Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 631
Healthy volunteers: no

Brief summary:
This international, multicenter, randomized, double-blinded, placebo-controlled study is designed to compare the efficacy and safety of taselisib + fulvestrant with that of placebo + fulvestrant in postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, oncogene that encodes for phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA)-mutant, unresectable, locally advanced or metastatic breast cancer after recurrence or progression during or after an aromatase inhibitor (AI) therapy. There will be a 2:1 randomization to the taselisib arm versus the placebo arm. Enrollment will be enriched for participants with PIK3CA mutant tumors via central testing. The anticipated duration of the study is approximately 3.5 years.

Detailed description:

Arms:
arm 1: Participants received taselisib 4 milligrams (mg) taken orally QD beginning at Cycle 1, Day 1 and fulvestrant 500 mg by IM injection at Cycle 1, Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle until disease progression, unacceptable toxicity, or study termination by the Sponsor. arm 2: Participants received placebo taken orally once daily (QD) beginning at Cycle 1, Day 1, and fulvestrant 500 mg administered by intramuscular (IM) injection at Cycle 1, Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle until disease progression, unacceptable toxicity, or study termination by the Sponsor.

Interventions: intervention 1: Taselisib intervention 2: Placebo intervention 3: Fulvestrant
Intervention descriptions: intervention 1: Taselisib 4 mg was administered as two tablets of 2 mg each as per the schedule specified in the respective arm. intervention 2: Placebo matching to taselisib was administered as per the schedule specified in the respective arm. intervention 3: Fulvestrant 500 mg was administered as two IM injections of 250 mg each as per the schedule specified in the respective arms.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase III, Double-Blind, Placebo-Controlled, Randomized 
Study of Taselisib Plus Fulvestrant Versus Placebo Plus 
Fulvestrant in Postmenopausal Women With Estrogen Receptor-
Positive and HER2-Negative Locally Advanced or Metastatic 
Breast Cancer Who Have Disease Recurrence or Progression 
During or After Aromatase Inhibitor Therapy 
NCT Number: 
NCT02340221 
Document Dates: 
Protocol Version 4: 24 June 2018 
Statistical Analysis Plan (SAP) Version 2: 3 March 2017 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
TaselisibF. Hoffmann-La Roche Ltd
Protocol GO29058, Version 4
PROTOCOL
TITLE:
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED STUDY OF TASELISIB PLUS 
FULVESTRANT VERSUS PLACEBO PLUS FULVESTRANT 
IN POSTMENOPAUSAL WOMEN WITH ESTROGEN 
RECEPTOR-POSITIVE AND HER2-NEGATIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER WHO
HAVE DISEASE RECURRENCE OR PROGRESSION 
DURING OR AFTER AROMATASE INHIBITOR THERAPY
PROTOCOL NUMBER:
VERSION NUMBER:
EUDRACT NUMBER:
IND NUMBER:
TEST PRODUCT:
MEDICAL MONITOR:
GO29058/ NCT02340221
4
2014-003185-25
121658
Taselisib (RO5537381, GDC-0032) 
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
13 October 2014
DATES AMENDED:
Version 2:  10 December 2015
Version 3:  15 January 2017
Version 4: See electronic date stamp below.
24-Jun-2018 10:41:30
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Taselisib—F. Hoffmann-La Roche Ltd
2/Protocol GO29058, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
The primary progression-free survival (PFS) analysis was conducted in January 2018.  
At that time, the addition of taselisib to fulvestrant showed a statistically significant 
improvement in investigator-assessed PFS in patients with PIK3CA-mutant tumors. 
Median PFS increased from 5.4 months in the placebo arm to 7.4 months in the taselisib 
arm (stratified hazard ratio0.70, p-value0.0037). Patients treated with taselisib 
(versus placebo) experienced more serious adverse events (32.0% vs 8.9%), had higher 
rates of Grade 3 adverse events  (49.5% vs 16.4%), had more frequent adverse events 
leading to discontinuation of taselisib/placebo (16.8% vs 2.3%), and had a slightly 
increased incidence of Grade 5 adverse events (1.9% vs 0.5%). The clinical benefit of 
the combination of taselisib and fulvestrant was considered modest, and the overall 
tolerability was limited.
On the basis of the results, the Sponsor decided to simplify or limit certain protocol 
assessments because sufficient data have been gathered for these assessments.  
Therefore, the primary goals of this amendment are to simplify regular tumor 
assessments, reduce the timeframe of the overall survival (OS) follow-up, and limit 
assessments in support of exploratory analyses.  Safety assessments and regular clinic 
visits (days that fulvestrant is administered) will remain unchanged.
Changes to the protocol, along with a rationale for each change, are summarized below:

Sections 1.3.2, 5.1.1.1.1, and 5.1.1.1.8 were updated with new taselisib adverse 
drug reactions detected in the primary PFS analysis and with management 
guidelines for infection.

Sections 3.1, 4.5.3, 4.5.5, and Appendix 1 were updated to indicate that, after 
approximately the end of August 2018, tumor assessments may be conducted per 
local standard of care because sufficient data have been gathered for these 
assessments.

Sections 3.1, 4.5.3, 4.5.5, 4.5.6, 4.5.11, 4.6.1, Appendix 1, and Appendix 2 were 
updated to indicate that, after approximately the end of August 2018, the following 
assessment are no longer required as sufficient data have been gathered for these 
assessments:
Tumor assessments for patients who are discontinued from study treatment for 
reasons other than disease progression and tumor assessments 46 weeks after 
disease progression
All patient-reported outcome (PRO) assessments
Survival and subsequent anti-cancer therapies after study treatment 
discontinuation
Eastern Cooperative Oncology Group (ECOG) Performance Status
Optional post-progression core tumor biopsy and Roche Clinical Repository 
(RCR) blood samples (for DNA extraction)


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3/Protocol GO29058, Version 4
Plasma samples for pharmacokinetic (PK) and exploratory research and blood 
samples for next-generation sequencing (NGS) and pharmacogenetic 
assessment

Sections 3.1, 5.3.5.7, 5.7, 6.9.1, and 9.4 were updated to clarify the independent 
Data Monitoring Committee (iDMC) will only oversee safety monitoring until the 
primary PFS analysis has been completed and the Sponsor is unblinded.

Section 3.2 was updated to change the definition for the end of the global study to 
when the last patient, last visit (LPLV) has occurred or safety follow-up is received 
from the last patient (28 days after the last dose of study drug), whichever occurs 
later, or when the Sponsor decides to stop the study.

Sections 4.2 and 6.4.2.2 were updated to clarify that, after approximately the end of 
August 2018, unblinding is permitted at the discretion of the investigator or Sponsor 
because the primary PFS analysis will have been competed, and blinding is no 
longer required.

Section 4.4.2 was updated to reduce, after approximately the end of August 2018, 
the list of prohibited therapies requiring Medical Monitor approval to initiate because
the primary PFS analysis has been completed and these restrictions are no longer 
required.

Section 4.6.2 was updated to indicate that patients must discontinue study drugs if 
they experience disease progression (as assessed by the investigator) in order to 
align with Section 3.1.

Sections 5.5.1 and Appendix 1 were updated to clarify that adverse event follow-up 
will not be done after a patient is no longer being followed for survival because
patients will have been withdrawn from the study at that point.

Sections 6.4.2.2 and 6.9.1 were updated to indicate that the OS follow-up has been 
limited to one additional analysis because sufficient data have been gathered for 
this assessment. This additional OS analysis coincides with the originally planned 
second OS interim analysis.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Taselisib—F. Hoffmann-La Roche Ltd
4/Protocol GO29058, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Estrogen ReceptorPositive, 
HER2-Negative Advanced or Metastatic Breast 
Cancer................................................................................... 26
1.2
Background on the PI3K/AKT/MTOR Pathway 
and Breast Cancer................................................................. 27
1.3
Background on Taselisib ....................................................... 29
1.3.1
Taselisib Nonclinical Data...................................................... 29
1.3.2
Taselisib Clinical Data ........................................................... 30
1.3.3
Clinical Pharmacokinetics of Taselisib................................... 31
1.4
Background on Fulvestrant.................................................... 33
1.4.1
Clinical Pharmacokinetics of Fulvestrant ............................... 34
1.5
Study Rationale and Benefit-Risk Assessment...................... 34
2.
OBJECTIVES.............................................................................................. 37
2.1
Efficacy Objectives ................................................................ 37
2.2
Safety Objective .................................................................... 38
2.3
Pharmacokinetic Objective .................................................... 38
2.4
Patient-Reported Outcome Objective .................................... 38
2.5
Exploratory Objectives........................................................... 38
3.
STUDY DESIGN......................................................................................... 39
3.1
Description of Study .............................................................. 39
3.2
End of Study.......................................................................... 42
3.3
Rationale for Study Design.................................................... 42
3.3.1
Rationale for Patient Population ............................................ 42
3.3.2
Rationale for China Extension Cohort ................................... 43
3.3.3
Rationale for the Control Treatment ...................................... 43
3.3.4
Rationale for Double-Blind Design......................................... 43
3.3.5
Rationale for Taselisib Dose and Schedule........................... 43
3.3.5.1
Safety Rationale .................................................................... 43


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3.3.5.2
Efficacy-Response Rationale................................................. 44
3.3.6
Rationale for PK Sampling and Schedule.............................. 44
3.3.7
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 44
3.3.8
Rationale for Biomarker Assessments................................... 45
3.3.9
Tissue and Circulating Biomarker Assessments.................... 45
3.3.9.1
PIK3CA Mutation Status........................................................ 45
3.3.9.2
Phosphatase Tensin Homolog Expression 
Analysis ................................................................................. 45
3.3.9.3
Estrogen Receptor and Progesterone Receptor 
Analysis ................................................................................. 46
3.3.9.4
Sequencing of Genes Related to Resistance to 
PI3K Inhibitors ....................................................................... 46
3.3.9.5
Blood Sample for Next-Generation Sequencing.................... 46
3.3.9.6
RNA and DNA Analysis ......................................................... 46
3.3.9.7
Plasma Sample for Somatic Tumor Mutation 
Analysis ................................................................................. 46
3.3.9.8
Blood Sample for the Detection of Plasma 
Protein Biomarkers ................................................................ 47
3.3.9.9
Optional Tumor Biopsy Sample at the Time of 
Disease Progression ............................................................. 47
3.3.9.10
Pharmacokinetic Sample Collection Schedule ...................... 47
3.3.9.11
DNA for Exploratory Pharmacogenetic 
Polymorphisms...................................................................... 48
3.4
Outcome Measures ............................................................... 49
3.4.1
Efficacy Outcome Measures.................................................. 49
3.4.2
Safety Outcome Measures .................................................... 49
3.4.3
Pharmacokinetic Outcome Measure...................................... 49
3.4.4
Patient-Reported Outcome Measure ..................................... 49
3.4.5
Exploratory Outcome Measures ............................................ 50
3.4.6
Exploratory Health Economic Outcome Measure.................. 50
4.
MATERIALS AND METHODS .................................................................... 50
4.1
Patients.................................................................................. 50
4.1.1
Inclusion Criteria.................................................................... 50
4.1.2
Exclusion Criteria................................................................... 52


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4.2
Method of Treatment Assignment and Blinding..................... 54
4.3
Study Treatment.................................................................... 56
4.3.1
Formulation, Packaging, and Handling.................................. 56
4.3.1.1
Taselisib ................................................................................ 56
4.3.1.2
Fulvestrant............................................................................. 56
4.3.2
Dosage, Administration, and Compliance.............................. 56
4.3.2.1
Taselisib ................................................................................ 56
4.3.2.2
Placebo.................................................................................. 56
4.3.2.3
Fulvestrant............................................................................. 57
4.3.3
Investigational Medicinal Product Accountability ................... 57
4.3.4
Post-Study Access to Taselisib ............................................. 57
4.4
Concomitant Therapy ............................................................ 58
4.4.1
Permitted Therapy................................................................. 58
4.4.2
Prohibited Therapy ................................................................ 59
4.5
Study Assessments ............................................................... 60
4.5.1
Informed Consent Forms and Screening Log........................ 60
4.5.2
Medical History and Demographic Data ................................ 61
4.5.3
Physical Examinations........................................................... 61
4.5.4
Vital Signs.............................................................................. 62
4.5.5
Tumor and Response Evaluations......................................... 62
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64
4.5.7
Assay Methods...................................................................... 66
4.5.7.1
Mutational Analysis for PIK3CA............................................. 66
4.5.7.2
Analysis of Phosphatase Tensin Homolog 
Expression............................................................................. 67
4.5.7.3
Progesterone Receptor Analysis ........................................... 67
4.5.7.4
Circulating Tumor DNA Analysis ........................................... 67
4.5.7.5
Messenger RNA Expression Profiling.................................... 67
4.5.7.6
Tumor Somatic Mutation Analysis ......................................... 67
4.5.7.7
Copy Number Analysis .......................................................... 68
4.5.7.8
Plasma Biomarker Analyses.................................................. 68
4.5.7.9
Plasma Pharmacokinetic Samples ........................................ 68
4.5.7.10
Pharmacogenetic Polymorphism Assay ................................ 68


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4.5.8
Electrocardiograms................................................................ 68
4.5.9
Patient-Reported Outcomes .................................................. 69
4.5.10
Assessments at Study Drug Discontinuation Visit ................. 70
4.5.11
Follow-Up Assessments ........................................................ 70
4.5.12
Samples for Roche Clinical Repository.................................. 71
4.5.12.1
Overview of the Roche Clinical Repository............................ 71
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 71
4.5.12.3
Sample Collection.................................................................. 71
4.5.12.4
Confidentiality........................................................................ 72
4.5.12.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 73
4.5.12.6
Withdrawal from the Roche Clinical Repository..................... 73
4.5.12.7
Monitoring and Oversight....................................................... 73
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 74
4.6.1
Patient Discontinuation.......................................................... 74
4.6.2
Study Drug(s) Discontinuation............................................... 74
4.6.3
Study and Site Discontinuation.............................................. 75
5.
ASSESSMENT OF SAFETY....................................................................... 75
5.1
Safety Plan ............................................................................ 75
5.1.1
Management of Selected Toxicities Observed 
with Taselisib in Clinical Studies............................................ 75
5.1.1.1
Dose Modification of Taselisib/Placebo due to 
Toxicity .................................................................................. 76
5.1.2
Safety Plan for Fulvestrant .................................................... 85
5.1.2.1
General Guidance for Dose Modifications and 
Delays for Fulvestrant............................................................ 85
5.2
Safety Parameters and Definitions ........................................ 86
5.2.1
Adverse Events ..................................................................... 86
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 86
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 87
5.2.4
Events to Monitor................................................................... 88


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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 88
5.3.1
Adverse Event Reporting Period ........................................... 88
5.3.2
Eliciting Adverse Event Information....................................... 88
5.3.3
Assessment of Severity of Adverse Events ........................... 89
5.3.4
Assessment of Causality of Adverse Events ......................... 89
5.3.5
Procedures for Recording Adverse Events............................ 90
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 90
5.3.5.2
Adverse Events that are Secondary to Other 
Events.................................................................................... 90
5.3.5.3
Persistent or Recurrent Adverse Events................................ 91
5.3.5.4
Abnormal Laboratory Values ................................................. 91
5.3.5.5
Abnormal Vital Sign Values ................................................... 92
5.3.5.6
Abnormal Liver Function Tests.............................................. 93
5.3.5.7
Deaths ................................................................................... 93
5.3.5.8
Preexisting Medical Conditions.............................................. 94
5.3.5.9
Lack of Efficacy or Worsening of Metastatic 
Breast Cancer........................................................................ 94
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 94
5.3.5.11
Adverse Events Associated with an Overdose ...................... 94
5.3.5.12
Patient-Reported Outcome Data ........................................... 95
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 95
5.4.1
Emergency Medical Contacts................................................ 96
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 96
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 96
5.4.2.2
Events That Occur after Study Drug Initiation........................ 96
5.4.3
Reporting Requirements for Pregnancies.............................. 97
5.4.3.1
Pregnancies in Female Patients............................................ 97
5.4.3.2
Abortions ............................................................................... 97
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 97
5.5
Follow-Up of Patients after Adverse Events .......................... 97
5.5.1
Investigator Follow-Up........................................................... 97


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5.5.2
Sponsor Follow-Up ................................................................ 98
5.6
Post-Study Adverse Events................................................... 98
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 98
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 99
6.1
Determination of Sample Size ............................................... 99
6.2
Summaries of Conduct of Study.......................................... 101
6.3
Summaries of Treatment Group Comparability ................... 101
6.4
Efficacy Analyses ................................................................ 101
6.4.1
Primary Efficacy Endpoint.................................................... 101
6.4.2
Secondary Efficacy Endpoints............................................. 103
6.4.2.1
Overall Objective Response Rate........................................ 103
6.4.2.2
Overall Survival ................................................................... 103
6.4.2.3
Clinical Benefit Rate ............................................................ 105
6.4.2.4
Duration of Objective Response.......................................... 105
6.4.2.5
BICR-Assessed PFS ........................................................... 105
6.5
Safety Analyses................................................................... 105
6.6
Pharmacokinetic Analyses................................................... 106
6.7
Patient-Reported Outcome Analyses .................................. 106
6.8
Exploratory Analyses........................................................... 107
6.8.1
Biomarker Analyses............................................................. 107
6.8.2
Pharmacokinetic Assays...................................................... 107
6.8.3
Pharmacogenetic Analysis .................................................. 107
6.9
Interim Analysis ................................................................... 107
6.9.1
Planned Interim Analysis ..................................................... 107
6.10
China Subpopulation Analysis............................................. 109
7.
DATA COLLECTION AND MANAGEMENT ............................................. 109
7.1
Data Quality Assurance....................................................... 109
7.2
Electronic Case Report Forms............................................. 110
7.3
Source Data Documentation................................................ 110
7.4
Use of Computerized Systems ............................................ 111
7.5
Retention of Records........................................................... 111


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8.
ETHICAL CONSIDERATIONS.................................................................. 111
8.1
Compliance with Laws and Regulations .............................. 111
8.2
Informed Consent................................................................ 112
8.3
Institutional Review Board or Ethics Committee.................. 113
8.4
Confidentiality...................................................................... 113
8.5
Financial Disclosure ............................................................ 114
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 114
9.1
Study Documentation .......................................................... 114
9.2
Protocol Deviations.............................................................. 114
9.3
Site Inspections ................................................................... 114
9.4
Administrative Structure....................................................... 114
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 115
9.6
Protocol Amendments ......................................................... 116
10. REFERENCES ......................................................................................... 117
LIST OF TABLES
Table 1
Clinical Pharmacology Studies in Healthy Subjects.................... 32
Table 2
Overall Dose Modification Guideline for Taselisib-Related 
Adverse Events........................................................................... 76
Table 3
Management Guidelines for Diarrhea and Colitis........................ 78
Table 4
Management Guidelines for Stomatitis and Oral Mucositis......... 80
Table 5
Management Guidelines for Pneumonitis ................................... 81
Table 6
Management Guidelines for Rash............................................... 82
Table 7
Management Guidelines for Hyperglycemia ............................... 83
Table 8
Taselisib/Placebo Dose Delay and Modification Guidelines 
for Other Clinically Significant Adverse Events ........................... 85
Table 9
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in National Cancer Institute Common 
Terminology Criteria for Adverse Events .................................... 89
Table 10
Causal Attribution Guidance ....................................................... 90
Table 11
PFS Analyses ........................................................................... 102
Table 12
Analyses for OS if the First Interim OS Analysis Occurs at 
the Time of the Interim Efficacy Analysis of 
Investigator-Assessed PFS....................................................... 104


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Table 13
Analyses for OS if the First Interim OS Analysis Occurs at 
the Time of the Final Efficacy Analysis of 
Investigator-Assessed PFS....................................................... 104
LIST OF FIGURES
Figure 1
Schematic of Randomized Controlled Study GO29058 
(Global Study)............................................................................. 40
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 124
Appendix 2
Schedule for Collection of Pharmacokinetic and Exploratory 
Biomarker Samples................................................................... 131
Appendix 3
Mutations Detected by the cobas PIK3CA Mutation Test ......... 132
Appendix 4
Eastern Cooperative Oncology Group Performance Status...... 133
Appendix 5
Inhibitors of PI3K/AKT/mTOR Signaling Pathway..................... 134
Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1 
Modified Excerpt from Original Publication ............................... 135
Appendix 7
Patient-Reported Outcome Measure:  QLQ-C30 ...................... 146
Appendix 8
Patient-Report Outcome Measure:  Modified QLQ-BR23 ......... 148
Appendix 9
Exploratory Health Economic Outcome Measure:  EQ-5D ....... 150


Taselisib—F. Hoffmann-La Roche Ltd
12/Protocol GO29058, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED STUDY OF 
TASELISIB PLUS FULVESTRANT VERSUS PLACEBO 
PLUS FULVESTRANT IN POSTMENOPAUSAL WOMEN
WITH ESTROGEN RECEPTOR-POSITIVE AND 
HER2-NEGATIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE DISEASE 
RECURRENCE OR PROGRESSION DURING OR AFTER 
AROMATASE INHIBITOR THERAPY
PROTOCOL NUMBER:
GO29058
VERSION NUMBER:
4
EUDRACT NUMBER:
2014-003185-25
IND NUMBER:
121658
TEST PRODUCT:
Taselisib (RO5537381, GDC-0032)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form to your local study monitor.  Please retain a 
copy for your study files.


Taselisib—F. Hoffmann-La Roche Ltd
13/Protocol GO29058, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED STUDY OF TASELISIB PLUS FULVESTRANT 
VERSUS PLACEBO PLUS FULVESTRANT IN 
POSTMENOPAUSAL WOMEN WITH ESTROGEN 
RECEPTOR-POSITIVE AND HER2-NEGATIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER WHO HAVE 
DISEASE RECURRENCE OR PROGRESSION DURING OR AFTER 
AROMATASE INHIBITOR THERAPY
PROTOCOL NUMBER:
GO29058
VERSION NUMBER:
4
EUDRACT NUMBER:
2014-003185-25
IND NUMBER:
121658
TEST PRODUCT:
Taselisib (RO5537381, GDC-0032)
PHASE:
III
INDICATION:
ER-positive/HER2-negative locally advanced or metastatic breast 
cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To compare the efficacy between taselisib fulvestrant versus placebo fulvestrant as 
measured by investigator-assessed progression-free survival (PFS) in patients with 
PIK3CA-mutant tumors
The secondary efficacy objectives for this study are as follows:

To compare the efficacy between taselisibfulvestrant versus placebofulvestrant as 
measured by overall survival (OS) in patients with PIK3CA-mutant tumors

To compare the overall objective response rate (ORR) between taselisib fulvestrant versus 
placebofulvestrant in patients with PIK3CA-mutant tumors, on the basis of tumor 
assessments made by the investigator

To estimate the duration of objective response (DOR) within taselisibfulvestrant versus 
placebofulvestrant in patients with PIK3CA-mutant tumors, on the basis of tumor 
assessments made by the investigator

To compare the clinical benefit rate (CBR) between taselisib fulvestrant versus 
placebo fulvestrant in patients with PIK3CA-mutant tumors, on the basis of tumor 
assessments made by the investigator

To compare the efficacy between taselisib fulvestrant versus placebo fulvestrant as 
measured by PFS determined by blinded independent central review (BICR) in patients with 
PIK3CA-mutant tumors


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Safety Objective
The safety objective for this study is to evaluate the safety of taselisib fulvestrant versus 
placebo fulvestrant in patients with locally advanced or metastatic breast cancer (MBC) in all 
randomized patients who receive at least one dose of taselisib/placebo or fulvestrant, 
regardless of the PIK3CA-mutation status of their tumors, and separately in the subgroups of 
patients with and without detectable PIK3CA-mutant tumors.
Pharmacokinetic Objective
The pharmacokinetic objective for this study is to evaluate the pharmacokinetics of taselisib 
when taken with fulvestrant
Patient-Reported Outcome Objective
The patient-reported outcome (PRO) objective for this study is as follows:

To evaluate and compare PROs of treatment-related symptoms, patient functioning, and 
health-related quality-of-life (HRQoL) as measured by the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 
Core 30 (QLQ-C30) and the modified Breast Cancer Module (QLQ-BR23) between the 
taselisib fulvestrant versus placebo fulvestrant treatment arms
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the PFS, ORR, CBR, and DOR of taselisib fulvestrant versus 
placebo fulvestrant in patients with locally advanced or MBC where a PIK3CA mutation 
was not detected

To evaluate PFS, ORR, CBR, and DOR of taselisib fulvestrant versus placebo fulvestrant
in patients with locally advanced or MBC whose tumor PIK3CA-mutation status is 
determined by plasma DNA analysis

To explore the potential relationship between pharmacogenetic differences in 
drug-metabolizing enzymes, transporters, and other patient-specific covariates with 
pharmacokinetics and safety of taselisib when administered in combination with fulvestrant 
in patients with locally advanced or MBC

To explore the potential taselisib exposure-response (efficacy and safety) relationship in 
patients with locally advanced or MBC receiving taselisib in combination with fulvestrant

To explore fulvestrant concentrations in patients with locally advanced or MBC who receive 
fulvestrant alone or in combination with taselisib

To evaluate predictive and prognostic plasma or tissue biomarkers associated with disease 
activity status or response to treatment

To identify possible mechanisms of resistance to fulvestrant taselisib through the 
comparative analysis of potential biomarkers in the pretreatment and post-progression 
biopsy tissue samples and in blood

To assess health status as measured using the EuroQol 5-Dimension Questionnaire 
(EQ-5D) for health economic modeling
Study Design
Description of Study
Study GO29058 (SANDPIPER) is a Phase III, randomized, multicenter, international, 
double-blind, placebo-controlled clinical study designed to compare the efficacy, as measured 
by PFS, and safety of fulvestrant taselisib with that of fulvestrant placebo after recurrence or 
progression following treatment with an AI for patients with ER, HER2-negative, 
PIK3CA-mutant, unresectable, locally advanced or MBC.  PIK3CA-mutation status in all patients 
will be assessed by a central laboratory using the cobasPIK3CA mutation test.  In order to 
explore efficacy and differential benefit-risk in patients without a detectable PIK3CA mutation, 
120 patients belonging to this category are planned for enrollment.


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Study GO29058 will consist of a global study that will provide the evidence to determine the 
benefit-risk of taselisib plus fulvestrant in the target population; a possible extension cohort may 
continue to enroll only in China to meet local regulatory requirements.
In the global study, approximately 600 patients will be randomized in a 2:1 ratio to either 
fulvestrant taselisib or fulvestrant placebo unless the independent Data Monitoring 
Committee (iDMC) recommends stopping the study early and the Sponsor accepts the iDMC’s 
recommendation.  Patients whose tumors contain a PIK3CA-mutation (n 480) and patients 
whose tumors do not contain a detectable PIK3CA-mutation (n 120) will be randomized 
separately. After the global enrollment closes, additional Chinese patients may continue to be 
recruited into the China extension cohort. A total of up to 150 Chinese patients with detectable 
PIK3CA-mutant tumors may be enrolled as part of the global study population and extension 
cohort combined.  Patients enrolled as part of the China extension cohort will also be 
randomized in a 2:1 ratio to either fulvestrant taselisib or fulvestrant placebo.
Number of Patients
Approximately 600 patients are planned for enrollment.  After the global enrollment closes, 
additional Chinese patients may continue to be recruited into the China extension cohort.  A 
total of up to 150 Chinese patients with detectable PIK3CA-mutant tumors may be enrolled as 
part of the global study population and extension cohort combined.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
Disease-Specific Inclusion Criteria

Women with histologically or cytologically confirmed invasive, ERbreast cancer:  
metastatic or inoperable (not amenable to resection or other local therapy with curative 
intent) locally advanced breast cancer

Patients for whom endocrine therapy (e.g., fulvestrant) is recommended and treatment with 
cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or 
local treatment guidelines.

Radiologic/objective evidence of recurrence or progression to the most recent systemic 
therapy for breast cancer

Radiologic/objective evidence of breast cancer recurrence or progression while on or within 
12 months of the end of adjuvant treatment with an AI, or progression while on or within 
1 month of the end of prior AI treatment for locally advanced or MBC.  The AI (letrozole, 
anastrozole, or exemestane) does not have to be the most recent treatment before 
randomization.

Measurable disease via RECIST v1.1 or non-measurable, evaluable disease with at least 
one evaluable bone lesion via RECIST v1.1.  Bone lesions that have been irradiated are not 
evaluable.
General Inclusion Criteria

Able and willing to provide written informed consent and to comply with the study protocol

Age 18 years

ECOG Performance Status of 0 or 1

Postmenopausal status defined as one of the following:
Age 60 years
Age 60 years and postmenopausal as defined by documented follicle-stimulating 
hormone and estradiol in the postmenopausal ranges in addition to being amenorrheic 
for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian 
suppression
Prior bilateral oophorectomy (28 days prior to first fulvestrant treatment on 
Cycle 1 Day 1)


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
Consent to provide a formalin-fixed paraffin-embedded (FFPE) tissue block (preferred) or a 
minimum of 20 (25 preferred) freshly cut unstained tumor slides from the most recently 
collected, available tumor tissue for PIK3CA-mutation testing and for other protocol-
mandated exploratory assessments

A valid cobas PIK3CA mutation result (per central testing) is required for all patients 
(e.g., patients with an “invalid” or “failed” PIK3CA mutation result are not permitted to enroll)
After 120 patients whose breast cancers have a “wild-type” (mutation not detected 
result) PIK3CA status have been enrolled, all remaining enrolled patients must have a 
breast cancer sample that tests positive for PIK3CA mutation to be eligible.

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 28 days prior to Cycle 1 Day 1:
ANC 1500/L (1.5 109/L)
Platelet count 100,000/L (100 109/L)
Hemoglobin 9.0 g/dL (90 g/L)
Total bilirubin 1.5 upper limit of normal (ULN) except in patients with previously 
documented Gilbert’s syndrome, in which case total bilirubin 3 mg/dL
AST and ALT1.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5.0 ULN
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min based on 
CockcroftGault glomerular filtration rate estimation
(140 age) (weight in kg) (0.85 if female)
72 (serum creatinine)
INR 1.5 and aPTT (or PTT) 1.5 ULN; for patients requiring therapeutic 
anticoagulation therapy, a stable INR 2.5

Fasting glucose 125 mg/dL (6.94 mmol/L)

For enrollment into the China extension cohort, residence in the People’s Republic of China
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Disease-Specific Exclusion Criteria

HER2-positive disease by local laboratory testing (IHC 3staining or in situ 
hybridization positive)

Prior treatment with fulvestrant

Prior treatment with a PI3K inhibitor, mTOR inhibitor (such as everolimus), or AKT inhibitor.

Prior anti-cancer therapy within 2 weeks prior to Cycle 1 Day 1

Prior radiation therapy within 2 weeks prior to Cycle 1 Day 1

All acute treatment-related toxicity must have resolved to Grade 1 or be deemed stable 
by the investigator

Prior treatment with 1 cytotoxic chemotherapy regimen for MBC

Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab 
therapy
Use of bisphosphonate therapy or denosumab for other reasons (e.g., bone metastasis, 
osteoporosis, etc.) is allowed

Concurrent hormone replacement therapy

Known untreated or active CNS metastases (progressing or requiring anticonvulsants or 
corticosteroids for symptomatic control); a computed tomography (CT) scan or magnetic 
resonance imaging (MRI) of the brain will be performed at screening if required by the local 
health authority


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17/Protocol GO29058, Version 4
Patients with a history of treated CNS metastases are eligible, provided they meet all 
of the following criteria:
Evaluable or measurable disease per inclusion criteria outside the CNS is present.
Radiographic demonstration of improvement upon the completion of CNS-directed 
therapy and no evidence of interim progression between the completion of 
CNS-directed therapy and the screening radiographic study
No history of intracranial hemorrhage or spinal cord hemorrhage
Minimum of 2 weeks between completion of radiotherapy and Cycle 1 Day 1 and 
recovery from significant (Grade 3) acute toxicity with no ongoing requirement 
for 10 mg of prednisone per day or an equivalent dose of other corticosteroid

History of other malignancy within the previous 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
patients who have undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to be at low risk for recurrence
General Exclusion Criteria

Type 1 or Type 2 diabetes mellitus requiring anti-hyperglycemic medications

Clinically significant cardiac or pulmonary dysfunction, including the following:
Current uncontrolled Grade 2 hypertension or unstable angina
Symptomatic congestive heart failure or serious cardiac arrhythmia requiring treatment, 
with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia or 
a conduction abnormality that has been treated and for which the patient is no longer 
at risk for serious arrhythmia (e.g., Wolff-Parkinson-White syndrome treated with 
surgical ablation)

Current dyspnea at rest or any requirement for supplemental oxygen therapy to perform 
activities of daily living

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption

Inability or unwillingness to swallow pills or receive intramuscular injections

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or 
current known active infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV)
Active infection is defined as requiring treatment with antiviral therapy or presence of 
positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B
core antibody) or HCV antibody.  Unless required by local regulations, patients are not 
required to have HIV, HBV, or HCV assessments at screening if these assessments 
have not been previously performed.
Patients who test positive for hepatitis B core antibody are eligible only if test 
results are also positive for hepatitis B surface antibody and polymerase chain 
reaction (PCR) is negative for HBV DNA.
Patients who are positive for HCV serology are only eligible if testing for 
HCV RNA is negative.

History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis)

Active bowel inflammation (e.g., diverticulitis)

Immunocompromised status due to current known active infection with HIV or because of 
the use of immunosuppressive therapies for other conditions

Need for current chronic corticosteroid therapy (10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids)
Stable use (i.e., no change in dose within 3 months prior to Cycle 1 Day 1) of inhaled 
corticosteroids is allowed.

Pregnancy, lactation, or breastfeeding


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
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, or metabolic or infectious disease)

Major surgical procedure or significant traumatic injury within 28 days prior to Cycle 1 Day 1 
or anticipation of the need for major surgery during the course of study treatment

Inability to comply with study and follow-up procedures

Inability to understand the local language(s) for which the EORTC QLQ-C30, the modified 
Breast Cancer module QLQ-BR23, and the EQ-5D questionnaires are available
Length of Study
The enrollment duration will be driven by enrollment of patients with PIK3CA-mutant tumors and 
is projected to be approximately 28 months (after first patient enrolled).  The last PFS event (the 
287th PFS event) for the final PFS analysis in patients with PIK3CA-mutant tumors is projected 
to occur approximately 29 months after the first patient is enrolled. 
End of Study
The global study will be considered completed when the last patient, last visit or safety 
follow-up with the last patient has occurred (28 days after the last dose of study drug), 
whichever occurs later, or when the Sponsor decides to stop the study.
Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

Investigator-assessed PFS, defined as the time from randomization to the first occurrence 
of disease progression, as determined with the use of Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 or death from any cause (whichever occurs earlier)

Objective response (PR CR) as determined by using RECIST v1.1

OS, defined as the time from randomization to death from any cause

Clinical benefit, defined as objective response or no disease progression lasting for 
24 weeks since randomization

DOR, defined as the time from the first occurrence of a documented objective response to 
the time of the first documented disease progression, as determined by the investigator 
using RECIST v1.1, or death from any cause (whichever occurs earlier)

BICR-assessed PFS, defined as the time from randomization to the first occurrence of 
disease progression, as determined by the BICR with the use of RECIST v1.1, or death 
from any cause (whichever occurs earlier)
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, type, and severity of adverse events (based on the National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 4.0 [NCI CTCAE v4.0])

Incidence, type, and severity of serious adverse events

Incidence of adverse events leading to study treatment discontinuation, modification, or 
interruption

Abnormal laboratory values

Death and cause of death
Pharmacokinetic Outcome Measure
The pharmacokinetic (PK) outcome measure for this study is:

Taselisib PK parameters including but not limited to plasma Cmax and minimum plasma 
concentration under steady-state conditions within a dosing interval


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19/Protocol GO29058, Version 4
Patient-Reported Outcome Measure
The PRO measure for this study is as follows:

HRQoL, including treatment-related symptoms (e.g., oral mucositis, diarrhea, skin problems) 
and patient functioning, as measured by the EORTC QLQ–C30 and the modified 
QLQ-BR23 breast cancer module
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Correlation of efficacy with molecular markers related to the mechanism of action of 
taselisib and endocrine therapy that include the following:
Alterations in DNA and RNA, including DNA mutational status, RNA expression levels, 
DNA copy number and protein expression
Alteration in tumor tissue biomarkers including but not limited to PTEN
Assessment of PI3K pathway status (e.g., PIK3CA mutation status) in ctDNA from 
peripheral blood, as well as additional cancer related mutations (e.g., ESR1)
Cancer-related plasma biomarkers including assessment of cytokines and chemokines

Association between genetic polymorphisms of drug metabolic enzymes or transporters and 
taselisib pharmacokinetics

Fulvestrant concentration in the presence and absence of taselisib

Genetic variants and association with drug-related safety assessments, including but not 
limited to HLA
Investigational Medicinal Products
Test Product
The test product for this study is taselisib.  The taselisib tablet is a white to off-white, film coated, 
immediate release formulation of 2-mg strength.  The taselisib 4-mg dose will be taken orally 
(PO) once a day (QD).  Taselisib is formulated as 2-mg tablets, so patients will take 
two 2-mg tablets daily to receive a 4-mg dose.  Taselisib will be administered in the clinic on 
Cycle 1 Day 1 and Cycle 1 Day 15 and on each subsequent day that a cycle visit is scheduled, 
after the predose assessments and procedures, and after the fulvestrant administration (except 
for Cycle 2 Day 15).  Taselisib will be administered at home on all non-clinic visit days.  Patients 
should take the taselisib dose at the same approximate time each day without regard to the 
timing of administration of food.  If a dose is missed (not taken within 6 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.
Placebo
The taselisib placebo (corresponding to a 4-mg dose) will be two tablets taken PO QD.  
Taselisib placebo will be administered in the clinic on Cycle 1 Day 1 and Cycle 1 Day 15 and on 
each subsequent day that a cycle visit is scheduled, after the predose assessments and 
procedures, and after the fulvestrant administration (except for Cycle 2 Day 15).  Taselisib 
placebo will be administered at home on all non-clinic visit days.  Taselisib placebo should be 
taken at the same approximate time each day without regard to the timing of administration of 
food.  If a dose is missed (not taken within 6 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.
Background Therapy
Fulvestrant will be supplied by the Sponsor per country-specific requirements.  For countries in 
which the Sponsor is supplying fulvestrant, it will be supplied in sterile, single-patient, prefilled 
syringes containing 50 mg/mL fulvestrant as a 5-mL injection.  Fulvestrant 500 mg will be 
administered in the clinic (before administration of taselisib or placebo) as two intramuscular 
injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day 
cycle.


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Non-Investigational Medicinal Products
None.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is investigator-assessed PFS (PFS in this document refers to 
investigator-assessed PFS, unless stated otherwise).  The primary efficacy analysis population 
will include all randomized patients with PIK3CA-mutant tumors.  The primary efficacy endpoint, 
PFS, and the secondary efficacy endpoints will be analyzed in this population as the primary 
and the secondary objectives.
In addition, these efficacy endpoints, unless otherwise specified, will be analyzed in all 
randomized patients without detectable PIK3CA-mutant tumors at the same time as the 
analyses are conducted for the patients with PIK3CA-mutant tumors.
PIK3CA-mutant tumor status will be determined by the cobas PIK3CA mutation test of the 
patient’s tissue sample.
The primary PFS analysis will be conducted in all randomized patients with PIK3CA-mutant 
tumors, with patients grouped according to the treatment arm assigned at randomization.
An interim efficacy analysis will be conducted for investigator-assessed PFS at the time of 
172 investigator-assessed PFS events (expected 21 months after the first patient is enrolled), and 
the final efficacy analysis will be conducted at the time 287 investigator-assessed PFS events 
(expected 29 months after the first patient is enrolled) are observed in patients with 
PIK3CA-mutant tumors. The -spending function is specified as Gamma (-16), which allocates 
two-sided 1.7 10-5 at the interim efficacy analysis of investigator-assessed PFS, when 
172 PFS events have occurred and preserves the two-sided 1% -level at the final PFS analysis.  
The exact boundary will be calculated on the basis of the exact number of PFS events observed 
at the interim analysis.  The associated minimal detectable difference for the investigator-
assessed PFS hazard ratio at the interim efficacy analysis is 0.5 (i.e., 100% improvement in 
median investigator-assessed PFS from 4.5 months in the control arm to 9 months in the 
treatment arm).
An exploratory analysis for investigator-assessed PFS will also be conducted in all randomized 
patients without detectable PIK3CA-mutant tumors at the time of the primary PFS analysis in all 
randomized patients with PIK3CA-mutant tumors.
Data for patients without the occurrence of disease progression or death as of the clinical data 
cutoff date 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).
Determination of Sample Size   
The global study plans to enroll approximately 600 patients, including 480 patients with 
detectable PIK3CA-mutant tumors, and 120 patients without detectable PIK3CA-mutant tumors 
(tumor status determined by the cobas PIK3CA mutation test).
After the global enrollment closes, additional Chinese patients may continue to be recruited into 
the China extension cohort.  A total of up to 150 patients with detectable PIK3CA-mutant tumors 
may be enrolled as part of the global study population and the China extension cohort combined. 
The sample size of 480 patients with PIK3CA-mutant tumors is determined on the basis of the 
power calculation for the PFS and the OS endpoints, whichever requires a larger sample size.  
In this case, the sample size is driven by OS.
In 480 patients with PIK3CA-mutant tumors, approximately 287 investigator-assessed PFS 
events will be required to detect a hazard ratio of 0.59 in PFS (3.1 months of improvement in 
median PFS) with 95% power at the a two-sided significance level of 1%, assuming a median 
PFS of 4.5 months in the control arm (Mauriac et al. 2009; Johnston et al. 2013).  One interim 
efficacy analysis of investigator-assessed PFS will be conducted at 60% of PFS.  The 
-spending function specified as Gamma (-16), which allocates two-sided 1.7 10-5 at the 
interim efficacy analysis of investigator-assessed PFS, when 172 investigator-assessed PFS 
events have occurred.   The minimal detectable difference for investigator-assessed PFS 
hazard ratio at final PFS analysis is 0.72 (i.e., 39% improvement in median investigator-
assessed PFS from 4.5 months in the control arm compared with 6.2 months in the treatment 
arm), when 287 investigator-assessed PFS events have occurred.


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With the aforementioned sample size of 480 patients with PIK3CA-mutant tumors, the OS 
analyses in this population will require 330 deaths to detect an hazard ratio of 0.7 in OS 
(11.1 months of improvement in median OS) with 80% power at a two-sided significance level of 
5%, assuming a median OS of 26 months in the control arm based on the OS of 26.4 months in 
patients treated with 500 mg fulvestrant in the CONFIRM study, which investigated 500 mg 
fulvestrant versus 250 mg fulvestrant in a similar patient population (Di Leo et al. 2014).  
The study plans to enroll 120 patients who do not have a detectable PIK3CA-mutant tumor, on 
the basis of the result of the cobas PIK3CA mutation test, to evaluate the clinical benefit in this 
population.  If the observed hazard ratio in investigator-assessed PFS is 1 (no benefit), 
approximately 111 investigator-assessed PFS events will be observed at the analysis, and the 
90% confidence interval will exclude a true hazard ratio 0.72 (i.e., 1.8-month improvement in 
median PFS).
In total, approximately 400 patients will be treated with the combination of taselisib fulvestrant 
in this study (320 patients with PIK3CA-mutant tumors and 80 patients without detectable 
PIK3CA-mutant tumors), which will enable the Sponsor to better characterize any rare but 
clinically significant safety events (e.g., for an adverse event with 4% frequency, there is 96% 
probability to observe 10 patients with such adverse event on the basis of
400 taselisib fulvestrant-treated patients) to help enable the development of effective toxicity 
prevention and management guidelines for patients treated with the combination of taselisib and 
fulvestrant.
Interim Analyses
The iDMC will convene to review cumulative safety data approximately every 6 months.  Data on 
serious adverse events, death, and adverse events of special interest will be monitored by the 
iDMC approximately every 3 months.
One efficacy and one futility analysis for investigator-assessed PFS will be conducted in the 
patients with PIK3CA-mutant tumors when approximately 172 (60% of the information, expected 
at 21 months after the first patient is enrolled) investigator-assessed PFS events have occurred in 
patients with PIK3CA-mutant tumors.  Approximately 320 patients with PIK3CA-mutant tumors 
and approximately 120 patients without detectable PIK3CA-mutant tumors will have been 
randomized into the study by the time of the interim analysis.  The actual timing of the interim 
analysis and the number of patients randomized will depend on the accrual rate and actual 
accumulation of PFS events observed in the study.
The iDMC will review the efficacy data , while the Sponsor and investigators remain blinded to the 
treatment assignment until the iDMC recommends stopping the study for efficacy or futility at the 
specified interim analysis and the Sponsor decides to stop the study. 
The iDMC may recommend stopping the study for efficacy at the interim efficacy analysis of 
investigator-assessed PFS, when the two-sided p-value 1.7 10-5, with approximately 
172 investigator-assessed PFS events at the interim efficacy analysis.  The -spending function 
specified as Gamma (-16), which allocates two-sided 1.7 10-5 at the interim efficacy 
analysis, when approximately 172 PFS events are reached and preserves the two-sided 1% 
-level at the final PFS analysis.  The actual boundary will be adjusted based on the actual 
number of investigator-assessed PFS events at IA.  Should the iDMC recommend stopping the 
study for efficacy at interim analysis and the Sponsor decides to stop the study, the study team 
will be unblinded, and the investigators and patients will remain blinded to individual patient-level 
treatment assignment until the final OS analysis. 
The iDMC may recommend stopping the study for futility at the interim efficacy analysis of 
investigator-assessed PFS, when the observed PFS hazard ratio is above 0.85, which provides a 
probability of approximately 85% to stop the study if the true PFS hazard ratio is 1.0 (i.e., no 
treatment benefit).  The purpose of the futility analysis is not to stop the study for a positive 
(significant) efficacy PFS outcome.  Therefore, statistical significance level for the interim or final 
efficacy analysis of PFS does not need to be adjusted for this futility analysis.  The overall type I 
error is under strong control.
Three interim analyses for OS were originally planned in patients with PIK3CA-mutant tumors 
on the basis of the cobas PIK3CA mutation test.  As a result of the completion of the primary 
PFS analysis, the Sponsor has decided to limit the additional OS follow-up to one additional 


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analysis.  This additional OS analysis coincides with the originally planned second OS 
interim analysis.
The type I error is under strong control by using the Generalized Haybittle-Peto method.
No formal interim analysis is planned for the patients without detectable PIK3CA mutations.
The responsibility, membership, and communication flow of the iDMC are specified in the iDMC 
Charter.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AI
aromatase inhibitor
AKT
protein kinase B
BICR
blinded independent central review
BRAF
murine sarcoma viral oncogene homolog B
AUC
area under the concentration–time curve
AUC024
area under the concentration–time curve from 
0 to 24 hours
AUC0-
area under the concentration–time curve from Time 0 
to infinity
CFDA
China Food and Drug Administration
CBR
clinical benefit rate
Cmax
maximum observed plasma concentration
CR
complete response
CT
computed tomography
ctDNA
circulating-tumor DNA
CV
coefficient of variation
CYP3A4
cytochrome P450 3A4
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
EGFR
epidermal growth factor receptor
EORTC
European Organisation for Research and Treatment 
of Cancer
EQ-5D
EuroQol 5-Dimension Questionnaire
ER
estrogen receptor
FA
final analysis
FDA
(U.S.) Food and Drug Administration
FDG-PET
fluorodeoxyglucose positron emission tomography
FFPE
formalin-fixed paraffin-embedded
HbA1c
glycosylated hemoglobin
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal receptor 2
HIPAA
Health Insurance Portability and Accountability Act


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Abbreviation
Definition
HLA
human leukocyte antigen
HR
hazard ratio
HR
hormone receptor positive
HRQoL
health-related quality of life
IA
interim analysis
ICH
International Conference on Harmonisation
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IM
intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
ISH
in situ hybridization
IxRS
interactive voice/Web response system
MAPK
mitogen-activated protein kinase
MBC
metastatic breast cancer
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events
NSAID
nonsteroidal anti-inflammatory drug
NGS
next-generation sequencing
ORR
objective response rate
OS
overall survival
pAKT
phosphorylated form of protein kinase B
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PIK3CA
oncogene that encodes for 
phosphatidylinositol-4,5-bisphosphate 3-kinase
PIP2
4,5-phosphatidylinositol bisphosphate
PIP3
3,4,5-phosphatidylinositol triphosphate
PK
pharmacokinetic
PgR
progesterone receptor
PO
by mouth; orally


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Abbreviation
Definition
PR
partial response
PRO
patient-reported outcome
PTEN
phosphatase and tensin homolog
QD
once daily
QLQ-BR23
Quality of Life Questionnaire Breast Cancer Module
QLQ-C30
Quality of Life Questionnaire Core 30
QoL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
RCR
Roche Clinical Repository
RT-PCR
reverse transcriptase polymerase chain reaction
SD
stable disease
SmPC
summary of product characteristics
TGI
tumor growth inhibition
TSC
tuberous sclerosis
TTD
time to deterioration
ULN
upper limit of normal
WT
wild type


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1.
BACKGROUND
1.1
BACKGROUND ON ESTROGEN RECEPTORPOSITIVE, 
HER2-NEGATIVE ADVANCED OR METASTATIC BREAST 
CANCER
Breast cancer is the most frequent cancer diagnosed in women, with an estimated global 
incidence of 1.67 million new cases reported in 2012 (Ferlay et al. 2013). Breast cancer 
accounts for approximately 15% (approximately 522,000 cases) of all cancer deaths.  
Breast cancer mortality rates differ by geographical region, with more favorable survival 
rates in more developed regions of the world (Ferlay et al. 2013).
Estrogen receptor-positive (ER)/human epidermal growth factor 
receptor 2 (HER2)-negative breast cancer accounts for 60%70% of all breast cancers.  
The standard-of-care treatment for patients with ERbreast cancer takes several factors 
into consideration including the stage of disease and recurrence score
(Senkus et al. 2013; NCCN Clinical Practice Guideline in Oncology 2014).  In the 
adjuvant treatment setting, endocrine therapy alone may be considered for patients with 
low volume disease (tumor size 0.5 cm, node-negative disease) and in patients with a 
low (18) recurrence score using a 21-gene reverse transcriptase polymerase chain 
reaction (RT-PCR) assay.  Sequential treatment with chemotherapy followed by 
endocrine treatment should be considered for those patients with node-positive cancers 
or tumors 0.5 cm in size, and intermediate (1830) to high (31) recurrence scores. 
Administration of tamoxifen with consideration for ovarian ablation or suppression is 
recommended in premenopausal women (Senkus et al. 2013). The administration of 
aromatase inhibitors as initial treatment or as a sequential treatment following tamoxifen 
has been recommended for postmenopausal women (Burstein et al. 2010;
Senkus et al. 2013).
Treatment for patients whose disease recurs following adjuvant treatment may include 
continued endocrine therapy (including combination endocrine therapy) or chemotherapy.  
Chemotherapy is indicated in patients with symptomatic visceral disease or in patients 
with disease progression after multiple consecutive endocrine therapy regimens
(Senkus et al. 2013). The appropriate endocrine agent used in the metastatic setting is 
dependent on the menopausal status of the patient.  In premenopausal women, ovarian 
ablation or suppression is generally recommended.
Endocrine treatment options in the treatment of postmenopausal women whose cancer 
has recurred after adjuvant therapy include nonsteroidal aromatase inhibitors
(anastrozole, letrozole), steroidal aromatase inhibitors (exemestane), estrogen receptor 
down-regulators (fulvestrant), and estrogen receptor modulators (tamoxifen, toremifene).
Meta-analyses suggest that aromatase inhibitors may be superior to tamoxifen in 
prolonging the time to disease progression in this treatment setting 
(Bonneterre et al. 2000; Nabholtz et al. 2000; Paridaens et al. 2008; Gibson et al. 2009).  
Treatment with fulvestrant may offer a survival advantage over anastrozole


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(Gibson et al. 2009). Very little evidence is available to support an optimal endocrine 
therapy sequence in the metastatic setting (NCCN Clinical Practice Guideline in 
Oncology 2014). The choice of agent, sequence of agents, and duration of treatment 
should be guided by practical considerations, such as prior endocrine treatment 
response and each agent’s safety profile.
Not all ERbreast cancers respond optimally to endocrine therapy and recently, CDK4/6 
inhibitors such as palbociclib and ribociclib have been shown to significantly improve 
progression-free survival (PFS) over endocrine therapy alone (Finn et al. 2015; 
Cristofanilli et al. 2016; Hortobagyi et al. 2016).  Mechanisms that can lead to primary 
and/or secondary hormonal resistance in ERbreast cancer include a decrease or loss 
of ER expression or an up-regulation of growth factor signaling pathways, such as the 
epidermal growth factor receptor (EGFR) or HER2, the mitogen-activated protein kinase 
(MAPK), or the PI3K/AKT/mTOR pathways (Johnston 2009; 
Musgrove and Sutherland 2009).  Recently, mutations in the gene that encodes 
ER (ESR1) have been identified in metastatic ERtumors and are associated with 
resistance to anti-estrogen therapies (Robinson et al. 2013; Toy et al. 2013; 
Jeselsohn et al. 2014).
1.2
BACKGROUND ON THE PI3K/AKT/MTOR PATHWAY AND 
BREAST CANCER
The 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 phospolipids for intracellular signal transduction.
There are three classes of PI3K, with Class I being the most responsive to external 
stimuli.  Class I PI3Ks comprise 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 product of three genes: PIK3CA, PIK3CB, 
and PIK3CD.
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 cancer (Gustin et al. 2008). Pathway activation may occur through 
multiple mechanisms: the 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, loss of liver kinase B1 (LKB1), 
type II inositol polyphosphate-4-phosphatase (INPP4B), or tuberous sclerosis (TSC) 
(Staal 1987; Cheng et al. 1992; Bellacosa et al. 1995; Li et al. 1997; Steck et al. 1997; 


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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 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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 enhances anti-tumor activity more 
than either agent alone (Boulay et al. 2005). A baseline protein signature of 
PI3K activation was found to be predictive of a poor prognosis after adjuvant endocrine 
therapy (Miller et al. 2010).
These nonclinical data provide support to the hypothesis that blocking PI3K/AKT/mTOR 
pathway signaling may have a therapeutic benefit in patients with ER, HER2-negative 
breast cancer. The combination of everolimus and exemestane has received regulatory 
approval, and many agents that target PI3K and AKT are in various stages of 
development.
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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 in advanced disease. 
Median PFS in the everolimus group was 6.9 months, compared with 2.8 months in the 
placebo group.  The hazard ratio (HR) for PFS by investigator assessment was 0.43 (95%
CI: 0.35, 0.54; p0.001).  The magnitude of the effect was even greater with central 
independent review: HR0.36 (95% CI: 0.27, 0.47; p0.001).  In the open-label Phase 
II TAMRAD study, patients with aromatase inhibitor (AI)-resistant metastatic breast 
cancer (MBC) received tamoxifen plus everolimus or tamoxifen alone (Bachelot et al.
2012). The 6-month clinical benefit rate was 61% (95% CI: 47%, 74%) with tamoxifen 
plus everolimus and 42% (95% CI: 29%, 56%) with tamoxifen alone. Time to 
progression increased from 4.5 months with tamoxifen alone to 8.6 months with 
tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with 
the combination (HR0.54; 95% CI: 0.36, 0.81).  The risk of death was reduced by 55% 
with tamoxifen plus everolimus versus tamoxifen alone (HR0.45; 95% CI: 0.24,0.81).
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 up-regulation of the phosphorylated form of 
AKT (pAKT), resulting in feedback PI3K/AKT/mTOR pathway activation 


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(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.
1.3
BACKGROUND ON TASELISIB
1.3.1
Taselisib Nonclinical Data
Taselisib (RO5537381, GDC-0032) is a potent selective inhibitor of Class I PI3K 
andisoforms, with 30-fold less potent biochemical inhibition of the isoform and 
increased potency in tumor cells bearing mutant PI3K over wild-type (WT) PI3K cells.
Taselisib exerts its activity by binding to the ATP binding site of PI3K, thereby inhibiting 
the phosphorylation of membrane-bound 4,5-phosphatidylinositol bisphosphate (PIP2) to 
3,4,5-phosphatidylinositol triphosphate (PIP3). Inhibiting the phosphorylation of PIP2 to 
PIP3 decreases downstream activation of AKT and mTOR, resulting in decreased 
cellular proliferation, metabolism, and angiogenesis (Ndubaku et al. 2013). Nonclinical 
studies demonstrate that taselisib inhibits proliferation and induces apoptosis of 
PI3K-mutant breast cell lines, inhibits tumor growth in human breast xenograft models 
harboring PI3K mutations, and reduces downstream PI3K-pathway markers, including 
pAKT, pPRAS40, and pS6.
Results of in vitro combination studies indicated positive combination effects between 
taselisib and endocrine therapies.  In the PIK3CA-mutant aromatase-expressing breast 
cancer cell line (MCF7X2.3.ARO), taselisib alone caused growth inhibition 
(50% effective concentration [i.e., concentration resulting in one-half the maximum 
effect]95 nM). Effects on growth were also observed with letrozole and fulvestrant.  
Combined treatment of cells with taselisib and letrozole caused dose-dependent 
inhibition of cell viability at lower concentrations of either taselisib or letrozole resulting in 
enhanced activity for the combination. In addition, combination activity was 
demonstrated in the PIK3CA WT cell line ZR75-1 when taselisib was added to either 
fulvestrant or tamoxifen endocrine therapies (combination with letrozole is not available 
in this cell line).  However, in vivo data in a PIK3CA WT model are not available because 
these cell lines do not grow as xenografts.
Enhanced efficacy was demonstrated in combination with tamoxifen, another endocrine 
therapy used in the treatment of hormone receptorpositive (HR) advanced breast 
cancer.  In the human MCF7-neo/HER2 (PIK3CA mutant [MT]) breast cancer xenograft 
model in immune-compromised nude mice, administration of taselisib at all doses tested 
(5, 10, or 20 mg/kg) in combination with tamoxifen (5-mg/pellet) resulted in greater 
efficacy (shown as a percentage of tumor growth inhibition [TGI]: 82% TGI, 80% TGI, 
and 102% TGI, respectively) compared with tamoxifen alone (73% TGI) or taselisib as a 
single agent (71% TGI at 20 mg/kg).  All combinations were well-tolerated with no 
increase in mortality and no greater body weight loss than with single agents alone.


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In vivo anti-tumor activity by taselisib, as characterized by TGI and PI3K pathway 
inhibition, was demonstrated in pharmacology studies with human tumor xenograft 
models with use of differing mechanisms of PI3K pathway activation in 
immunocompromised mice (see the Taselisib Investigator’s Brochure).  All dosing 
regimens in the summarized efficacy studies were tolerated with generally 20% body 
weight loss.  A summary of findings included the following:

Administration of single-agent taselisib resulted in 128% TGI at a maximum 
efficacious dose of 25 mg/kg once daily (QD) (7 partial responses [PRs] and 
1 complete response [CR] out of 8 animals) in the KPL 4 human breast cancer 
xenograft model, which contains a PIK3CA mutation in the catalytic domain of 
p110(H1047R).

Efficacy was improved when taselisib was used in combination with fulvestrant, 
leading to 83% TGI (10 mg/kg taselisib QD 5 mg fulvestrant subcutaneously) 
compared with 63% TGI for taselisib and 34% for fulvestrant for either agent alone.

PI3K pathway markers pAKT, pPRAS40, and pS6 were reduced from 124 hours in 
response to a single dose of taselisib, and a substantial reduction of pathway 
markers was associated with plasma concentrations 2.7 M in the KPL4 breast 
cancer xenograft model (see the Taselisib Investigator’s Brochure).
No safety pharmacology findings were noted, including cardiovascular effects of taselisib 
in telemetry-instrumented dogs, neurobehavioral and/or motor activity effects in rats, or 
respiratory effects in dogs.
1.3.2
Taselisib Clinical Data
As of 30 April 2014, 191 patients have been treated with taselisib capsules in the 
Phase I/II study PMT4979g, either as single agent (n108) or in combination with 
fulvestrant (n83).
As of 30 April 2014, enrollment into the single-agent dose-escalation stage of 
Study PMT4979g was completed with 34 patients enrolled at taselisib doses ranging 
from 3 to 16-mg capsules daily.  Taselisib was well-tolerated in the first three cohorts 
(3, 5, and 8 mg), with no patients experiencing a dose-limiting toxicity (DLT).  At the 
16-mg dose level, 2 of the 11 safety-evaluable patients experienced a DLT 
(Grade 4 hyperglycemia and Grade 3 fatigue).  At the 12-mg dose level, 1 of the 
10 safety-evaluable patients experienced a DLT of Grade 3 acute renal failure.  Although 
the single-agent taselisib maximum tolerated dose was not exceeded at the 16-mg dose 
level, the recommended taselisib dose and schedule for the single-agent expansion 
cohorts is 9 mg daily on the basis of long-term safety data through multiple treatment 
cycles.  As of the cutoff date, a total of 74 patients had been enrolled in the 9-mg daily 
dosing expansion cohorts.
As of 30 April 2014, adverse events of any grade that occurred in 10% of the 
108 patients treated with daily single-agent taselisib capsules and were assessed by the 


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investigator as taselisib-related were as follows:  diarrhea (54%), nausea (36%), 
hyperglycemia (35%), fatigue (32%), decreased appetite (26%), rash (19%), 
stomatitis (15%), vomiting (13%), and mucosal inflammation (12%).  Grade 3 
and 4 adverse events assessed by the investigator as taselisib-related included 
hyperglycemia (14%), colitis (7%), rash (5%), pneumonitis (4%), diarrhea (4%), 
fatigue (4%), pruritus (2%), stomatitis (2%), vomiting (1%), increased alanine 
aminotransferase levels (1%), anemia (1%), increased blood creatinine (1%), 
exfoliative rash (1%), hypokalemia (1%), hypophosphatemia (1%), lung infection (1%), 
pneumonia (1%), erythematous rash (1%), generalized rash (1%), maculopapular 
rash (1%), skin exfoliation (1%), diabetic ketoacidosis (1%), enterocolitis (1%), impaired 
glucose intolerance (1%), mucosal inflammation (1%), neutropenia (1%), and acute 
renal failure (1%).
As of 30 April 2014, a total of 83 patients have been treated with a combination of 
taselisibfulvestrant as part of the PMT4979g study. Of the 83 patients, 27 have been 
enrolled in the expansion cohort of taselisib at dose levels of 6 mg (21 patients) and 
9 mg (6 patients) daily in combination with fulvestrant (Cohort F).  No DLTs were 
observed at either dose level.  An additional 56 patients have been enrolled in the Phase 
II part of Study PMT4979g with 6 mg taselisib administered in combination with 
fulvestrant.  Adverse events assessed by the investigator as taselisib-related and of any 
grade that occurred in 10% of the 83 patients treated with a combination of 
taselisibfulvestrant were diarrhea (59%), nausea (31%), fatigue (28%), decreased 
appetite (23%), rash (21%), mucosal inflammation (19%), hyperglycemia (18%), 
stomatitis (17%), asthenia (16%), and dry skin (13%).  Grade 3 and 4 adverse events 
assessed by the investigator as taselisib-related included colitis (8%), diarrhea (8%), 
hyperglycemia (7%), rash (4%), hyponatremia (2%), mucosal inflammation (2%), 
maculopapular rash (1%), anemia (1%), asthenia (1%), cytomegalovirus colitis (1%), 
dyspnea (1%), enterocolitis (1%), flank pain (1%), neutropenia (1%), pruritis (1%), 
transaminases increased (1%), and vomiting (1%).
Refer to the current Taselisib Investigator’s Brochure for further details and the most
recent data.
In addition, after unblinding and completion of the primary PFS analysis of this 
Study GO29058, the following new taselisib adverse drug reactions were detected: 
infection (including serious infection), alopecia, fever, dyspepsia, and weight loss.
1.3.3
Clinical Pharmacokinetics of Taselisib
The pharmacokinetics of taselisib have been characterized in patients with cancer,
following oral administration after single and multiple dosing in the Phase Ia 
dose-escalation portion of Study PMT4979g.  After a single dose of a 316-mg taselisib
capsule, the mean half-life (t1/2: time for drug in the body to be reduced by one-half) is 
approximately 40 hours. The apparent taselisib clearance at steady state (CLss/F) had 
a range of 43209170 mL/hr. Taselisib demonstrated a moderate rate of absorption with 


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a median time to maximum concentration of 3 hours. Following a dosage of 6-mg 
taselisib capsule QD, the mean (CV%) maximum observed plasma concentration (Cmax)
and area under the concentration–time curve from 0 to 24 hours (AUC0-24) at steady 
state were 0.172 M (51%) and 3.024 M hr (56%), respectively.  The taselisib 
exposures, as measured by Cmax and AUC0-24, were approximately dose-proportional 
with 2- to 4-fold accumulation and moderate variability in Cmax and AUC0-24.  No apparent 
time-dependent changes in pharmacokinetic (PK) exposure were observed.
Taselisib has also been administered to healthy subjects in the clinical pharmacology 
studies summarized in Table 1.
Table 1
Clinical Pharmacology Studies in Healthy Subjects
Study 
Number
Study Objective
Taselisib Formulation
No. of 
PK-Evaluable 
Subjects
GP28617
To determine the effect of steady-state rifampicin or 
itraconazole on the PK of taselisib capsule
Capsule
29
GP28755
To characterize the mass balance and
metabolite profile of taselisib capsule by comparing 
oral and IV administration of taselisib
Capsule, IV solution
14
GP28619
Part 1: To determine relative bioavailability of 
taselisib tablet vs. capsule; to determine the effect 
of a high fat meal on the PK of taselisib tablet
Part 1:  Prototype tablet, 
capsule
22
Part 2: To determine the effect of particle size on 
the oral bioavailability of taselisib tablet
Part 2:  Prototype tablet 
with 2 different API 
particle sizes
12
Part 3: To determine the relative bioavailability of 
2 different lots of taselisib API in capsule 
formulation under fasting conditions
Part 3:  Capsule with 
2 different API particle 
sizes
20
Part 4 : To investigate the effect of formulation on 
taselisib administered as a 2 mg tablet relative to 
the 3 mg original powder-in capsule
Part 4:  Phase III tablet, 
capsule
20
APIactive pharmaceutical ingredient; IVintravenous; PKpharmacokinetic.
Results from the food-effect study in healthy volunteers (Study GP28619) indicate that 
the pharmacokinetics of the prototype taselisib tablet is minimally altered by food.  The 
food-effect results in healthy volunteers are consistent with those observed in the pilot 
food-effect study, Study PMT4979 (n10 patients), conducted in patients with cancer 
that utilized a capsule formulation of taselisib.
The relative bioavailability of a 3-mg taselisib tablet versus 3-mg capsule formulation
was 152% (142%163%) for taselisib AUC and 196% (177%217%) for taselisib Cmax in 
healthy volunteers (Study GP28619).  In Part 4 of the same study, the 2-mg taselisib 
tablet demonstrated pharmacokinetics comparable to the 3-mg capsule dose.  Relative 


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bioavailability of a 2-mg tablet versus a 3-mg capsule was 101% (90% CI: 94.8%107%) 
for AUC and 117% (90% CI: 106%128%) for Cmax.  A 4-mg taselisib tablet dose is 
estimated to provide an AUC equivalent to a 6-mg capsule dose due to the ability of 
taselisib to demonstrate linear, dose-proportional pharmacokinetics over a broad 
dose-range (316 mg).
Results from the mass-balance study suggest that hepatic elimination of unchanged 
taselisib represents the predominant pathway of elimination, and renal clearance 
represents a very small contribution of total taselisib clearance. The mean (range) 
absolute bioavailability of the taselisib capsule was approximately 64% (40.8%91.5%).  
No [14C] taselisib-related metabolites were present in systemic circulation.
In vitro metabolism studies with taselisib indicate that it is a substrate of CYP3A4.  In 
clinical studies in healthy subjects, the pharmacokinetics of taselisib were minimally 
affected by rifampicin, a potent CYP3A4 inducer, and moderately altered by 
itraconazole, a potent CYP3A4 inhibitor.  Rifampicin was found to produce an 
approximate 16% decrease in taselisib Cmax (90% CI: 73.5%, 96.9%) and an 
approximate 23% decrease in taselisib area under the concentration–time curve from 
Time 0 to infinity (AUC0-) (90% CI: 70.2%, 82.4%). After co-administration with 
itraconazole, there was an approximate 9% increase in Cmax (90% CI: 89.8%, 131%) and 
an approximate 49% increase in taselisib AUC0-(90% CI: 128%, 173%).
In vitro, taselisib was not a potent inhibitor of CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19, 
2D6, or 3A4 (IC50 30 M) but displayed weak time-dependent inhibition of CYP3A4.  In 
patients with cancer (Study PMT4979g), the pharmacokinetics of midazolam, an in vivo 
marker of CYP3A4 enzymatic activity, were unaffected by taselisib (geometric mean 
ratio [90% CI] of 0.98 [0.701.37] for Cmax and 1.04 [0.681.60] for AUC0-24).  Consistent 
with these findings, codaminstration of taselisib with letrozole or fulvestrant in cancer 
patients (Study PMT4979g) did not result in any apparent change in the 
pharmacokinetics of these CYP3A4 substrates.  For more information, refer to the 
Taselisib Investigator’s Brochure.
1.4
BACKGROUND ON FULVESTRANT
Fulvestrant is an ER antagonist approved for the treatment of postmenopausal patients 
with HRbreast cancer who have disease progression following other anti-estrogen 
therapy (MedImmune 2013). Fulvestrant binds to the ER, disrupting the signaling 
pathway, which leads to ER degradation.  The recommended dose of fulvestrant is 
500 mg given by intramuscular (IM) injection on Days 1, 15, and 29 of the first month, 
then monthly thereafter.  This dose 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 (progression-free 
survival HR0.80; 95% CI: 0.68, 0.94; p0.006) compared with a 250-mg dose, but 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 compared 


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with the 250-mg fulvestrant dose (median duration of overall survival [OS] is 
26.4 months vs. 22.3 months).  The lower dose of fulvestrant (250 mg) is recommended 
in patients who have liver dysfunction (Child-Pugh Class B disease).
Clinical studies comparing fulvestrant 250 mg given once a month with anastrozole 1 mg 
daily have demonstrated similar efficacy between the two agents (Osborne et al 2002;
Robertson et al. 2009).  Similar rates of objective responses (15%20%), median time to
progression (3.45.5 months), and duration of OS (2530 months) were reported and 
were not statistically different.  Similar efficacy (measured by median time to progression) 
between fulvestrant and exemestane has also been demonstrated in postmenopausal
women who had received prior aromatase-inhibitor therapy for advanced breast cancer
(Chia et al. 2008).
The common adverse events associated with the use of fulvestrant include injection site 
pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, extremity pain, hot 
flashes, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and 
constipation.  Increases in liver enzymes (AST, ALT, alkaline phosphatase [ALP]) have 
also been reported in approximately 15% of patients.  In randomized studies that 
compared fulvestrant with anastrozole, similar rates of common adverse events were 
reported, with the exception of injection-site pain.
1.4.1
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 
clearance (meanSD) 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.
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, 
coadministration of fulvestrant with either rifampicin (a potent CYP3A4 inducer) or 
ketoconazole (a potent CYP3A4 inhibitor) had no effect on its pharmacokinetics. 
Preliminary PK data of fulvestrant from 14 postmenopausal patients with HRbreast 
cancer were evaluated in Study PMT4979g.  Results of the study suggest that the 
pharmacokinetics of fulvestrant is comparable with historical data, which suggest that
taselisib does not alter the pharmacokinetics of fulvestrant.
For more information, refer to the local prescribing information for fulvestrant 
(i.e., package insert or Summary of Product Characteristics [SmPC]).
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The activity of endocrine therapy, including tamoxifen and AIs, is the primary reason for 
the sustained improvement in survival for patients with HRbreast cancer.  However, 


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nearly half of the patients that present with HRMBC do not respond to front-line 
endocrine treatment, and nearly all patients who do respond eventually develop 
resistance to endocrine therapy.
The mechanisms of resistance to hormonal therapies in HRMBC patients are likely 
multifactorial: estrogen-independent tumor growth; loss of ER expression; or activation of 
intracellular signaling pathways, including MAPK and PI3K (Acconcia et al. 2005; 
Björnström and Sjöberg 2005; Gutierrez et al. 2005; Johnston et al. 2009; 
Osborne and Schiff 2011).
The scientific rationale for combining a PI3K pathway inhibitor 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breast 
cancer models (Shou et al. 2004; Miller et al. 2009, 2010).  Proteomic and transcriptional 
profiling of human HR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 (PgR)
expression (Creighton et al. 2010) and enhance the anti-tumor effect of letrozole 
(Boulay et al. 2005). Retrospective analyses of tumor samples from patients who are 
HRtreated with tamoxifen lend support to the nonclinical observations linking the PI3K 
pathway to resistance to anti-estrogen therapy; 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 two Phase II studies and one Phase III study suggest 
that the combined inhibition of the PI3K/mTOR and estrogen-signaling pathways may 
provide superior benefit when compared with single-agent endocrine therapies.  
Administration of an mTOR inhibitor, everolimus, increased the efficacy of letrozole in 
the neoadjuvant setting in patients with ERcancer evidenced by increased clinical 
response rate (68% vs. 59%) and by a reduction in Ki67 expression in patients who 
received everolimus and letrozole compared with those who received letrozole 
(Baselga et al. 2009).  The addition of everolimus to tamoxifen in a Phase II study with 
ERpatients who received prior treatment with an AI significantly improved the clinical 
benefit rate (CBR), time to progression, and overall survival compared with single-agent 
tamoxifen (Bachelot et al. 2012).  Finally, 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 ER, HER2-negative MBC patients whose 
disease was refractory to prior treatment with letrozole or anastrozole 
(Baselga et al. 2012).  Therefore, the combined inhibition of the ER and PI3K-pathways 
may prove to be an effective therapeutic approach in patients with MBC who experience 
recurrent or progressive disease (PD) while receiving treatment with an AI.


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Activating mutations of PIK3CA (the PI3K isoform), which belongs to the class IA PI3K 
family, have been observed in a number of different tumor types, including breast cancer 
(Bachman et al. 2004; Samuels et al. 2004).  These activating mutations have been 
shown to promote growth and invasion in cancer cells, effects that are abrogated by 
PI3K inhibitors.
As described in Section 1.3.1, taselisib is a very potent PI3K inhibitor.  Sixty percent TGI 
was observed when taselisib was administered to a PIK3CA-mutant breast cancer 
xenograft model (KPL4) at a nonclinical dose of 0.5 mg/kg, which is equivalent to the 
AUC exposure corresponding to the 3 mg capsule QD dose in humans.  Further, 
taselisib in combination with fulvestrant showed greater efficacy than either agent 
administered alone in another breast cancer xenograft model (MCF7).  On the basis of 
data in these two breast cancer models, the Sponsor estimated that robust pathway 
inhibition and anti-tumor activity could occur with a 3-mg capsule clinical dose as a 
single agent and when administered in combination with fulvestrant. In addition, clinical 
data from Study PMT4979g further support the finding that taselisib inhibits the PI3K 
pathway in patient samples and, importantly, has demonstrable anti-tumor activity when 
given as a single agent or when combined with endocrine therapy, as summarized below.

Inhibition of the PI3K pathway was observed in paired tumor biopsy tissue samples 
(pretreatment and during taselisib treatment) at the lowest dose tested of 
single-agent 3-mg capsule QD.

Decreases in the mean standardized uptake value via fluorodeoxyglucose positron 
emission tomography (FDG-PET) analysis that correlate with inhibited glucose 
uptake are another pharmacodynamic marker of PI3K pathway inhibition.  Such 
decreases have also been observed beginning at the lowest dosage of single-agent 
taselisib tested, 3-mg capsule QD.
In addition, clinical efficacy data from patients with breast cancer treated with 
single-agent taselisib support the proposed Phase III dose and schedule.  Confirmed 
partial responses in patients with breast cancer treated with single-agent taselisib have 
only been observed in those with PIK3CA-mutant tumors, including 1 patient with a 
PIK3CA-mutant tumor at the 5-mg capsule QD single-agent dose.  Although the 3-mg 
capsule dose has demonstrated evidence of pharmacodynamic modulation and 
anti-tumor activity, it is thought that increasing the drug exposure will lead to increased 
inhibition of the PI3K pathway and enhance tumor shrinkage.  While the number of 
patients in the 12-mg cohort was small, there did appear to be a higher confirmed 
response rate (3 out of 4 patients with breast cancer with PIK3CA-mutant tumors).  
However, given the overall tolerability with the 12-mg dose and evidence of strong 
activity with the 6-mg capsule dose, particularly in combination with fulvestrant, a 6-mg 
capsule dose is thought to maximize dose intensity and drug exposure while maintaining 
a suitable safety profile in this patient population.


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The clinical efficacy data observed at the 6-mg capsule taselisib dose in combination 
with fulvestrant in the Phase I/II study also support further testing of this regimen in the 
Phase III Study in the proposed biomarker-positive subgroup of patients with 
PIK3CA-mutant breast cancer.  Of the Phase Ib and Phase II patients in 
Study PMT4979g who were treated at the 6-mg capsule dose level, confirmed partial 
responses were observed in patients with PIK3CA-mutant breast cancer.  These findings 
are consistent with the hypothesis that the combination of taselisib and fulvestrant will 
provide the most benefit to this patient population.
Although letrozole is a different endocrine therapy than fulvestrant, clinical efficacy data 
of letrozole in combination with taselisib is also supportive of the 4-mg tablet dose
(equivalent to 6-mg capsule dose, see Section 1.3.3).  In a heavily pretreated Phase Ib 
population, confirmed partial responses were also observed in multiple patients with 
PIK3CA-mutant breast cancer.
In summary, the available nonclinical and clinical data for taselisib support the proposed 
Phase III dosing regimen of taselisib in combination with fulvestrant.  On the basis of
taselisib bioavailability data, the Phase III dosing regimen with tablets will be 4-mg QD to 
deliver exposure equivalent to the 6-mg QD capsule exposure that was tested in 
Study PMT4979g.  The proposed Phase III population usually receives single-agent 
endocrine therapy, which has a very favorable toxicity profile.  However, it is clear that 
second- or third-line regimens that contain only endocrine therapies have not 
demonstrated impressive activity in randomized controlled studies when administered as 
single agents (Chia et al. 2008) or in combinations (Johnston et al. 2013).  The 
anticipated or potential safety issues associated with the administration of taselisib in 
combination with fulvestrant and the measures to be taken that are intended to avoid or 
minimize such toxicities in this study are described in detail in Section 5.1.
There is a need to develop improved anti-cancer therapies in ERadvanced breast 
cancer.  Because of this need and on the basis of the clinical and nonclinical data 
available for taselisib, the Sponsor has assessed the benefit-risk profile of taselisib in 
combination with fulvestrant to be appropriate for initiating the proposed clinical study.
2.
OBJECTIVES
The efficacy, safety, pharmacology, and patient-reported outcome (PRO) objectives of 
this study will be evaluated in postmenopausal women with ER, HER2-negative, locally 
advanced or MBC and who have had recurrence or progression of disease on or after 
administration of an aromatase-inhibitor therapy.
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To compare the efficacy between taselisibfulvestrant versus placebofulvestrant
as measured by investigator-assessed PFS in patients with PIK3CA-mutant tumors


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The secondary efficacy objectives for this study are as follows:

To compare the overall objective response rate (ORR) between 
taselisibfulvestrant versus placebofulvestrant in patients with PIK3CA-mutant 
tumors, on the basis of tumor assessments made by the investigator

To compare the efficacy between taselisibfulvestrant versus placebofulvestrant
as measured by OS in patients with PIK3CA-mutant tumors

To estimate the duration of objective response (DOR) within taselisibfulvestrant 
versus placebofulvestrant in patients with PIK3CA-mutant tumors, on the basis of 
tumor assessments made by the investigator

To compare the clinical benefit rate (CBR) between taselisibfulvestrant versus 
placebofulvestrant in patients with PIK3CA-mutant tumors, on the basis of tumor 
assessments made by the investigator

To compare the efficacy between taselisibfulvestrant versus placebofulvestrant
as measured by PFS determined by blinded independent central review (BICR) in 
patients with PIK3CA-mutant tumors
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of taselisibfulvestrant
versus placebofulvestrant in patients with locally advanced or MBC in all randomized 
patients who receive at least one dose of taselisib/placebo or fulvestrant, regardless of 
the PIK3CA mutation status of their tumors, and separately in the subgroups of patients 
with and without detectable PIK3CA-mutant tumors.
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to evaluate the pharmacokinetics of taselisib when 
taken with fulvestrant
2.4
PATIENT-REPORTED OUTCOME OBJECTIVE
The PRO objective for this study is as follows:

To evaluate and compare PROs of treatment-related symptoms, patient functioning, 
and health-related quality of life (HRQoL) as measured by the European 
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module 
(QLQ-BR23) between the taselisibfulvestrant versus placebofulvestrant
treatment arms
2.5
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate the PFS, ORR, CBR, and DOR of taselisibfulvestrant versus
placebofulvestrant in patients with locally advanced or MBC where a 
PIK3CA mutation was not detected


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
To evaluate PFS, ORR, CBR, and DOR of taselisibfulvestrant versus
placebofulvestrant in patients with locally advanced or MBC whose tumor 
PIK3CA-mutation status is determined by plasma DNA analysis

To explore the potential relationship between pharmacogenetic differences in 
drug-metabolizing enzymes, transporters, and other patient-specific covariates with 
pharmacokinetics and safety of taselisib when administered in combination with 
fulvestrant in patients with locally advanced or MBC

To explore the potential taselisib exposure-response (efficacy and safety) 
relationship in patients with locally advanced or MBC receiving taselisib in 
combination with fulvestrant

To explore fulvestrant concentrations in patients with locally advanced or MBC who 
receive fulvestrant alone or in combination with taselisib

To evaluate predictive and prognostic plasma or tissue biomarkers associated with 
disease activity status or response to treatment

To identify possible mechanisms of resistance to fulvestranttaselisib through the 
comparative analysis of potential biomarkers in the pretreatment and 
post-progression biopsy tissue samples and in blood

To assess health status as measured using the EuroQol 5-Dimension Questionnaire 
(EQ-5D) for health economic modeling
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
Study GO29058 (SANDPIPER) is a Phase III, randomized, multicenter, international, 
double-blind, placebo-controlled clinical study designed to compare the efficacy, as 
measured by PFS, and safety of fulvestranttaselisib with that of fulvestrantplacebo
after recurrence or progression following treatment with an AI for patients with ER, 
HER2-negative, PIK3CA-mutant, unresectable, locally advanced or MBC.  PIK3CA 
mutation status in all patients will be assessed by a central laboratory using the cobas®
PIK3CA mutation test.  In order to explore efficacy and differential benefit-risk in patients 
without a detectable PIK3CA mutation, 120 patients belonging to this category are 
planned for enrollment.
Study GO29058 will consist of a global study that will provide the evidence to determine
the benefit-risk of taselisib plus fulvestrant in the target population; a possible extension 
cohort may continue to enroll only in China to meet local regulatory requirements.
In the global study, approximately 600 patients will be randomized in a 2:1 ratio to either 
fulvestranttaselisib or fulvestrantplacebo (see Figure 1). unless the independent Data 
Monitoring Committee (iDMC) recommends stopping the study early and the Sponsor 
accepts the iDMC’s recommendation.  Patients whose tumors contain a 
PIK3CA-mutation (n480) and patients whose tumors do not contain a detectable 
PIK3CA-mutation (n120) will be randomized separately.  After the global enrollment 


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closes, additional Chinese patients may continue to be recruited into the China 
extension cohort. A total of up to 150 Chinese patients with detectable PIK3CA-mutant 
tumors may be enrolled as part of the global study population and extension cohort 
combined (see Section 6.10).  Patients enrolled as part of the China extension cohort 
will also be randomized in a 2:1 ratio to either fulvestranttaselisib or 
fulvestrantplacebo.

Taselisib Arm:  Taselisib 4-mg tablet dose (22 mg tablet formulation) taken orally 
(PO) QD beginning at Cycle 1, Day 1 and fulvestrant 500 mg administered by IM 
injection at Cycle 1, Days 1 and 15, and then on Day 1 of each subsequent 28-day 
cycle

Control Arm:  Placebo taken PO QD beginning at Cycle 1, Day 1 and fulvestrant 
500 mg administered by IM injection at Cycle 1, Days 1 and 15, and then on Day 1 
of each subsequent 28-day cycle
Figure 1
Schematic of Randomized Controlled Study GO29058 (Global 
Study)
AKT protein kinase B; AIaromatase inhibitor; ECOG Eastern Cooperative Oncology Group; 
ERestrogen receptor-positive; FFPET formalin-fixed paraffin-embedded tissue; 
HER2human epidermal growth factor receptor 2-negative; MBCmetastatic breast cancer; 
MT mutation; mTORmammalian target of rapamycin; non-MT no detectable mutation; 
PDprogressive disease; PI3Kphosphatidylinositol 3-kinase; PSperformance status; 
QDonce daily.
A permuted block randomization scheme will be used to ensure an approximate 
2:1 allocation of patients who receive active taselisibfulvestrant versus patients who 
receive placebofulvestrant with respect to the following stratification factors per local 
assessment:

Visceral versus non-visceral disease


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
Sensitivity versus non-sensitivity to their most recently administered endocrine 
therapy, with sensitivity defined as patients who meet either criterion listed below:
For patients with no endocrine treatment in the advanced or metastatic setting, 
at least 24 months of adjuvant endocrine therapy prior to disease recurrence
Documented clinical benefit (CR, PR, or stable disease [SD] 24 weeks) to 
most recent endocrine treatment in the advanced or metastatic treatment 
setting

Geographical region
Prior to enrollment but after signing the informed consent document, patients will have 
the PIK3CA-mutant status of their tumor assessed by the central laboratory using the 
cobas PIK3CA mutation test. Patients may be prescreened for PIK3CA-mutation status 
using the cobas PIK3CA mutation test by participating in a separate prescreening 
consent or as part of the eligibility evaluation for this study.  Patients whose tumor 
samples have invalid test results will not be permitted to enroll in the study.
Patients may have either measurable disease (per Response Evaluation Criteria in Solid 
Tumors, Version 1.1 [RECIST v1.1]; see Appendix 6) and/or non-measurable, but 
evaluable, locally advanced or metastatic disease with at least one evaluable bone 
lesion.  Detailed information is listed in the inclusion and exclusion criteria in Section 4.1. 
Locally advanced disease must not be amenable to resection or other local therapy with 
curative intent.
Until approximately the end of August 2018, tumor assessments will be conducted for 
all patients 8 weeks (5 days) from the date of randomization and then every 8 weeks
(5 days) thereafter, regardless of dose delays or dose interruptions, until 46 weeks 
after investigator-assessed disease progression or until death, whichever occurs first.  
After approximately the end of August 2018, tumor assessments may be conducted per 
local standard of care.
Patients may remain on study treatment until disease progression (as assessed by the 
investigator), unmanageable toxicity, or study termination by the Sponsor.  Patients who 
discontinue taselisib/placebo due to toxicity may continue on single-agent fulvestrant at 
the discretion of the investigator. Discontinuation of fulvestrant for adverse events is very 
rare.  However, in the unlikely event that the patient discontinues fulvestrant and is able
to continue on taselisib/placebo, the investigator should contact the Medical Monitor to 
discuss the benefit-risk assessment of continuing with single-agent taselisib/placebo.  All 
patients who are discontinued from all study treatment will return for a study drug 
discontinuation visit within 28 days after the last dose of study treatment (see 
Section 4.5.10 for additional details).
Until approximately the end of August 2018, patients who are discontinued from study 
treatment for reasons other than disease progression will be asked to continue to have 


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tumor assessments performed and to complete the PRO assessments approximately 
every 8 weeks (5 days) until disease progression. 
Until approximately the end of August 2018, after study treatment discontinuation, 
patients will be followed for survival and subsequent anti-cancer therapies approximately 
every 3 months until death, loss to follow-up, withdrawal of consent, or study termination 
by the Sponsor.  
Until approximately the end of August 2018, after experiencing disease progression, 
patients will also be asked to return to the clinic approximately 46 weeks (for tumor and 
PRO assessments) and 12 weeks ([1 week] for PRO assessments), even if a patient 
initiates anti-cancer therapy subsequent to study drug discontinuation.
Until the primary PFS analysis has been completed, an iDMC will monitor accumulating 
patient safety data and will also review efficacy data at the time of the interim analysis of 
investigator-assessed PFS (see Section 6.9). The iDMC will convene to review 
cumulative safety data approximately every 6 months. The data regarding serious 
adverse events, death, and adverse events of special interest will be monitored by the 
iDMC approximately every 3 months. Further specific details are listed in Section 5.3.
3.2
END OF STUDY
The global study will be considered completed when the last patient, last visit (LPLV) or 
safety follow-up with the last patient has occurred (28 days after the last dose of study 
drug), whichever occurs later, or when the Sponsor decides to stop the study.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
The population described by the proposed eligibility criteria reflects patients for whom 
fulvestrant represents an appropriate standard of care therapy.  Postmenopausal women 
with advanced ER, HER2-negative breast cancer could have clinical benefit from the 
addition of a PI3K inhibitor, especially if their breast tumors contain the PIK3CA mutation.  
The requirement for prior treatment with an aromatase inhibitor identifies patients who 
have become resistant to endocrine therapy and would be an appropriate population for 
a fulvestrant-based endocrine combination. The allowance of up to one prior cytotoxic 
chemotherapy regimen in the metastatic setting is consistent with prior studies with 
fulvestrant in a similar patient population, as well as a more recent study for patients who 
had become resistant to prior aromatase inhibitor treatment.  Patients treated with one 
prior metastatic chemotherapy regimen are not expected to be predisposed to having 
more severe drug-related toxicities.  The inclusion criterion of Eastern Cooperative 
Oncology Group (ECOG) Performance Status of 01 has been selected to test a more 
homogeneous patient population and to mitigate potential extra toxicities incurred by the 
addition of taselisib to fulvestrant treatment.


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3.3.2
Rationale for China Extension Cohort
In order to characterize the efficacy and safety profile of taselisib in combination with 
fulvestrant in Chinese patients and to potentially support a regulatory submission in 
China, a China extension cohort is planned in the study.  After the global enrollment 
closes, additional Chinese patients may continue to be recruited into the China 
extension cohort. A total of up to 150 Chinese patients with detectable PIK3CA-mutant 
tumors may be enrolled as part of the global study population and extension cohort 
combined.
3.3.3
Rationale for the Control Treatment
Treatment for HR, HER2-negative breast cancer usually consists of multiple rounds of 
single-agent endocrine therapy followed by cytotoxic chemotherapy once all endocrine 
therapy options have been exhausted or symptomatic or rapid disease progression 
warrants the use of cytotoxic chemotherapy.  Fulvestrant has been approved by the 
U.S. Food and Drug Administration (FDA) and European Medicines Agency for the 
treatment of HRor ER, locally advanced or MBC in postmenopausal women with 
disease progression following prior anti-estrogen therapy (Howell et al. 2002; 
Osborne et al. 2002; Di Leo et al. 2010).
Fulvestrant is not indicated for use in the adjuvant setting, whereas AIs are currently 
approved for use and are considered the standard of care (in the United States and 
European Union) in this setting.  Therefore, given the unique mechanism of action and 
the current treatment paradigm that indicates the sequential use of endocrine therapies 
for patients without visceral crisis (Senkus et al. 2013) for treatment of locally recurrent 
or MBC, fulvestrant represents an appropriate treatment option for patients whose 
disease failed to respond to prior AI therapy.
3.3.4
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.
3.3.5
Rationale for Taselisib Dose and Schedule
3.3.5.1
Safety Rationale
The clinical safety profile of taselisib at the 4-mg tablet dose level in combination with 
fulvestrant is expected to be acceptable for the intended Phase III population. Adverse 
events associated with the combination of the equivalent exposure of taselisib in capsule 
form are those that have been observed with other PI3K pathway inhibitors and include
diarrhea, colitis, pneumonitis, rash, and hyperglycemia.  These adverse events are 
monitorable, manageable, and reversible.  Preliminary clinical safety data from the open-


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label Phase Ib and II portions of Study PMT4979g with a taselisib 6-mg capsule dose 
QD in combination with fulvestrant also support testing the 4-mg tablet dose in the 
Phase III population.  No DLTs were observed at either the 6-mg or 9-mg capsule dose 
levels in the Phase Ib Study PMT4979g; however, patients treated with the 9-mg 
capsule dose of taselisib experienced a Grade 3 adverse event more frequently than 
patients treated at the 6-mg capsule dose level of taselisib.
No QT prolongation risk was observed at tested doses.  On the basis of the acceptable 
safety profile for the taselisib 6-mg capsule QD dose in combination with fulvestrant and 
the expected equivalent exposure of the 4-mg tablet dose and 6-mg capsule dose, a 
4-mg dose of taselisib tablet is the Phase III dose used in this study.
3.3.5.2
Efficacy-Response Rationale
When administered to a PIK3CA-mutant breast cancer xenograft model (KPL4) at a 
preclinical dose that is equivalent to the 3-mg QD capsule dose in humans, 60% TGI 
was observed in the KPL4 mouse model. Furthermore, PK and pharmacodynamic
modeling and human PK simulations based on these preclinical data suggest that 
80% of the patient population receiving taselisib is likely to achieve the efficacious 
exposure target at a 3-mg QD capsule dose.
The taselisib dose and schedule was derived from data generated in the Phase I/II 
open-label Study PMT4979g where taselisib doses ranging between 3 and 16 mg were 
administered to patients with solid tumor malignancies. Enrollment in the Phase II part 
of the study was enriched for patients with breast cancer.  In addition to the finding of a 
linear- and dose-proportional PK profile within this dose range, the mean elimination 
half-life of taselisib ranged between 37 and 44 hours, which support a QD dosing 
schedule. Additional information for the choice of dose and schedule is found in the 
Taselisib Investigator’s Brochure.
3.3.6
Rationale for PK Sampling and Schedule
A sparse sampling strategy will be applied in the study on the basis of the PK data 
already obtained for taselisib, which supports an expected half-life of approximately 
40 hours.  PK data from the taselisib arm will allow comparison to single-agent taselisib 
data to evaluate whether taselisib exposures are altered when administered in 
combination with fulvestrant.  The data collected from this study will enable a further 
understanding of taselisib pharmacokinetics and identification of potential sources of 
variability influencing taselisib pharmacokinetics.
3.3.7
Rationale for Patient-Reported Outcome Assessments
MBC is not currently considered curable; therefore, a patient’s HRQoL is an important 
multi-dimensional construct to measure because impairment of function and experience 
of treatment-related symptoms affect patient outcomes (Beslija et al. 2009; 
Irwin et al. 2011). Elucidating treatment effect on HRQoL, specifically during PFS, 


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provides supportive evidence to the benefit-risk assessment of a medicine and informs
the treatment decision-making between patient and clinician.
PRO measures will contextualize a patient’s experiences in the study. Since 
treatment-related side effects (e.g., oral mucositis, diarrhea, and skin problems) have the 
potential to affect HRQoL, it is crucial to characterize not only the incidence of these side 
effects but also the impact from the patient’s perspective. Assessment of global quality 
of life, impairment of function, and symptoms of special interest will provide a more 
comprehensive understanding of treatment impact and tolerability. 
The EORTC QLQ-C30 and QLQ-BR23 demonstrate strong psychometric properties, of 
both reliability and validity, and capture important constructs of interest.  The QLQ-BR23 
will be modified to include validated items on oral mucositis (2 items) and skin problems 
(2 items) to characterize these symptoms of special interest.
3.3.8
Rationale for Biomarker Assessments
Breast cancer is a heterogeneous disease, and PIK3CA-mutation status has been 
shown to vary among patients (The Cancer Genome Atlas Network 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 
taselisib and/or fulvestrant.
3.3.9
Tissue and Circulating Biomarker Assessments
3.3.9.1
PIK3CA Mutation Status
Mutations in PIK3CA occur at a frequency of approximately 40% in MBC and have been 
shown to correlate with response to PI3K inhibitors (O’Brien et al. 2010; 
Schleifman et al. 2014). Taselisib is a potent PI3K inhibitor, and a strong correlation has 
been observed between PIK3CA-mutant tumors and response to taselisib. PIK3CA
mutation status will be determined using the Roche cobas PIK3CA mutation test that 
detects 17 of the most frequent PIK3CA mutations in human cancer. Based on data 
from the COSMIC database (v66), the assay covers approximately 92% of the reported 
PIK3CA mutations in breast cancer that have been identified; all detected mutations are 
known or suspected to be oncogenic (Kang et al. 2005; Bader et al. 2006). Previous 
studies suggest that the acquisition of PIK3CA mutations is an early event in breast 
cancer (Miron et al. 2010), and a 84%90% concordance rate has been observed when 
comparing primary to matched MBC samples, suggesting that analysis of archival tissue 
is a sufficient surrogate for the identification of patients with PIK3CA-mutant tumors 
(Aurthur et al. 2014; Schleifman et al. 2014).
3.3.9.2
Phosphatase Tensin Homolog Expression Analysis
Published data suggests that loss of the tumor suppressor PTEN can activate the PI3K
pathway through the isoform of p110 (PIK3CB) (Jia et al. 2008). PTEN expression
may be assessed using established immunohistological techniques, or mutations within 
PTEN may be assessed using next-generation sequencing techniques.


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3.3.9.3
Estrogen Receptor and Progesterone Receptor Analysis
Expression of PgR is a favorable prognostic factor in ERpositive breast cancer, and 
expression has been demonstrated to be discordant among pathology laboratories 
(Arpino et al. 2005). Expression of PgR has been linked to estrogen sensitivity and 
response to anti-hormone agents (Elledge et al. 2000; Arpino et al. 2005;
Stuart-Harris et al. 2009), and receptor expression can change over the course of 
anti-estrogen therapy (Broom et al. 2009; DeDuenas et al. 2014). PgR and 
ER expression may be determined using established immunohistochemistry (IHC)
techniques.
3.3.9.4
Sequencing of Genes Related to Resistance to PI3K Inhibitors
Next-generation sequencing (NGS) techniques, such as targeted exome sequencing, 
may offer a unique opportunity to identify biomarkers of response.  For example, using 
whole genome sequencing, a two base-pair deletion in the TSC1 gene was found in a 
patient with metastatic bladder cancer with a prolonged response (2 years) to 
everolimus as single agent (Iyer et al. 2012). Similar approaches could be of great value 
when analyzing responses to agents targeting the PI3K/AKT/mTOR pathway, especially 
in the metastatic setting. In addition, mutations in the ESR1 gene are more prevalent in 
metastatic ERtumors and have been correlated with resistance to anti-estrogen 
therapies (Robinson et al. 2013; Toy et al. 2013; Jeselsohn et al. 2014). Sequencing of 
cancer-related genes may result in the identification of de novo mechanisms of 
resistance to taselisib. 
3.3.9.5
Blood Sample for Next-Generation Sequencing
NGS technologies generate a large quantity of sequencing data.  Tumor DNA can 
contain both reported and unreported chromosomal alterations because of the 
tumorigenesis process.  To help control for sequencing calls in previously unreported 
genomic alterations, a blood sample will be taken during predose to determine whether 
the alteration is somatic.
3.3.9.6
RNA and DNA Analysis
In addition to mutational activation of proteins, levels of RNA and DNA can also activate 
the PI3K pathway.  For example, increases in DNA copy number in genes such as 
CCND1, FGFR1/2 and IGF-1R, which occur at some frequency in breast cancer, can 
activate downstreamcell cycle and PI3K pathway.  HRbreast cancer can be divided 
into luminal A and luminal B subtypes, with the luminal B subtype displaying a higher 
proliferative index and a poorer prognosis.  Therefore, the RNA profiling of tumors will 
allow intrinsic subtyping of patients enrolled onto study.  In addition, PI3K transcription 
activation signatures may identify additional patients who could respond to PI3K 
inhibitors independent of PIK3CA mutation status.
3.3.9.7
Plasma Sample for Somatic Tumor Mutation Analysis
There is increasing evidence that circulating DNA obtained from blood specimens of 
cancer patients is representative of the DNA and mutational status of tumor cells 


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(Diehl et al. 2008; Maheswaran et al. 2008).  Assays are available that can detect the 
major PIK3CA mutations (and other cancer-related genes) in plasma, and results from 
this analysis may be correlated with the mutation result in tumor specimens. The use of 
circulating tumor DNA (ctDNA) to monitor response to treatment is an area of great 
interest.  It could allow for an early, non-invasive, and quantifiable method for use in the 
clinical setting to identify candidates for specific therapies and monitoring of disease 
mutation status over time (Higgins et al. 2012).
3.3.9.8
Blood Sample for the Detection of Plasma Protein Biomarkers
Emerging evidence indicates that increases in levels of systemic cytokines and 
chemokines, such as receptor tyrosine kinase growth factors, can attenuate response 
to drugs, particularly, targeted agents such as taselisib (Wilson et al. 2012).  Assays that 
assess the expression of soluble, systemic cytokines and chemokines from the plasma 
of patients may be performed using ELISA-based, mass spectrometry or appropriate 
methodologies.
3.3.9.9
Optional Tumor Biopsy Sample at the Time of Disease 
Progression
Tumor tissue may be collected at the time of progression for DNA and/or RNA extraction 
for exploratory NGS or other research on non-inherited biomarkers (including but not 
limited to cancer-related genes and biomarkers associated with common molecular and 
biological pathways). Understanding the mechanisms of resistance to taselisib is critical 
for the development of agents in the PI3K pathway and may provide an opportunity to 
develop next-generation inhibitors to prevent resistance. Notable examples include the 
T790M gatekeeper acquired mutation in EGFR in patients who progress on EGFR 
inhibitors and reactivation of the MAPK pathway in murine sarcoma viral oncogene 
homolog B (BRAF)-mutant melanoma cancers that progress on BRAF inhibitors. 
Obtaining progression biopsy tissue samples will aid in determining a resistance 
mechanism to taselisib and potentially influence future therapies for patients who 
progress on a PI3K inhibitor and may be part of a potential substudy. NGS may be 
performed by a clinical cancer genomic profiling laboratory (e.g., Foundation Medicine).  
If performed, the investigator can obtain results from the samples collected at the time of 
disease progression in the form of an NGS report, which is available upon request 
directly from the clinical cancer genomic profiling laboratory (e.g., Foundation Medicine).  
The investigator may share and discuss the results with the patient, unless the patient 
chooses otherwise.  The Foundation Medicine NGS assay has not been cleared or 
approved by the U.S. FDA or is it CE marked in Europe; results from these 
investigational tests are intended for exploratory purposes only and should not be used 
to guide future treatment decisions.
3.3.9.10
Pharmacokinetic Sample Collection Schedule
A sparse sampling strategy will be applied in the study.  A total of four plasma samples 
will be collected as outlined in Appendix 2.  Samples will be collected at Cycle 1, Day 1, 
Cycle 2, Day 1, and Cycle 6, Day 1.  The sampling schedule is designed to enable 


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characterization of taselisib pharmacokinetics using population PK methodology
following first dose (Cycle 1, Day 1) and steady-state (Cycle 2, Day 1 and Cycle 6,
Day 1) as well as exploration of fulvestrant concentrations at steady state (Cycle 6, 
Day 1).
3.3.9.11
DNA for Exploratory Pharmacogenetic Polymorphisms
Blood samples will be used for the evaluation of genetic polymorphisms of drug 
metabolic enzymes (including but not limited to CYP2C9, CYP3A4/5, and UGT1A1 and 
transporters [e.g., OATP1B1]) and genetic variants that could contribute to a potentially 
drug-related rash and/or colitis safety assessments (including but not limited to human 
leukocyte antigen [HLA]).  For sample handling procedures, storage conditions, and 
shipment instructions, see the laboratory manual. Only in circumstances where there is 
concern for the collection of this genetic material for the above evaluations can this 
assessment be considered not mandatory as part of study assessments in this study.  
Results of any analyses from these samples will be reported outside the clinical study 
report.
It is established that genetic variants of drug-metabolizing enzymes and transporters can 
affect the pharmacokinetics of drugs, which affects their safety and efficacy.  For 
example, patients who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1, which facilitates the metabolism and excretion of SN-38 
(the active metabolite of irinotecan), are at a higher risk for adverse effects associated 
with the use of standard doses of irinotecan (O’Dwyer and Catalano 2006).  Preliminary 
results from in vitro metabolism studies with taselisib suggest that taselisib is partially 
metabolized by multiple phase I cytochrome P450 enzymes, including CYP3A4.  
Although in vitro studies can help elucidate the roles of enzymes in the metabolism of 
the drug, these results are not always predictive of in vivo metabolism for a number of 
reasons, such as differences in drug concentrations that the enzymes encounter in vitro 
and in vivo.  For this reason, a blood sample for DNA isolation is to be collected from all 
patients in this study for potential pharmacogenetic analysis of genes or biomarkers that 
may affect the pharmacokinetics or response to taselisib.  The decision to analyze the 
samples will be based on a review of the pharmacokinetics and response data.  Most 
recently, HLA has been demonstrated to play an important role in the development of 
drug-induced rash for some drugs (carbamazepine, abacavir, and allopurinol).  
Therefore, evaluation of genetic variants of genes that may regulate the immune 
response (including but not limited to HLA) may also be investigated to characterize 
unusual safety responses that are not predicted by taselisib pharmacokinetics.


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3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

Investigator-assessed PFS, defined as the time from randomization to the first 
occurrence of disease progression, as determined with the use of Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death from any cause 
(whichever occurs earlier)

Objective response (PRCR) as determined by using RECIST v1.1

OS, defined as the time from randomization to death from any cause

Clinical benefit, defined as objective response or no disease progression lasting for
24 weeks since randomization

DOR, defined as the time from the first occurrence of a documented objective 
response to the time of the first documented disease progression, as determined by 
the investigator using RECIST v1.1, or death from any cause (whichever occurs 
earlier)

BICR-assessed PFS, defined as the time from randomization to the first occurrence 
of disease progression, as determined by the BICR with the use of RECIST v1.1, or 
death from any cause (whichever occurs earlier)
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, type, and severity of adverse events (based on the National Cancer 
Institute Common Terminology Criteria for Adverse Events Version 4.0 
[NCI CTCAE v4.0])

Incidence, type, and severity of serious adverse events

Incidence of adverse events leading to study treatment discontinuation, modification, 
or interruption

Abnormal laboratory values

Death and cause of death
3.4.3
Pharmacokinetic Outcome Measure
The PK outcome measure for this study is as follows:

Taselisib PK parameters including but not limited to plasma Cmax and minimum 
plasma concentration under steady-state conditions within a dosing interval
3.4.4
Patient-Reported Outcome Measure
The PRO measure for this study is as follows:

HRQoL, including treatment-related symptoms (e.g., oral mucositis, diarrhea, skin 
problems) and patient functioning, as measured by the EORTC QLQ–C30 and the 
modified QLQ–BR23 breast cancer module


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3.4.5
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Correlation of efficacy with molecular markers related to the mechanism of action of 
taselisib and endocrine therapy that include the following:
Alterations in DNA and RNA, including DNA mutational status, RNA expression 
levels, DNA copy number and protein expression
Alteration in tumor tissue biomarkers including but not limited to PTEN
Assessment of PI3K pathway status (e.g., PIK3CA mutation status) in ctDNA 
from peripheral blood, as well as additional cancer related mutations
(e.g., ESR1)
Cancer-related plasma biomarkers including assessment of cytokines and 
chemokines

Association between genetic polymorphisms of drug metabolic enzymes or 
transporters and taselisib pharmacokinetics

Fulvestrant concentration in the presence and absence of taselisib

Genetic variants and association with drug-related safety assessments, including 
but not limited to HLA
3.4.6
Exploratory Health Economic Outcome Measure
The EQ-5D will be used to obtain health status information for health economic modeling
(see Appendix 9).
The EQ-5D is a generic, preference-based health utility measure with questions about 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that are used 
to build a composite of the patient’s health status.  A single summary index from the 
EQ-5D health states will be utilized in this study for economic modeling.
4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
Disease-Specific Inclusion Criteria

Women with histologically or cytologically confirmed invasive, ERbreast cancer:  
metastatic or inoperable (not amenable to resection or other local therapy with 
curative intent) locally advanced breast cancer

Patients for whom endocrine therapy (e.g., fulvestrant) is recommended and 
treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, 
as per national or local treatment guidelines.

Radiologic/objective evidence of recurrence or progression to the most recent 
systemic therapy for breast cancer


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
Radiologic/objective evidence of breast cancer recurrence or progression while on 
or within 12 months of the end of adjuvant treatment with an AI, or progression while 
on or within 1 month of the end of prior AI treatment for locally advanced or MBC. 
The AI (letrozole, anastrozole, or exemestane) does not have to be the most recent 
treatment before randomization.

Measurable disease via RECIST v1.1 or non-measurable, evaluable disease with at 
least one evaluable bone lesion via RECIST v1.1.  Bone lesions that have been 
irradiated are not evaluable.
General Inclusion Criteria

Able and willing to provide written informed consent and to comply with the study 
protocol

Age 18 years

ECOG Performance Status of 0 or 1

Postmenopausal status defined as one of the following:
Age 60 years
Age 60 years and postmenopausal as defined by documented 
follicle-stimulating hormone and estradiol in the postmenopausal ranges in 
addition to being amenorrheic for 12 months in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression
Prior bilateral oophorectomy (28 days prior to first fulvestrant treatment at 
Cycle 1, Day 1)

Consent to provide a formalin-fixed, paraffin-embedded (FFPE) tissue block
(preferred) or a minimum of 20 (25 preferred) freshly cut unstained tumor slides 
from the most recently collected, available tumor tissue for PIK3CA-mutation testing
and for other protocol-mandated exploratory assessments

A valid cobas PIK3CA mutation result (per central testing) is required for all patients 
(e.g., patients with an “invalid” or “failed” PIK3CA mutation result are not permitted 
to enroll)
After 120 patients whose breast cancers have a “wild-type” (mutation not 
detected result) PIK3CA status have been enrolled, all remaining enrolled 
patients must have a breast cancer sample that tests positive for PIK3CA
mutation to be eligible.

Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 28 days prior to Cycle 1 Day 1:
ANC 1500/L (1.5109/L)
Platelet count 100,000/L (100109/L)
Hemoglobin 9.0 g/dL (90 g/L)
Total bilirubin 1.5upper limit of normal (ULN) except in patients with
previously documented Gilbert’s syndrome, in which case total
bilirubin 3 mg/dL


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AST and ALT1.5ULN, with the following exceptions:
Patients with documented liver metastases: AST and/or ALT 5.0ULN
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min based on 
CockcroftGault glomerular filtration rate estimation
(140age)(weight in kg)(0.85 if female)
72(serum creatinine)
INR 1.5 and aPTT (or PTT) 1.5ULN; for patients requiring therapeutic 
anticoagulation therapy, a stable INR 2.5

Fasting glucose 125 mg/dL (6.94 mmol/L) 

For enrollment into the China extension cohort, residence in the People’s Republic 
of China
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Disease-Specific Exclusion Criteria

HER2-positive disease by local laboratory testing (IHC 3staining or in situ 
hybridizationpositive)

Prior treatment with fulvestrant

Prior treatment with a PI3K inhibitor, mTOR inhibitor (such as everolimus), or AKT 
inhibitor.  See Appendix 5 for a comprehensive list of excluded treatments.

Prior anti-cancer therapy within 2 weeks prior to Cycle 1 Day 1

Prior radiation therapy within 2 weeks prior to Cycle 1 Day 1

All acute treatment-related toxicity must have resolved to Grade 1 or be deemed 
stable by the investigator

Prior treatment with 1 cytotoxic chemotherapy regimen for MBC

Symptomatic hypercalcemia requiring continued use of bisphosphonate or 
denosumab therapy
Use of bisphosphonate therapy or denosumab for other reasons (e.g., bone 
metastasis, osteoporosis, etc.) is allowed

Concurrent hormone replacement therapy

Known untreated or active CNS metastases (progressing or requiring 
anticonvulsants or corticosteroids for symptomatic control); a computed tomography 
(CT) scan or magnetic resonance imaging (MRI) of the brain will be performed at 
screening if required by the local health authority
Patients with a history of treated CNS metastases are eligible, provided they 
meet all of the following criteria: 
Evaluable or measurable disease per inclusion criteria outside the CNS is 
present.


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Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic study
No history of intracranial hemorrhage or spinal cord hemorrhage
Minimum of 2 weeks between completion of radiotherapy and 
Cycle 1, Day 1 and recovery from significant (Grade 3) acute toxicity with 
no ongoing requirement for 10 mg of prednisone per day or an equivalent 
dose of other corticosteroid

History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
Stage I uterine cancer, or patients who have undergone potentially curative therapy 
with no evidence of disease and are deemed by the treating physician to be at low 
risk for recurrence
General Exclusion Criteria

Type 1 or Type 2 diabetes mellitus requiring anti-hyperglycemic medications

Clinically significant cardiac or pulmonary dysfunction, including the following:
Current uncontrolled Grade 2 hypertension or unstable angina
Symptomatic congestive heart failure or serious cardiac arrhythmia requiring 
treatment, with the exceptions of atrial fibrillation and paroxysmal 
supraventricular tachycardia or a conduction abnormality that has been treated 
and for which the patient is no longer at risk for serious arrhythmia 
(e.g., Wolff-Parkinson-White syndrome treated with surgical ablation)

Current dyspnea at rest or any requirement for supplemental oxygen therapy to 
perform activities of daily living

History of malabsorption syndrome or other condition that would interfere with 
enteral absorption

Inability or unwillingness to swallow pills or receive intramuscular injections

Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, or current known active infection with HIV, hepatitis B virus (HBV), 
or hepatitis C virus (HCV)
Active infection is defined as requiring treatment with antiviral therapy or 
presence of positive test results for hepatitis B (hepatitis B surface antigen
and/or total hepatitis B core antibody) or HCV antibody.  Unless required by 
local regulations, patients are not required to have HIV, HBV, or HCV 
assessments at screening if these assessments have not been previously 
performed.
Patients who test positive for hepatitis B core antibody are eligible only if 
test results are also positive for hepatitis B surface antibody and 
polymerase chain reaction (PCR) is negative for HBV DNA.


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Patients who are positive for HCV serology are only eligible if testing for 
HCV RNA is negative.

History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis)

Active bowel inflammation (e.g., diverticulitis)

Immunocompromised status due to current known active infection with HIV or 
because of the use of immunosuppressive therapies for other conditions

Need for current chronic corticosteroid therapy (10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids)
Stable use (i.e., no change in dose within 3 months prior to Cycle 1 Day 1) of 
inhaled corticosteroids is allowed.

Pregnancy, lactation, or breastfeeding

Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, or metabolic or infectious disease)

Major surgical procedure or significant traumatic injury within 28 days prior to 
Cycle 1, Day 1 or anticipation of the need for major surgery during the course 
of study treatment

Inability to comply with study and follow-up procedures

Inability to understand the local language(s) for which the EORTC QLQ-C30, the 
modified Breast Cancer module QLQ-BR23, and the EQ-5D questionnaires are 
available (see Appendix 7, Appendix 8, and Appendix 9).
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
After written informed consent has been obtained and eligibility has been established 
and approved, the study site will obtain the patient’s identification number and treatment 
assignment from the interactive voice/Web response system (IxRS). Patients will be 
randomized to receive either taselisibfulvestrant or the placebofulvestrant on the 
basis of a 2:1 randomization ratio. Patients with PIK3CA-mutant tumors and patients 
without detectable PIK3CA-mutant tumors will be randomized separately using a 
permuted-block randomization method.
Randomization will be stratified by the following criteria:

Visceral versus non-visceral disease
Visceral disease: Metastatic disease in the lung, liver, adrenal glands, brain,
heart, pericardium, pleura, peritoneum, or other end-organs of the chest, 
abdomen, and pelvis
Non-visceral disease: Absence of metastatic disease in visceral organs. 
Pleural effusions, ascites, disease involving lymph nodes, and disease involving 
bone are not considered to be visceral disease.


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
Sensitivity versus non-sensitivity to the patient’s most recently administered 
endocrine therapy
Sensitive to most recently administered endocrine therapy (fulfilling either of the 
criteria below:
For patients with no endocrine treatment in the advanced or metastatic 
setting, at least 24 months of adjuvant endocrine therapy prior to 
disease recurrence
Documented clinical benefit (CR, PR, or SD 24 weeks) to most 
recent endocrine treatment in the advanced or metastatic treatment 
setting
Non-sensitive: not satisfying criteria listed as sensitive

Geographical region:
Western Europe, United States, Canada, Australia
Asia
Rest of World (remaining countries)
The iDMC, the independent statistical group (an independent vendor) facilitating the 
iDMC meetings, and the Sponsor-independent PK bioanalytical personnel will be 
unblinded to the treatment assignment.  The study team will be unblinded at the time 
when the iDMC recommends to stop the trial and the Sponsor decides to stop the trial or 
at the time of the final PFS analysis if the study is not stopped early.  Investigators and 
patients will remain blinded to individual patient-level treatment assignment until 
approximately the end of August 2018, at which time unblinding is permitted at the 
discretion of the investigator or Sponsor.
Although PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  Sponsor 
personnel responsible for performing PK assays will be unblinded to patients’ treatment 
assignments to identify appropriate PK samples to be analyzed.  Samples from patients 
assigned to the comparator arm will not be analyzed except by request (i.e., to evaluate 
a possible error in dosing).
Until approximately the end of August 2018, if unblinding is necessary for patient 
management (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.  Treatment codes should not be 
broken except in emergency situations.  If the investigator wishes to know the identity of 
the study drug for any other reason, he or she should contact the Medical Monitor 
directly.  The investigator should document and provide an explanation for any 
premature unblinding (e.g., accidental unblinding or unblinding due to a serious adverse 
event).


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For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or the Sponsor to be 
related to study drug.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Taselisib
The taselisib tablet is a white to off-white, film-coated, immediate-release formulation of 
2 mg strength.
4.3.1.2
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
Dosage, Administration, and Compliance
4.3.2.1
Taselisib
The taselisib 4-mg dose will be taken orally once a day (4 mg PO QD).  Taselisib is 
formulated as 2-mg tablets, so patients will take two 2-mg tablets daily to receive a 
4-mg dose.  Taselisib will be administered in the clinic at Cycle 1, Day 1 and Cycle 1 
Day 15 and on each subsequent day that a cycle visit is scheduled, after the predose 
assessments and procedures, and after the fulvestrant administration (except for Cycle 2 
Day 15). Taselisib will be administered at home on all non-clinic visit days.  Patients 
should take the taselisib dose at the same approximate time each day without regard to 
the timing of administration of food.  If a dose is missed (not taken within 6 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. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.1.1.
4.3.2.2
Placebo
The taselisib placebo (corresponding to 4-mg dose) dosage will be supplied as 2 tablets 
PO QD. Taselisib placebo will be administered in the clinic at Cycle 1, Day 1 and Cycle 
1, Day 15 and on each subsequent day that a cycle visit is scheduled, after the predose 
assessments and procedures, and after the fulvestrant administration (except for Cycle 2,
Day 15). Taselisib placebo will be administered at home on all non-clinic visit days.  
Taselisib placebo should be taken at the same approximate time each day without 
regard to the timing of administration of food.  If a dose is missed (not taken within 
6 hours after the scheduled dosing time), the patient should resume dosing with the next 


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scheduled dose.  Missed or vomited doses will not be made up. For additional details, 
see Appendix 1.
4.3.2.3
Fulvestrant
Fulvestrant 500 mg will be administered in the clinic (before administration of 
taselisib/placebo) as two IM injections of 250 mg each at Cycle 1, Days 1 and 15 and 
Day 1 of each subsequent 28-day cycle.  For details regarding the dosing instructions 
and safety profile of fulvestrant, refer to the fulvestrant package insert or SmPC.
The fulvestrant dose level cannot be modified. In general, the investigator may consider 
continuing fulvestrant if the adverse event observed is not thought to be 
fulvestrant-related. See Section 5.1.2.1 for guidelines for treatment interruption or 
discontinuation of fulvestrant.
4.3.3
Investigational Medicinal Product Accountability
Taselisib and placebo will be supplied by the Sponsor in all participating countries.  
Fulvestrant will be supplied by the Sponsor in all participating countries except the 
countries where procurement will be reimbursed. The study site will acknowledge 
receipt of Sponsor-supplied study drugs using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.
Sponsor-supplied study drugs will either be disposed of at the study site according to the 
study site’s institutional standard operating procedure or returned to the Sponsor with 
the appropriate documentation.  The Sponsor must agree with the method of destruction 
at each investigational site.  The site must obtain written authorization from the Sponsor 
before any Sponsor-supplied medication is destroyed, and destruction must be 
documented on the appropriate form.
Accurate records of all Sponsor-supplied medications received at, dispensed from, 
returned to, and disposed of by the study site should be recorded on the Drug Inventory 
Log.
4.3.4
Post-Study Access to Taselisib
Currently, the Sponsor does not have any plans to provide taselisib or any other study 
treatments or interventions after the end of the study or for any patient who has 
discontinued or withdrawn from the study.  Crossover from the control arm to the 
taselisib arm is not allowed.  The Sponsor will evaluate whether to continue providing 
taselisib after the main study is over in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product.
In the event that the Sponsor deems post-trial access to taselisib to be appropriate, the 
Sponsor may offer post-trial access to the study drug (taselisib) free of charge to eligible 
patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.


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A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being.

There are no appropriate alternative treatments available to the patient.

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them.
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient).

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for ER, HER2-negative MBC.

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for ER, HER2-negative MBC.

Provision of study drug is not permitted under the laws and regulations of the 
patient's country.
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf.
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy
Concomitant therapy includes any prescription medication, over-the-counter 
preparations, herbal or homeopathic remedies, and nutritional supplements used by a 
patient from 7 days prior to the screening visit through to Study Drug Discontinuation 
Visit. All concomitant medications should be reported to the investigator and recorded 
on the Concomitant Medications electronic Case Report Form (eCRF).
Patients who experience toxicities should be treated symptomatically as clinically 
indicated.  Patients treated with anti-seizure medications should have levels monitored 
regularly.
Patients who require maintenance therapy as specified in the eligibility criteria 
(see Sections 4.1.1 and 4.1.2) should continue to receive maintenance therapy.
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drug.  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.


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Pain medications administered per standard clinical practice are acceptable while the 
patient is enrolled in the study.
4.4.2
Prohibited Therapy
Use of the following concomitant therapies is prohibited for at least 7 days prior to 
Cycle 1, Day 1 dosing (unless a longer washout is required as outlined in the exclusion 
criteria in Section 4.1.2) and during the study treatment unless otherwise specified below:

Therapy intended for the treatment of cancer (regulatory-approved or experimental), 
including chemotherapy, radiation therapy, immunotherapy, biologic therapy, herbal 
therapy, radiopharmaceutical therapy, or endocrine therapy.
Until approximately the end of August 2018, local radiotherapy is not 
permitted.  It is understood that there may be extreme circumstances requiring 
local radiotherapy in which the investigator does not believe that the symptoms 
are a result of disease progression (e.g., impending fracture) and the radiation 
field does not encompass a target/non-target lesion.  In such cases, the 
investigator must obtain approval from the Medical Monitor, and such patients 
should have a tumor assessment of the lesion(s) before they actually receive 
the radiotherapy. If a patient received radiation therapy and a target or non-
target lesion is included in the field of radiation, the lesion(s) will become 
unevaluable for tumor response.
Further reasons for avoiding local radiotherapy include the difficulty in 
distinguishing new symptomatic pain or worsening of lytic bone lesions from 
disease progression. Radiation therapy to a specific site renders that lesion 
unevaluable for tumor response.  Few clinical data are available about potential 
toxicities of radiation and treatment with taselisib.  Previous clinical experience 
also suggests that new bone pain is frequently a symptom of disease 
progression. Bone pain secondary to fulvestrant treatment can be treated with 
pain medications, nonsteroidal anti-inflammatory drugs (NSAIDs), or 
corticosteroids.
After approximately the end of August 2018, local radiotherapy is permitted at 
the discretion of the investigator.  Disease progression should be ruled out as 
taselisib/placebo and fulvestrant must be permanently discontinued for disease 
progression. It is recommended to hold taselisib/placebo for the duration of the 
local radiotherapy.

Until approximately the end of August 2018, initiation of bisphosphonate or 
denosumab therapy or modification of the pre-study bisphosphonate or denosumab 
treatment regimen (e.g., for bone metastasis) should be strongly avoided. Such 
actions would require the approval of the Medical Monitor.  After approximately the 
end of August 2018, initiation of bisphosphonate or denosumab therapy or 
modification of the pre-study bisphosphonate or denosumab treatment regimen (e.g., 
for bone metastasis) is permitted at the discretion of the investigator.


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
Until approximately the end of August 2018, hematopoietic growth factors (e.g.,
erythropoietins, G-CSF, and GM-CSF) are not to be administered prophylactically. 
Use of these agents should be reserved for cases of severe neutropenia and 
anemia per the labeling of these agents and require the approval of the Medical 
Monitor.  After approximately the end of August 2018, prophylactic administration 
of hematopoietic growth factors (e.g., erythropoietins, G-CSF, and GM-CSF) is 
permitted at the discretion of the investigator.

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.
In vitro data with taselisib indicate that it is a substrate of CYP3A4, and results of a 
clinical study with a potent CYP3A4 inhibitor (itraconazole) suggest that there is a 
moderate potential for a drug-drug interaction between taselisib and any medication that 
strongly inhibits CYP3A4. Therefore, the concomitant use of strong CYP3A4 inhibitors 
including but not limited to ketoconazole, itraconazole, clarithromycin, atazanavir, 
telithromycin, ritonavir, indinavir, and voriconazole, should be avoided.  Caution should 
be exercised when moderate CYP3A4 inhibitors, including but not limited to fluconazole, 
ciprofloxacin, cyclosporine, and verapamil are co-administered with taselisib.
On the basis of findings from a clinical study with a potent CYP3A4 inducer (rifampicin), 
there is a low potential for a drug-drug interaction when taselisib is co-administered with 
a strong CYP3A4 inducer. Therefore, caution should be exercised when strong CYP3A4 
inducers, including but not limited to St John’s wort, phenytoin, carbamazepine, 
rifampicin, rifabutin, and phenobarbital are co-administered with taselisib.
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
when determining whether a certain medication strongly induces or moderately inhibits 
CYP3A4.
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above.
Food to Avoid
Grapefruit or grapefruit juice (strong CYP3A4 inhibitor) should be avoided during the 
study and for at least 7 days prior to Cycle 1 Day 1 of study treatment.
4.5
STUDY ASSESSMENTS 
See Appendix 1 and Appendix 2 for the schedule of assessments performed during the 
study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Prior to signing the main 


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consent form for the study, patients may specifically allow for the collection and testing 
of archival tumor tissue or fresh tumor tissue (e.g., biopsy of a new metastatic lesion) by 
signing the prescreening consent form.  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 randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases that have occurred within the 
previous 5 years before Cycle 1, Day 1, breast cancer history (including tumor 
characteristics such as hormone receptor status, prior cancer therapies, surgeries, and 
procedures), smoking history, and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 7 days prior to the screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity in accordance 
with the applicable laws (e.g., health authority requirements).
4.5.3
Physical Examinations
A complete physical examination should include measurement of height (at screening 
visit only) and weight; an evaluation of the head, eyes, ears, nose, and throat; and an 
evaluation of the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.
Until approximately the end of August 2018, an assessment of the patient’s ECOG 
Performance Status (see Appendix 4) will be completed at screening and as specified in 
the schedule of assessments (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 (e.g., diarrhea, colitis, pneumonitis).  
Changes from baseline abnormalities should be recorded in patient notes.  New or
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
Until approximately the end of August 2018, as part of tumor assessments, physical 
examinations should also include the evaluation of the presence and degree of enlarged 
lymph nodes, hepatomegaly, and splenomegaly.  After approximately the end of 
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enlarged lymph nodes, hepatomegaly, and splenomegaly by physical examination should 
be included per local standard of care.
4.5.4
Vital Signs
Vital signs, collected at screening and at each subsequent visit, will include 
measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressures
(while the patient is in a seated position), temperature, and pulse oximetry for oxygen
saturation measurement.
4.5.5
Tumor and Response Evaluations
All known sites of disease must be documented at screening (within 28 days prior to 
Cycle 1, Day 1) and, until approximately the end of August 2018, re-assessed at each 
subsequent tumor evaluation (every 8 weeks 5 days from the date of randomization).  
After approximately the end of August 2018, subsequent tumor evaluations may be 
conducted per local standard of care. 
Screening assessments must include CT scans of the chest, abdomen, and pelvis; CT 
scans of the neck and brain imaging should be included if clinically indicated.  A 
documented standard-of-care tumor assessment performed within 28 days 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 this schedule regardless of 
dose delay or early discontinuation until disease progression.
Until approximately the end of August 2018, response assessment will be made by the 
investigator on the basis of physical examinations, CT scans, or MRI, and/or bone scans
using criteria outlined in RECIST v1.1 (Appendix 6).  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.  After approximately the end of 
August 2018, subsequent tumor evaluations may be conducted per local standard of 
care.
Until approximately the end of August 2018, CT scans throughout the study should
include chest, abdomen, and pelvic scans. CT scans of the neck and brain imaging
should be included if clinically indicated.  At the investigator’s discretion, CT scans may 
be repeated at any time if progressive disease is suspected.  After approximately the 
end of August 2018, subsequent tumor evaluations may be conducted per local standard 
of care.
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 6). 


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Bone scans and/or skeletal survey should be performed within 28 days prior to Cycle 1,
Day 1. Positive areas on bone scans must be assessed by either CT scan with bone 
windows, MRI, or X-ray prior to randomization.  Bone lesions identified at baseline by CT 
scan, MRI or X-ray should be assessed using the same modality (CT scan, MRI, or 
X-ray) and following the same schedule for measurable lesions until disease progression,
as described above. Additional bone scans or skeletal surveys should be performed if 
clinically indicated. Until approximately the end of August 2018, for patients with bone-
only disease not visible on CT/MRI scan or X-ray at baseline, additional bone scans 
should be repeated every 8 weeks (5 days) from the date of randomization and when 
clinically indicated until disease progression.  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 Sponsor (e.g., sodium fluoride [NaF]).  
After approximately the end of August 2018, subsequent tumor evaluations may be 
conducted per local standard of care.
Until approximately the end of August 2018, abnormalities found on subsequent bone 
scans must also be confirmed by CT scan, MRI scan, or X-ray assessment.  After 
approximately the end of August 2018, subsequent tumor evaluations may be conducted 
per local standard of care.
If the patient presents with both irradiated and non-irradiated bone lesions, only the 
non-irradiated lesions should be followed for tumor assessments unless progression is 
documented after the radiation.
In the absence of measurable disease at baseline, the following will be considered 
progression among patients with lytic or mixed (lyticsclerotic) bone lesions:

The appearance of one or more new lytic lesions in bone

The appearance of one or more new lesions outside of bone

Unequivocal progression of existing bone lesions
Note: Pathologic fracture, new compression fracture, or bone metastases complications 
will not be considered as evidence of disease progression unless one of the above-
mentioned criteria is fulfilled. Patients with symptoms of rapidly progressing disease 
without radiological (or photographical) evidence will not be considered to have 
progressed for efficacy analyses. The evaluation of overall lesion response will be 
performed according to RECIST, v1.1 as described in Appendix 6. For patients with only 
bone lesions, RECIST, v1.1 will be extended to include the evaluation of overall lesion 
response, which will be based solely on non-target lesion responses. Specifically, in the 
absence of new lesions, the overall lesion response at each assessment will be one of 
the following: CR, SD, unknown, or PD based on non-target lesion responses. Stable 
disease would include all assessments not qualifying for complete response, progressive 
disease, or unknown. In the presence of any new lesion, the overall lesion response will 
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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:

Until approximately the end of August 2018, all lesions identified at baseline 
(target and non-target) will be reassessed using the same method throughout the 
course of the study. After approximately the end of August 2018, tumor 
assessments may be conducted per local standard of care. 

All CT scans and MRIs obtained for all patients enrolled at the center should be 
reviewed by the local radiologist who, together with the investigator, will determine 
the local assessment of response and progression. All bone scans obtained from 
the patient with bone metastases at baseline also should be reviewed similarly.

Until the clinical cutoff date for the primary PFS analysis, which was 15 October
2017, all radiologic data (CT scan, MRI and bone scan, etc.) and photos 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 blinded independent central review (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.
Until approximately the end of August 2018, patients who discontinue study treatment 
for any reason other than disease progression will continue to undergo tumor-response 
evaluations until progressive disease.  Until approximately the end of August 2018, 
patients who are discontinued from study treatment because of disease progression will 
be asked to return for a repeat tumor assessment 4-6 weeks after experiencing disease 
progression.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for hematology, blood chemistries, and urinalysis will be analyzed at the study 
site’s local laboratory.  Samples for biologic markers and pharmacokinetics will be sent 
to one or more central laboratories or to the Sponsor or designee for analysis.
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.
All screening laboratory assessments should be obtained within 28 days prior to Cycle 1,
Day 1.
Laboratory assessments will include the following:

Hematology:  Hemoglobin, hematocrit, RBC count, platelet count, WBC count, and 
WBC differential count (neutrophils, bands [optional], lymphocytes, eosinophils, 
basophils, monocytes)


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Reporting the differential as absolute counts is preferred, but percent is 
accepted.

Fasting blood chemistry (8 hours):  ALT, AST, ALP, total bilirubin, total protein, 
albumin, BUN [or urea], creatinine, glucose, calcium, phosphorus, sodium, 
potassium, chloride, magnesium, and bicarbonate
Note:  For investigational sites in countries where bicarbonate may not be 
collected as part of the standard chemistry panel, bicarbonate will not be 
measured.

Fasting lipid profile (8 hours): total cholesterol, high-density lipoprotein, 
low-density lipoprotein, triglycerides, amylase, and lipase

Glycosylated hemoglobin (HbA1c)

Plasma samples for determination of taselisib concentrations

Coagulation: INR and aPTT (or PTT) required for all patients within 28 days prior to 
Cycle 1 Day 1 and then as clinically indicated
Patients taking warfarin or its equivalent:  INR and aPTT (or PTT) twice in the 
first week of taselisib administration, then weekly for 3 weeks, and then as 
clinically necessary

Urinalysis: Specific gravity, pH, glucose, protein, ketones, and blood. Required for 
all patients within 28 days prior to Cycle 1, Day 1 and then as clinically indicated
Until approximately the end of August 2018, the following assessments will be 
performed at an investigational testing site.  Instruction manuals outlining sampling 
procedures, storage conditions, and shipment instructions and supply kits will be 
provided for all investigational assessments:

Tumor tissue samples. All patients must consent to PIK3CA-mutation testing as 
well as to other protocol-mandated exploratory assessments at baseline.
Tumor tissue should be of good quality on the basis of total and evaluable tumor 
content.  Evaluation of the patient’s tumor sample for adequate tumor tissue content 
and determination of PIK3CA-mutation status by a central laboratory must occur 
prior to initiation of study treatment.  A tumor block or a minimum of 20 (25 preferred) 
unstained slides from a FFPE tissue sample will be required for enrollment eligibility 
purposes. An associated pathology report should also be sent with the sample.  If 
slides are provided, the 2025 slides should originate from the same tumor block. If 
fewer than 20 slides are available, the Medical Monitor should be consulted.  
Alternatively, the patient may agree to the collection of a fresh tumor sample if 
feasible.  Tissue samples, including tumor blocks, from patients who are not eligible 
to enroll in the study will be returned as soon as possible but no later than 4 weeks 
after eligibility determination.  If a patient is determined to be eligible for the study, 
the remaining tumor block will be returned once all sections required for the protocol 
assessments have been obtained or upon request.  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.


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The specimens will be used for central assessment of PIK3CA mutation status 
and PgR expression.  In addition, other exploratory assessments, including but 
not limited to PI3K signaling pathway status may be evaluated, including protein 
expression (e.g., PTEN) and molecular profiling studies such as NGS and
gene-expression.

Enrolled patients who are willing to consent will also undergo an optional
post-progression core biopsy of the tumor if it is anatomically feasible and if there 
are no medical contraindications, if the biopsy can be obtained prior to the initiation 
of new cancer treatment, or within approximately 14 days of the start of the new 
cancer treatment as long it is deemed safe by the investigator to obtain the biopsy, 
and the procedure does not impede or delay planned cancer treatment.  If the 
patient consents and is medically fit (ECOG Performance Status of 0 or 1), no 
anti-coagulation therapy and no acetylsalicylic acid (aspirin) or NSAIDs should be 
taken prior to the procedure.  The obtained tissue sample will be used for DNA 
and/or RNA extraction for exploratory NGS or other research on non-inherited 
biomarkers (including but not limited to cancer-related genes and biomarkers 
associated with common molecular pathways). See Section 3.3.9.9 for additional 
details. Collection Instructions for post-progression biopsies will be provided in a 
separate Laboratory Manual. Priority should be given to the submission of a FFPE 
tissue block over a minimum of 20 (25 preferred) slides.

Plasma samples for exploratory research on candidate biomarkers (e.g., PIK3CA) 
include but are not limited to the following: ctDNA and plasma protein biomarkers

Baseline (pretreatment) plasma sample to be banked for future blood-based 
biomarker discovery and/or development

Blood for NGS (if approved by local regulatory authorities)

Blood for pharmacogenetic assessment (if approved by local regulatory authorities)
4.5.7
Assay Methods
4.5.7.1
Mutational Analysis for PIK3CA
The PIK3CA-mutation assay will be performed by a central investigational testing site.
Somatic mutations in the PIK3CA gene are found in approximately 40% of MBCs and 
occur most commonly in exons 9 and 20 in the codons encoding amino acids E542, 
E545, and H1047 (Saal et al. 2005).  RT-PCR assays that amplify exons that are 
commonly mutated in PIK3CA offer a sensitive and quantitative method to detect 
mutations from a tumor specimen.  DNA will be extracted from tumor samples and 
subjected to allele-specific PCR assays that detect the WT allele as well as to assays for 
nucleotide substitutions that include but are not limited to the following amino acid 
changes:  R88Q, N345K, C420R, E542K, E545K/A/G/D, E546K/E/R/L, M1043I, 
H1047R/L/Y, and H1049R.  Following histopathological review, samples 
with 10% tumor content may not be evaluable for the PIK3CA assay. Samples will be 
run on cobas 4800 platform, and PIK3CA-mutation status (mutation detected or mutation 
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A designation of PIK3CA-status unknown will be assigned to a sample wherein any one 
of the predefined mutations was not conclusively assessed (e.g., patients with an “invalid” 
or “failed” PIK3CA-mutation result will not be eligible for enrollment).
If multiple tumor samples that were surgically obtained at different times are submitted to 
satisfy this enrollment criterion, the PIK3CA-mutation status will be on the basis of a 
valid result on the tumor sample that was most recently collected. If the most recently 
collected tumor tissue does not provide a valid result, mutation status will be determined 
using other available tissue.
If multiple tumor samples that were surgically obtained at the same time are submitted to 
satisfy this enrollment criterion, the patient will be categorized as containing a 
PIK3CA-mutant tumor based on a valid PIK3CA-detectable result from either tumor 
sample.
4.5.7.2
Analysis of Phosphatase Tensin Homolog Expression
PTEN status may be examined by IHC or NGS using appropriate platforms.  For IHC, 
tumor specimens will be scored only if appropriate staining is observed in internal control 
stromal or normal (non-tumor) tissue elements.
4.5.7.3
Progesterone Receptor Analysis
PgR status will be determined at a central laboratory using standardized 
immunohistochemical procedures.
4.5.7.4
Circulating Tumor DNA Analysis
ctDNA will be extracted from plasma samples collected from patients and used for the 
detection of oncogenic mutations and DNA methylation using appropriate technologies.  
The prevalence of the mutations measured at baseline and post-treatment may provide 
information on response or resistance to therapy.
4.5.7.5
Messenger RNA Expression Profiling
In cases where there is sufficient archival tissue to isolate RNA, gene expression may be 
performed using gene expression assays conducted using appropriate technologies.
Analysis may include but is not limited to a panel of genes that are important for intrinsic 
subtyping, breast cancer biology, and immune-related and PI3K signaling.  The goal will 
be to generate a database of expression status to examine whether there are gene 
expression patterns associated with clinical response to taselisib.
4.5.7.6
Tumor Somatic Mutation Analysis
In cases where there is sufficient material to isolate DNA, NGS may be performed using 
an appropriate NGS platform, such as Illumina or an equivalent. The goal will be to 
determine whether the somatic mutations are associated with clinical response to 
taselisib.


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4.5.7.7
Copy Number Analysis 
The level of copy number alterations in cancer-related genes may be determined using 
DNA-based technologies, either cytogenetically, using chromosomal in situ hybridization 
(ISH), next-generation sequencing platforms, RT-PCRbased or using equivalent
technologies.  For cytogenetic assays, detection may be either fluorescence-based 
(fluorescence ISH assay) or chromogenic-based (chromogenic ISH).  Data on increased 
copy number of PI3K pathwaysactivating genes may provide information on response 
or resistance to therapy.
4.5.7.8
Plasma Biomarker Analyses
Assays that assess the expression of soluble, systemic cytokines, and chemokines from 
the plasma of patients will be completed using appropriate methodologies, such as 
ELISA-based, mass spectrometry-based or equivalent technologies.
4.5.7.9
Plasma Pharmacokinetic Samples
Plasma samples will be evaluated for taselisib concentrations through the use of a 
validated liquid chromatography tandem mass spectrometry assay.  Plasma samples 
may be used for the exploratory evaluation of safety and/or response biomarkers, the 
identification and profiling of potential taselisib-related metabolites, ex-vivo protein 
binding, PK or pharmacodynamic assay development purposes, and/or determination of 
fulvestrant levels.
4.5.7.10
Pharmacogenetic Polymorphism Assay
If approved by the local regulatory authority, gene mutations will be assayed using 
multiplex PCR, allele-specific PCR, direct sequencing, or other acceptable methods.  
Results may be correlated to taselisib exposure or other clinical measures to better 
understand the impact of genetic variants on drug metabolism, exposure, adverse events, 
and/or response.
A blood sample will also be utilized as a source of normal DNA to determine whether 
sequence variants in the PIK3CA gene and in other relevant oncogenes in the tumor DNA 
are somatic mutations or single nucleotide polymorphisms.
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4.
4.5.8
Electrocardiograms
An ECG (12-lead) is required at screening and may be repeated during the study as 
clinically indicated.
All ECG recordings should be performed using a standard high-quality, high-fidelity 
digital electrocardiograph machine equipped with computer-based interval 
measurements.  Lead placement should be as consistent as possible.  ECG recordings 
must be performed after the patient has been resting in a supine position for at least 


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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.
Clinically significant abnormalities observed during screening will be recorded on the 
General Medical History and Baseline Conditions eCRF.  New or worsened clinically 
significant abnormalities will be recorded on the Adverse Event eCRF.
4.5.9
Patient-Reported Outcomes
PRO data will be elicited from the patients to more fully characterize the clinical profile of 
taselisib.  The PRO instruments, translated as required into the local language, will be 
distributed by the investigator or research staff and must be completed in their entirety 
by the patient.  To ensure instrument validity and that data standards meet health 
authority requirements, PRO questionnaires should be self-administered at the 
investigational site prior to the completion of other study assessments and the 
administration of study treatment.
The EORTC QLQ-C30 (see Appendix 7) and the modified Breast Cancer module 
QLQ-BR23 (see Appendix 8) questionnaires will be used to assess HRQoL, including 
side effects of therapy (e.g., oral mucositis, diarrhea, and skin issues) and patient 
functioning (refer to Schedule of Assessments in Appendix 1 for detailed description of 
timepoints).
The EORTC QLQ-C30 is a validated and reliable self-reported measure 
(Aaronson et al. 1993; Sprangers et al. 1998; Fitzsimmons et al. 1999) that consists of 
30 questions that comprise five aspects of patient functioning assessment (physical, 
emotional, role, cognitive, and social); three symptom scales (fatigue; nausea, vomiting, 
and pain; and the global health/quality of life [QoL]); and six single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties), within a recall 
period of “the past week.”  Scale scores can be obtained for each of the multi-item 
scales, the global health status/QoL scale, and the six single items by using a linear 
transformation for standardization of the calculated raw score.
The EORTC QLQ-BR23 breast cancer module, which was first validated for use in 1995, 
uses a recall period of “the past week,” and is intended for use across multiple treatment 
modalities (i.e., surgery, chemotherapy, radiotherapy, and hormonal treatment).  As oral 
mucositis (2 items) and skin problems (2 items) are key symptoms of therapy that are 
not assessed by currently available tools, validated items from the EORTC item bank will 


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be added to assess these treatment-related symptoms.  Data analysis will be performed 
on the final modified BR23 data set in parallel with the final data analysis to assess the 
psychometric properties of the modified instrument and will be reported along with the 
clinical trial results.  Scale scores can be obtained for each of the multi-item and 
single-item scales by using a linear transformation for standardization of the calculated 
raw score.
The EQ-5D will be used to obtain health status information for health economic 
modeling.  The EQ-5D is a generic, preference-based health utility measure with 
questions about mobility, self-care, usual activities, pain and discomfort, and anxiety and 
depression that are used to build a composite of the patient’s health status
(see Appendix 9).  A single summary index from the EQ-5D health states will be utilized 
in this study for economic modeling.  These data will not be reported in the clinical study 
report.
4.5.10
Assessments at Study Drug Discontinuation Visit
All patients who are discontinued from all study treatments will return for a study drug 
discontinuation visit within 28 days after the last dose of study treatment.  If study 
treatment had been interrupted for 28 days before the decision to permanently 
discontinue all study treatment, the study drug discontinuation visit should be performed 
as soon as possible after permanent study drug discontinuation.
The visit at which disease progression is recorded may serve as the study drug 
discontinuation visit, provided that all tests required at the study drug discontinuation 
visit are performed. See Appendix 1 and Appendix 2 for the schedule of assessments 
performed at the study drug discontinuation visit.
4.5.11
Follow-Up Assessments
Until approximately the end of August 2018, patients who are discontinued from study 
treatment for reasons other than disease progression will be asked to continue to have 
tumor assessments performed and complete the PRO assessments approximately every 
8 weeks (5 days) until disease progression.
Until approximately the end of August 2018, after study treatment discontinuation, 
patients will be followed for survival and subsequent anti-cancer therapies approximately 
every 3 months until death, loss to follow-up, withdrawal of consent, or study termination 
by the Sponsor.  
Until approximately the end of August 2018, after experiencing disease progression, 
patients will also be asked to return to the clinic 46 weeks (for tumor and PRO 
assessments) and 12 weeks 7 days (for PRO assessments), even if a patient initiates 
anti-cancer therapy subsequent to study drug discontinuation.


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4.5.12
Samples for Roche Clinical Repository
4.5.12.1
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens 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.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (see Section 4.5.12) will not be 
applicable at that site.
4.5.12.3
Sample Collection
The following samples will be used for research purposes, including but not limited to 
research on dynamic (non-inherited) biomarkers related to taselisib, PI3K, or breast 
cancer:

Remaining plasma samples

Remaining whole blood for DNA/RNA extraction
The following sample may be collected for research purposes, including but not limited 
to research on genetic (inherited) biomarkers related to taselisib, PI3K or breast cancer:  
whole blood for DNA extraction.
The following sample may be collected for research purposes, including for DNA and/or 
RNA extraction for exploratory NGS or other research on non-inherited biomarkers 


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(including but not limited to cancer-related genes and biomarkers associated with 
common molecular pathways).  See Section 3.3.9.9 for additional details:

An optional post-progression core biopsy of the tumor 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database. The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.
The following sample may be collected for research purposes to enable a more detailed 
analysis of specific adverse events:

Tissue (e.g., biopsies from colitis or rash, if appropriate)
For these samples, dates of consent and specimen collection should be recorded in the 
eCRF.  For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
4.5.12.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.


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Patient medical information associated with RCR specimens 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.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.12.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens 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 RCR specimens.  
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 by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.12.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study GO29058 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study GO29058.
4.5.12.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 


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management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB or 
EC review, and health authority inspections by providing direct access to source data 
and documents related to the RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from study drug or withdraw from the 
study at any time for any reason.  In addition, the investigator has the right to withdraw a 
patient from the study at any time.  Reasons for withdrawal from the study may include, 
but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if the patient continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, defined as failure to comply with the protocol requirements 
for assessments of safety and efficacy of the study medications, as well as failure to 
comply with study drug administration.
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Until approximately the end of August 2018, patients who 
withdraw from study drug may decide to continue on study to allow follow-up for survival.  
Patients who withdraw from the study will not be replaced.
4.6.2
Study Drug(s) Discontinuation
Patients must discontinue study drugs if they experience any of the following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if the patient continues to receive study drug(s)

Disease progression (as assessed by the investigator)

Unacceptable toxicity

Non-compliance with protocol specified drug administration and follow-up tests
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.


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4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) 
guidelines for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Taselisib is not approved and is currently in clinical development.  Thus, the entire safety 
profile is not known at this time.  The safety plan for this study is designed to ensure 
patient safety and will include specific eligibility criteria and appropriate safety 
assessments.
5.1.1
Management of Selected Toxicities Observed with Taselisib in 
Clinical Studies
Experience with PI3K inhibitors to date has demonstrated that the agents are generally 
well-tolerated.  Common adverse events seen in ongoing clinical trials that are testing 
PI3K inhibitors include fatigue, diarrhea, skin rash, altered taste, pneumonitis, and 
hyperglycemia.  In general, these agents appear to be reasonably well-tolerated at 
doses examined to date without irreversible and/or intolerable toxicities.
The toxicities observed with taselisib are consistent with those observed with other PI3K 
inhibitors.  Selected toxicities of interest for taselisib include gastrointestinal toxicities, 
pneumonitis, rash, stomatitis, and hyperglycemia. Certain adverse events (e.g., rash, 
colitis, and pneumonitis) may also occur within 4 weeks of holding or stopping 
taselisib.On the basis of prior clinical experience with the taselisib and fulvestrant 
combination, some patients have continued to derive clinical benefit with single-agent 
fulvestrant even after discontinuation of taselisib.  Therefore, in some cases per 


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investigator assessment, fulvestrant dosing may be continued while taselisib or placebo 
is being held or discontinued (e.g., for adverse events).  The fulvestrant dose level 
should not be modified.
5.1.1.1
Dose Modification of Taselisib/Placebo due to Toxicity
The taselisib or placebo dose reduction instructions provided in Table 2 are intended to 
serve as recommended guidelines to allow ongoing treatment for patients experiencing 
clinical benefit without signs or symptoms of progression while monitoring patient safety.  
In addition to these guidelines, more conservative drug interruptions or dose reductions 
for the management of adverse events are permitted at the discretion of the investigator 
when deemed to be in the best interest of the patient.
Due to the approximately 40-hour half-life for taselisib, investigators should consider 
holding taselisib or placebo for certain Grade 2 toxicities until the adverse events resolve 
to Grade 1 as discussed below (e.g., stomatitis, oral mucositis, rash, diarrhea).  Certain 
toxicities may occur or worsen within 4 weeks of holding or discontinuing taselisib 
(e.g., pneumonitis, colitis, rash).  These adverse events may eventually resolve but also 
may require the use of corticosteroids.  Investigators should follow management 
guidelines for toxicities as described below, including administration of topical or 
systemic corticosteroids as appropriate.
Table 2
Overall Dose Modification Guideline for Taselisib-Related 
Adverse Events
Taselisib/Placebo
Starting dose
4 mg QD
First reduction
2 mg QD
Second reduction
2 mg QOD a
QDonce daily; QODevery other day.
a If the patient continues to experience specified drug-related adverse 
events after the second dose reduction, taselisib/placebo should be 
discontinued.
The investigator may temporarily suspend taselisib/placebo dosing in the patient due to
a taselisib-related toxicity or an unanticipated medical event not associated with study 
treatment toxicity or with disease progression.  Depending on the nature and the severity 
of the taselisib-related toxicity, the investigator may resume taselisib/placebo dosing in 
the patient at the same dose or at one dose level lower (as detailed in Tables 38).
5.1.1.1.1
Gastrointestinal Toxicity
Nausea, vomiting, dyspepsia, diarrhea, stomatitis, and oral mucositis have been 
observed in patients who receive taselisib.  Colitis was diagnosed by several methods, 
including endoscopy and abdominal imaging (CT scans).  Pathology from biopsies 
obtained from endoscopy confirmed colitis.  Patients usually present with Grade 2 or 
Grade 3 diarrhea that has been refractory to antidiarrheal agents.  The time (from the 


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first dose of study treatment) to onset (formal diagnosis of colitis) ranged from 
approximately 28 months.  Patients had resolution or improvement of gastrointestinal 
toxicities upon holding study drug and/or initiating corticosteroid therapy.  Perforated 
duodenal ulcer was observed in 2 patients (1 patient at 6-mg capsule dose in 
combination with letrozole; another patient at 6-mg capsule dose in combination with 
fulvestrant).  Appropriate caution should be taken with the administration of medications 
such as aspirin, NSAIDs, and corticosteroids, which can increase the risk of gastritis, 
peptic ulcers, or gastrointestinal perforation.
Patients with inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, 
are excluded from this study. Patients who resume taselisib/placebo treatment should 
be monitored closely for signs of renewed diarrhea.
Dose delay and modification guidelines for patients who experience gastrointestinal 
toxicities (diarrhea, colitis, stomatitis and oral mucositis) can be found in Table 3 and 
Table 4.


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Table 3
Management Guidelines for Diarrhea and Colitis
Grade
Taselisib/Placebo Dose Modification and Management
1
Manage per standard-of-care with anti-diarrheal agents a (e.g., loperamide)
For Grade 1 diarrhea occurring after Cycle 2 that persists 5 days despite 
treatment with anti-diarrheal agents, obtain stool culture for infectious workup b.  
Infections (e.g., Clostridium difficile, enteric bacteria, CMV) should be treated with 
the appropriate antibiotic.
For non-infectious diarrhea, consider holding taselisib/placebo and treating with a 
corticosteroid taper (2040 mg prednisone PO QD starting dose) or budesonide 
9 mg PO QD.  Upon completion of corticosteroid treatment, resume 
taselisib/placebo dosing at same dose or one dose level lower per investigator 
evaluation.
(Note: Table continued on next page)
2
Hold taselisib/placebo and initially manage with anti-diarrheal agents a.  Obtain stool 
culture for infectious workup b.  Infections (e.g., Clostridium difficile, enteric bacteria, 
CMV) should be treated with the appropriate antibiotic.
For non-infectious Grade 2 diarrhea that has not improved to Grade 1 despite 
48 hours of anti-diarrheal treatment or for Grade 2 colitis, treat with corticosteroid 
taper (2040 mg prednisone PO QD starting dose) or budesonide 9 mg PO QD.  
Steroid dosage can be increased if diarrhea does not improve.
If diarrhea or colitis does not improve after 48 hours of corticosteroid treatment, a 
colonoscopy should be considered to evaluate for other causes of diarrhea 
(e.g., CMV colitis).
If Grade 2 diarrhea occurred after Cycle 2 or improved with corticosteroid treatment 
or for Grade 2 colitis, resume taselisib/placebo dosing at one dose level lower upon 
improvement to Grade 1 and after completion of any corticosteroid taper.
If Grade 2 diarrhea occurred before Cycle 2 and did not require corticosteroid 
treatment, resume taselisib/placebo dosing at the same dose level or one dose level 
lower per investigator evaluation upon improvement to Grade 1.
For recurrent Grade 2 diarrhea, resume taselisib/placebo dosing at one dose level 
lower upon improvement to Grade 1.  For patients with a second Grade 2 diarrhea 
event that is confirmed to be infectious on the basis of results from the stool culture, 
taselisib/placebo may be resumed at the same dose level if approved by the 
Medical Monitor.


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Table 3
Management Guidelines for Diarrhea and Colitis (cont.)
Grade
Taselisib/Placebo Dose Modification and Management
3
Hold taselisib/placebo dosing and initially manage with anti-diarrheal agents a.  
Obtain stool culture for infectious workup b.  Infections (e.g., Clostridium difficile, 
enteric bacteria, CMV) should be treated with the appropriate antibiotic.
For Grade 3 diarrhea or colitis, treat with systemic corticosteroids (IV solumedrol 
1620 mg every 8 hours or prednisone 6080 mg PO QD equivalent to start).  Can 
increase steroid dosage if diarrhea does not improve.
Consider colonoscopy as part of further gastrointestinal workup.  If diarrhea does 
not improve after 48 hours of corticosteroid treatment, a colonoscopy should be 
considered to evaluate for other causes of diarrhea (e.g., CMV colitis).
If diarrhea or colitis improves to Grade 1 and upon completion of any steroid taper, 
resume taselisib/placebo dosing at one dose level lower.  For patients with Grade 3 
diarrhea that is confirmed to be infectious on the basis of results from the stool 
culture, taselisib/placebo may be resumed at the same dose level if approved by the 
Medical Monitor.
Patients with recurrent Grade 3 diarrhea or colitis must be permanently discontinued 
from taselisib/placebo.
4
Permanently discontinue taselisib/placebo.  Manage as per Grade 3 diarrhea 
guidelines.
IVintravenous; POtaken by mouth; QDonce daily.
a Suggested anti-diarrheal medications include the following:

Loperamide (initial: 4 mg, followed by 2 mg after each loose stool, up to 16 mg/day)

Diphenoxylate and atropine (diphenoxylate 5 mg, four times daily, until control achieved 
[maximum: 20 mg/day], then reduce dose as needed; some patients may achieve control 
with doses of 5 mg/day)

Tincture of opium (6 mg of undiluted opium tincture [10 mg/mL] four times daily).
b Non-infectious diarrhea can be diagnosed by stool culture with work-up for Clostridium difficile
and for various enteric bacteria.  Fecal calprotectin is a possible marker for bowel inflammation.  
Blood-based cytomegalovirus polymerase chain reaction test can also be used to detect 
cytomegalovirus infection.


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Table 4
Management Guidelines for Stomatitis and Oral Mucositis
Grade
Taselisib/Placebo Dose Modification and Management Guidelines
All grades
Aggressive mouth care that includes mouthwash formulations (e.g., combinations 
of local anesthetic, antihistamine, corticosteroid, antacid, anti-fungal and/or 
antibiotics) may be implemented to help manage symptoms
Diet management (e.g., avoidance of spicy foods)
1
Monitor symptoms and initiate management (see above). Re-evaluate within 
4872 hours.
2
Hold taselisib/placebo, and manage until Grade 1.
If stomatitis or mucositis improves to Grade 1, resume taselisib/placebo dosing 
at the same dose or one dose level lower per investigator evaluation.
For recurrent Grade 2 stomatitis or mucositis, resume taselisib/placebo dosing at 
one dose level lower.
3
Hold taselisib/placebo and manage until Grade 1.
If stomatitis or mucositis improves to Grade 1, resume taselisib/placebo dosing 
at one dose level lower.
4
Permanently discontinue taselisib/placebo.
5.1.1.1.2
Pneumonitis
Pneumonitis has been observed in patients treated with taselisib.  Symptoms associated 
with pneumonitis were reversible upon treatment with corticosteroids. Dose delay and 
modification guidelines for patients who experience pneumonitis are presented in 
Table 5.


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Table 5
Management Guidelines for Pneumonitis
Pneumonitis
Grade
Intervention
Investigations
Taselisib/Placebo Dose 
Modification and Management
1
No specific 
therapy required
Consider infectious 
work-up a.
CT scan and consider 
PFTs b.
Repeat CT Q8W until 
return to baseline.
No change
2
Symptomatic only.  
Prescribe 
corticosteroids if 
cough is 
troublesome and 
infectious etiology 
is ruled out.
Infectious work-up a.
CT scan.  Repeat CT 
Q4W until return to 
baseline.
Consider PFTs b and 
bronchoscopy.
Hold taselisib/placebo as long as
corticosteroids are being given.
If pneumonitis improves to 
Grade 1 and upon completion of 
any corticosteroid treatment, 
resume taselisib/placebo dosing
at the same taselisib dose or one 
dose level lower per investigator 
evaluation.
For recurrent Grade 2 event, 
resume taselisib/placebo dosing 
at one dose level lower.
3
Prescribe 
corticosteroids if 
infectious etiology 
is ruled out.
Taper as clinically 
indicated.
Infectious work-up a.
CT scan.  Repeat CT 
Q4W until return to 
baseline.
Consider PFTs b and 
bronchoscopy.
Hold taselisib/placebo as long as 
corticosteroids are being given.
If pneumonitis improves to 
Grade 1 and upon completion of 
any corticosteroids, resume 
taselisib/placebo dosing at one 
dose level lower.
4
Prescribe 
corticosteroids if 
infectious etiology 
is ruled out.
Taper as clinically 
indicated.
Infectious work-up a.
CT scan.  Repeat CT 
Q4W until return to 
baseline.  Consider 
PFTs b.
Bronchoscopy is 
recommended.
Permanently discontinue 
taselisib/placebo.
CT computed tomography; PFT pulmonary function test; Q4W every 4 weeks; Q8W every 
8 weeks.
a Such as for bacterial, viral, or fungal pneumonia (e.g. Pneumocystis jiroveci pneumonia or 
pneumonia aspergillus).
b PFTs may be useful to monitor the effect of interventions such as dose 
reduction/discontinuation and corticosteroids, in conjunction with imaging (White et al. 2010).  
It is strongly recommended to perform disease monitoring according to guidelines from White 
et al. if possible or according to clinical practice.


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5.1.1.1.3
Rash
Treatment-related rash is commonly manifested as maculo-papular with or without 
pruritus. The rash has usually resolved upon holding taselisib and/or giving supportive 
therapy (e.g., topical or systemic steroids).  Dose delay and modification guidelines for 
patients who experience rash are presented in Table 6.
Table 6
Management Guidelines for Rash
a Suggested topical steroids include hydrocortisone 2.5% to face twice daily, triamcinolone 0.1% 
or fluocinonide 0.1% cream to body twice daily.
b Suggested oral steroids include methylprednisolone dose pack or prednisone 60 mg daily 
followed by a taper (e.g., 60 mg2 days, 40 mg2 days, 20 mg2 days, etc.).
5.1.1.1.4
Hyperglycemia
Hyperglycemia has been observed in patients who received taselisib while participating 
in other studies. Hyperglycemia has been reversible upon holding taselisib and/or 
initiating anti-hyperglycemic medication (e.g., metformin).
Patients with diabetes requiring anti-hyperglycemic medication or who have a fasting 
blood glucose level 125 mg/dL will be excluded from the study.  HbA1c and fasting 
glucose levels will be monitored at baseline, and regular monitoring of fasting glucose 
Grade of
Rash
Taselisib/Placebo Dose Modification and Management Guidelines
1
Continue dosing at current taselisib/placebo dose, and monitor for change in severity.
Consider prescribing topical corticosteroids a.
2
Hold taselisib/placebo.
Treat rash with topical corticosteroids.
Consider treatment of rash with oral corticosteroids b. Hold taselisib/placebo treatment 
as long as oral corticosteroids are being administered.
If rash improves to Grade 1 and upon completion of any systemic corticosteroids, 
resume taselisib/placebo at the same dose or one dose level lower per investigator 
evaluation.
For recurrent Grade 2 rash, resume taselisib/placebo at one dose level lower.
3 
Hold taselisib/placebo
Treat rash with topical corticosteroids and/or systemic corticosteroids (oral or 
intravenous). Hold taselisib/placebo as long as systemic corticosteroids are being
administered.
Consider dermatological consultation and skin biopsy.
If rash improves to Grade 1 and upon completion of any systemic corticosteroids, 
resume taselisib/placebo at one dose level lower.
4
Permanently discontinue taselisib/placebo.
Treat with topical corticosteroids and/or systemic corticosteroids.
Consider dermatological consultation and skin biopsy.


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levels will occur during the study. Dose delay and modification guidelines for patients 
who experience hyperglycemia are presented in Table 7.
Table 7
Management Guidelines for Hyperglycemia
Grade of 
Hyperglycemia
Taselisib/Placebo Dose Modification and Management Guidelines
1 or 2
Initiation of or an increase a in the dose of an anti-hyperglycemic agent 
(e.g., metformin) and additional glucose monitoring will be implemented.
Taselisib/placebo dosing may either be held or continued per investigator 
evaluation.
3 (asymptomatic)
Hold taselisib/placebo.
Treat hyperglycemia per standard of care, including implementation of 
additional glucose monitoring and initiation of or an increase in the dose of 
an anti-hyperglycemic therapy (e.g., metformin).
If improves to Grade 1, may resume taselisib/placebo dosing at one 
dose level lower.
3 (symptomatic),
3 (requiring 
hospitalization), or 
4
Hold taselisib/placebo.
Treat hyperglycemia per standard of care, including implementation of 
additional glucose monitoring and initiation of or an increase in the dose of 
anti-hyperglycemic therapy.
If improves to Grade 1, may resume taselisib/placebo dosing at one 
dose level lower.
For recurrent symptomatic Grade 3 or Grade 4 hyperglycemic event, 
taselisib/placebo must be permanently discontinued.
a If initiated after randomization, because patients with diabetes who require anti-hyperglycemic 
medications are not eligible.
5.1.1.1.5
Potential Abnormal Liver Function Tests
Some patients have experienced elevations of liver function test results (e.g., AST or 
ALT) while receiving taselisib in prior clinical studies.  Patients will be monitored 
throughout the study treatment for changes in liver function tests.  Given the potential for 
hepatic toxicity, all patients must have adequate liver function as manifested by 
measurements of serum bilirubin and hepatic transaminases for initial and continued 
dosing.  Separate criteria for eligibility are given for patients with hepatic metastases.
For new abnormal liver function test results (e.g., elevated AST or ALT), a standard 
clinical work-up to understand the etiology of the abnormality should take place per local 
guidelines.  In many cases, elevated liver function test results may be a result of liver 
metastases, concomitant medications, or biliary obstruction. Dose delay and 
modification for patients who experience abnormal liver function test results can also 
follow the guidelines in Table 8 if deemed clinically appropriate by the investigator.
5.1.1.1.6
Management of Asymptomatic Lipase and/or Amylase 
Elevations
Some patients who have been treated with taselisib have experienced asymptomatic 
lipase and/or amylase elevations in blood tests without any clinical or radiographic 


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symptoms of pancreatitis or another clear etiology for the abnormal laboratory test
values.  Elevated lipase may sometimes be associated with corticosteroid treatment.  
Upon discussion with the Medical Monitor and after a benefit-risk assessment, 
investigators may consider continuing taselisib therapy in such patients at the same 
dose or one dose level lower.  Investigators should have a low threshold for interrupting 
taselisib/placebo for any clinical gastrointestinal toxicities of concern.
5.1.1.1.7
Potential Inflammatory or Immunosuppressant Effects
On the basis of taselisib data from nonclinical toxicity studies showing changes in WBC 
and absolute lymphocyte and/or neutrophil counts, patients will be required to have 
adequate hematologic function to participate in the study, and any bone marrow 
toxicities from prior therapies must be resolved before initiation of taselisib.  Patients will 
be monitored throughout the study treatment for changes in blood counts and signs of 
infection. Dose delay and modification for patients who experience changes in blood
counts or show signs of infections can also follow the guidelines in Table 8 if deemed 
clinically appropriate by the investigator.
5.1.1.1.8
Infection
At the time of the primary PFS analysis of Study GO29058, 41.8% of patients in the 
taselisib arm had developed infections compared with 23.9% of patients in the control 
(placebo) arm.  Serious infections occurred in 7.5% of patients in the taselisib arm
compared with 0.9% of patients in the control (placebo) arm.  A total of 0.5% of 
patients died on account of infection in the taselisib arm compared with no patients in 
the control (placebo) arm.
Urinary tract infections were the most commonly reported infection; however,
respiratory tract, gastrointestinal tract, and skin infections were also common in the 
taselisib arm.
Investigators and patients should be aware of the increased risk of infection with 
taselisib.  If a diagnosis of infection is made, appropriate treatment should be initiated 
promptly and consideration given to holding or discontinuing taselisib/placebo as per 
the guidelines in Table 8.
5.1.1.1.9
Management of Other Clinically Significant Adverse Events
See Table 8 for the dose modifications for other clinically significant adverse events.


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Table 8
Taselisib/Placebo Dose Delay and Modification Guidelines for 
Other Clinically Significant Adverse Events
Grade
Taselisib/Placebo
3, first event
Hold taselisib/placebo until Grade 1.
Resume taselisib/placebo at the same dose or one dose level 
lower per investigator evaluation.
3, recurrent or
4, nonlife threatening
Hold taselisib/placebo until Grade 1.  Resume taselisib/placebo
dosing at one dose level lower.
4, life-threatening
Permanently discontinue taselisib/placebo.
Single-agent fulvestrant may be continued per investigator 
evaluation.
5.1.2
Safety Plan for Fulvestrant
Fulvestrant is an ER antagonist indicated for the treatment of HRMBC in 
postmenopausal women with disease progression following anti-estrogen therapy.
In a study with postmenopausal women with advanced breast cancer who had disease 
recurrence on or after adjuvant endocrine therapy or progression following endocrine 
therapy for advanced disease, the most frequently reported adverse events were 
injection-site pain (11.6% of patients), nausea (9.7%), and bone pain (9.4%).  Because 
fulvestrant is administered intramuscularly, it should be used with caution in patients with 
bleeding diatheses, thrombocytopenia, or anticoagulant use.  For details regarding the 
safety profile of fulvestrant, refer to the fulvestrant package insert or SmPC.
Discontinuation of fulvestrant for adverse events is very rare.  However, in the unlikely 
event that the patient discontinues fulvestrant and is able to continue on taselisib or 
placebo, the investigator should contact the Medical Monitor to discuss the benefit-risk 
assessment of continuing with single-agent taselisib or placebo.
There are no expected significant overlapping toxicities between taselisib and fulvestrant.  
Routine safety monitoring and periodic laboratory tests for the fulvestrant and taselisib
combination will occur throughout the study.
5.1.2.1
General Guidance for Dose Modifications and 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.
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.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest,
measurement of protocol-specified safety laboratory assessments, measurement of 
protocol-specified vital signs, and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study.
Certain types of adverse events require immediate reporting to the Sponsor, as outlined
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), except as described
Section 5.3.5.9

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test results (e.g., ECG, X-ray) 
that is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to 
NCI CTCAE v4.0 criteria (see Section 5.3.3); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
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 
include the following serious and non-serious events:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Grade 3 symptomatic hyperglycemia

Grade 2 colitis or enterocolitis

Grade 2 diarrhea

Grade 3 rash

Grade 2 pneumonitis


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
Grade 3 stomatitis
5.2.4
Events to Monitor
Additional data collection will occur for all grades of specific adverse events
(e.g., symptomatic hyperglycemia, colitis, enterocolitis, diarrhea, stomatitis, pneumonitis,
and rash) 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).
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5.7.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2), severity (see Section 5.3.3), and 
causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
last dose of study drug.  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment
(see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 9 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 9
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in National Cancer Institute Common Terminology Criteria 
for Adverse Events
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see 
Table 10):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 10 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology and concepts when recording 
adverse events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
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 


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severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
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.  For specific adverse events (hyperglycemia, colitis or enterocolitis, diarrhea, rash, 
pneumonitis, and stomatitis), all grade changes will be tracked on a supplemental eCRF.
If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions). The Adverse Event eCRF should be updated by 
changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
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:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
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:

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

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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 


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changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
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.  
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 5.3.5.4) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
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 only on 
the Study Discontinuation eCRF.  All other on-study deaths, regardless of relationship to 
study drug, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.2.2).  Until the primary PFS analysis has been completed, 
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" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
During survival follow-up, deaths attributed to progression of underlying breast cancer
should be recorded only on the Study Discontinuation eCRF.


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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 Metastatic 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.
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

Hospitalization due solely to progression of the underlying cancer

Planned hospitalization required by the protocol 

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
5.3.5.11
Adverse Events Associated with an Overdose
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 


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associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills serious 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2).
No safety data related to taselisib overdose is available.
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
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

Non-serious adverse events of special interest

Pregnancies
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor:
, M.D.
Telephone No.:
Alternate No.:
+1 (888) 835-2555
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 
Monitor, 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 and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators"). 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to Roche Safety Risk Management or its designee immediately 
(i.e., no more than 24 hours after learning of the event), with use of the fax numbers 
provided to investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 28 days after the last dose of study drug.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.
Instructions for reporting post-study adverse events are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the last 
dose of fulvestrant.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.
In the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the pregnancy), using the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.
5.4.3.2
Abortions
Any 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).
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, the patient withdraws consent, or the patient is no longer being followed for 
survival.  Every effort should be made to follow all serious adverse events considered to 
be related to study drug or trial-related procedures until a final outcome can be reported.


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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious
adverse event that occur after the end of the adverse event reporting period (defined as 
28 days after the last dose of study drug [see Section 5.3.1]), if the event is believed to 
be related to prior study drug treatment.
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Taselisib Investigator's Brochure

Fulvestrant SmPC
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.


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Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.  These anticipated events include, but are not limited to, the following:

Nausea

Vomiting

Fatigue

Injection-site pain

Injection-site reaction

Muscle pain

Joint pain

Tumor pain

Hot flashes

Weakness

Loss of appetite

Weight loss

Worsening of general condition

Failure to thrive
Until the primary PFS analysis has been completed, an iDMC will monitor the incidence 
of the above-listed anticipated events during the study.  An aggregate report of any 
clinically relevant imbalances that do not favor the test product will be submitted to 
health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
The global study plans to enroll approximately 600 patients, including 480 patients with 
detectable PIK3CA-mutant tumors, and 120 patients without detectable PIK3CA-mutant
tumors (tumor status determined by the cobas PIK3CA mutation test).
After the global enrollment closes, additional Chinese patients may continue to be 
recruited into the China extension cohort.  A total of up to 150 patients with detectable 
PIK3CA-mutant tumors may be enrolled as part of the global study population and the 
China extension cohort combined (see Section 6.10 for further details). 
The sample size of 480 patients with PIK3CA-mutant tumors is determined on the basis 
of the power calculation for the PFS and the OS endpoints, whichever requires a larger 
sample size.  In this case, the sample size is driven by OS.
In 480 patients with PIK3CA-mutant tumors, approximately 287 investigator-assessed 
PFS events will be required to detect a hazard ratio of 0.59 in PFS (3.1 months of 


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improvement in median PFS) with 95% power at the a two-sided significance level of 1%, 
assuming a median PFS of 4.5 months in the control arm (Mauriac et al. 2009; Johnston 
et al. 2013). One interim efficacy analysis of investigator-assessed PFS will be 
conducted at 60% of PFS information (see Section 6.9.1 for more details).  The 
-spending function specified as Gamma (-16), which allocates two-sided 1.710-5 at 
the interim efficacy analysis of investigator-assessed PFS, when 172 
investigator-assessed PFS events have occurred.  The minimal detectable difference for 
investigator-assessed PFS hazard ratio at final PFS analysis is 0.72 (i.e., 39% 
improvement in median investigator-assessed PFS from 4.5 months in the control arm 
compared with 6.2 months in the treatment arm), when 287 investigator-assessed PFS 
events have occurred.
With the aforementioned sample size of 480 patients with PIK3CA-mutant tumors, the 
OS analyses in this population will require 330 deaths to detect an hazard ratio of 0.7 in 
OS (11.1 months of improvement in median OS) with 80% power at a two-sided 
significance level of 5%, assuming a median OS of 26 months in the control arm based 
on the OS of 26.4 months in patients treated with 500 mg fulvestrant in the CONFIRM 
study, which investigated 500 mg fulvestrant versus 250 mg fulvestrant in a similar 
patient population (Di Leo et al. 2014). 
The study plans to enroll 120 patients who do not have a detectable PIK3CA-mutant 
tumor, on the basis of the result of the cobas PIK3CA mutation test, to evaluate the 
clinical benefit in this population.  If the observed hazard ratio in investigator-assessed 
PFS is 1 (no benefit), approximately 111 investigator-assessed PFS events will be 
observed at the analysis, and the 90% confidence interval will exclude a true hazard 
ratio 0.72 (i.e., 1.8-month improvement in median PFS).
In total, approximately 400 patients will be treated with the combination of 
taselisibfulvestrant in this study (320 patients with PIK3CA-mutant tumors and 
80 patients without detectable PIK3CA-mutant tumors), which will enable the Sponsor to 
better characterize any rare but clinically significant safety events (e.g., for an adverse 
event with 4% frequency, there is 96% probability to observe 10 patients with such 
adverse event on the basis of 400 taselisibfulvestrant-treated patients) to help enable 
the development of effective toxicity prevention and management guidelines for patients 
treated with the combination of taselisib and fulvestrant.
Assuming a 12-month site ramp-up period and a total of 200 sites, the enrollment 
duration will be driven by enrollment of patients with PIK3CA-mutant tumors and is 
projected to be approximately 28 months (from the first patient enrolled).  The last 
PFS event (the 287th investigator-assessed PFS event) for the final PFS analysis in 
patients with PIK3CA-mutant tumors is projected to occur approximately 29 months after 
the first patient is enrolled.


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6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment, follow-up duration, study discontinuation, and discontinuation 
reasons will be summarized by treatment arm for all randomized patients. In addition, 
major protocol violations, including violations of inclusion and/or exclusion criteria, will be 
summarized by treatment arm. All of the analyses will be performed separately for 
patients with PIK3CA-mutant tumors and for patients without detectable PIK3CA-mutant 
tumors.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
The evaluation of treatment group comparability between the two treatment arms will 
include demographics summaries, baseline disease characteristics (including 
PIK3CA-mutation status), and patient treatment history.
Descriptive summaries of continuous data will present the group mean, standard 
deviation, median, minimum, and maximum. Descriptive summaries of discrete data will 
present the category counts as frequencies and percentages.
All of the analyses will be performed separately for patients with PIK3CA-mutant tumors 
and for patients without detectable PIK3CA-mutant tumors.
6.4
EFFICACY ANALYSES
The primary efficacy analysis population will include all randomized patients with 
PIK3CA-mutant tumors. The primary efficacy endpoint, investigator-assessed PFS, and 
the secondary efficacy endpoints will be analyzed in this population as the primary and 
the secondary objectives.
In addition, these efficacy endpoints, unless otherwise specified, will be analyzed in all 
randomized patients without detectable PIK3CA-mutant tumors at the same time as the 
analyses are conducted for the patients with PIK3CA-mutant tumors.
PIK3CA-mutant tumor status will be determined by the cobas PIK3CA mutation test of 
the patient’s tissue sample.
The treatment arm assigned at randomization will be used for all efficacy analyses.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is investigator-assessed PFS (PFS in this document refers 
to investigator-assessed PFS, unless stated otherwise).  The primary PFS analysis will 
be conducted in all randomized patients with PIK3CA-mutant tumors, with patients 
grouped according to the treatment arm assigned at randomization.
An interim efficacy analysis will be conducted for investigator-assessed PFS at the time 
of 172 investigator-assessed PFS events (expected 21 months after the first patient is 
enrolled), and the final efficacy analysis will be conducted at the time 


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287 investigator-assessed PFS events (expected 29 months after the first patient is 
enrolled) are observed in patients with PIK3CA-mutant tumors.  The -spending function 
is specified as Gamma (-16), which allocates two-sided 1.710-5 at the interim 
efficacy analysis of investigator-assessed PFS, when 172 PFS events have occurred 
and preserves the two-sided 1% -level at the final PFS analysis.  The exact boundary 
will be calculated on the basis of the exact number of PFS events observed at the 
interim analysis.  The associated minimal detectable difference for the investigator-
assessed PFS hazard ratio at the interim efficacy analysis is 0.5 (i.e., 100% 
improvement in median investigator-assessed PFS from 4.5 months in the control arm to 
9 months in the treatment arm). Refer to Section 6.9.1 for additional details on the 
interim analysis.
Table 11
PFS Analyses
Estimated Timing 
(Clinical Data Cutoff)
PFS 
Events
Two-Sided 
p-Value 
Boundary
Rejection 
HR 
Boundary a
Percentage 
Information
PFS IA
~21 months after FPI
~172
1.710-5
0.5
60%
PFS FA
~29 months after FPI
~287
0.01
0.72
100%
IA interim analysis; FA final analysis; FPI first patient in; HR hazard ratio; 
PFS progression-free survival.
a Assuming exponential distributions for the PFS event time of the two treatment arms.
An exploratory analysis for investigator-assessed PFS will also be conducted in all 
randomized patients without detectable PIK3CA-mutant tumors at the time of the primary 
PFS analysis in all randomized patients with PIK3CA-mutant tumors.
Data for patients without the occurrence of disease progression or death as of the 
clinical data cutoff date 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 two-sided log-rank test stratified by the three stratification factors will be used as the 
primary analysis to compare investigator-assessed PFS between the two treatment arms.  
The three stratification factors are:  1) visceral versus non-visceral, 2) sensitivity versus 
non-sensitivity to their most recently administered endocrine therapy, and 
3) geographical regions (details in, Section 3.1).  The Kaplan-Meier approach will be 
used to estimate median investigator-assessed PFS for each treatment arm.  Cox 
proportional-hazards models stratified by the three stratification factors will be used to 
estimate the HR and its 95% CI.  The results from the unstratified log-rank test will also 
be provided.


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6.4.2
Secondary Efficacy Endpoints
Assuming that the primary endpoint PFS is statistically significant, the first 
two secondary endpoints are planned to be tested in the following hierarchical order: 

Overall ORR 

OS
6.4.2.1
Overall Objective Response Rate
The analysis of ORR will include only patients who have measurable disease per 
RECIST v1.1 at baseline as a secondary endpoint of the study and will be tested on the 
basis of a hierarchical testing procedure to preserve the type I error.  That is, the ORR 
analysis will be conducted at at the significance level of two-sided 5% at the time that a 
statistically significant benefit is observed for the investigator-assessed PFS at either the 
interim efficacy or final PFS analysis.
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 ORRs between the two arms will be determined using the normal 
approximation to the binomial distribution.
6.4.2.2
Overall Survival
The analyses for OS will be conducted in all randomized patients with PIK3CA-mutant
tumors as a secondary endpoint of the study and will be tested on the basis of a 
hierarchical testing procedure to preserve type I error.  That is, the OS analysis will be
tested only if both investigator-assessed PFS and ORR have reached their respective 
significance levels.  The overall type I error for OS is preserved at two-sided 5%.
OS will be analyzed with patients grouped according to the treatment arm assigned at 
randomization. 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.
The analyses will be conducted using the stratified two-sided log-rank test, and the 
results from the unstratified log-rank test will also be provided.  The OS curve for each 
treatment arm will be estimated by the Kaplan-Meier methodology, and the HR and its 
95% CI will be estimated by the Cox proportional-hazards models.
Three interim analyses and one final analysis for OS were originally planned in patients 
with PIK3CA-mutant tumors on the basis of the results from the cobas PIK3CA mutation 
test (see Table 12 and Table 13). As a result of the completion of the primary PFS 
analysis, the Sponsor has decided to limit the additional OS follow-up to one additional 
analysis. This additional OS analysis coincides with the originally planned second OS 
interim analysis.


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1.
The first interim OS analysis will be conducted at the time when both 
investigator-assessed PFS and ORR have reached their respective significance 
levels, so it could occur at the time of the interim efficacy or the final efficacy 
analysis for investigator-assessed PFS. 
2.
The second OS analysis will be conducted approximately 10 months after the first 
interim analysis. 
Table 12
Analyses for OS if the First Interim OS Analysis Occurs at the 
Time of the Interim Efficacy Analysis of Investigator-Assessed PFS
Estimated 
Timing (Clinical 
Data Cutoff)
OS 
Events
Two-Sided 
p-Value 
Boundary
Rejection HR 
Boundary a
Percentage 
Information
First OS IA
~21 months 
after FPI
~63
0.001
0.44
19%
Second OS 
analysis
~10 months 
after first OS IA
~134
0.010
0.65
41%
IA interim analysis; FPI first patient in; HR hazard ratio; OS overall survival;
PFS progression-free survival.
a
Assuming exponential distributions for the OS event time of the two treatment arms.
Table 13 Analyses for OS if the First Interim OS Analysis Occurs at the 
Time of the Final Efficacy Analysis of Investigator-Assessed PFS
Estimated 
Timing (Clinical 
Data Cutoff)
OS 
Events
Two-Sided 
p-Value 
Boundary
Rejection HR 
Boundary a
Percentage 
Information
First OS IA
~29 months 
after FPI
~118
0.001
0.53
36%
Second OS 
analysis
~10 months 
after first OS IA
~188
0.010
0.67
57%
IA interim analysis; FPI first patient in; HR hazard ratio; PFS progression-free survival.
a
Assuming exponential distributions for the OS event time of the two treatment arms.
The stopping boundaries are computed using the generalized Haybittle-Peto boundaries 
with unequal p-values being used in the -spending function and will be adjusted on the 
basis of the actual number of OS events observed at each interim OS analysis. 
The timing of the analyses are based on an assumption of an annual loss-to-follow-up 
rate of 5%.  The study team will be unblinded at the time when the iDMC recommends to 
stop the study and the Sponsor decides to stop the study, or at the time of the final PFS 
analysis if the study is not stopped early.  Investigators and patients will remain blinded 
to individual patient-level treatment assignment until approximately the end of August
2018, at which time unblinding is permitted at the discretion of the investigator or 
Sponsor.


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6.4.2.3
Clinical Benefit Rate
The analysis of CBR will be performed for patients with PIK3CA-mutant tumors with 
measurable disease per RECIST v1.1 at baseline and will be repeated for the group of 
patients with PIK3CA-mutant tumors regardless of measurable disease at baseline.  An 
estimate of CBR and its 95% confidence interval will be calculated using the Blyth-Still-
Casella method for each treatment arm.  The clinical benefit rates in the treatment 
groups will be compared using the stratified Mantel-Haenszel test. Confidence intervals 
for the difference in clinical benefit rates between the two arms will be determined using 
the normal approximation to the binomial distribution.
6.4.2.4
Duration of Objective Response
The analysis of DOR will include only patients who achieved an objective response to 
study treatment, among patients with measurable disease per RECIST v1.1 at baseline.
DOR will be estimated using the Kaplan-Meier methodology, with patients grouped 
according to the treatment arm assigned at randomization.  Comparisons between 
treatment arms using stratified and unstratified log rank test will be made for descriptive 
purposes.  Because the determination of DOR is based on a nonrandomized subset of 
patients, formal hypothesis testing will not be performed.
6.4.2.5
BICR-Assessed PFS
While the primary efficacy endpoint is investigator-assessed PFS in patients with 
PIK3CA-mutant tumors, a blinded independent central review (BICR) of progression will 
be conducted in all patients based on RECIST v1.1 as described in a separate charter. 
The BICR-assessed PFS in patients with PIK3CA-mutant tumors is not intended to 
provide an alternative means of definitive analysis but to show that there is no potential 
bias in the investigator assessment.  The BICR-assessed PD date and events will be 
defined based on the BICR assesement only.  The BICR-assessed PFS analysis will be 
identical to the investigator-assessed PFS analysis and will also be conducted in all 
randomized patients with PIK3CA-mutant tumors, with patients grouped according to the 
treatment arm assigned at randomization.
The Kaplan-Meier approach will be used to estimate median BICR-assessed PFS for 
each treatment arm.  Cox proportional-hazards models stratified by the three 
stratification factors will be used to estimate the HR and its 95% CI.  
6.5
SAFETY ANALYSES
Safety analyses will be performed for all randomized patients who receive at least one 
dose of taselisib or placebo or fulvestrant (the safety population), regardless of the 
PIK3CA-mutation status of their tumors and separately for the subgroups of patients with 
and without detectable PIK3CA-mutant tumors, with patients allocated to the treatment 
arm associated with the regimen actually received. Specifically, a patient will be 


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included in the taselisibfulvestrant arm in the safety analyses if the patient receives 
any amount of taselisib, regardless of the initial treatment assignment at randomization.
Safety endpoints will include incidence, severity, and relationship to the study drugs;
outcome and seriousness of adverse events; death; laboratory data; and vital signs.
Drug exposure will be summarized to include duration of treatment, number of doses, 
and intensity of dose.
Adverse events will be summarized by mapped term, appropriate thesaurus level, and 
toxicity grade according to NCI CTCAE v4.0.  All adverse events occurring during or 
after the first study drug dose will be summarized by treatment arm and 
NCI CTCAE grade.  In addition, serious adverse events, severe adverse events 
(Grade 3), adverse events of special interest, and adverse events leading to study drug 
discontinuation or interruption will be summarized accordingly.  Multiple occurrences of 
the same event will be counted once at the maximum severity.
Deaths reported during the study treatment period and those reported during the safety 
follow-up period (that is, within 28 days after the last dose of treatment) after treatment 
discontinuation will be summarized by treatment arm.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized by treatment arm and grade.
Clinically significant changes in vital signs will be summarized by treatment arm and 
grade.
6.6
PHARMACOKINETIC ANALYSES
Taselisib plasma concentration versus time data will be tabulated and summarized.  
Additional analyses such as population PK analysis with covariate evaluation may be 
conducted, and data from other clinical trials may be pooled as appropriate.  
Exposure-response (i.e., efficacy, safety, and pharmacodynamic biomarkers) 
relationships may be explored. Additional analyses may be performed as appropriate.
6.7
PATIENT-REPORTED OUTCOME ANALYSES
HRQoL data will be captured using the following questionnaires:  the EORTC QLQ-C30 
and the modified breast cancer module, QLQ-BR23 (see Appendix 7).
The population for analysis will be defined as all randomized patients that have 
completed baseline and at least one post-baseline assessment.  Summary statistics 
(mean, SD, median, 25th and 75th percentiles, and range) of linear transformed scores 
will be reported for selected subscales of the EORTC QLQ-C30 questionnaire and the 
modified BR23 (including oral mucositis and skin problems) according to the EORTC 
scoring manual guidelines for each assessment time point. The mean change of the 


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linear transformed scores from baseline (and 95% CI using the normal approximation) 
will also be assessed.  Line charts depicting the mean changes (and standard errors) of 
items and subscales over time will be provided for each treatment arm from the baseline 
assessment.  Only patients with a baseline assessment and at least one post-treatment 
assessment will be included in the analyses.
The HRQoL/global health scale (Items 29 and 30 of the EORTC QLQ-C30) will assess 
time-to-deterioration (TTD).  Deterioration of HRQoL/GHS is defined as a decrease of 
10 points or more from the baseline scale score with no subsequent increase above this 
threshold.  A 10-point change is defined as the minimally important difference (Osoba et 
al. 1998).  Data for patients who do not achieve a 10-point decrease will be censored at 
the last time PRO data are available.  The KaplanMeier approach will be used to 
estimate median TTD for each treatment arm.  Cox proportional hazard models stratified 
by the three stratification factors will be used to estimate the HR and its 95% CI.  Data 
for patients without at least one post-baseline assessment will be censored at the date of 
randomization.  Patients who had no definitive deterioration events will be censored at 
the time of the last available assessment prior to disease progression.  Additional 
analyses may be conducted.
Completion rates for each PRO measure will be summarized at each timepoint by 
treatment arm.
6.8
EXPLORATORY ANALYSES
6.8.1
Biomarker Analyses
Exploratory biomarker analyses may be performed in an effort to understand the 
association of these markers with study treatment response.  Results will be presented 
in a separate report.
6.8.2
Pharmacokinetic Assays
Plasma samples may be used for exploratory evaluation of safety and/or response 
biomarkers, potential taselisib-related metabolites, and/or determination of fulvestrant 
levels.
6.8.3
Pharmacogenetic Analysis
Blood samples may be used for the evaluation of genetic polymorphisms of drug 
metabolic enzymes, such as CYP3A4/5 and UGT1A1; transporters, such as OATP1B1 
and BCRP; and genetic variants, which could contribute to potential drug-related safety 
assessments (including but not limited to HLA).
6.9
INTERIM ANALYSIS
6.9.1
Planned Interim Analysis
Until the primary PFS analysis has been completed, the iDMC will convene to review 
cumulative safety data approximately every 6 months. Data on serious adverse events, 


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death, and adverse events of special interest will be monitored by the iDMC 
approximately every 3 months.
One efficacy and one futility analysis for investigator-assessed PFS will be conducted in 
the patients with PIK3CA-mutant tumors when approximately 172 (60% of the 
information, expected at 21 months after the first patient is enrolled) 
investigator-assessed PFS events have occurred in patients with PIK3CA-mutant tumors.
Approximately 320 patients with PIK3CA-mutant tumors and approximately 120 patients 
without detectable PIK3CA-mutant tumors will have been randomized into the study by 
the time of the interim analysis. The actual timing of the interim analysis and the number 
of patients randomized will depend on the accrual rate and actual accumulation of PFS 
events observed in the study.
The iDMC will review the efficacy data, while the Sponsor and investigators remain 
blinded to the treatment assignment until the iDMC recommends stopping the study for 
efficacy or futility at the specified interim analysis and the Sponsor decides to stop the 
study. 
The iDMC may recommend stopping the study for efficacy at the interim efficacy 
analysis of investigator-assessed PFS, when the two-sided p-value 1.710-5, with 
approximately 172 investigator-assessed PFS events at the interim efficacy analysis.  
The -spending function specified as Gamma (-16), which allocates two-sided 
1.710-5 at the interim efficacy analysis, when approximately 172 PFS events are 
reached and preserves the two-sided 1% -level at the final PFS analysis.  The actual 
boundary will be adjusted based on the actual number of investigator-assessed PFS 
events at IA.  Should the iDMC recommend stopping the study for efficacy at interim 
analysis and the Sponsor decides to stop the study, the study team will be unblinded, 
and the investigators and patients will remain blinded to individual patient-level treatment 
assignment until the final OS analysis. 
The iDMC may recommend stopping the study for futility at the interim efficacy analysis 
of investigator-assessed PFS, when the observed PFS hazard ratio is above 0.85, which 
provides a probability of approximately 85% to stop the study if the true PFS hazard ratio 
is 1.0 (i.e., no treatment benefit).  The purpose of the futility analysis is not to stop the 
study for a positive (significant) efficacy PFS outcome.  Therefore, statistical significance 
level for the interim or final efficacy analysis of PFS does not need to be adjusted for this 
futility analysis.  The overall type I error is under strong control.
Three interim analyses for OS were originally planned in patients with PIK3CA-mutant
tumors on the basis of the cobas PIK3CA mutation test. As a result of the completion of 
the primary PFS analysis, the Sponsor has decided to limit the additional OS follow-up 
to one additional analysis. This additional OS analysis coincides with the originally 
planned second OS interim analysis.  The timing, the expected number of deaths, and 


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the decision boundary at each analysis are described in Section 6.4.2.2. The type I error 
is under strong control by using the Generalized Haybittle-Peto method.
No formal interim analysis is planned for the patients without detectable PIK3CA
mutations.
The responsibility, membership, and communication flow of the iDMC are specified in 
the iDMC Charter.
6.10
CHINA SUBPOPULATION ANALYSIS
After the global enrollment closes, additional Chinese patients may continue to be 
recruited into the China extension cohort. A total of up to 150 Chinese patients with 
detectable PIK3CA-mutant tumors may be enrolled as part of the global study population 
and the China extension cohort combined.  The objective of this extension cohort is to 
assess the treatment effect of taselisib plus fulvestrant on efficacy and safety in the 
subpopulation of patients from China, including those enrolled originally during the global 
portion and the China extension cohort combined, and to investigate the consistency in 
treatment effect between the China subpopulation and global patients for the purpose of 
registration in China. 
The analysis of PFS among Chinese patients will be performed when approximately 
56 PFS events have occurred among the 150 Chinese patients.  A total of 56 PFS 
events in the China subpopulation will provide approximate 85% probability of observing 
at least 50% of the risk reduction in the PFS expected to be observed in the global 
population.  Data from patients in the China extension cohort will not be included in the 
analyses of the global phase of the study but instead will be combined with data from 
Chinese patients in the global phase of the study and summarized as China 
subpopulation analysis in a separate report.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A contract research organization will be responsible for the data management of this 
study, including quality checking of the data.  Data entered manually will be collected via 
EDC through use of eCRFs.  Sites will be responsible for data entry into the EDC system.  
In the event of discrepant data, the contract research organization will request data 
clarification from the sites, which the sites will resolve electronically in the EDC system.
The Sponsor will perform oversight of the data management of this study.  The Sponsor 
will produce an EDC Study Specification document that describes the quality checking to 
be performed on the data.  Other electronic data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.


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The 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.
PRO data will be collected through use of an electronic device.  The device will be 
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 electronic 
PRO device data are available for view access only via secure access. Only identified 
and trained users may view the data, and their actions become part of the audit trail.  
The Sponsor will have view access only.  System backups for data stored by the 
Sponsor and records retention for the study data will be consistent with the Sponsor’s 
standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
The eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and will have access to a manual for appropriate eCRF 
completion.  The eCRFs will be submitted electronically to the Sponsor, and should be 
handled in accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, 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 study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
investigational medicinal product (IMP), including eCRFs, electronic PRO data 
(if applicable), Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with 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).


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Caregiver's Informed Consent Form, if applicable) will be provided to 
each site.  If applicable, it will be provided in a certified translation of the local language.  
The Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens 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 allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, 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 


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


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last 
visit).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. Hoffman-La Roche Ltd.  Approximately 200 study centers 
will participate in this study, globally, enrolling a total of approximately 600 patients as 
part of the global portion of the study unless the iDMC recommends stopping the study 
early and the sponsor decides to accept iDMC’s recommendation.  After the global
enrollment closes, additional Chinese patients may continue to be recruited into the 
China extension cohort. A total of up to 150 Chinese patients whose tumors contain a 
detectable PIK3CA mutation may be enrolled as part of the global study population and 


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the China extension cohort combined. An IxRS will be used to manage site drug supply 
and to randomize patients to study drug.
Tumor tissue will be sent to a central laboratory for analysis of PIK3CA-mutation status.  
Serum samples of pharmacokinetics will be sent to a central laboratory for storage.  
Blood samples for exploratory biomarkers will be sent to a central laboratory for analysis 
and sample storage.  Sample analysis will be performed by an external vendor or the 
Sponsor.
Until the primary PFS analysis has been completed, an iDMC, whose membership is
independent of the Sponsor, will oversee safety monitoring and the results of the interim 
efficacy analyses for investigator-assessed PFS.  The procedures of the iDMC conduct 
will be described in a separate Charter.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pd
f
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies 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 study results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical studies 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.


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Assessments
Screening a
Cycle 1
Cycle 2
Cycles 3
Cycles 3
Study Drug 
Discontinuation 
Visit c
(within 28 days 
after last dose)
Post
Progressive 
Disease
Assessment
Follow-Up d
(every 
3 months 
7 days)
Day
(Window)
28 to 1
1
15
(2) b
1
(2) b
15
(2)
1
(3)
15
(3)
Informed consent
x
Medical history and 
demographic data e
x
Concomitant medications f
x
x
x
x
x
x
x
Adverse events g
x
x
x
x
x
x
x h
x
x aa
Vital signs i
x
x
x
x
x
x
x
Oxygen saturation (pulse 
oximetry)
x
x
x
x
x
x
x
Complete physical 
examination, weight j
x
Limited physical 
examination, weight k
x
x
x
x
x
x
ECOG Performance 
Status
x
x
x
x
x
x aa
x aa
Single 12-lead ECG z
x
As clinically indicated
x
Tumor assessment l
x
Every 8 weeks (5 days) regardless of dose 
delay or early discontinuation until disease 
progression aa
x aa
x aa
Bone scan and/or skeletal 
X-rays m
x
Per clinical indication or to confirm a complete 
response m


Appendix 1 
Schedule of Assessments (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
125/Protocol GO29058, Version 4
Screening a
Cycle 1
Cycle 2
Cycles 3
Cycles 3
Study Drug 
Discontinuation 
Visit c
(within 28 days 
after last dose)
Post
Progressive 
Disease
Assessment
Follow-Up d
(every 
3 months 
7 days)
Day
(Window)
28 to 1
1
15
(2) b
1
(2) b
15
(2)
1
(3)
15
(3)
CBC with differential and 
platelets n
x
x
x
x
x
x
x
Fasting blood chemistry o
x
x
x
x
x
x
x
HbA1c
x
x
Coagulation (INR, aPTT
[or PTT])
x
As clinically indicated
Patients taking warfarin or its equivalent:  twice 
in the first week of administration, then weekly 
for 3 weeks, and then as clinically necessary
Fasting lipid profile p
x
x
x
x
Urinalysis q
x
As clinically indicated
Archival FFPE tumor 
tissue r
x
Tumor biopsy sample at 
progression s
Collected following disease progression after the patient signs the 
optional informed consent aa
Plasma sample:  Somatic 
tumor mutations
See Appendix 2 aa
Pharmacogenetic sample
Blood sample for NGS
Plasma sample: 
exploratory biomarkers
Optional RCR sample 
(blood for DNA extraction)
PRO assessments t
x
x
x aa
x aa
x aa
X aa


Appendix 1 
Schedule of Assessments (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
126/Protocol GO29058, Version 4
Screening a
Cycle 1
Cycle 2
Cycles 3
Cycles 3
Study Drug 
Discontinuation 
Visit c
(within 28 days 
after last dose)
Post
Progressive 
Disease
Assessment
Follow-Up d
(every 
3 months 
7 days)
Day
(Window)
28 to 1
1
15
(2) b
1
(2) b
15
(2)
1
(3)
15
(3)
Fulvestrant administration u
x
x
x
x
Taselisib/placebo, 
administration in the clinic v
x
x
x
x
x
Pharmacokinetic 
assessments w
See Appendix 2 aa
Drug accountability 
x
x
x
x
x
Anticancer therapies given 
after discontinuation of 
study treatment
x aa
X aa
Follow-up assessment for 
survival x
X aa
CTcomputed tomography; ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; EORTCEuropean Organisation 
for Research and Treatment of Cancer; EQ-5DEuroQol 5-Dimension Questionnaire; FFPEformalin-fixed paraffin-embedded; 
HbA1cglycosylated hemoglobin; MRImagnetic resonance imaging; NGSnext-generation sequencing; PRO patient-reported outcomes; 
QLQ-BR23Quality of Life Questionnaire Breast Cancer Module; QLQ-C30Quality of Life Questionnaire Core 30; RCRRoche Clinical 
Repository.
Notes:  Assessments scheduled on the day of study drug administration in the clinic (e.g., Cycle 2, Day 1) should be performed prior to study drug 
administration, unless otherwise noted. Visits are based on a 28-day cycle. If the timing of a protocol-mandated procedure coincides with a 
holiday and/or weekend that preclude the procedure within the allotted window, the procedure should be performed on the nearest following date.  
Patients should receive their first dose of study treatment on the day of randomization if possible, but no later than 5 business days after 
randomization.
a Results of screening tests or examinations performed as standard of care prior to obtaining informed consent and within 28 days prior to 
randomization may be used rather than repeating required tests. Note that standard of care tumor and laboratory assessments should be done 
within 28 days prior to Cycle 1, Day 1.
b The window for Cycle 1, Day 15 and Cycle 2, Day 1 assessment is 2 days since fulvestrant administration should not occur prior to 
Cycle 1, Day 15 or Cycle 2, Day 1 (Day 29).


Appendix 1 
Schedule of Assessments (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
127/Protocol GO29058, Version 4
c The visit at which disease progression is recorded may serve as the study drug discontinuation visit, provided that all tests required at the study 
drug discontinuation visit are performed.  If study treatment had been interrupted for 28 days before the decision to permanently discontinue all 
study treatment and the study drug discontinuation visit can no longer occur within 28 days after the last dose of study treatment, the visit 
should be performed as soon as possible after permanent study drug discontinuation.
d Only serious adverse events considered to be related to study medication should be reported. Until approximately the end of August 2018,
patients will also be followed for survival and subsequent anti-cancer therapies approximately every 3 months.
e Medical history includes clinically significant diseases within the previous 5 years before Cycle 1 Day 1, smoking history, breast cancer history 
(including tumor characteristics such as hormone receptor status, prior cancer therapies, surgeries, and procedures).  Demographic data include 
age, sex, and self-reported race/ethnicity.
f
Until approximately the end of August 2018, concomitant medications include prescription medication, over-the-counter preparations, and 
herbal or homeopathic remedies and supplements used within 7 days prior to the screening visit through the study drug discontinuation visit.  
After this visit, only medications administered for ongoing or new treatment-related adverse events will be collected.  After approximately the 
end of August 2018, concomitant medications include prescription medication, over-the-counter preparations, and herbal or homeopathic 
remedies and supplements used within 7 days prior to the screening visit through the study drug discontinuation visit or until 28 days after 
the last dose of study drug, whichever occurs later.
g After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the last dose of study drug.  
After this period, investigators should report any deaths, serious adverse events, or other adverse events of concern that are believed to be 
related to prior treatment with study drug.  The investigator should follow each adverse event until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, the patient withdraws consent, or the patient is no 
longer followed for survival.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-
related procedures until a final outcome can be reported.
h Until approximately the end of August 2018, phone call from the site to the patient to assess adverse events as in footnote g.  The rationale for 
this phone call is that some adverse events have a delayed onset (e.g., diarrhea), and follow-up that is more frequent than the visit, which is
every 4 weeks, will be useful in management.  After approximately the end of August 2018, the phone call from the site to the patient is no 
longer required for patients continuing on single-agent fulvestrant.
i
Vital signs include measurements of respiratory rate, pulse, systolic and diastolic blood pressure while the patient is in a seated position, and
temperature.
j
Complete physical examination should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems and measurement of weight and height (height is 
measured at the screening visit only).  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.
k Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.


Appendix 1 
Schedule of Assessments (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
128/Protocol GO29058, Version 4
l
Perform tumor assessments at screening (within 28 days prior to Cycle 1 Day 1) and, until approximately the end of August 2018, every 8 
weeks (5 days) from date of randomization, and when clinically indicated for all patients including those with bone-only disease.  This schedule 
is to be maintained and will not be shifted for treatment delays. Screening assessments must include CT scans of the chest, abdomen, and 
pelvis; CT scans of the neck and brain imaging should be included if clinically indicated.  A documented standard-of-care tumor assessment 
performed within 28 days before Cycle 1 Day 1 may be used for the screening assessment, provided it meets the above requirements.  The 
same imaging method used at screening must be used throughout the study.  Response assessments will be performed by the investigator, on 
the basis of physical examinations and imaging scans, through the use of RECIST, Version 1.1.  Until approximately the end of August 2018, 
patients who are discontinued from study treatment for reasons other than disease progression will be asked to continue to have tumor 
assessments every 8 weeks (5 days) until disease progression.  Until approximately the end of August 2018, patients who are discontinued 
from study treatment because of disease progression will be asked to return for a repeat tumor assessment 46 weeks after experiencing 
disease progression. In addition, until approximately the end of August 2018, bone disease identified on bone imaging must be evaluated 
radiographically by CT scan, MRI, or X-ray.  Until approximately the end of August 2018, the same modality used at screening should be used 
throughout the study. After approximately the end of August 2018, subsequent tumor assessments may be conducted per local standard of 
care.
m An isotope bone scan (e.g., technetium) and/or skeletal X-rays will be performed at screening and, until approximately the end of August 2018, 
should be repeated in the event of clinical suspicion of progression of existing bone lesions and/or the development of new bone lesions or for 
confirmation of complete response for all patients. For patients with bone-only disease not visible on CT or MRI scans or X-ray at baseline (see 
Section 4.5.5), until approximately the end of August 2018, bone scans should be repeated every 8 weeks (5 days) from the date of 
randomization and when clinically indicated until disease progression. After approximately the end of August 2018, subsequent tumor 
assessments may be conducted per local standard of care.
n Includes RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, bands [optional], eosinophils, basophils, lymphocytes, 
and monocytes), and platelet count. Reporting the differential as absolute counts is preferred, but percent is accepted. Laboratory samples are 
required at screening (within 28 days prior to Cycle 1, Day 1). If screening laboratory samples are drawn within 2 days prior to Cycle 1, Day 1, 
they do not have to be repeated on Cycle 1, Day 1. All other predose laboratory samples may also be drawn within 2 days prior to the cycle visit.
o Fasting (8 hours) bloodchemistry includes glucose, BUN (or urea), creatinine, sodium, potassium, magnesium, bicarbonate, chloride, calcium, 
phosphorus, total protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase.  Laboratory 
samples are required at screening (within 28 days prior to Cycle 1, Day 1). If screening laboratory samples are drawn within 2 days prior to 
Cycle 1, Day 1, they do not have to be repeated on Cycle 1, Day 1. All other predose laboratory samples may also be drawn within 2 days prior 
to the cycle visit.
p Fasting (8 hours) lipid profile should be performed at screening (within 28 days prior to Cycle 1, Day 1), and on Day 1 of Cycles 1 and 3 and 
every 3 cycles thereafter and include total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, amylase, and lipase. If 
screening laboratory samples are drawn within 2 days prior to Cycle 1, Day 1, they do not have to be repeated on Cycle 1, Day 1. All other 
predose laboratory samples may also be drawn within 2 days prior to the cycle visit.
q Specific gravity, pH, glucose, protein, ketones, and blood.


Appendix 1 
Schedule of Assessments (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
129/Protocol GO29058, Version 4
r
Archival tumor tissue blocks or a minimum of 20 (25 preferred) freshly cut unstained slides from the most recent tumor tissue will be collected at 
screening for molecular characterization of the tumor tissue including but not limited to PIK3CA mutation. If a tissue sample from the site(s) of 
metastasis was collected to meet enrollment criteria, a minimum of five additional formalin-fixed paraffin-embedded tissue slides of the primary 
lesion should be provided, if available.
s Tumor biopsy collection at the time of disease progression is not required for study participation but, until approximately the end of August
2018, is strongly recommended and will be collected for patients who sign the Optional Research Informed Consent Form.
t
Until approximately the end of August 2018, the PRO questionnaires (EORTC QLQ-C30, modified QLQ-BR23) and EQ-5D will be completed 
by the patients at the investigational site during treatment. All questionnaires must be administered prior to any other study assessment(s), 
health care provider interaction, and administration of study drug, to ensure that the validity of the instrument is not compromised and that data 
quality meets regulatory requirements. Until approximately the end of August 2018, patients who are discontinued from study treatment for 
reasons other than disease progression will be asked to continue to complete the PRO assessments approximately every 8 weeks (5 days) 
until disease progression. Additionally, until approximately the end of August 2018, all patients will also complete the PRO measures once at 
46 weeks (5 days) and once at 12 weeks (7 days) after disease progression.
u Fulvestrant will be administered in the clinic (before administration of taselisib/placebo) as two intramuscular injections of 250 mg each 
on Days 1 and 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle.
v Taselisib/placebo will be taken orally once daily beginning at Cycle 1, Day 1.  Taselisib/placebo will be administered in the clinic on Cycle 1,
Day 1 and Cycle 1, Day 15 and on each subsequent day that a cycle visit is scheduled, after the predose assessments and procedures, and at 
home on all non-clinic visit days.  During clinic visits, taselisib/placebo will be administered after the fulvestrant injections (except for Cycle 2,
Day 15). A sufficient number of taselisib/placebo tablets will be provided to last until the next visit, or, at the investigator’s discretion, to last until 
the next administration of fulvestrant.  Extra tablets may be dispensed if there is a reasonable possibility that the patient’s next visit may be 
delayed (e.g., because of inclement weather or distance between the patient’s home and study center).  Until approximately the end of August
2018, patients will also receive a medication diary.  Instruct the patient to record the time and date she takes each treatment dose in the diary 
and to return all unused tablets at each study visit, to assess compliance.  Collect and review medication diary and unused tablets and assess 
compliance at each subsequent visit.  After approximately the end of August 2018, collect and review unused tablets and assess compliance at 
each subsequent visit.  At the study drug discontinuation visit, do not dispense any additional study drug tablets or provide a new medication 
diary.
w Taselisib plasma samples may be used for exploratory pharmacokinetics, metabolism, biomarker and/or safety analyses, which may include 
determination of fulvestrant concentration.
x Until approximately the end of August 2018, all patients who discontinue from the treatment phase will be followed for survival information 
unless the patient requests to be withdrawn from study-survival follow-up.  Survival follow-up information will be collected via telephone calls, 
patient’s medical records, and/or clinic visits approximately every 3 months until death, loss to follow-up, or study termination by the Sponsor.
z An ECG (12-lead) is required at screening and may be repeated during the study as clinically indicated. All ECG recordings should be 
performed using a standard high-quality, high-fidelity digital electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be performed after the patient has been resting in a supine position 


Appendix 1 
Schedule of Assessments (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
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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. Clinically significant abnormalities observed during screening will be recorded on the General Medical 
History and Baseline Conditions eCRF.  New or worsened clinically significant abnormalities will be recorded on the Adverse Event eCRF.
aa Until approximately the end of August 2018.


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Appendix 2
Schedule for Collection of Pharmacokinetic and Exploratory 
Biomarker Samples
Study Visit
Timepoint
Sample Type
Pretreatment
7 days before first dose
Plasma (somatic tumor mutations) a
Optional RCR Blood (for DNA 
extraction) b
Cycle 1, Day 1
Prior to taselisib/placebo 
administration
Plasma (somatic tumor mutations) a, d
Plasma (exploratory biomarkers) a
Pharmacogenetic blood sample a
Blood for NGS a, c
14 hours post-taselisib/placebo 
administration
PK plasma sample for taselisib
Cycle 1, Day 15
Prior to taselisib/placebo 
administration
Plasma (somatic tumor mutations) a, d
Plasma (exploratory biomarkers) a
Cycle 2, Day 1 e
03 hours prior to taselisib/placebo 
and fulvestrant administration
PK plasma sample for taselisib
26 hours post-taselisib/placebo 
and fulvestrant administration
PK plasma sample for taselisib
Cycle 3, Day 1
and Cycles 5, 7, 
9, etc., Day 1 
Prior to taselisib/placebo 
administration
Plasma (somatic tumor mutations) a, d
Cycle 6, Day 1 e
03 hours prior to taselisib/placebo 
and fulvestrant administration
PK plasma sample for taselisib f
SDDV
At visit
Plasma (somatic tumor mutations) a, d
Plasma (exploratory biomarkers) a
NGSnext-generation sequencing; PKpharmacokinetic; RCRRoche Clinical Repository; 
SDDVstudy drug discontinuation visit.
Notes:  Predose blood samples may be drawn within 2 days prior to the cycle visit.  All samples 
in Appendix 2 are no longer required after approximately the end of August 2018.
a Not applicable for a site that has not been granted approval by its local regulatory authorities.
b The optional RCR blood sample (for DNA extraction) requires an additional informed consent 
and can be collected at any time during the course of the study.
c A blood sample will also be collected as a source of normal DNA to determine whether or not 
sequence variants are somatic mutations or single nucleotide polymorphisms if approved by 
local regulatory authorities.
d Blood will be collected for ctDNA analysis prior to dosing at, Cycle 1, Days 1 and 15, prior to 
dosing on Day 1 of Cycles 3, 5, 7, 9, 11 etc., and SDDV
e The date and time of the previous taselisib/placebo dose prior to the Cycle 2 Day 1 and Cycle 
6 Day 1 samples for PK analysis will need to be recorded.
f
Back-up plasma sample at this timepoint may be used for determination of fulvestrant 
concentration as this is an exploratory objective.


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Appendix 3
Mutations Detected by the cobas® PIK3CA Mutation Test
Exon
Mutation ID
Amino-Acid
Change
cobas® Test 
Result
1
263 G>A
R88Q
R88Q
4
1035 T>A
N345K
N345K
7
1258 T>C
C420R
C420R
9
1624 G>A
E542K
E542K
9
1634 A>C
E545A
E545X
9
1635 G>T
E545D
E545X
9
1634 A>G
E545G
E545X
9
1633 G>A
E545K
E545X
9
1636 C>G
Q546E
Q546X
9
1636 C>A
Q546K
Q546X
9
1637 A>T
Q546L
Q546X
9
1637 A>G
Q546R
Q546X
20
3129 G>T
M1043I
M1043I
20
3140 A>T
H1047L
H1047X
20
3140 A>G
H1047R
H1047X
20
3139 C>T
H1047Y
H1047X
20
3145 G>C
G1049R
G1049R


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Appendix 4
Eastern Cooperative Oncology Group Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without 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 5
Inhibitors of PI3K/AKT/mTOR Signaling Pathway
Phosphatidylinositol 3-kinase (PI3K) inhibitors include but are not limited to the following:

Idelalisib (GS-1101), pictilisib (GDC-0941), apitolisib (GDC-0980), taselisib 
(GDC-0032), buparlisib (BKM120), copanlisib (BAY80-6946), alpelisib (BYL719), 
MLN1117, IPI-145, GSK2636771, PF-04691502, BEZ235, LY294002, PIK-75, TGX-
221, XL147, XL765, SF1126, PX-866, D-106669, GSK615
Mammalian target of rapamycin (mTOR) inhibitors include but are not limited to the 
following:

Everolimus, temsirolimus, ridaforolimus, MLN0128
Protein kinase B (AKT) inhibitors include but are not limited to the following:

MK-2206, ipatasertib (GDC-0068)


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Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
Measurability of Tumor at Baseline
Definitions
At baseline, tumor lesions and/or lymph nodes will be categorized as measurable or 
non-measurable as described below.
MEASURABLE TUMOR LESIONS
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and at follow-up, only 
the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
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NON-MEASURABLE TUMOR LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions.  
However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
137/Protocol GO29058, Version 4
Target Lesions:  Specifications by Methods of Measurements

Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if 
clinically assessed.  All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment.

Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the 
study.  Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not-evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality.


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
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Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to 
a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, but in addition should 
lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
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 


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
139/Protocol GO29058, Version 4
node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
140/Protocol GO29058, Version 4
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of 10 mm.
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (BML is equivalent to a “less than” sign.) (Note:  It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well 
and BML should also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and in that case BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol.
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
141/Protocol GO29058, Version 4
All lymph nodes must be non-pathological in size (10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits
PD:  Unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable disease 
is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is 
seen, the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
142/Protocol GO29058, Version 4
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly, possible “new” disease).  New lesions on the 
basis of FDG-PET imaging can be identiﬁed according to the following algorithm: 

A negative FDG-PET scan at baseline with a positive3 FDG-PET scan during the 
study is a sign of PD based on a new lesion. 

In the case of no FDG-PET scan at baseline and a positive FDG-PET scan during 
the study:
If the positive FDG-PET scan during the study corresponds to a new site of 
disease confirmed by CT, this will be considered PD.
If the positive FDG-PET scan during the study is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine whether 
there is truly progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan).
If the positive FDG-PET scan during the study corresponds to a preexisting site 
of disease on CT that is not progressing on the basis of the anatomic images, 
this will not be considered PD.
                                           
3 A “positive” FDG-PET scan lesion means one that is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation-corrected image.


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
143/Protocol GO29058, Version 4
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.
Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised.


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
144/Protocol GO29058, Version 4
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.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.


Appendix 6
Response Evaluation Criteria in Solid Tumors, V 1.1
Modified Excerpt from Original Publication (cont.)
Taselisib—F. Hoffmann-La Roche Ltd
145/Protocol GO29058, Version 4
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.


Taselisib—F. Hoffmann-La Roche Ltd
146/Protocol GO29058, Version 4
Appendix 7
Patient-Reported Outcome Measure: QLQ-C30


Taselisib—F. Hoffmann-La Roche Ltd
147/Protocol GO29058, Version 4
Appendix 7
Patient-Reported Outcome Measure:  QLQ-C30 (cont.)


Taselisib—F. Hoffmann-La Roche Ltd
148/Protocol GO29058, Version 4
Appendix 8
Patient-Report Outcome Measure: Modified QLQ-BR23


Taselisib—F. Hoffmann-La Roche Ltd
149/Protocol GO29058, Version 4
Appendix 8
Patient-Report Outcome Measure:  Modified QLQ-BR23 (cont.)


Taselisib—F. Hoffmann-La Roche Ltd
150/Protocol GO29058, Version 4
Appendix 9
Exploratory Health Economic Outcome Measure: EQ-5D


Taselisib—F. Hoffmann-La Roche Ltd
151/Protocol GO29058, Version 4
Appendix 9
Exploratory Health Economic Outcome Measure:  EQ-5D (cont.)


Taselisib—F. Hoffmann-La Roche Ltd
152/Protocol GO29058, Version 4
Appendix 9
Exploratory Health Economic Outcome Measure:  EQ-5D (cont.)


STATISTICAL ANALYSIS PLAN APPROVAL 
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Taselisib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29058, Version 2 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED STUDY OF TASELISIB PLUS FULVESTRANT 
VERSUS PLACEBO PLUS FULVESTRANT IN 
POSTMENOPAUSAL WOMEN WITH ESTROGEN 
RECEPTOR-POSITIVE AND HER2-NEGATIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER WHO 
HAVE DISEASE RECURRENCE OR PROGRESSION 
DURING OR AFTER AROMATASE INHIBITOR THERAPY 
PROTOCOL NUMBER: 
STUDY DRUG: 
VERSION NUMBER: 
IND NUMBER: 
EUDRACT NUMBER: 
SPONSOR: 
PLAN PREPARED BY: 
DATE FINAL: 
DATE AMENDED: 
GO29058/ NCT02340221 
Taselisib (RO5537381) 
2 
121658 
2014-003185-25 
F. Hoffmann-La Roche Ltd 
, Ph.D.
30 June 2015
See electronic date stamp below.
Name
Reason for Signing
Date and Time
(UTC)
03-Mar-2017 22:30:02
Company Signatory (Clinical)


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Taselisib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29058, Version 2 
4 
4.5 
Pharmacokinetic, Pharmacodynamic, and 
Biomarker Analyses ............................................................... 17 
4.6 
Safety Analyses ..................................................................... 17 
4.6.1 
Exposure of Study Medication ............................................... 17 
4.6.2 
Adverse Events ..................................................................... 17 
4.6.3 
Laboratory Data ..................................................................... 18 
4.6.4 
Vital Signs .............................................................................. 18 
4.7 
Missing Data .......................................................................... 18 
4.8 
Interim Analyses .................................................................... 19 
5. 
CHINA SUBGROUP ANALYSIS ................................................................. 20 
6. 
REFERENCES ........................................................................................... 22 
 
 
LIST OF TABLES 
Table 1 
Progression-Free Survival Analyses ........................................... 10 
Table 2 
Interim Analyses for Overall Survival if the First Interim 
Overall Survival Analysis Occurs at the Time of the Interim 
Efficacy Analysis of Investigator-Assessed Progression-Free 
Survival ....................................................................................... 13 
Table 3 
Interim Analyses for Overall Survival if the First Interim 
Overall Survival Analysis Occurs at the Time of the Final 
Efficacy Analysis of Investigator-Assessed Progression-Free 
Survival ....................................................................................... 14 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 23 
Appendix 2 
Schedule of Assessments ........................................................... 33 
 


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Taselisib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29058, Version 2 
9 
cumulative safety data approximately every 6 months.  The data on serious adverse 
events, death, and adverse events of special interest will be monitored by iDMC 
approximately every 3 months. 
In addition, one efficacy and futility analysis for investigator-assessed PFS will be 
conducted in patients with PIK3CA-mutant tumors.  The iDMC will review the data 
and may recommend stopping the study for efficacy or futility (details described 
in Section 4.8). 
4. 
STATISTICAL METHODS 
This section applies only to the global study.  See Section 5 for the China subgroup 
analysis. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population includes all randomized patients regardless of 
whether they receive any amount of study treatment.  Treatment assignment will be 
defined according to the treatment assigned at randomization by the interactive voice or 
Web response system (IxRS). 
The ITT population will form the basis for efficacy analyses.  The analyses for the 
primary and the secondary efficacy endpoints will be conducted in patients with 
PIK3CA-mutant tumors.  These endpoints will also be evaluated in patients without 
detectable PIK3CA-mutant tumors as the exploratory analyses. 
4.1.2 
Safety Population 
The safety population includes all randomized patients who receive at least one dose of 
taselisib or placebo or fulvestrant.  Specifically, a patient will be included in the 
taselisib + fulvestrant arm in the safety analyses if the patient receives any amount of 
taselisib, regardless of the initial treatment assignment at randomization.  The safety 
population will form the basis for safety analyses. 
4.1.3 
Pharmacokinetic Population 
The pharmacokinetic population will include all patients who have received at least 
one dose of taselisib and provided valid (adequately documented dose time and 
pharmacokinetic sample time) pharmacokinetic assessments.  The pharmacokinetic 
population at specific timepoints will vary, depending on the availability of results at 
confirmed dosing and pharmacokinetic assessment times. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Patient enrollment, duration of follow-up, and discontinuation from the study and 
discontinuation reasons will be summarized by treatment arm for all randomized patients.  
In addition, major protocol deviations, including violations of inclusion or exclusion 


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Taselisib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29058, Version 2 
18 
All deaths reported, deaths reported within (i.e., less than or equal to) 28 days of last 
dose of study drug, and deaths reported after 28 days of last dose of study treatment will 
be summarized separately by treatment arm, including the reasons for the deaths. 
4.6.3 
Laboratory Data 
Selected laboratory data such as fasting glucose level, absolute neutrophil count, 
hemoglobin level, platelet count, lymphocyte count, serum creatinine level, and liver 
function test results (AST and ALT) with values outside the normal ranges will be 
summarized by treatment arm.  For the selected laboratories, toxicity grade shift 
from baseline will be summarized by treatment arm. 
4.6.4 
Vital Signs 
Change from baseline in vital signs will be summarized by treatment arm and grade. 
4.7 
MISSING DATA 
For the analysis of OS, data from patients who are alive at the time of the analysis data 
cutoff will be censored at the last date they are known to be alive.  Data from patients 
without post-baseline information will be censored at the date of randomization. 
For the analyses of PFS and DOR, data from patients who are lost to follow-up or 
without disease progression or death as of the clinical data cutoff date will be 
censored at the time of the last tumor assessment when the patient is known to be 
progression-free (i.e., an overall response other than “progressive disease” or “not 
evaluable”) or at the time of randomization if there is no post-baseline tumor assessment 
or all post-baseline tumor assessments have overall responses of “not evaluable.” 
For the FDA, the primary efficacy analysis for investigator-assessed PFS will be 
censored additionally for patients experiencing a progression event preceded by two or 
more missing tumor assessments before the disease progression (i.e., the duration 
between the date of first documented PD deemed by investigator per RECIST v1.1 and 
the date of the last tumor assessment when the patient is known to be progression-free 
> 122 days).  These patients will be censored at the last tumor assessment prior to the 
missed visits that is known to be progression-free (i.e., an overall response other than 
“progressive disease,” or “not evaluable”) or at randomization if there is no post-baseline 
tumor assessment or all post-baseline tumor assessments have overall responses of 
“not evaluable” in between the randomization and the first documented PD per 
RECIST v 1.1. 
For the analysis of ORR, patients with measurable disease at baseline but with no 
post-baseline tumor assessment or post-baseline tumor assessments that all have 
overall responses of “not evaluable” will be categorized as non-responders. 


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Taselisib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29058, Version 2 
21 
tumor assessments have overall responses of “not evaluable.”  The unstratified Cox 
proportional hazards model will be used to estimate investigator-assessed PFS HR 
between the two treatment groups and its 95% CI.  An unstratified two-sided log-rank 
test will provide a comparison for investigator-assessed PFS in this subgroup in a 
descriptive manner.  Plots of the Kaplan-Meier estimate for investigator-assessed PFS 
will be produced, including medians and confidence limits. 
Safety data for the China subgroup will be analyzed as described in Section 4.6. 


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Appendix 1  
Protocol Synopsis (cont.) 
Taselisib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29058, Version 2 
30 
Investigational Medicinal Products 
Test Product 
The test product for this study is taselisib.  The taselisib tablet is a white to off-white, film coated, 
immediate release formulation of 2-mg strength.  The taselisib 4-mg dose will be taken orally 
(PO) once a day (QD).  Taselisib is formulated as 2-mg tablets, so patients will take 
two 2-mg tablets daily to receive a 4-mg dose.  Taselisib will be administered in the clinic on 
Cycle 1 Day 1 and Cycle 1 Day 15 and on each subsequent day that a cycle visit is scheduled, 
after the predose assessments and procedures, and after the fulvestrant administration (except 
for Cycle 2 Day 15).  Taselisib will be administered at home on all non-clinic visit days.  Patients 
should take the taselisib dose at the same approximate time each day without regard to the 
timing of administration of food.  If a dose is missed (not taken within 6 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. 
Placebo 
The taselisib placebo (corresponding to a 4-mg dose) will be two tablets taken PO QD.  
Taselisib placebo will be administered in the clinic on Cycle 1 Day 1 and Cycle 1 Day 15 and on 
each subsequent day that a cycle visit is scheduled, after the predose assessments and 
procedures, and after the fulvestrant administration (except for Cycle 2 Day 15).  Taselisib 
placebo will be administered at home on all non-clinic visit days.  Taselisib placebo should be 
taken at the same approximate time each day without regard to the timing of administration of 
food.  If a dose is missed (not taken within 6 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. 
Background Therapy 
Fulvestrant will be supplied by the Sponsor per country-specific requirements.  For countries in 
which the Sponsor is supplying fulvestrant, it will be supplied in sterile, single-patient, prefilled 
syringes containing 50 mg/mL fulvestrant as a 5-mL injection.  Fulvestrant 500 mg will be 
administered in the clinic (before administration of taselisib or placebo) as two intramuscular 
injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day 
cycle. 
Non-Investigational Medicinal Products 
None. 
Statistical Methods 
Primary Analysis 
The primary efficacy endpoint is investigator-assessed PFS (PFS in this document refers to 
investigator-assessed PFS, unless stated otherwise).  The primary efficacy analysis population 
will include all randomized patients with PIK3CA-mutant tumors.  The primary efficacy endpoint, 
PFS, and the secondary efficacy endpoints will be analyzed in this population as the primary 
and the secondary objectives. 
In addition, these efficacy endpoints, unless otherwise specified, will be analyzed in all 
randomized patients without detectable PIK3CA-mutant tumors at the same time as the 
analyses are conducted for the patients with PIK3CA-mutant tumors. 
PIK3CA-mutant tumor status will be determined by the cobas PIK3CA mutation test of the 
patient’s tissue sample. 
The primary PFS analysis will be conducted in all randomized patients with PIK3CA-mutant 
tumors, with patients grouped according to the treatment arm assigned at randomization. 
An interim efficacy analysis will be conducted for investigator-assessed PFS at the time of 
172 investigator-assessed PFS events (expected 21 months after the first patient is enrolled), and 
the final efficacy analysis will be conducted at the time 287 investigator-assessed PFS events 
(expected 29 months after the first patient is enrolled) are observed in patients with 


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Appendix 2  
Schedule of Assessments (cont.) 
Taselisib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29058, Version 2 
39 
v Taselisib/placebo will be taken orally once daily beginning at Cycle 1, Day 1.  Taselisib/placebo will be administered in the clinic on Cycle 1, 
Day 1 and Cycle 1, Day 15 and on each subsequent day that a cycle visit is scheduled, after the predose assessments and procedures, and at 
home on all non-clinic visit days.  During clinic visits, taselisib/placebo will be administered after the fulvestrant injections (except for Cycle 2, 
Day 15).  A sufficient number of taselisib/placebo tablets will be provided to last until the next visit, or, at the investigator’s discretion, to last until 
the next administration of fulvestrant.  Extra tablets may be dispensed if there is a reasonable possibility that the patient’s next visit may be 
delayed (e.g., because of inclement weather or distance between the patient’s home and study center).  Patients will also receive a medication 
diary.  Instruct the patient to record the time and date she takes each treatment dose in the diary and to return all unused tablets at each study 
visit, to assess compliance.  Collect and review medication diary and unused tablets and assess compliance at each subsequent visit.  At the 
study drug discontinuation visit, do not dispense any additional study drug tablets or provide a new medication diary. 
w Taselisib plasma samples may be used for exploratory pharmacokinetics, metabolism, biomarker and/or safety analyses, which may include 
determination of fulvestrant concentration. 
x All patients who discontinue from the treatment phase will be followed for survival information unless the patient requests to be withdrawn from 
study-survival follow-up.  Survival follow-up information will be collected via telephone calls, patient’s medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, or study termination by the Sponsor. 
z An ECG (12-lead) is required at screening and may be repeated during the study as clinically indicated.  All ECG recordings should be 
performed using a standard high-quality, high-fidelity digital electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be performed after the patient has been resting in a supine position 
for at least 10 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood 
draws) and should not be obtained within 3 hours after any meal.  Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting period and during ECG recording.  For safety 
monitoring purposes, the investigator must review, sign, and date all ECG tracings.  Paper copies of ECG tracings will be kept as part of the 
patient's permanent study file at the site.  Clinically significant abnormalities observed during screening will be recorded on the General Medical 
History and Baseline Conditions eCRF.  New or worsened clinically significant abnormalities will be recorded on the Adverse Event eCRF.