid treatment, 
resume inavolisib/placebo 
dosing at one dose level 
lower. 
 
Permanently discontinue 
palbociclib. 
 

 
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Table 8  
Management of Pneumonitis (cont.) 
Grade 
4 
 
Prescribe 
corticosteroids 
if infectious 
etiology is ruled 
out. 
 
Taper as 
clinically 
indicated. 
 
Chest CT scan. 
 
Repeat CT at least every 
8 weeks until return to 
baseline. 
 
Consider PFTs. 
 
Obtain pulmonologist/ 
respirologist consult 
 
Bronchoscopy is 
recommended. 
 
Permanently discontinue 
inavolisib/placebo. 
 
Permanently discontinue 
palbociclib. 
CT  computed tomography (scan); PFTs  pulmonary function tests 
 
5.1.2.8 
Management of Other Clinically Significant Adverse Events 
Inavolisib may be continued without interruption for uncomplicated Grade 3 hematologic 
toxicities with the exception of neutropenic fever where inavolisib should be interrupted 
until neutrophil count recovers to Grade  2.  Inavolisib then may resume at same dose.  
For uncomplicated Grade 4 neutropenia, inavolisib may be continued without 
interruption.  Interrupt inavolisib for Grade 4 thrombocytopenia until recovery to 
Grade  2, and then resume inavolisib at same dose. 
See Table 9 for inavolisib/placebo dose modifications for other clinically significant 
adverse events attributed to inavolisib. 
Table 9 
Inavolisib/Placebo Dose Delay and Modification Guidelines for 
Other Clinically Significant Adverse Events Attributed to 
Inavolisib 
Grade 
Inavolisib/Placebo 
Grade 3, first event 
 Hold inavolisib/placebo until Grade  1. 
 Resume inavolisib/placebo at the same dose or one dose level 
lower per investigator evaluation. 
Grade 3, recurrent or 
Grade 4, 
nonlife‑threatening 
 Hold inavolisib/placebo until Grade  1.  Resume 
inavolisib/placebo dosing at one dose level lower. 
Grade 4, life‑threatening 
 Permanently discontinue inavolisib/placebo. 
 Single-agent fulvestrant may be continued per investigator 
evaluation. 
 
5.1.2.9 
Safety Monitoring for Fulvestrant 
Fulvestrant is an ER antagonist indicated for the treatment of HR-positive metastatic 
breast cancer in postmenopausal women and for the treatment of HR-positive, 
HER2‑negative metastatic breast cancer in combination with palbociclib in patients with 

 
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disease progression after endocrine therapy.  There are no expected significant 
overlapping toxicities between inavolisib and fulvestrant.   
The common adverse events associated with the use of fulvestrant include 
hypersensitivity reactions, hot flushes, nausea, elevated hepatic enzymes (ALT, AST, 
ALP), rash, joint and musculoskeletal pain, asthenia, injection site reactions, urinary tract 
infections, reduced platelet count, anorexia, headache, venous thromboembolism, 
vomiting, diarrhea, elevated bilirubin, back pain, vaginal hemorrhage, peripheral 
neuropathy, and sciatica.  In randomized studies with fulvestrant, injection site pain was 
commonly reported.  Because fulvestrant is administered intramuscularly, it should be 
used with caution in patients with bleeding diatheses, thrombocytopenia, or 
anticoagulant use. 
Fulvestrant should be used with caution in patients with mild to moderate hepatic 
impairment.  Fulvestrant should be used with caution in patients with severe renal 
impairment (creatinine clearance  30 mL/min). 
Refer to the fulvestrant local prescribing information for additional information. 
5.1.2.10 
General Guidance of Dose Modifications or Delays for 
Fulvestrant 
The fulvestrant dose level cannot be modified.  In general, the investigator may consider 
continuing fulvestrant if the observed adverse event is not thought to be 
fulvestrant-related.  Decisions on interruption of any of the study treatment components 
(inavolisib/placebo, palbociclib, fulvestrant) should be made independently of the other 
study treatment components (i.e., one study treatment component alone may be 
interrupted for adverse events associated with that medication without mandatory 
interruptions of the other study treatment components). 
If a scheduled dose coincides with a holiday or inclement weather or other conditions 
that preclude dosing, dosing should commence on the nearest following date, and 
subsequent dosing can continue on a new 28-day schedule on the basis of the new 
IM injection date. 
5.1.2.11 
Safety Monitoring for Palbociclib 
In the Phase III PALOMA-3 study of palbociclib plus fulvestrant compared with 
fulvestrant, hematological Grade  3 adverse events observed in patients who received 
palbociclib plus fulvestrant were neutropenia (65%), leukopenia (28%), anemia (3%), 
and thrombocytopenia (3%).  Febrile neutropenia was reported in 1% of patients.  
Granulocyte-CSF support was reported in 12% of patients treated with palbociclib plus 
fulvestrant compared with 1% of patients who received placebo plus fulvestrant.  
Non-hematological Grade  3 adverse events were observed in 2% or less of patients.  
In the palbociclib plus fulvestrant arm, dose interruptions and cycle delays occurred in 
54% and 36% of patients, respectively.  At least one dose reduction of palbociclib due to 

 
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an adverse event was observed in 34% of patients.  Permanent discontinuation due to 
adverse events was 4% in the palbociclib plus fulvestrant arm (Verma et al. 2015; 
Cristofanilli et al. 2016). 
In addition, an increase in the rate of infections and events of pulmonary embolism have 
been reported with palbociclib combination therapies.  
Patients will have complete blood counts assessed prior to the start of palbociclib and 
will be monitored frequently throughout the study and as clinically indicated. 
For hematologic toxicities assessed by the investigator as related to palbociclib, 
suggested guidelines for palbociclib dose modification are shown in Table 10.  Refer to 
the palbociclib local prescribing information for additional information.  See 
Section 5.1.2.8 for inavolisib management guidelines.   
Table 10 Palbociclib Dose Modification and Management:  Hematologic 
Toxicities 
CTCAE Grade 
Dose Modification 
Grade 1 or 2 
 
No dose adjustment is required. 
Grade 3 
 
Day 1 of any cycle: 
Withhold palbociclib; repeat complete blood count monitoring 
within 1 week.  When recovered to Grade  2, re-start 
palbociclib at the same dose. 
 
Day 8 and/or 15 of the first 3 cycles: 
Continue palbociclib at current dose and repeat complete 
blood count monitoring within 1 week. 
 
Consider dose reduction in cases of prolonged ( 1 week) 
recovery from Grade 3 neutropenia or recurrent Grade 3 
neutropenia in subsequent cycles. 
Grade 3 neutropenia with 
fever  38.3°C and/or 
infection 
 
Withhold palbociclib until recovery to Grade  2. 
 
Resume at the next lower dose. 
Grade 4 a 
 
Withhold palbociclib until recovery to Grade  2 
 
Resume at the next lower dose. 
CTCAE  Common Terminology Criteria for Adverse Events. 
a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). 
 
Granulocyte-CSF may be used in the management of febrile neutropenia as clinically 
indicated. 
CDK4/6 inhibitors, including palbociclib, may cause rare but severe inflammation of the 
lungs, resulting in serious cases including fatalities.  All patients receiving palbociclib 
should be monitored for pulmonary symptoms indicative of ILD/pneumonitis 
(e.g., hypoxia, cough, dyspnea).  In patients who have new or worsening respiratory 

 
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symptoms and are suspected to have developed ILD/pneumonitis, interrupt palbociclib 
immediately and evaluate the patient.  Permanently discontinue palbociclib in patients 
with severe ILD/pneumonitis.  See Table 8 for management pneumonitis management 
guidelines. 
For all other non-hematologic toxicities assessed by the investigator as related to 
palbociclib, suggested guidelines for palbociclib dose modification are shown in Table 11 
(see local prescribing information). 
In general, the investigator may consider continuing palbociclib if the observed adverse 
event is not thought to be palbociclib-related.  Palbociclib does not need to be 
interrupted for hyperglycemia; however, careful consideration should be given to 
toxicities known to be associated with palbociclib.  Decisions on interruption of any of the 
study treatment components (inavolisib/placebo, palbociclib, fulvestrant) should be made 
independently of the others; i.e., one study treatment component alone may be 
interrupted for AE(s) associated with that medication without mandatory interruptions of 
the other study treatment components.  For non-hematologic toxicities attributed to the 
combination of inavolisib, palbociclib and fulvestrant, it is preferred to initially 
dose-reduce one drug (i.e., inavolisib or palbociclib), then the other drug (e.g., if 
inavolisib dose was reduced but toxicity persisted, then reduce the dose of palbociclib), 
depending upon the nature and severity of the toxicity.  However, if based on the 
investigator’s judgment there is a concern for overlapping toxicity then the doses of both 
drugs may be reduced.  Further dose de-escalation may be considered if the same 
toxicity recurs. 
Table 11 Palbociclib Dose Modification and Management:  
Non-Hematologic Toxicities 
CTCAE 
Grade 
Dose Modification 
Grade 1 or 
2 
 No dose adjustment is required. 
Grade  3 a 
 Withhold palbociclib until symptoms resolve to Grade  1 or Grade  2 (if not 
considered a safety risk for the patient). 
 Resume at the next lower dose. b 
CTCAE  Common Terminology Criteria for Adverse Events 
a If persisting despite optimal medical treatment. 
b See the local prescribing information for recommended dose reductions. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 

 
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signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
a study drug 

 
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 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above).  All adverse events, including those that lead to dose modifications or 
study treatment discontinuation, should be carefully evaluated for medical 
significance. 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
Grade  3 hyperglycemia 
 
Grade  3 rash 
 
Grade  3 diarrhea 
 
Grade  2 pneumonitis 
 
Grade  2 colitis or enterocolitis 
 
Grade  3 stomatitis or mucosal inflammation 
 
Grade  3 ALT or AST elevation 
 
Adverse events of special interest for general drug development: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6) 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 

 
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infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.2.4 
Selected Adverse Events to Monitor 
Additional data collection may occur for all grades of specific adverse events 
(e.g., pneumonitis, colitis/enterocolitis, rash, stomatitis, and ocular events) to enable a 
more detailed analysis of these events.  The Sponsor may ask sites to send confirmatory 
data for adverse events (e.g., CT scans and reports for pneumonitis or colitis; biopsy 
reports for colitis, rash).  The Sponsor may also ask sites to send tissue (e.g., biopsies 
from colitis or rash, if appropriate) and photographs (e.g., stomatitis, rash, or ocular 
events, if appropriate and with consent). 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.  
For each adverse event recorded on the Adverse Event eCRF, the investigator will 
assess seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
Mobile nurses will be properly trained by the MN vendor on how to identify and record all 
adverse events in accordance with the instructions and within the protocol-mandated 
reporting period.  The investigator must review and assess the adverse events prior to 
recording of the events in eCRF. 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 30 days after the 
final dose of any study drug (i.e., 30 days after the final study treatment with 
inavolisib/placebo or palbociclib or fulvestrant, whichever is last), or until initiation of 
another anti-cancer therapy, whichever occurs first.  After this period, the investigator 
should report any serious adverse events that are believed to be related to prior study 
drug treatment (see Section 5.6). 

 
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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 12 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 12 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily 
living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If any event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 

 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
(Table 13): 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 13 Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be individually assessed for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 

 
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5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe 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. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 

 
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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. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L (Normal Range: 3.5–5.0 mEq/mL) 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, unless the known or 
suspected cause changes (see Section 5.3.5.4 for details on recording persistent 
adverse events); while recurrent clinically significant laboratory abnormalities should be 
entered as separate Adverse Events. 

 
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5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF, unless the known or 
suspected cause changes (see Section 5.3.5.4 for details on recording persistent 
adverse events); while recurrent clinically significant vital sign abnormalities should be 
entered as separate Adverse Events. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 

 
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5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of underlying breast cancer should be recorded 
on the Death Attributed to Progressive Disease eCRF.  All other deaths that occur during 
the adverse event reporting period, regardless of relationship to study drug, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor (see 
Section 5.4.2).  An independent monitoring committee will monitor the frequency of 
deaths from all causes.  
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" may 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"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Breast Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.  Cases of clinical/symptomatic progression will not be considered 
as objective disease progression per RECIST v1.1, and should be reported only as a 

 
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reason for End of Treatment, when appropriate.  The Overall Tumor Assessment at such 
a timepoint should be reported strictly per RECIST v1.1. 
5.3.5.10 
 Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., biopsy, for study drug 
administration, perform an efficacy measurement for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
Hospitalization due solely to progression of the underlying cancer 
 
The following hospitalization scenario is not considered to be a serious adverse event, 
but should be reported as an adverse event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 

 
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 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, qualifies as an AESI or is a pregnancy, the event should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4).  For inavolisib/placebo, adverse events associated with special 
situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with inavolisib/placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 

 
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 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO-CTCAE or other PRO data by the 
Sponsor.  In addition, the Sponsor will make no attempt to reconcile patient reports of 
treatment-related symptoms (via PRO-CTCAE) with investigator reports of adverse 
events.  Sites are not expected to review the PRO-CTCAE or other PRO data for 
adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events  
(defined in Section 5.2.2; see Section 5.4.2 for details on reporting requirements)  

 
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 
Adverse events of special interest  
(defined in Section 5.2.3; see Section 5.4.2 for details on reporting requirements)  
 
Pregnancies  
(see Section 5.4.3 for details on reporting requirements)  
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Telephone No.: 
 44 1707 368309 (Welwyn Garden City, UK) 
Mobile Telephone No.: 
 44 (0) 7826066306 (Welwyn Garden City, UK) 
 
Telephone No.: 
 1 (650) 467-4557 (South San Francisco, CA, USA) 
Mobile Telephone No.: 
 1 (650) 438-8853 (South San Francisco, CA, USA) 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  

 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained, but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 30 days after the final dose of study drug, or until initiation 
of another anti-cancer therapy, whichever occurs first.  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 EDC system.  A report 
will be generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations 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.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur  30 days after the final dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 60 days after the final dose of study treatment.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study treatment 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 

 
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Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
98 days after the final dose of study drug.  The investigator should report the pregnancy 
on the paper Clinical Trial Pregnancy Reporting Form and submit the form to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form with additional 
information on the pregnant partner and the course and outcome of the pregnancy as it 
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 

 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures and all adverse events of special interest until a final outcome can be 
reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow-up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (defined as 30 days after the final 
dose of study treatment), all deaths, regardless of cause or relatedness, should be 
reported through use of the Long-Term Survival Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 

 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Inavolisib 
Inavolisib Investigator's Brochure 
Palbociclib 
Palbociclib SmPC 
Fulvestrant 
Fulvestrant SmPC 
SmPC  Summary of Product Characteristics. 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary efficacy objective for this study is to evaluate the efficacy of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the 
basis of PFS.  The primary efficacy analysis population will consist of all randomized 
patients grouped according to their assigned treatment at randomization based on IxRS. 
The safety analysis population consists of all patients who received at least one dose of 
study drug and is based on the treatment the patients actually received, that is, all 
patients who received at least one dose of inavolisib are included in the inavolisib plus 
palbociclib and fulvestrant group and all patients who received at least one dose of 
palbociclib and/or fulvestrant (and no inavolisib) are included in the palbociclib and 
fulvestrant group. 
The primary analysis is triggered by the number PFS events required to achieve 
85% power with 5% level of significance based on the assumptions outlined in 
Section 6.1.  The 194 events are expected to have occurred approximately 50 months 
after first patient randomized. 
Method for type I error control of secondary endpoints, detailed list of planned sensitivity 
analyses and further additional information to the protocol are specified in the Statistical 
Analysis Plan (SAP).  The SAP may override the analyses as described in the study 
protocol, as applicable.  Details on the planned interim futility analysis and safety reviews 
are outlined in the iDMC charter. 

 
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6.1 
DETERMINATION OF SAMPLE SIZE 
Estimates of the number of events required to demonstrate efficacy with regard to PFS 
are based on the following assumptions: 
 
Two-sided log-rank test at the 0.05 level of significance 
 
85% power to detect a hazard ratio for inavolisib plus palbociclib and fulvestrant 
versus placebo plus palbociclib and fulvestrant of 0.65, corresponding to an 
improvement in median PFS from 11 to 16.9 months 
 
Exponential distribution of PFS 
 
An annual dropout rate of 15% 
 
With these assumptions, 194 PFS events are required to achieve 85% power for the 
primary analysis.  The 320 patients will be enrolled over approximately 43 months and 
the primary analysis is expected to occur approximately 50 months after the first patient 
randomized. 
The minimal detectable difference for the PFS hazard ratio is 0.754 (i.e., an 
improvement from 11 to 14.6 months in median PFS). 
Of the 320 patients, no more than 60 patients will be allowed to have a PIK3CA tumor 
mutation not confirmed by the central F1LCDx assay.  As such, at least 260 patients will 
have the presence of (one or more) PIK3CA mutation(s) confirmed by the central 
F1LCDx assay (see Appendix 10). 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature treatment and study discontinuation will be listed 
and summarized.  Major protocol deviations, including violations of inclusion and/or 
exclusion criteria, will be listed and evaluated for their potential effects on the 
interpretation of study results. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (including age, disease history, and stage at 
study entry) will be summarized using means, standard deviations, medians, and ranges 
for continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall and by treatment group. 
6.4 
EFFICACY ANALYSES 
The analysis population for the efficacy analyses will consist of all randomized patients, 
with patients grouped according to their assigned treatment based on IxRS. 

 
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6.4.1 
Primary Efficacy Endpoint 
The primary efficacy objective for this study is to evaluate the efficacy of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant on the 
basis of the following endpoint: 
 
PFS, defined as the time from randomization to the first occurrence of disease 
progression or death from any cause (whichever occurs first), according to RECIST 
v1.1 
 
Data for patients without the occurrence of disease progression or death will be 
censored at the time of the last tumor assessment (or at the time of randomization if no 
tumor assessment was performed after the baseline visit).   
The primary efficacy analysis population will consist of all randomized patients grouped 
according to their assigned treatment at randomization.   
The primary analysis of the study will test the equality of PFS distributions in the 
inavolisib plus palbociclib and fulvestrant and placebo plus palbociclib and fulvestrant 
arms, as follows: 
H0:  PFS inavolisib plus palbociclib and fulvestrant = PFS placebo plus 
palbociclib and fulvestrant  
 
versus  
 
H1:  PFS inavolisib plus palbociclib and fulvestrant ≠ PFS placebo plus 
palbociclib and fulvestrant 
 
The treatment arms will be compared using a two-sided stratified log-rank test.  The 
stratification factors that will be used are the same as those for randomization:  
 
Visceral disease (yes or no)  
 
Endocrine resistance  
(primary or secondary according to ESMO ABC4 guidelines [Cardoso et al. 2018])  
 
Geographic region (North American/Western Europe, Asia, or other)  
The results from the unstratified log-rank test also will be provided.  
Survival curves in each treatment arm will be estimated using Kaplan-Meier estimates.  
The Kaplan-Meier estimates will provide a visual description of the survival curves and 
the difference across treatment arms.  In addition, the Kaplan-Meier approach will be 
used to estimate median PFS for each treatment arm.  The treatment effect will be 
quantified via a hazard ratio, computed from a stratified Cox proportional-hazards 
regression, including a 95% CI. 

 
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Sensitivity analyses will be conducted including only patients whose tumor PIK3CA 
mutation status has been confirmed centrally in blood and based on independent central 
review of response.  Further sensitivity analyses are defined in the SAP.  
6.4.2 
Secondary Efficacy Endpoints 
The type I errorcontrolled secondary endpoint of this study is OS, objective response 
rate, BOR, CBR, TTD in pain, TTD in physical functioning (PF), TTD in role functioning 
(RF), and TTD in Global Health Status/Quality of Life (GHS/QoL). OS will be formally 
tested only if PFS is statistically significant. For additional details, please refer to the 
SAP.  The primary efficacy analysis population is used for all secondary endpoints 
unless otherwise specified. 
6.4.2.1 
Overall Survival 
Overall survival after randomization is defined as the time from randomization to death 
from any cause.  Data for patients who are alive at the time of the analysis data cutoff 
will be censored at the last date they were known to be alive.  Data from patients without 
post-baseline information will be censored at the date of randomization. 
Analysis methodology is as outlined for the primary endpoint, PFS. 
An interim analysis of OS will be performed at the time of the primary analysis of PFS.  
In addition to the fixed sequence testing approach described before, a group-sequential 
design (Lan-DeMets with O’Brien-Fleming stopping boundaries) will be used to control 
the overall type I error rate (Lan and DeMets 1983) for OS interim and final analyses , 
which will occur approximately 19 months later, as defined in Section 6.9.1.1. 
The median OS in the control arm is assumed to be 35 months and the expected median 
OS in the experimental treatment arm is assumed to be 50 months, equating to a hazard 
ratio of 0.7.  At the time of the primary PFS analysis, on the basis of the above 
assumptions, 105 OS events are expected to have occurred. 153 OS events are expected 
to have occurred at the final analysis, which will occur approximately 19 months later.  
Of note, the endpoint of OS may not be met at the time of the final analysis because the 
data may not be mature.  Therefore, additional exploratory analyses of OS may be 
conducted after the final analysis at timepoints defined through study milestones, such 
as Health Authority interactions.  Please refer to the SAP for further details. 
6.4.2.2 
Objective Response Rate 
Objective response rate is defined as the proportion of patients with a CR and/or PR on 
at least two consecutive occasions  4 weeks apart, according to RECIST v1.1.  Patients 
who did not achieve a confirmed response and patients with no response assessments 
(for whatever reason) will be considered non-responders. 

 
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An estimate of the response rate and its 95% CI will be calculated using the 
Blyth-Still-Casella method for each treatment arm.  Response rates in the treatment 
arms will be compared using the stratified Mantel-Haenszel test.  Confidence intervals 
for the difference in objective response rates between the two arms will be determined 
using the normal approximation to the binomial distribution. 
6.4.2.3 
Best Overall Response Rate 
Best overall response rate is defined as the proportion of patients with a CR or PR, as 
determined according to RECIST v1.1.  Patients who did not achieve a CR or PR and 
patients with no response assessments (for whatever reason) will be considered non-
responders. 
Analysis methodology is as outlined for objective response rate.  
6.4.2.4 
Clinical Benefit Rate 
Clinical benefit rate is defined as the proportion of patients with a CR, PR, and/or SD for 
at least 24 weeks, as determined according to RECIST v1.1.  Patients who did not 
achieve clinical benefit and patients with no response assessments (for whatever 
reason) will be considered non-responders. 
Analysis methodology is as outlined for objective response rate. 
6.4.2.5 
Duration of Objective Response 
The analysis of DOR will include only patients who achieved an objective response to 
study treatment.  DOR is defined as the time from the first occurrence of a PR or CR to 
the first occurrence of disease progression or death from any cause (whichever occurs 
first), as determined according to RECIST v1.1.  Data for patients without the occurrence 
of disease progression or death will be censored at the time of the last tumor 
assessment. 
Analysis methodology is as outlined for the primary endpoint, PFS.  Comparisons 
between treatment arms using stratified and unstratified log rank test will be made for 
descriptive purposes.  Because the determination of DOR is based on a non-randomized 
subset of patients, formal hypothesis testing will not be performed. 
6.4.2.6 
Patient- Reported Outcomes (TTD of Pain, PF, RF, and 
GHS/QoL)  
To evaluate TTD in pain, the “worst pain” item from the BPI-SF will be assessed.  TTD is 
defined as the time from randomization to the first documentation of a 2-point increase 
from baseline in “worst pain.”  A 2-point change is defined as clinically meaningful 
(Mathias et al. 2010).  Patients who do not have an observed deterioration at the time of 
the clinical data cutoff will be censored at the last non-missing assessment date.  
Patients without a post-baseline assessment will be censored at the time of 
randomization. 

 
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Time to deterioration in PF, RF, and GHS/ QoL will be assessed.  TTD is defined as the 
time from randomization to the first documentation of a  10-point decrease from 
baseline in the specific scale: 
 
Physical Function (items 1 through 5) 
 
Role Function (items 6 and 7) 
 
Global Health Status (GHS)/Quality of Life (QoL) (items 29 and 30) 
Patients who do not have an observed deterioration at the time of the clinical data cutoff 
will be censored at the last non-missing assessment date.  Patients without a 
post-baseline assessment will be censored at the time of randomization. 
A  10-point change is defined as a clinically meaningful difference (Osoba et al. 1998) 
on all scales of the EORTC-QLQ-C30. 
6.4.3 
Exploratory Efficacy Endpoints 
6.4.3.1 
Exploratory Clinical Outcomes  
 
Time to end of next-line treatment (proxy for time to second objective disease 
progression [PFS2]), defined as the time from randomization to end or 
discontinuation of next-line treatment, or death from any cause (whichever occurs 
first).  Data for patients without the occurrence of second objective disease 
progression or death and patients who have not started next-line treatment will be 
censored at the last date they were known to be alive.  Data from patients without 
post-baseline information will be censored at the date of randomization.  Analysis 
methodology is as outlined for the primary endpoint, PFS. 
 
Time to first SRE, defined as the time from randomization to the first occurrence of 
an SRE.  An SRE is a pathologic fracture, radiation therapy to bone, cancer-related 
surgery to bone, or spinal cord compression.  Data from patients without the 
occurrence of an SRE will be censored at the last valid visit.  Data from patients 
without post-baseline information will be censored at the date of randomization.  
Analysis methodology is as outlined for the primary endpoint, PFS. 
 
6.4.3.2 
Exploratory Patient Reported-Outcome Analyses  
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) of linear 
transformed scores will be reported for the “worst pain” item of the BPI-SF, as well as all 
scales (symptoms, functional domains, and GHS/QoL) of the EORTC QLQ-C30 and 
BR23 questionnaire for each assessment timepoint.  The mean change of the linear 
transformed scores from baseline (and 95% CI using the normal approximation) will also 
be reported independently for each treatment arm.  Line charts depicting the mean and 
mean changes from the baseline assessment (and 95% CIs) of items and scales over 
time will be provided for each treatment arm.  In the event of incomplete data, for all 
questionnaire scales, if more than 50% of the constituent items are completed, a 
prorated score will be computed consistent with the scoring manuals and validation 
papers.  For scales with less than 50% of the items completed, the scale will be 

 
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considered as missing in accordance with the EORTC scoring manual guidelines 
(Fayers 2001). 
Patient-reported outcome completion, compliance rates, and reasons for missing data 
will be summarized at each timepoint by treatment arm for each measure in ITT patients.  
The compliance rate will be based on the total number of patients expected to complete 
the questionnaire at a particular timepoint. 
6.5 
SAFETY ANALYSES 
The safety analysis population consists of all patients who received at least one dose of 
study drug and is based on the treatment the patients actually received; that is, all 
patients who received at least one dose of inavolisib are included in the inavolisib plus 
palbociclib and fulvestrant group and all patients who received at least one dose of 
palbociclib and/or fulvestrant (and no inavolisib) are included in the palbociclib and 
fulvestrant group. 
The safety objective for this study is to evaluate the safety of inavolisib plus palbociclib 
and fulvestrant compared with placebo plus palbociclib and fulvestrant on the basis of 
the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
NCI CTCAE v5.0 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 
 
The exploratory safety objective for this study is to evaluate tolerability of inavolisib plus 
palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant from 
the patient's perspective, on the basis of the following endpoints: 
 
Presence, frequency of occurrence, severity, and/or degree of interference with 
daily function of selected symptomatic treatment toxicities as assessed through use 
of the NCI PRO-CTCAE and the “bother from side effects” item 
 
Change from baseline in symptomatic treatment toxicities, as assessed through use 
of the PRO-CTCAE and the “bother from side effects” item  
 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) and dose intensity will be summarized with descriptive 
statistics. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  All adverse events, serious adverse events, adverse 

 
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events leading to death, adverse events of special interest, and adverse events leading 
to study treatment discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment-emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized. 
Additionally, a shift table of selected laboratory tests will be used to summarize the 
baseline and maximum post-baseline severity grade.  Changes in vital signs and ECGs 
will be summarized.  
6.5.1 
Exploratory Analyses of PRO-CTCAE Data 
Patient-Reported Outcome-Common Terminology Criteria for Adverse Events analyses 
will be descriptive, with a focus on characterizing the pattern of symptomatic treatment 
toxicities over the course of the study.  The number and percentage of patients reporting 
each symptom and the change from baseline by category (frequency of occurrence, 
severity, interference) will be summarized at each assessment timepoint by treatment 
arm.  For items that are rated on a 5-point Likert scale, the maximum post-baseline 
score and change from baseline will be summarized by treatment arm.  
Results from these exploratory analyses will be presented separately from the safety 
analyses.  PRO-CTCAE data will be analyzed at the item level in line with current 
NCI recommendations for data handling (Basch et al. 2014).  Graphical representation of 
PRO-CTCAE data over time will also be provided.  PRO-CTCAE data will be 
summarized over time.  These analyses will also apply to the “bother from side effects of 
treatment” item.  The proportion of missing data at each assessment timepoint will also 
be summarized to facilitate interpretation of data. 
6.6 
PHARMACOKINETIC ANALYSES 
The PK analysis population will consist of patients who received at least one dose of 
study drug and is based on the treatment patients actually received; that is, all patients 
who received at least one dose of inavolisib are included in the inavolisib plus palbociclib 
and fulvestrant group and all patients who received at least one dose of palbociclib 
and/or fulvestrant (and no inavolisib) are included in the palbociclib and fulvestrant 
group. 
Individual and mean plasma concentration of inavolisib, palbociclib, and fulvestrant 
versus time data will be tabulated and plotted.  Inavolisib plasma concentration versus 
time data, together with information on dosing and patient characteristics, will be pooled 
and analyzed using a population PK (PopPK) analysis approach, as appropriate.  
Non-linear mixed-effect modeling will be used for the estimation of PopPK parameters 
for inavolisib.  Covariates such as patient demographics (e.g., age, sex, body size) may 
be tested for significance on PK parameters of interest. 

 
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The PK data may be combined with the safety, efficacy, and biomarker data for 
exposure-response modeling as an exploratory objective.  PK and 
PK/pharmacodynamics analyses may be reported in separate standalone reports.  
Additional PK analyses will be conducted as appropriate. 
6.7 
EXPLORATORY BIOMARKER ANALYSES  
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies to understand the association of these markers with study treatment response.  
Results will be presented in a separate report.   
6.8 
HEALTH STATUS UTILITY ANALYSES  
The EQ-5D-5L will be scored according to its manual (van Reenen and Janssen. 2015) 
(see Appendix 8).  Absolute score and change from baseline in EQ-5D-5L health utility 
index-based and VAS scores will be calculated at over time. 
6.9 
INTERIM ANALYSIS 
6.9.1 
Planned Interim Analysis 
An iDMC will convene to review cumulative safety data approximately every 4 months 
(see Section 3.1.2).  
One interim analysis for futility will be conducted after approximately 75 PFS events 
(33% of information) are observed.  The futility boundary is non-binding.  The cutoff is 
expected to occur 18 months after first patient enrolled and, hence, approximately 
265 patients will have been enrolled when the decision is available.  
As an additional safety monitoring measure, an interim safety review will be performed 
after the enrollment of the first 25 patients and treatment for at least three cycles. 
One interim analysis will be performed for OS at the time of the primary endpoint 
analysis. 
6.9.1.1 
Alpha-Spending Function for OS Analysis 
The type I error probability will be controlled by using a Lan-DeMets (O’Brien 
Fleming) α-spending function for the secondary endpoint, OS, at a 5% overall level of 
significance. The stopping boundaries to be used for the efficacy test will be calculated 
using the α-spending function approach described by Lan and DeMets (1983).  This 
function generates stopping boundaries that closely resemble the O’Brien-Fleming 
boundaries (O’Brien and Fleming 1979) (see Table 14). 

 
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Table 14 Stopping Boundaries for Efficacy at the Interim or Final OS 
Analysis 
Look 
p-Value Stopping 
Boundary  
(Effect Scale) 
Information 
Fraction 
First interim analysis 
0.0132 
(or hazard ratio 0.615) 
68% (105/153) 
Final analysis 19 months 
later 
0.0460 
(or hazard ratio 0.724) 
100% (153/153) 
 
The actual boundaries will be calculated at the time of OS analysis based on the 
observed information fraction (i.e. actual number of events observed at time of analysis 
over the total planned target number of events). For further details, refer to the SAP. 
6.10 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and data from 
other external vendors such as analytical labs will be sent directly to the Sponsor, using 
the Sponsor's standard procedures to handle and process the electronic transfer of 
these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
Patient-reported outcome data will be collected through the use of an electronic device 
provided by a vendor (see Section 6.12 for details). 
6.11 
ELECTRONIC CASE REPORT FORMS  
Electronic case report forms are to be completed through use of a Sponsor-designated 
EDC system.  Sites will receive training and have access to a manual for appropriate 
eCRF completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 

 
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All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
6.12 
ELECTRONIC PATIENT REPORTED OUTCOME DATA  
An electronic device will be used to capture PRO data.  The device is designed for entry 
of data in a way that is attributable, secure, and accurate, in compliance with FDA 
regulations for electronic records (21 CFR Part 11).  The data will be transmitted to a 
centralized database maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
6.13 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 

 
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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 6.15. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
6.14 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
6.15 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
study drugs, including eCRFs, electronic PRO data, Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for 15 years after completion or discontinuation of the study or for the length 
of time required by relevant national or local health authorities, whichever is longer.  
After that period of time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
7. 
ETHICAL CONSIDERATIONS 
7.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 

 
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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 or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
7.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Mobile Nursing Informed Consent Form, if applicable) will be provided 
to each site.  If applicable, it will be provided in a certified translation to the local 
language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain separate sections for any optional procedures.  
The investigator or authorized designee will explain to each patient the objectives, 
methods, and potential risks associated with each optional procedure.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
for any reason.  A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures.  Patients who decline to participate will 
not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before participation in the study.  The case history or clinical 
records for each patient shall document the informed consent process and that written 
informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy).  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 

 
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each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
7.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 8.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
7.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 

 
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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from FMI or the 
alternative, Sponsor-designated central testing laboratory where applicable).  The 
aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy in the study data publication (see Section 8.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 8.6). 
7.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.1.2). 
8. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
8.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
8.2 
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 

 
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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. 
8.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
8.4 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
8.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 200 sites globally will participate to enroll approximately 320 patients.  
Enrollment and randomization to treatment arms will occur through an IxRS, which will 
also be utilized to manage site drug supply.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
An iDMC will be utilized to monitor and evaluate patient safety throughout the study.  
The procedures describing the conduct of, and communication with, the iDMC will be 
described in a separate Charter.  
8.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 

 
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comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 7.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
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. 
8.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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9. 
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Appendix 1: Schedule of Activities 
  
Inavolisib—F. Hoffmann-La Roche Ltd 
 
164/Protocol WO41554, Version 8 
Assess.  assessment; BPI-SF  Brief Pain Inventory- Short Form; C  cycle; C1D1  Cycle 1, Day 1; CT  computed tomography; ctDNA  circulating 
tumor DNA; Discon  discontinuation; eCRF  electronic Case Report Form; ECOG PS  Eastern Cooperative Oncology Group Performance Status; 
EORTC QLQ-C30  European Organisation for Research and Treatment of Cancer Quality of Life–Core 30 Questionnaire; 
EORTC BR23  European Organisation for Research and Treatment of Cancer Breast Cancer 23 item Questionnaire; EQ-5D-5L  European Quality 
of Life 5-Dimension, 5-Level questionnaire; F/U  follow-up; FMI  Foundation Medicine Inc.; HbA1c  glycosylated hemoglobin; HDL  high-density 
lipoprotein; IM  intramuscular; INR  international normalized ratio; LDL  low-density lipoprotein; LHRH  luteinizing hormonereleasing hormone; 
MN  mobile nursing; MRI  magnetic resonance imaging; NCI  National Cancer Institute; NGS  next-generation sequencing; 
PK  pharmacokinetic; PRO  patient-reported outcome; PRO-CTCAE  Patient-Reported Outcomes Common Terminology Criteria for Adverse 
Events; PO  by mouth; progress.  progression; PTT  partial thromboplastin time; Q8W  every 8 weeks; Q12W  every 12 weeks ;QD  once a day; 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; TX  treatment; WGS  whole genome sequencing; yrs  years. 
Notes:  The study consists of a screening period of up to 28 days, a treatment period, a post-treatment follow-up period (which includes a “30-day 
safety follow-up” for all patients, and when applicable, a “post-treatment hyperglycemia follow-up”, and/or a “post-treatment tumor assessment 
follow-up with PRO collection”), and a survival follow-up period.  In the absence of unacceptable toxicities or unequivocal disease progression as 
determined by the investigator, patients may continue treatment with inavolisib/placebo plus palbociclib and fulvestrant until the end of the study.  
All assessments should be performed within 2 days of the scheduled visit, unless otherwise specified.  On treatment days, all assessments should 
be performed prior to dosing, unless otherwise specified.  Additional assessments may also be done at unplanned visits if clinically indicated.  The 
investigator should review local laboratory results, including CBC, chemistry panel, and glucose, prior to study treatment administration. 
 

Appendix 1: Schedule of Activities 
  
Inavolisib—F. Hoffmann-La Roche Ltd 
 
165/Protocol WO41554, Version 8 
For patients at participating sites who have provided written informed consent to participate in mobile nursing (MN) visits, the assessments or 
procedures shaded in gray in the table above may be performed by a trained mobile nurse at the patient's home. 
a SCREENING PERIOD - Perform within 28 days prior to Cycle 1, Day 1, with the exception of laboratory assessments, which must be obtained 
within 14 days prior to Cycle 1, Day 1.  Written informed consent is required before performing any study-specific tests or procedures and may 
be obtained at any time prior to such tests or procedures.  Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Day 1 may be used; such tests do not need to be repeated for screening.  Unless otherwise stated, 
screening assessments that are done within 2 days prior to Cycle 1, Day 1 do not need to be repeated on Cycle 1, Day 1.  Please note, a 
prescreening ICF may be signed and blood sample submitted for PIK3CA mutation assessment by the central F1Liquid assay before other 
screening procedures initiated.  
b TREATMENT DISCONTINUATION VISIT - Patients who discontinue study treatment permanently will return to the clinic for a treatment 
discontinuation visit within 30 days after their final dose of study drug (inavolisib/placebo, palbociclib, or fulvestrant, whichever is discontinued 
last).  The visit at which response assessment shows progressive disease may be used as the treatment discontinuation visit. 
c 30-DAY SAFETY FOLLOW-UP - Following study treatment discontinuation, all patients will be followed for safety for 30 days after final study 
treatment (including a 30-day follow-up clinic visit), or until the initiation of another anti-cancer therapy, whichever occurs first. 
d POST-TREATMENT HYPERGLYCEMIA FOLLOW-UP - Patients on anti-hyperglycemic agents for the treatment of hyperglycemia during the 
study treatment and those patients with events of hyperglycemia ongoing at the end of the 30-day safety follow-up, will undergo additional safety 
follow-up assessments monthly until resolution of their fasting glucose to baseline levels, complete down-titration of their anti-hyperglycemic 
medications, or up to approximately 3 months after the final dose of study treatment, even if the patient initiates another anti-cancer therapy 
subsequent to study treatment discontinuation.   
e POST-TREATMENT TUMOR ASSESSMENT FOLLOW-UP WITH PRO COLLECTION - Patients who discontinue active study treatment for 
reasons other than progression of disease or death will continue to have tumor assessments performed every 8 weeks (  7 days) for the first 
2 years from randomization and every 12 weeks ( 7 days) thereafter, and complete PRO assessments at those timepoints until documented 
disease progression or the initiation of another anti-cancer therapy, whichever occurs first.   
f SURVIVAL FOLLOW-UP PERIOD - After study treatment discontinuation and post-treatment follow-up, all patients will be followed for survival 
and all subsequent anti-cancer therapies.  These data will be collected approximately every 3 months until death, loss to follow-up, withdrawal of 
consent, or study termination by the Sponsor, whichever occurs first. 
g INFORMED CONSENT - Informed consent must be documented before any study-specific screening procedure is performed and may be 
obtained more than 28 days before initiation of study treatment. 
h VITAL SIGNS - Includes height, weight, respiratory rate, pulse rate, blood oxygenation (pulse oximetry), and systolic and diastolic blood pressure 
while the patient is in a seated position, and temperature.   

Appendix 1: Schedule of Activities 
  
Inavolisib—F. Hoffmann-La Roche Ltd 
 
166/Protocol WO41554, Version 8 
i COMPLETE PHYSICAL EXAMINATION - Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.   
j LIMITED PHYSICAL EXAMINATION - Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.   
k OPHTHALMIC EXAMINATION - Patients will undergo ophthalmic examinations at baseline during the screening period, at Cycle 6 ( 2 weeks) 
during the study treatment period, at study treatment discontinuation, and based on any ocular disturbances.  The ophthalmic examination 
should consist of a full ophthalmic exam with dilation and refraction with specific attention paid to lens examination and detailed documentation.  
In addition, patients will be asked if they have experienced any significant visual changes, pain, or sensitivity to light at each clinic visit.  Any new 
eye-related symptoms including significant change in vision, eye pain, or photophobia will be evaluated by an ophthalmologist.  All clinically 
significant findings must be reported as adverse events. 
l ECG - Triplicate 12-lead ECG recordings will be obtained at baseline to determine eligibility; otherwise, single 12-lead ECG recordings will be 
performed.  
m HEMATOLOGY- Hematology panel includes:  RBC count, hemoglobin, hematocrit, reticulocyte count, platelet count, WBC count with differential 
count (neutrophils, bands [optional], eosinophils, basophils, monocytes, lymphocytes, other cells; i.e., must be sufficient for the determination of 
ANCs, lymphocytes).  Laboratory samples should be drawn within 24 hours (all Cycle 1 and Cycle 2 visits) or within 48 hours prior to study drug 
administration at the clinic; results should be available to assess prior to dosing.  
n FASTING CHEMISTRY - Fasting (8-hour fast) blood chemistry panel (serum or plasma) includes: sodium, potassium, chloride, bicarbonate (or 
total carbon dioxide if considered standard-of-care for the region), BUN or urea, creatinine, glucose, calcium, magnesium, phosphate, total 
protein, albumin, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), total and direct bilirubin, and alkaline 
phosphatase (ALP).  Laboratory samples should be drawn within 24 hours (all Cycle 1 and Cycle 2 visits) or within 48 hours prior to study drug 
administration at the clinic; results for glucose, bilirubin, ALP, AST, and ALT should be available prior to dosing.  
o FSH AND PLASMA ESTRADIOL – For women not definitively confirmed as post-menopausal, FSH and plasma estradiol levels testing are 
required during screening to establish menopausal status.  For some localities, estradiol levels may also be determined from serum. 
p PREGNANCY TEST - Women of childbearing potential must have a negative serum pregnancy test result within 14 days of first dose of study 
treatment and serum or urine pregnancy tests will be performed on Day 1 of Cycles  2 and at study treatment discontinuation visit.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  For all other women, documentation must be present in medical 
history confirming that patient is not of childbearing potential.  
q URINALYSIS - Urinalysis (dipstick allowed) includes pH, specific gravity, glucose, protein, ketones, and blood; if clinically indicated, microscopic 
examination including sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria. 
r HbA1c - Assess at screening, every 3 cycles starting on Day 1 of Cycle 3 (e.g., Day 1 of Cycles 1, 3, 6, etc.), at treatment discontinuation visit, 
and monthly during the hyperglycemia safety follow-up. 

Appendix 1: Schedule of Activities 
  
Inavolisib—F. Hoffmann-La Roche Ltd 
 
167/Protocol WO41554, Version 8 
s FASTING GLUCOSE AND INSULIN - Fasting (8-hour fast) insulin and glucose sample.  Glucose levels may be obtained by glucometer 
(fingerstick).  Samples should be drawn within 24 hours (all Cycle 1 and Cycle 2 visits) or within 48 hours prior to study drug administration at the 
clinic; glucose results must be available and reviewed prior to dosing.  In addition, patients may be instructed to monitor fasting glucose more 
frequently via use of home glucometer.   
t FASTING LIPID PROFILE PLUS AMYLASE AND LIPASE - Fasting (8-hour fast) lipid profile (includes total cholesterol, HDL, LDL, and 
triglycerides), amylase and lipase will be assessed at screening, every 3 cycles (e.g., Day 1 of Cycles 3, 6, etc.), and at treatment discontinuation 
visit. 
u TUMOR ASSESSMENT - Tumor assessments are performed according to RECIST v1.1.  Post-baseline tumor assessments should be 
performed every 8 weeks (7 days) from Cycle 1, Day 1 during the first 2 years, and every 12 weeks (7 days) thereafter, regardless of dose 
delay, treatment interruption or early treatment discontinuation, and until disease progression.  At screening, bone scans or other institutional 
standard bone imaging should be acquired in all patients.  The method used for a patient (CT or MRI scan or photographic measurements) must 
be the same throughout the study.  A missed tumor assessment should be rescheduled as soon as possible.  Patients who discontinue study 
treatment for reasons other than disease progression or death will continue onto the “post-treatment tumor assessment follow-up with PRO 
collection” (refer to footnote “hh”). 
v PRE-TREATMENT TUMOR TISSUE SAMPLE (FRESH OR ARCHIVAL) FOR BIOMARKERS - Pre-treatment tumor tissue samples for 
biomarkers are mandatory and are to be collected fresh (preferred) within the study screening period or a recent archival tumor tissue sample 
can be submitted.  If only an archival tumor tissue sample is available, the sample should preferably be from the patient’s metastatic disease.  If 
none of these options are possible, please contact the Sponsor. 
w FRESH TUMOR TISSUE BIOPSY SAMPLE (OPTIONAL) - Patients may consent for fresh biopsies to be collected during treatment and/or at 
the time of disease progression.  Optional on-treatment fresh biopsies are to be performed between Days 15 and 22 of Cycle 1, approximately 
14 hours post-dose.  If possible, optional fresh biopsies at the time of disease progression should be obtained within 48 hours of the patient’s 
final dose of study treatment, but no later than initiation of subsequent anti-cancer therapy.  Whenever possible, optional on-treatment and 
disease progression tumor biopsies should be collected from the same or similar location as the pre-treatment tumor tissue sample.  
Participation in the Optional Research portion of the study is not available at sites in China.  
x BLOOD SAMPLE FOR ctDNA - Fresh blood sample collected at screening is required from all patients for submission to FMI, or to the 
alternative Sponsor-designated central testing laboratory in regions where FMI is not available. 
y PLASMA SAMPLE FOR SOMATIC MUTATION DETERMINATION - Plasma samples for somatic mutation determination are to be collected 
prior to dosing on Days 1 and 15 of Cycle 1, Day 1 of Cycle 2, then Day 1 of every third cycle thereafter beginning with Cycle 3 (i.e., Cycles 3, 6, 
9, etc.), and at the treatment discontinuation visit.  In the event of repeated attempts at a Cycle “x” Day 1, this sample is only collected at the first 
Day 1 attempt and not repeated.  For sites in China, only plasma samples collected at Cycle 1 Day 15 and the treatment discontinuation visit are 
required. 

Appendix 1: Schedule of Activities 
  
Inavolisib—F. Hoffmann-La Roche Ltd 
 
168/Protocol WO41554, Version 8 
z BLOOD SAMPLE FOR BIOMARKER NGS - Blood sample for NGS is to be collected prior to dosing on Day 1 of Cycle 1.  These samples are 
not to be collected at sites in China. 
aa BLOOD SAMPLE FOR WGS - Blood sample for WGS is to be collected prior to dosing on Day 1 of Cycle 1 unless prohibited by local 
regulations.  These samples are not to be collected at sites in China. 
bb Inavolisib/PLACEBO ADMINISTRATION - Inavolisib/placebo will be administered as 9-mg tablet dose PO QD on Days 128 of each 28-day 
cycle, beginning on Day 1 of Cycle 1.  In the event of a palbociclib dosing cycle delay on the planned Day 1 of any Cycle, inavolisib may continue 
QD dosing if medically appropriate.  For patients participating in MN, the mobile nurse will coordinate the administration of inavolisib/placebo, 
and can advise on the completion of the patient dosing diary. 
cc PALBOCICLIB ADMINISTRATION - Palbociclib will be administered as 125-mg capsule or tablet dose taken PO QD on Days 121 of each 28-
day cycle, beginning on Day 1 of Cycle 1.  In the event palbociclib administration is held due to an adverse event on Day 1 of a given cycle, the 
palbociclib dosing cycle should not begin until the patient is able to resume administration, which will correspond to a delayed Day 1 visit.  All 
subsequent visits in that cycle will be based on the delayed Day 1 visit.  As such, the cycle will be extended past 28 days.  If appropriate, 
Inavolisib/Placebo administration may be continued daily, and fulvestrant administration may be continued approximately every 4 weeks, 
independently from the start of the palbociclib dosing cycle.  For patients participating in MN, the mobile nurse will coordinate the administration 
of palbociclib if the MN visit corresponds with a palbociclib dosing day and can advise on the completion of the patient dosing diary. 
dd FULVESTRANT ADMINISTRATION - Fulvestrant will be administered as 500-mg IM injection (two IM injections of 250 mg each) on Days 1 and 
15 of Cycle 1, and then on Day 1 of each subsequent 28-day cycle, or approximately every 4 weeks independent of palbociclib cycles.  In the 
event of a palbociclib dosing cycle delay on the planned Day 1 of any Cycle, fulvestrant may continue dosing approximately every 4 weeks if 
medically appropriate.  For patients participating in MN, fulvestrant may be administered by a mobile nurse. 
ee CONCOMITANT MEDICATIONS - Medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment until 
30 days after the final dose of study treatment.  In addition, an Analgesics eCRF will be utilized to collect specific information regarding pain 
management at specific timepoints. 
ff LHRH AGONIST TREATMENT & MONITORING – When applicable, treatment with an LHRH agonist must begin  14 days prior to C1D1.  
LHRH agonist should be administered in a monthly formulation.  Patients receiving an LHRH agonist should be monitored at least every 3 
months to confirm complete ovarian function suppression.  For patients receiving LHRH agonist and participating in MN, LHRH agonist may be 
administered by a mobile nurse. 

Appendix 1: Schedule of Activities 
  
Inavolisib—F. Hoffmann-La Roche Ltd 
 
169/Protocol WO41554, Version 8 
gg ADVERSE EVENTS - After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by 
a protocol-mandated intervention should be reported. After initiation of study treatment, all adverse events will be reported until 30 days after the 
final dose of study treatment, or until initiation of another anti-cancer therapy, whichever occurs first.  After the end of treatment and the 30-day 
safety follow-up visit, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related 
to study drug treatment.  Mobile nurses will be properly trained by MN vendor on how to identify and record all adverse events in accordance 
with the instructions and within protocol-mandated reporting period.  The investigator must review and assess the adverse events prior to 
recording of the events in eCRF (Section 5.3). 
hh PATIENT-REPORTED OUTCOMES - Questionnaires will be self-administered before the patient receives any information on disease status, 
prior to the performance of all other assessments, and prior to the administration of study treatment, except that clinical laboratory samples may 
be collected prior to administration of PRO questionnaires.  Questionnaires EORTC QLQ-C30 (Appendix 4), BPI-SF worst pain item and EQ-5D-
5L (Appendix 8) will be administered at baseline (i.e., Day 1 of Cycle 1), on planned Day 1 of Cycles 2 and 3, at planned Day 1 of every other 
cycle starting at Cycle 5 (i.e., Cycle 5, Cycle 7, etc.), at the treatment discontinuation visit; during the post-treatment follow-up they will be 
completed every 8 weeks during the first 2 years, then every 12 weeks thereafter until PD.  The BR23 will be administered at baseline, planned 
Day 1 of Cycles 5, 11, 17 and every 6 cycles (e.g., Cycle 23, Cycle 29) through planned Cycle 47 Day 1, at the treatment discontinuation visit; 
during the post-treatment follow-up they will be completed every 8 weeks during the first 2 years, then every 12 weeks thereafter until PD.  On 
those cycles, the BR23 is to be given immediately after the QLQ-C30.  The NCI PRO-CTCAE (Appendix 7) will be administered at baseline 
(i.e., Day 1 of Cycle 1), on planned Days 1 and 15 of Cycles 13, on planned Day 1 of every other cycle thereafter (Cycle 5, Cycle 7, etc.), at 
treatment discontinuation visit, and during the “Post-treatment Tumor Assessment follow-up with PRO Collection”, when applicable (refer to 
footnote “u”).  The Day 1 PROs for any cycle are not to be completed again in the event that it is determined following completion of the PROs 
that the day 1 of the given palbociclib cycle will be delayed.  Additionally, the timing of any subsequent PRO assessments will be based on the 
actual Day 1 of the given cycle (e.g., if it is determined that the start of palbociclib at Cycle 3 will be delayed a week, the Day 15 PRO-CTCAE 
will occur two weeks after the start of palbociclib, and the Cycle 4 Day 1 assessment will occur when the next Day 1 administration of palbociclib 
is planned.  For patients participating in MN, if the Day 15 of Cycle 2 or 3 visit is conducted via MN, the mobile nurse should confirm that the 
PRO-CTCAE questionnaire has been completed via website prior to beginning the MN assessments.  For patients who permanently discontinue 
study treatment for reasons other than progressive disease, PROs will be completed according to the schedule of tumor assessments.  
Following disease progression, patients should have an additional PRO assessment during survival follow-up (i.e., at the first 90-day/3-month 
mark).  This PRO assessment may be conducted in clinic or via web portal if the patient is unable to attend. 
ii MID-CYCLE TELEPHONE CALL - Mid-cycle telephone call starting on Day 15 of Cycle 4 and continuing on Day 15 of every cycle thereafter.  
Telephone call from the site to the patient to assess adverse events as well as concomitant medications.  This telephone call will allow site staff 
to implement adequate adverse event management in a timely manner once clinic visits decrease to every 28 days. 

Appendix 1: Schedule of Activities 
  
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170/Protocol WO41554, Version 8 
jj POST-TREATMENT ANTI-CANCER THERAPY - After study treatment discontinuation, all patients will be followed for subsequent anti-cancer 
therapies.  These data will be collected via telephone calls and/or clinic visits during the post-treatment follow-up and survival follow-up, 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor, whichever occurs first. 
kk SURVIVAL - After study treatment discontinuation and post-treatment follow-up, all patients will be followed for survival.  These data will be 
collected via telephone calls and/or clinic visits approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study 
termination by the Sponsor, whichever occurs first. 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
172/Protocol WO41554, Version 8 
Appendix 3  
Schedule of Intense Pharmacokinetic Sampling in 
Chinese Patients 
Visit 
Timepoint 
Sample Type 
Cycle 1, Day 1 
Predose a 
Inavolisib PK (plasma) 
Palbociclib PK (plasma) 
Fulvestrant PK (plasma) 
0.5 hour post-dose ( 5 min) 
Inavolisib PK (plasma) 
1 hour post-dose ( 5 min) 
Inavolisib PK (plasma) 
2 hours post-dose ( 15 min) 
Inavolisib PK (plasma) 
3 hours ( 30 min)  
post-dose 
Inavolisib PK (plasma) 
Palbociclib PK (plasma) 
Fulvestrant PK (plasma) 
8 hours post-dose ( 30 min) 
Inavolisib PK (plasma) 
Cycle 1, Day 2 
24 hours post-dose ( 2 hr) 
Inavolisib PK (plasma) 
Cycle 1, Day 8 
Predose a 
Inavolisib PK (plasma) 
Palbociclib PK (plasma) 
Fulvestrant PK (plasma) 
Cycle 1, Day 15 
Predose a 
Inavolisib PK (plasma) 
Palbociclib PK (plasma) 
Fulvestrant PK (plasma) 
0.5 hour post-dose ( 5 min) 
Inavolisib PK (plasma) 
1 hour post-dose ( 5 min) 
Inavolisib PK (plasma) 
2 hours post-dose ( 15 min) 
Inavolisib PK (plasma) 
3 hours ( 30 min)  
post-dose 
Inavolisib PK (plasma) 
Palbociclib PK (plasma) 
Fulvestrant PK (plasma) 
8 hours post-dose ( 30 min) 
Inavolisib PK (plasma) 
Cycle 1, Day 16 
24 hours post-dose ( 2 hr) 
Inavolisib PK (plasma) 
Cycle 2, Day 15 
Predose a 
Inavolisib PK (plasma) 
Palbociclib PK (plasma) 
Fulvestrant PK (plasma) 
PK  pharmacokinetic. 
Notes:  Dose time on the day before and day of PK sampling should be accurately reported.   
PK sampling timepoint should be accurately reported. 
a 
The blood samples will optimally be obtained within 5 minutes prior to dosing but may be 
obtained up to 2 hours prior to dosing. 
 

 
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Appendix 4  
European Organisation for Research and Treatment of Cancer 
Quality of Life–Core 30 Questionnaire (EORTC QLQ-C30) 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study. 
 

Appendix 4: European Organisation for Research and Treatment of Cancer Quality of 
Life–Core 30 Questionnaire (EORTC QLQC30) 
 
Inavolisib—F. Hoffmann-La Roche Ltd 
174/Protocol WO41554, Version 8 
 
 

 
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Appendix 5  
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire, Breast Cancer Module 
(EORTC QLQ-BR23) 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study. 
 

Appendix 5: European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire, Breast Cancer Module (EORTC QLQ-BR23) 
 
Inavolisib—F. Hoffmann-La Roche Ltd 
176/Protocol WO41554, Version 8 

 
Inavolisib—F. Hoffmann-La Roche Ltd 
177/Protocol WO41554, Version 8 
Appendix 6  
Brief Pain Inventory-Short Form “Worst Pain” Item 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study. 
 
 
 

 
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Appendix 7  
National Cancer Institute Patient-Reported Outcomes Common 
Terminology Criteria for Adverse Events (NCI PRO-CTCAE) 
Items 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study. 
 
 

Appendix 7: National Cancer Institute Patient-Reported Outcomes Common Terminology 
Criteria for Adverse Events (NCI PRO-CTCAE) Items 
 
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Appendix 8  
European Quality of Life 5-Dimension, 5-Level (EQ-5D-5L) 
Questionnaire 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study. 
 
 
 
 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group

Appendix 8: European Quality of Life 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire 
 
Inavolisib—F. Hoffmann-La Roche Ltd 
181/Protocol WO41554, Version 8 

Appendix 8: European Quality of Life 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire 
 
Inavolisib—F. Hoffmann-La Roche Ltd 
182/Protocol WO41554, Version 8 

 
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Appendix 9  
Eastern Cooperative Oncology Group Performance Status 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light housework or office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.   
Up and about  50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair  50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead 
 

 
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Appendix 11  
Response Evaluation Criteria in Solid Tumors (RECIST):   
Modified Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions and/or lymph nodes will be categorized as measurable or 
non-measurable as described below. 
Measurable Tumor Lesions 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
                                            
 
 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid tumors: revised 
RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2 For consistency within this document, the section numbers and cross-references to other sections within 
the article have been deleted and minor formatting changes have been made. 

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Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be  15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and at follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement. 
Non-measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions.  
However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 

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Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 
Target Lesions:  Specifications by Methods of Measurements  
a. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
b. Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and  10 mm in diameter as assessed using calipers (e.g., skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When 
CT scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 

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be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised. 
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above. 
Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is  10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance the next largest lesion that can be measured reproducibly should 
be selected. 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of  15 mm by CT scan.  Only the short 

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axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm  30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis  10 mm but  15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of  10 mm are considered non-pathological and should not be 
recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
Response Criteria 
a. Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
 
Complete response (CR):  Disappearance of all target lesions 
 
Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum in the study (nadir), including baseline 
 
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 

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 
The appearance of one or more new lesions is also considered progression. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum in the study 
 
b. Special Notes on the Assessment of Target Lesions 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to  10 mm in the study.  This means 
that when lymph nodes are included as target lesions, the sum of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of  10 mm. 
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and in that case BML should not be ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion. 

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c. Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol. 
 
Complete response (CR):  Disappearance of all non-target lesions and 
(if applicable) normalization of tumor marker level 
 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
Progressive disease (PD):  Unequivocal progression of existing non-target lesions 
 
The appearance of one or more new lesions is also considered progression. 
 
d. Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will thus be extremely rare. 
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is 
seen, the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 

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Response Evaluation Criteria in Solid Tumors (RECIST):  Modified 
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nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial.  
Bone-Only Disease:3  Since bone lesions are not considered measurable, patients with 
bone-only disease will be evaluated for progression only.  Progression is defined as the 
appearance of new lytic lesions or other new bone destruction thought to be related to 
cancer by X-ray, CT scan or MRI, or a bone event requiring intervention (surgery) if not 
associated with trauma or other obvious cause.  Changes in bone scan or 18F NaF PET 
scan should not be used to define progression.  Any changes in bone imaging should be 
evaluated radiographically by X-ray, CT scan, or MRI to ascertain the presence of bone 
destruction versus a healing reaction.  The appearance of new lesions on bone scan or 
18F NaF PET scan may constitute progressive disease if associated with clinical 
symptoms suggestive of disease progression.  The occurrence of a pathologic fracture 
at a site previously recognized for bone disease may constitute progressive disease if 
not associated with trauma or other obvious cause.  Bone pain requiring radiation will 
constitute progressive disease.  Increase in pain at a site of previously recognized bone 
disease may constitute progressive disease if it is persistent and not associated with 
other obvious cause. 
e. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a 
CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
                                            
 
 
3  Reminder that patients with non-measurable (evaluable) bone-only disease are not to be 
enrolled in this study. 

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there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
Evaluation of Response 
a. Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (thus non-target) disease only, Table 2 is to be 
used. 
Table 1 
Timepoint Response:  Patients with Target Lesions 
(with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/-non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; 
PR  partial response; SD  stable disease. 
 

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Table 2 
Timepoint Response:  Patients with Non-Target Lesions 
Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since 
stable disease is increasingly used as an endpoint for assessment of efficacy in 
some trials; thus, assigning “stable disease” when no lesions can be measured is 
not advised. 
 
b. Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and during the study only two lesions were assessed, but 
those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint. 

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Table 3 
Best Overall Response When Confirmation Is Required 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration for SD 
was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration for SD 
was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration for SD 
was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration for SD 
was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration for SD 
was met; otherwise, NE 
NE 
NE 
NE 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the first 
timepoint.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
 
c. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size ( 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 

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descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment.  If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion. 
 

 
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Appendix 12  
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
Ductal carcinoma in situ 
Tis (Paget) 
Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast 
parenchyma.  Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and 
characteristics of the parenchymal disease, although the presence of Paget disease should still be noted 
T1 
Tumor  20 mm in greatest dimension 
   T1mi 
Tumor  1 mm in greatest dimension 
   T1a 
Tumor  1 mm but  5 mm in greatest dimension 
   T1b 
Tumor  5 mm but  10 mm in greatest dimension 
   T1c 
Tumor  10 mm but  20 mm in greatest dimension 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
 
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Tumor (T) 
T2 
Tumor  20 mm but  50 mm in greatest dimension 
T3 
Tumor  50 mm in greatest dimension 
T4 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules)a 
   T4a 
Extension to the chest wall b  
   T4b 
Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d'orange) of the skin that does not 
meet the criteria for inflammatory carcinoma 
   T4c 
Both T4a and T4b are present 
   T4d 
Inflammatory carcinoma 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Greene FL, Byrd DR, et al., eds.: AJCC Cancer Staging Manual. 8th ed.  New 
York, NY: Springer, 2017, pp 619620. 
DCIS  ductal carcinoma in situ. 
Note:  The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both.  Size 
should be measured to the nearest millimeter.  If the tumor size is slightly less than or greater than a cut-off for a given T classification, it is 
recommended that the size be rounded to the millimeter reading that is closest to the cut-off.  For example, a reported size of 1.1 mm is 
reported as 1 mm, or a size of 2.01 cm is reported as 2 cm.  Designation should be made with the subscript "c" or "p" modifier to indicate 
whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively.  In 
general, pathologic determination should take precedence over clinical determination of T size. 
a Invasion of the dermis alone does not qualify as T4.  
b 
Invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4. 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
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Regional Lymph Nodes (N) 
Clinical   
cNX a 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
cN0 
No regional lymph node metastases (by imaging or clinical examination) 
cN1 
Metastases to movable ipsilateral level I, II axillary lymph node(s) 
   cN1mi b Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm) 
cN2 
Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted 
   OR 
Metastases in ipsilateral mammary nodes in the absence of axillary lymph node metastases 
   cN2a 
Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures 
   cN2b 
Metastases only in ipsilateral internal mammary nodes and in the absence of axillary lymph node metastases 
cN3 
Metastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary lymph node involvement 
   OR 
Metastases in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases 
   OR 
Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement 
   cN3a 
Metastases in ipsilateral infraclavicular lymph node(s) 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
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Regional Lymph Nodes (N) 
Clinical   
   cN3b 
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
   cN3c 
Metastases in ipsilateral supraclavicular lymph node(s) 
Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle 
aspiration/core needle biopsy, respectively.  
a The eNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no 
documentation of physical examination of the axilla.  
b cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in 
cases treated with neoadjuvant therapy. 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
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Pathological (pN) 
pNX 
Regional lymph nodes cannot be assessed (e.g., not removed for pathologic study or previously removed) 
pN0 
No regional lymph node metastasis identified or ITCs only 
   pN0(i ) 
ITCs only (malignant cell clusters  0.2 mm) 
   pN0(mol ) 
Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detected 
pN1 
Micrometastases 
   OR 
Metastases in 1–3 axillary lymph nodes 
   AND/OR 
Clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy 
   pN1mi 
Micrometastases (approximately 200 cells  0.2 mm but none  2 mm) 
   pN1a 
Metastases in 1–3 axillary lymph nodes, at least one metastasis  2 mm 
   pN1b 
Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs 
   pN1c 
pN1a and pN1b combined 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
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Pathologic (pN) 
pN2 
Metastases in 4–9 axillary lymph nodes 
   OR 
positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases 
   pN2a 
Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit  2.0 mm) 
   pN2b 
Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative 
axillary nodes 
pN3 
Metastases in  10 axillary lymph nodes 
   OR 
Metastases in infraclavicular (Level III axillary) lymph nodes 
   OR 
Metastases in ipsilateral internal mammary lymph nodes detected by imaging in the presence of one or more positive Level I, II 
axillary lymph nodes 
   OR 
Metastases in  3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative 
ipsilateral internal mammary lymph nodes 
   OR 
Metastases in ipsilateral supraclavicular lymph nodes 
 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
Inavolisib—F. Hoffmann-La Roche Ltd 
203/Protocol WO41554, Version 8 
Pathologic (pN) 
   pN3a 
Metastases in  10 axillary lymph nodes (at least 1 tumor deposit  2.0 mm) 
   OR 
Metastases to the infraclavicular (Level III axillary lymph) nodes. 
   pN3b 
pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging) 
   OR 
pN2a in the presence of pN1b 
   pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
Note:  (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle 
biopsy, respectively, with NO further resection of nodes. 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
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Distant Metastases (M) 
M0 
No clinical or radiographic evidence of distant metastases* 
   cM0(i ) 
No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm 
detected  microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a 
patient without symptoms or signs of metastases 
M1 
Distant metastases detected by clinical and radiographic means (cM) and/or histologically proven metastases larger than 0.2 mm 
(pM) 
 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
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Anatomic Stage/Prognostic Groups a  
Stage 
T 
N 
Mc 
0 
Tis 
N0 
M0 
IA 
T1 
N0 
M0 
IB 
T0 
N1mi 
M0 
T1 
N1mi 
M0 
IIA 
T0 
N1 
M0 
T1 
N1 
M0 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
T1 
N2 
M0 
T2 
N2 
M0 
T3 
N1 
M0 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
T4 
N1 
M0 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 

Appendix 12: 
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
  
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Stage 
T 
N 
Mc 
IV 
Any T 
Any N 
M1 
a T1 includes T1mi.   
b T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.   
c M0 includes M0(i  ); The designation pM0 is not valid; any M0 should be clinical.  If a patient presents with M1 prior to neoadjuvant systemic 
therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.  Stage designation may be 
changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed within 4 months of 
diagnosis in the absence or disease progression, and provided the patient has not received neoadjuvant therapy.  
 

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