Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The open-label Phase Ib portion of this study will evaluate the safety and pharmacokinetics of ipatasertib in combination with palbociclib and fulvestrant to identify a dose of ipatasertib that can be combined with palbociclib and fulvestrant in the Phase III portion. The randomized Phase III portion of this study will evaluate the efficacy, safety, and patient-reported outcome (PRO) objectives of ipatasertib + palbociclib + fulvestrant compared with placebo + palbociclib + fulvestrant in patients with HR+ HER2-, locally advanced unresectable or metastatic breast cancer who had relapsed during adjuvant endocrine therapy or progressed during the initial 12 months of first-line endocrine therapy in locally advanced unresectable or metastatic breast cancer.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Ipatasertib intervention 2: Placebo intervention 3: Palbociclib intervention 4: Fulvestrant
Intervention descriptions: intervention 1: Phase 1b: Ipatasertib, 300 mg starting dose administered orally once daily (PO QD) during an initial 5-7 day run-in period, then continued on Days 1-21 during the first cycle. Starting with Cycle 2, Day 1 ipatasertib will be taken orally once daily on Days 1-21 of each 28-day cycle. Phase 3: Ipatasertib, administered PO QD on Days 1-21 of each 28-day cycle at the dose confirmed in the Phase Ib portion. intervention 2: Phase 3: Matching placebo, administered PO QD on Days 1-21 of each 28-day cycle at the dose confirmed in the Phase Ib portion. intervention 3: Palbociclib, administered PO QD on Days 1-21 of each 28-day cycle. intervention 4: Fulvestrant, 500 mg administered as two intramuscular injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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.
Ipatasertib—F. Hoffmann-La Roche Ltd
Protocol CO41012, Version 3
PROTOCOL
TITLE:
A PHASE IB/III STUDY OF IPATASERTIB PLUS 
PALBOCICLIB AND FULVESTRANT VERSUS 
PLACEBO PLUS PALBOCICLIB AND 
FULVESTRANT IN HORMONE RECEPTOR 
POSITIVE AND HER2 NEGATIVE LOCALLY 
ADVANCED UNRESECTABLE OR METASTATIC 
BREAST CANCER
PROTOCOL NUMBER:
CO41012
VERSION NUMBER:
3
EUDRACT NUMBER:
2019-001072-11
IND NUMBER:
133823
NCT NUMBER:
NCT04060862
TEST PRODUCT:
Ipatasertib (RO5532961, GDC-0068), palbociclib, 
fulvestrant
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
14 March 2019
DATES AMENDED:
Version 2: 14 October 2019
Version 3:  See electronic date stamp below.
 
12-Feb-2020 18:07:25
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Ipatasertib—F. Hoffmann-La Roche Ltd
2/Protocol CO41012, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol CO41012 has been amended primarily to revise some eligibility criteria 
especially for the patients in the Phase III portion to ensure a more homogeneous study 
population, as well as to update the patient-reported outcome (PRO) measures 
administered in the Phase III portion.  Overall changes to the protocol, along with a 
rationale for each change, are summarized below:

Relevant clinical data for the combination of an AKT inhibitor with endocrine therapy 
was added based on the randomized Phase II study FAKTION that investigated the 
AKT inhibitor capivasertib in combination with fulvestrant (Section 1.1 and
Section 3.3.5).

The Steering Committee (a group of trial investigators who provide scientific and 
medical guidance for Study CO41012) advised that the specific 5-year timeframe for 
relapse during endocrine therapy was unnecessary and considered patients with 
relapse at any time during adjuvant endocrine therapy a relevant study population 
for this trial with similar poor prognosis. Based on this recommendation, the 
restriction of relapse specifically during the initial 5 years was removed throughout 
the protocol (Sections 1.5, 2, 3.1, 4.1.1, and Figure 3).

For completeness and consistency with other sections, pneumonitis was added to
the list of potentially overlapping toxicities that may be exacerbated when combining 
ipatasertib and palbociclib (Section 1.5). 

The PRO measures and associated endpoints were updated, resulting in changes 
to the PRO-related secondary and exploratory objectives. The “worst pain” item 
from the Brief Pain Inventory-Short Form (BPI-SF) was added to better understand 
the impact of treatment on pain based on regulatory feedback on hormone 
receptorpositive (HR) breast cancer studies, while the European Organisation for 
Research and Treatment of Cancer Quality-of-Life Questionnaire Breast Cancer 
Module 23 (EORTC QLQ-BR23) was added to align with other HRBreast Cancer 
studies (Sections 2.1.2, 2.1.3, 3.3.9, 4.5.10 [and associated subsections], 6.4.2.5, 
and 6.4.3.3, and Appendices 1, 10, and 12). 

Text in Section 3.1.1 was simplified for consistency with other sections given the 
updates to the eligibility criteria described below.

The manufacturer is switching palbociclib from a capsule to a tablet formulation;
therefore, drug supply for palbociclib will transition from capsule to tablet during the 
course of this study and thus the tablet formulation was added in multiple sections 
(Sections 3.1.1, 3.1.2, 4.3.1.2, and 4.3.2.2). Palbociclib tablets, in contrast to 
capsules, can be taken with or without food (Section 4.3.2.2).

Figure 3 was updated to align the key eligibility portion of the study schema with the 
updated inclusion and exclusion criteria.

The timeframe of at least 14 days for goserelin or alternative luteinizing hormone 
releasing hormone (LHRH) agonist therapy in combination with fulvestrant was 
deemed sufficient by the Steering Committee and thus recommended to facilitate 


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3/Protocol CO41012, Version 3
initiation of study treatment. A recommendation for men to be treated with goserelin 
or alternative LHRH was added (Sections 3.1.3, 4.1.1, 4.3.2.4, 4.4.1, Appendices 1 
and 3).

Clarification of central laboratory next-generation sequencing (NGS) testing was 
provided in Sections 3.1.4, 4.1.1, and 4.5.8, and Appendices 1 and 3.  Text in the 
rationale for collection of tissue samples was updated and simplified for consistency 
with the description of NGS testing in Section 4.5.8 (Section 3.3.7.2).

The tumor assessment schedule for patients who discontinue study treatment for 
reasons other than radiographic disease progression was aligned with that prior to 
study treatment discontinuation based on regulatory feedback (Sections 3.1.5, 4.5.6,
and 4.6.1). In addition, the allowed window for tumor assessments and bone scans 
has been widened to 7 days from 5 days to facilitate scheduling (Section 4.5.6
and Appendix 1). 

The specific eligibility requirements for HER2 negativity were updated to be more 
complete within the text of the inclusion criterion and to provide additional clarity and 
facilitate eligibility determination (Section 4.1.1).  

The requirements for contraceptive methods for men were clarified, distinguishing 
the requirements if they are surgically sterile and whether the female partner of 
childbearing potential is pregnant or non-pregnant (Section 4.1.1).

The eligibility criteria for the Phase III portion were updated to no longer allow prior 
CDK4/6 inhibitor for locally advanced unresectable or metastatic breast cancer.  
This update was made to keep the patient population more homogeneous, since 
efficacy has not been established for sequential CDK4/6 inhibitor therapy 
(Sections 4.1.1, 4.1.2, and Figure 3). 

The cap of prior CDK4/6 inhibitor for Phase III patients treated in the adjuvant 
setting remains at 20%, but further clarifications were added to include neoadjuvant 
treatment and a disease-free interval of at least 12 months after the CDK4/6 
inhibitor portion, since sequential treatment with CDK4/6 inhibitors has not been 
established (Sections 4.1.1 and 4.1.2).

In the Phase Ib portion, patients who received prior CDK4/6 inhibitor treatment will 
be allowed based on consultation with the Steering Committee given the 
pharmacokinetic (PK) and safety objectives but such a patient should have been on 
the 125-mg dose at the end of their treatment period to ensure that they can tolerate 
the starting dose given the scope of the Phase Ib (Sections 4.1.1 and 4.1.2).

An additional exclusion criterion of no more than 1 prior line of endocrine-based 
therapy for Phase III patients was added for clarity and to maintain a more 
homogeneous patient population (Section 4.1.2 and Figure 3).

The HBV-related testing requirements were clarified (Section 4.1.2).

The exclusion criterion related to hypersensitivity to study treatment was updated for 
clarification and completeness (Section 4.1.2).

The stratification factor “prior CDK4/6 inhibitor” was removed given new restrictions 
on prior CDK4/6 inhibitor in the eligibility criteria.  In consultation with the Steering 


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4/Protocol CO41012, Version 3
Committee, it was deemed less meaningful relative to the stratification factor 
“baseline liver metastasis,” which was selected to replace it (Section 4.2).

Text describing the pharmacy manual was added for completeness (Section 4.3 and 
associated subsections).

Clarification was added on taking the dose of ipatasertib/placebo (Section 4.3.2.1) 
and palbociclib (Section 4.3.2.2) at home on non-clinic visit days based on the 21/7 
dose schedule.

Text related to the medication diary was updated for consistency with other sections 
in the protocol and for clarification (Sections 4.5.2 and 4.3.2.5).

Text was added that primary prophylactic use of hematopoietic growth factors is not 
permitted, but may be considered for treating treatment-emergent events and for 
secondary prophylaxis (Sections 4.4.1 and 4.4.3).

Text was added to clarify use of live vaccines (Section 4.4.2). 

Fasting requirements were updated to require fasting also beyond the Cycle 6 Day 1 
visit to allow for more consistent characterization in particular of hyperglycemia 
throughout the entire treatment period given that hyperglycemia is an identified risk 
with ipatasertib and that laboratory values are regularly analyzed independently of 
AE terms by health authorities (Section 4.5.8, Appendices 1 and 3).

Text was added to clarify that re-escalation of palbociclib is not permitted, 
regardless of the dose level (Section 5.1.4.2).

Text was updated to clarify that palbociclib local prescribing information may require 
more rigorous dose adjustments than provided in the corresponding adverse event
management guideline tables (Section 5.1.4.5 and associated subsections).

It was clarified that management guidelines for elevated glucose values 
250 mg/dL apply regardless of fasting status (Section 5.1.4.5.2) and that 
guidelines for glucose values 500 mg/dL also apply to patients with life-threatening 
consequences (Table 4).

A clarifying footnote was added to the rash management guidance in Table 6 that 
the Sponsor will monitor the incidence of rash and may advise investigators to 
consider antihistamine prophylaxis (Section 5.1.4.5.4).

Guidance for resuming palbociclib for Grade 1 interstitial lung disease/pneumonitis 
was provided for completeness in Table 7 (Section 5.1.4.5.5).

In the hematologic toxicity management guidance (Table 9), text related to dose 
modifications for ipatasertib/placebo and palbociclib was revised to better reflect the 
safety profile of the 2 study treatments given that neutropenia is included under the 
Warnings and Precautions for palbociclib (IBRANCEU.S. Package Insert) and thus 
palbociclib is considered the primary cause for neutropenia. An additional footnote 
referencing Sections 5.1.4.1 and 5.1.4.2 (dose modifications for ipatasertib/placebo
and palbociclib) was added in Table 9 for clarification (Section 5.1.4.5.7).

The two back-up Medical Monitors were replaced (Section 5.4.1). 


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5/Protocol CO41012, Version 3

A clarification was added that after the end of the adverse event reporting period, 
only patients in the Phase III portion of the study will be followed for long-term 
survival (Section 5.6).

A new section was added to describe the implementation of a system to manage the 
quality of the study (Section 9.3).

Text was modified to clarify that Roche's global policy on data sharing does not 
have requirements that must be met before study results can be made available 
(Section 9.6).

Text was added throughout the schedules of assessments for clarification and to 
align with other sections of the protocol (Appendices 1 and 3).

The schedule of the PRO measures collected for Phase III patients was updated to 
better reflect the schedule of each of the PRO assessments (Appendix 1). 

The sampling window for post-dose PK samples for Phase III patients on Cycle 1, 
Day 1 and Cycle 1, Day 15 were updated and aligned with that on Cycle 2, Day 15 
so that PK can be compared between cycles more easily (Appendix 2).

The screening windows for patients in Phase Ib were updated for consistency with 
the remainder of the protocol (Appendix 3).

The sampling window for pre-dose PK samples was clarified, and the footnote was 
updated to provide clarification on the PK sampling timepoints (Appendix 4).

Samples of the new PRO measures, Brief Pain Inventory-Short Form “worst pain” 
item (BPI-SF) and the EORTC QLQ-BR23, were added as Appendix 10 and 
Appendix 12, respectively.
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.


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6/Protocol CO41012, Version 3
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 15
PROTOCOL SYNOPSIS .................................................................................... 16
1.
BACKGROUND .......................................................................................... 32
1.1
Background on HR+ Breast Cancer ...................................... 32
1.2
Background on Ipatasertib..................................................... 34
1.3
Background on Palbociclib .................................................... 35
1.4
Background on Fulvestrant.................................................... 36
1.5
Study Rationale and Benefit-Risk Assessment...................... 36
2.
OBJECTIVES AND ENDPOINTS ............................................................... 38
2.1
Efficacy Objectives ................................................................ 39
2.1.1
Primary Efficacy Objective..................................................... 39
2.1.2
Secondary Efficacy Objective................................................ 39
2.1.3
Exploratory Efficacy Objective............................................... 40
2.2
Safety Objectives................................................................... 41
2.2.1
Safety Objective .................................................................... 41
2.2.2
Exploratory Safety Objective ................................................. 41
2.3
Pharmacokinetic Objectives .................................................. 42
2.4
Biomarker Objective .............................................................. 42
3.
STUDY DESIGN......................................................................................... 43
3.1
Description of the Study......................................................... 43
3.1.1
Open-label Phase Ib Portion.................................................. 43
3.1.2
Randomized Phase III Portion............................................... 45
3.1.3
Goserelin Treatment in Pre- and Peri-
menopausal Women and Men............................................... 46
3.1.4
Key Study Parameters........................................................... 47
3.1.5
Length of Treatment and Discontinuation.............................. 47
3.1.6
Independent Data Monitoring Committee .............................. 47
3.1.7
Potential China Extension Cohort.......................................... 48
3.2
End of Study and Length of Study......................................... 48
3.3
Rationale for Study Design.................................................... 48


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3.3.1
Rationale for Ipatasertib Dose and Schedule ........................ 48
3.3.2
Rationale for Fulvestrant Dose and Schedule ....................... 49
3.3.3
Rationale for Palbociclib Dose and Schedule........................ 49
3.3.4
Rationale for Patient Population and Control 
Group..................................................................................... 50
3.3.5
Rationale for Analysis Groups ............................................... 51
3.3.6
Rationale for Skeletal-Related Events 
Assessments ......................................................................... 51
3.3.7
Rationale for Biomarker Assessments................................... 52
3.3.7.1
Rationale for Using Circulating Tumor DNA 
(ctDNA) for Examining Tri-AKT Status .................................. 52
3.3.7.2
Rationale for the Collection of Tissue Samples ..................... 52
3.3.7.3
Rationale for Collection of DNA (Blood) for 
Exploratory Whole Genome Sequencing............................... 53
3.3.7.4
Rationale for Safety Biomarker Analysis................................ 54
3.3.8
Rationale for the Pharmacokinetic Evaluation 
Schedule................................................................................ 54
3.3.9
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 55
3.3.10
Rationale for Potential China Extension Cohort..................... 56
4.
MATERIALS AND METHODS .................................................................... 56
4.1
Patients.................................................................................. 56
4.1.1
Inclusion Criteria.................................................................... 56
4.1.2
Exclusion Criteria................................................................... 60
4.2
Method of Treatment Assignment and Blinding..................... 64
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 65
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 65
4.3.1.1
Ipatasertib and Placebo......................................................... 65
4.3.1.2
Palbociclib ............................................................................. 65
4.3.1.3
Fulvestrant............................................................................. 66
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 66
4.3.2.1
Ipatasertib and Placebo......................................................... 66


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4.3.2.2
Palbociclib ............................................................................. 67
4.3.2.3
Fulvestrant............................................................................. 68
4.3.2.4
Goserelin ............................................................................... 68
4.3.2.5
Loperamide............................................................................ 68
4.3.3
Investigational Medicinal Product Accountability ................... 69
4.3.4
Continued Access to Ipatasertib............................................ 69
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 69
4.4.1
Permitted Therapy................................................................. 69
4.4.2
Cautionary Therapy ............................................................... 70
4.4.2.1
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 71
4.4.2.2
Herbal Therapies................................................................... 72
4.4.3
Prohibited Therapy, Foods, and Supplements....................... 72
4.4.4
Additional Restrictions ........................................................... 73
4.5
Study Assessments ............................................................... 73
4.5.1
Informed Consent Forms and Screening Log........................ 73
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 73
4.5.3
Physical Examinations........................................................... 74
4.5.4
Vital Signs.............................................................................. 74
4.5.5
ECOG Performance Status ................................................... 74
4.5.6
Tumor and Response Evaluations......................................... 74
4.5.7
Skeletal-Related Events Assessment.................................... 77
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 77
4.5.9
Electrocardiograms................................................................ 80
4.5.10
Patient-Reported Outcomes .................................................. 80
4.5.10.1
BPI-SF “Worst Pain” Item.................................................... 81
4.5.10.2
EORTC QLQ-C30.................................................................. 81
4.5.10.3
EORTC QLQ-BR23............................................................... 82
4.5.10.4
PRO-CTCAE ......................................................................... 82
4.5.10.5
EQ-5D-5L .............................................................................. 82
4.5.11
Samples for Whole Genome Sequencing.............................. 83


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4.5.12
Optional Tumor Biopsies ....................................................... 84
4.5.13
Optional Samples for Research Biosample 
Repository ............................................................................. 84
4.5.13.1
Overview of the Research Biosample Repository.................. 84
4.5.13.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 85
4.5.13.3
Sample Collection.................................................................. 85
4.5.13.4
Confidentiality........................................................................ 86
4.5.13.5
Consent to Participate in the Research 
Biosample Repository............................................................ 86
4.5.13.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 86
4.5.13.7
Monitoring and Oversight....................................................... 87
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 87
4.6.1
Study Treatment Discontinuation........................................... 87
4.6.2
Patient Discontinuation from the Study.................................. 88
4.6.3
Study Discontinuation............................................................ 89
4.6.4
Site Discontinuation............................................................... 89
5.
ASSESSMENT OF SAFETY....................................................................... 89
5.1
Safety Plan ............................................................................ 89
5.1.1
Risks Associated with Ipatasertib .......................................... 90
5.1.2
Risks Associated with Palbociclib.......................................... 90
5.1.3
Risks Associated with Fulvestrant ......................................... 90
5.1.4
Management of Patients Who Experience 
Adverse Events ..................................................................... 91
5.1.4.1
Dose Modification for Ipatasertib ........................................... 91
5.1.4.2
Dose Modification for Palbociclib........................................... 91
5.1.4.3
Dose Modification for Fulvestrant .......................................... 92
5.1.4.4
Treatment Interruption ........................................................... 92
5.1.4.5
Adverse Event Management Guidelines................................ 92
5.2
Safety Parameters and Definitions ...................................... 105
5.2.1
Adverse Events ................................................................... 106
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 106


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5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 107
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 108
5.3.1
Adverse Event Reporting Period ......................................... 108
5.3.2
Eliciting Adverse Event Information..................................... 108
5.3.3
Assessment of Severity of Adverse Events ......................... 108
5.3.4
Assessment of Causality of Adverse Events ....................... 109
5.3.5
Procedures for Recording Adverse Events.......................... 110
5.3.5.1
Injection Reactions .............................................................. 110
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 110
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 111
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 111
5.3.5.5
Abnormal Laboratory Values ............................................... 111
5.3.5.6
Abnormal Vital Sign Values ................................................. 112
5.3.5.7
Abnormal Liver Function Tests............................................ 113
5.3.5.8
Deaths ................................................................................. 113
5.3.5.9
Preexisting Medical Conditions............................................ 114
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer ................. 114
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 114
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse ........................................................ 115
5.3.5.13
Patient-Reported Outcome Data ......................................... 117
5.3.5.14
Safety Biomarker Data......................................................... 117
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 117
5.4.1
Emergency Medical Contacts.............................................. 118
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 118
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 118
5.4.2.2
Events That Occur after Study Drug Initiation...................... 118
5.4.3
Reporting Requirements for Pregnancies............................ 119
5.4.3.1
Pregnancies in Female Patients.......................................... 119
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 119


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5.4.3.3
Abortions ............................................................................. 120
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 120
5.5
Follow-Up of Patients after Adverse Events ........................ 120
5.5.1
Investigator Follow-Up......................................................... 120
5.5.2
Sponsor Follow-Up .............................................................. 120
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 121
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 121
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 121
6.1
Determination of Sample Size ............................................. 122
6.1.1
Type I Error Control............................................................. 122
6.1.2
Co-Primary Endpoint: Progression-Free Survival................ 122
6.2
Summaries of Conduct of Study.......................................... 123
6.3
Summaries of Treatment Group Comparability ................... 123
6.4
Efficacy Analyses ................................................................ 123
6.4.1
Co-Primary Efficacy Endpoint.............................................. 123
6.4.2
Secondary Efficacy Endpoints............................................. 124
6.4.2.1
Objective Response Rate.................................................... 124
6.4.2.2
Duration of Response.......................................................... 124
6.4.2.3
Clinical Benefit Rate ............................................................ 124
6.4.2.4
Overall Survival ................................................................... 124
6.4.2.5
Patient- Reported Outcomes (TTD of Pain; TTD 
of PF, RF, and GHS/QoL) ................................................... 125
6.4.3
Exploratory Efficacy Endpoints............................................ 125
6.4.3.1
Progression-Free Survival 2 ................................................ 125
6.4.3.2
Time to First Skeletal-Related Event ................................... 125
6.4.3.3
Exploratory Patient-Reported Outcome Analyses ............... 126
6.4.3.4
Investigator-Assessed PFS in Patients with 
Tri-AKT+ Tumor Tissue and PTEN Loss in 
Tumor Tissue....................................................................... 126
6.5
Safety Analyses................................................................... 127
6.5.1
Analyses of Exposure, Adverse Event, 
Laboratory, and Vital Sign Data........................................... 127


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6.5.2
Exploratory Safety Analysis of Patient-Reported 
Symptomatic Adverse Events:  PRO CTCAE 
Data..................................................................................... 127
6.6
Pharmacokinetic Analyses................................................... 128
6.7
Exploratory Biomarker Analyses.......................................... 128
6.8
Interim Analyses .................................................................. 128
6.8.1
Planned Interim Safety Analyses......................................... 128
6.8.2
Planned Interim Efficacy Analyses ...................................... 129
6.8.3
Optional Interim Analysis..................................................... 129
6.9
China Subpopulation Analyses (As Applicable)................... 130
7.
DATA COLLECTION AND MANAGEMENT ............................................. 130
7.1
Data Quality Assurance....................................................... 130
7.2
Electronic Case Report Forms............................................. 131
7.3
Source Data Documentation................................................ 131
7.4
Use of Computerized Systems ............................................ 132
7.5
Retention of Records........................................................... 132
8.
ETHICAL CONSIDERATIONS.................................................................. 132
8.1
Compliance with Laws and Regulations .............................. 132
8.2
Informed Consent................................................................ 132
8.3
Institutional Review Board or Ethics Committee.................. 134
8.4
Confidentiality...................................................................... 134
8.5
Financial Disclosure ............................................................ 135
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 135
9.1
Study Documentation .......................................................... 135
9.2
Protocol Deviations.............................................................. 135
9.3
Management of Study Quality ............................................ 135
9.4
Site Inspections ................................................................... 136
9.5
Administrative Structure....................................................... 136
9.6
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 136
9.7
Protocol Amendments ......................................................... 137
10. REFERENCES ......................................................................................... 138


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LIST OF TABLES
Table 1
Dose Reductions for Ipatasertib/Placebo (Exemplified by the 
Starting Dose of 300 mg) ............................................................ 91
Table 2
Dose Reductions for Palbociclib ................................................. 91
Table 3
Diarrhea Management Guidelines .............................................. 94
Table 4
Fasting Hyperglycemia Management Guidelines........................ 96
Table 5
Nausea and Vomiting Management Guidelines .......................... 97
Table 6
Rash Management Guidelines.................................................... 98
Table 7
Interstitial Lung Disease/Pneumonitis Management
Guidelines ................................................................................. 100
Table 8
Mucositis Management Guidelines ........................................... 101
Table 9
Management of Hematologic Toxicities .................................... 102
Table 10
Hepatotoxicity Management Guidelines.................................... 104
Table 11
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 109
Table 12
Causal Attribution Guidance ..................................................... 110
LIST OF FIGURES
Figure 1
Overview of Open-Label Phase Ib Portion.................................. 44
Figure 2
Dose Schedule for Open-Label Phase Ib Portion ....................... 45
Figure 3
Study Schema for Randomized Phase III Portion....................... 46
Figure 4
Dose Schedule for Randomized Phase III Portion...................... 46
LIST OF APPENDICES
Appendix 1
Schedule of Activities (Phase III Portion).................................. 145
Appendix 2
Schedule of Pharmacokinetic Samples (Phase III portion) ....... 152
Appendix 3
Schedule of Activities (Phase Ib Portion).................................. 153
Appendix 4
Schedule of Pharmacokinetic Samples (Phase Ib portion) ....... 159
Appendix 5
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale.............................................................................. 160
Appendix 6
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations.................................................... 161
Appendix 7
ASCO/CAP HER2 Test Guideline Recommendations.............. 163
Appendix 8
Examples of Strong and Moderate CYP3A Inhibitors and 
Strong CYP3A Inducers............................................................ 167
Appendix 9
Response Evaluation Criteria in Solid Tumors,  Version 1.1 
(RECIST v1.1)........................................................................... 168
Appendix 10
Brief Pain Inventory-Short Form “Worst Pain” Item (BPI-
SF) ............................................................................................ 178


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Appendix 11
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire Core 30 (EORTC 
QLQ-C30) ................................................................................. 179
Appendix 12
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire Breast Cancer Module 
23 (EORTC QLQ-BR23) .......................................................... 181
Appendix 13
National Cancer Institute Patient-Reported Outcomes 
Version of the Common Terminology Criteria for Adverse 
Events (NCI PRO-CTCAE) Items.............................................. 183
Appendix 14
European Quality of Life 5Dimension, 5-Level questionnaire
(EQ-5D-5L) Health Questionnaire............................................. 185


Ipatasertib—F. Hoffmann-La Roche Ltd
15/Protocol CO41012, Version 3
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IB/III STUDY OF IPATASERTIB PLUS 
PALBOCICLIB AND FULVESTRANT VERSUS 
PLACEBO PLUS PALBOCICLIB AND 
FULVESTRANT IN HORMONE RECEPTOR 
POSITIVE AND HER2 NEGATIVE LOCALLY 
ADVANCED UNRESECTABLE OR METASTATIC 
BREAST CANCER
PROTOCOL NUMBER:
CO41012
VERSION NUMBER:
3
EUDRACT NUMBER:
2019-001072-11
IND NUMBER:
133823
TEST PRODUCT:
Ipatasertib (RO5532961, GDC-0068), palbociclib, 
fulvestrant
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 retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the Sponsor.


Ipatasertib—F. Hoffmann-La Roche Ltd
16/Protocol CO41012, Version 3
PROTOCOL SYNOPSIS
TITLE:
A PHASE IB/III STUDY OF IPATASERTIB PLUS PALBOCICLIB 
AND FULVESTRANT VERSUS PLACEBO PLUS PALBOCICLIB 
AND FULVESTRANT IN HORMONE RECEPTOR POSITIVE AND 
HER2 NEGATIVE LOCALLY ADVANCED UNRESECTABLE OR 
METASTATIC BREAST CANCER
PROTOCOL NUMBER:
CO41012
VERSION NUMBER:
3
EUDRACT NUMBER:
2019-001072-11
IND NUMBER:
CO41012
TEST PRODUCT:
Ipatasertib (RO5532961, GDC-0068), palbociclib, fulvestrant
PHASE:
III
INDICATION:
HR-positive/HER2-negative locally advanced unresectable or 
metastatic breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
The open-label Phase Ib portion of this study will evaluate the safety and pharmacokinetics of 
ipatasertib in combination with palbociclib and fulvestrant to identify a dose of ipatasertib that 
can be combined with palbociclib and fulvestrant in the Phase III portion. 
The randomized Phase III portion of this study will evaluate the efficacy, safety, and 
patient-reported outcome (PRO) objectives of ipatasertib palbociclib fulvestrant compared 
with placebo palbociclib fulvestrant in patients with hormone receptorpositive (HR+) human 
epidermal growth factor receptor 2 negative (HER2-), locally advanced unresectable or 
metastatic breast cancer who had relapsed during adjuvant endocrine therapy or progressed 
during the initial 12 months of first-line endocrine therapy in locally advanced unresectable or 
metastatic breast cancer.  
In this protocol, the term "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., ipatasertib/placebo, palbociclib, and fulvestrant). Treatment 
with placebo only applies to the Phase III portion of this study.
In this study, when describing the different analysis populations and endpoints, Tri-AKT positive 
(Tri-AKT+) corresponds to the presence of PIK3CA/AKT1/PTEN alterations. 
Efficacy objectives are applicable for only the randomized Phase III portion of this study as 
described below.
Primary Efficacy Objective
The primary efficacy objective for the randomized Phase III portion of this study is to evaluate 
the efficacy of ipatasertib palbociclib fulvestrant compared with 
placebo palbociclib fulvestrant on the basis of the following co-primary endpoints:

Progression-free survival (PFS) in intent-to-treat (ITT) patients, defined as the time from 
randomization to the first occurrence of disease progression as determined by the 
investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), or death from any cause, whichever occurs first 


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
Progression-free survival (PFS) in patients with Tri-AKT+ tumors, as defined by baseline 
ctDNA, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator according to RECIST v1.1, or death from any 
cause, whichever occurs first
Secondary Efficacy Objective
The secondary efficacy objective for the randomized Phase III portion of this study is to evaluate 
the efficacy of ipatasertibpalbociclibfulvestrant compared with 
placebopalbociclibfulvestrant on the basis of the following endpoints both in the ITT 
population and in patients with Tri-AKT+ tumors, as defined by baseline ctDNA:

Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) on two consecutive occasions 4 weeks apart, as 
determined by the investigator according to RECIST v1.1

Duration of objective response (DOR), defined as the time from the first occurrence of a 
documented objective response to the first occurrence of disease progression as 
determined by the investigator according to RECIST v1.1, or death from any cause, 
whichever occurs first

Clinical benefit rate (CBR), defined as the proportion of patients who have a CR or PR, or 
stable disease for at least 24 weeks, as determined by the investigator according to 
RECIST v1.1

Overall survival (OS), defined as the time from randomization to death from any cause

Time to deterioration (TTD) in severity of pain, defined as the time from randomization to 
the first documentation of a 2-point or more increase from baseline on the “worst pain” 
item from the Brief Pain Inventory-Short Form (BPI-SF)

TTD in presence and interference of pain, defined as the time from randomization to the 
first documentation of a 10-point or more increase from baseline in the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 
30 (EORTC QLQ-C30) pain scale (items 9 and 19)

TTD in physical functioning (PF), role functioning (RF), and Global Health Status 
(GHS)/Quality of Life (QoL) defined as the time from randomization to the first
documentation of a 10-point or more decrease from baseline in the following scales of the 
EORTC QLQ-C30:  PF, RF, and GHS/QoL
Exploratory Efficacy Objective
The exploratory efficacy objective for the randomized Phase III portion of this study is to 
evaluate the efficacy of ipatasertibpalbociclibfulvestrant compared with 
placebopalbociclibfulvestrant on the basis of the following endpoints both in the ITT patients 
and patients with Tri-AKT+ tumors, as defined by baseline ctDNA:

Mean and mean changes from baseline scores in all functions (physical, role, cognitive, 
emotional, and social), GHS/QoL, and disease/ treatment-related symptoms, as measured 
by the scales of the EORTC QLQ-C30 and the EORTC Breast Cancer Module 23 
Questionnaire (QLQ-BR23)

Health utility and visual analog score (VAS) of the European Quality of Life 5-Dimension 
5-Level (EQ-5D-5L) questionnaire for pharmacoeconomic modeling 

PFS2, defined as the time from randomization to second occurrence of objective disease 
progression through the use of RECIST v1.1, or death from any cause, whichever occurs 
first

Time to first skeletal–related event (SRE), defined as the time from randomization to the 
first occurrence of an SRE (an SRE is a pathologic fracture, radiation therapy to bone, 
surgery to bone, or spinal cord compression) 


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In addition, this study will evaluate the efficacy of ipatasertibpalbociclibfulvestrant compared 
with placebopalbociclibfulvestrant on the basis of the following endpoints in patients with 
Tri-AKT+ tumor tissue and PTEN loss in tumor tissue:

PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by the investigator according to RECIST v1.1, or death from any cause, 
whichever occurs first
Safety Objectives
Safety objectives are applicable for both the Phase Ib portion and the randomized Phase III 
portion of this study. The same endpoints as described below will be used for both portions.
Safety Objective
The safety objective for the Phase Ib portion of this study is to characterize the safety of 
combining ipatasertib with palbociclibfulvestrant using endpoints listed below for the Phase III 
portion. 
The safety objective for the randomized Phase III portion of this study is to evaluate the safety 
of ipatasertibpalbociclibfulvestrant compared with placebopalbociclibfulvestrant in all 
randomized patients as well as patients with Tri-AKT+ tumors, as defined by baseline circulating 
tumor DNA (ctDNA), who received at least one dose of study treatment on the basis of the 
following endpoints:

Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Exploratory Safety Objective
The exploratory safety objective for the randomized Phase III portion of this study is to evaluate 
patient-reported symptomatic adverse events of ipatasertibpalbociclibfulvestrant compared 
with placebopalbociclibfulvestrant in all randomized patients who received at least one dose 
of study treatment, on the basis of the following endpoints:

Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptomatic treatment toxicities (i.e., diarrhea, nausea, vomiting, 
decreased appetite, fatigue, mouth sores, and rash symptoms and an additional item 
regarding the overall bother experienced due to side effects of treatment), as measured by 
the NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) instrument

Change from baseline in symptomatic treatment toxicities, as measured by the 
PRO-CTCAE
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives are applicable for both the open-label Phase Ib portion 
and the randomized Phase III portion of this study, unless otherwise specified below.  The same 
endpoints, as described below, will be used for both portions, unless otherwise specified.  
The PK objective for the open-label Phase Ib portion is to evaluate the effect of palbociclib, a 
weak time-dependent inhibitor of CYP3A, on the PK profile of ipatasertib. 
The PK objective for the Phase III portion is to characterize the PK profiles of ipatasertib and its 
metabolite (G-037720) in combination with palbociclib and fulvestrant on the basis of the 
following endpoint:

Plasma concentration of ipatasertib and its metabolite, G-037720, at specified timepoints for 
analysis using population PK methodology
The exploratory PK objectives for this study are as follows:

To evaluate palbociclib trough concentrations and the effect of ipatasertib on palbociclib 
exposures in the open-label Phase Ib portion


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19/Protocol CO41012, Version 3

To evaluate potential relationships between drug exposure and the efficacy and safety of 
ipatasertibpalbociclibfulvestrant in the randomized Phase III portion based on the 
following endpoints:
-
Relationship between plasma concentration or PK parameters for ipatasertib and 
efficacy endpoints
-
Relationship between plasma concentration or PK parameters for ipatasertib and safety 
endpoints
Biomarker Objective
The exploratory biomarker objective for the open-label Phase Ib portion is to evaluate changes 
in plasma ctDNA levels.
The exploratory biomarker objectives for the randomized Phase III portion of this study are as 
follows:

Evaluate the effect of Tri-AKT status in tissue or plasma on treatment benefit to 
ipatasertibpalbociclibfulvestrant compared with placebopalbociclibfulvestrant 

Identify and evaluate predictive or prognostic biomarkers associated with disease activity 
status or response to treatment with ipatasertibpalbociclibfulvestrant 

Identify possible mechanisms of resistance to ipatasertibpalbociclibfulvestrant through 
the comparative analysis of potential biomarkers in pretreatment and post-progression 
biopsy tissue samples and in blood

Evaluate safety and pharmacodynamics biomarkers that may lead to improved monitoring 
and to provide evidence of activity of ipatasertibpalbociclibfulvestrant, respectively

Evaluate the relationship between tissue-based and blood-based biomarkers and patient 
clinical features (e.g., baseline features) and outcome (e.g., duration of PFS)

To increase the knowledge and understanding of disease biology and drug safety on the
basis of the following endpoint: 
-
Relationship between biomarkers in blood and tumor tissue and efficacy, safety, PK, or 
other biomarker endpoints including biomarker relevant therapies in development
Study Design
Description of Study
Study CO41012 is a Phase III, randomized, multicenter, international, double-blind, 
placebo-controlled clinical study with an initial open-label, Phase Ib, safety portion.  The 
open-label Phase Ib portion is intended to evaluate the safety of the triplet combination and to 
further characterize the potential drug-drug interaction between ipatasertib and palbociclib and 
to determine the ipatasertib dose to be combined with palbociclib and fulvestrant.  The 
randomized Phase III portion is designed to compare the efficacy, as measured by PFS, and 
safety of ipatasertib palbociclib fulvestrant with that of placebo palbociclib fulvestrant in 
patients with HR+ HER2- locally advanced unresectable or metastatic breast cancer who 
relapsed during adjuvant endocrine therapy or progressed during the initial 12 months of 
first-line endocrine therapy in locally advanced unresectable or metastatic breast cancer. 
Open-label Phase Ib Portion
Patients in the open-label Phase Ib portion are required to fulfill the same eligibility criteria as 
those in the randomized Phase III portion unless otherwise specified.  Approximately 
10 patients will initially be treated with a starting dose of 300 mg ipatasertib for 5-7 days as a 
single agent before palbociclib and fulvestrant will be started on Cycle 1, Day 1 (see additional 
details on the dose schedule below).  All patients will be followed to at least Cycle 2, Day 15 
before the initial safety review will be triggered. PK samples will be collected up to Cycle 3,
Day 15 and results will be included where available at the time of the safety review.  If multiple 
patients come off prior to Cycle 2, Day 15 for reasons other than toxicity, the Sponsor may elect 
to replace the patients. The internal safety review will be conducted by the Sponsor and will 
include members of the study team including, but not limited to, the study Medical Monitor, 
Safety Scientist, and Clinical Pharmacologist.  Further enrollment will be halted until after the 
internal safety review has been completed and a recommendation has been made to either 


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expand the original cohort or explore an alternative ipatasertib dose, if warranted.  In particular, 
if based on internal safety review, the 300 mg ipatasertib dose is comparable to the target 
400-mg dose based on PK data and provides acceptable tolerability relative to historical data in 
ipatasertib clinical studies taking into consideration the palbociclib safety profile, the 300-mg 
dose cohort will be expanded further by approximately 510 patients. These additional patients 
may be able to start all three study drugs on Cycle 1, Day 1 if warranted by the initial PK data. 
On the other hand, if the 300-mg dose results in unacceptable toxicity, and if ipatasertib 
exposure is considerably above the target 400-mg dose equivalent, a lower dose will be 
explored.  Depending on the safety and PK data, the Sponsor may also further explore the 
400 mg starting dose used in other ipatasertib studies.  For the second dose level, safety and 
PK data for up to 10 patients is expected to be sufficient to support the dose decision; however, 
the Sponsor may expand enrollment by approximately 510 patients if deemed necessary 
based on internal safety review.  
Patients will start with a 57 day run-in of single-agent ipatasertib (300-mg tablet dose once 
daily [QD]) prior to Cycle 1, Day 1. The single-agent run-in will allow ipatasertib to reach 
steady-state on Cycle 1, Day 1 and enable characterization of the potential drug-drug 
interaction between ipatasertib and palbociclib.  For the first cycle, ipatasertib will be 
administered continuously for 2628 days given the Day -7 to Day -5 window for the initial 
single-agent ipatasertib run-in; however, starting with Cycle 2, Day 1 ipatasertib will be taken 
orally (PO) QD on Days 121 of each 28-day cycle.  
Starting on Cycle 1, Day 1, palbociclib 125 mg (capsule/tablet) will be taken PO QD on 
Days 121 of each 28-day cycle.  Fulvestrant 500 mg will be administered by intramuscular (IM)
injection on Cycle 1, Days 1 and 15 and then on Day 1 of each subsequent 28-day cycle.  
Randomized Phase III Portion
Enrollment to the randomized Phase III portion will be initiated only after the Sponsor has 
confirmed a dose of ipatasertib that can be combined with palbociclib and fulvestrant based on 
the internal safety review of the Phase Ib data. If no appropriate dose can be identified, for 
example if the combination is associated with high discontinuation rates due to unacceptable 
toxicity, the Phase III portion will not be initiated. 
In the Phase III portion, approximately 340 patients will be randomized in a 1:1 ratio to either 
ipatasertib palbociclib fulvestrant or placebo palbociclib fulvestrant.

Ipatasertib Arm:  Ipatasertib tablet dose taken PO QD on Days 121 of each 28-day cycle 
beginning at Cycle 1, Day 1 and palbociclib 125-mg capsule/tablet dose taken PO QD on 
Days 121 of each 28-day cycle 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. The ipatasertib dose will be established in the Phase Ib portion.  

Control Arm:  Placebo taken PO QD on Days 121 of each 28-day cycle beginning at 
Cycle 1, Day 1 and palbociclib 125-mg capsule/tablet dose taken PO QD on Days 121 of 
each 28-day cycle 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 
Goserelin Treatment in Pre- and Peri-menopausal Women and Men
In both portions of the trial, pre- or peri-menopausal women must have started treatment with 
goserelin or an alternative luteinizing hormone releasing hormone (LHRH) agonist at least 
14 days prior to first dose of study treatment. If patients have received an alternative LHRH 
agonist prior to study entry, it is recommended that they switch to goserelin for the duration of 
the trial, whenever possible. For men, treatment with goserelin or alternative LHRH agonist 
therapy is recommended beginning at least 14 days prior to first dose of study treatment and 
continuing for the duration of study treatment.
Key Study Parameters
Prior to enrollment but after signing the informed consent form, patients enrolled in the Phase III 
portion will have the Tri-AKT ctDNA test done by the central laboratory next generation
sequencing (NGS) assay within 6 weeks of first dose of study treatment.  For patients enrolled 
in the Phase Ib portion, the test may be performed after enrollment.  A valid result (Phase III 
only) will be required for patient stratification and therefore patients whose ctDNA samples have 
invalid test results will not be permitted to enroll in the Phase III portion of the study.  


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21/Protocol CO41012, Version 3
Patients must have measurable disease per RECIST v1.1.  Primary endpoint is 
investigator-assessed PFS (Phase III).  Tumor assessments will be conducted as outlined in 
the schedule of assessments.
Number of Patients
Approximately 370 patients with HR+ HER2- locally advanced unresectable or metastatic breast 
cancer will be enrolled overall in this study in both the Phase Ib and the global enrollment 
portion of the Phase III.  After completion of the global enrollment phase, additional patients 
may be enrolled in an extended China enrollment phase.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Histologically documented HR+ HER2- adenocarcinoma of the breast that is locally 
advanced or metastatic and is not amenable to surgical or local therapy with curative intent

Documented estrogen receptor and/or progesterone receptor positivity defined as 1% of 
tumor cell nuclei immunoreactive to the respective hormonal receptor based on most recent 
evaluable tumor biopsy as assessed locally 

Documented HER2- as assessed locally based on most recent evaluable tumor biopsy 
defined as immunohistochemistry (IHC) score 0/1+ or an IHC score of 2accompanied by
a negative fluorescence, chromogenic, or silver in situ hybridization (FISH/CISH/SISH) 
indicating the absence of HER2 gene amplification, or a HER2/CEP17 ratio of 2.0

Either male 
OR

Postmenopausal, defined as:
-
Age 60 years -OR-
-
Age 60 years AND have undergone bilateral oophorectomy, medically confirmed 
ovarian failure -OR-
-
Age 60 years AND have had cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause and have serum levels of 
estradiol and follicle-stimulating hormone within the laboratory’s reference range for 
postmenopausal females
OR 

Pre- or peri-menopausal and amenable to being treated with the LHRH agonist goserelin 
Patients must have started treatment with goserelin or an alternative LHRH agonist at 
least 14 days prior to first dose of study treatment.  If patients have received an 
alternative LHRH agonist prior to study entry, it is recommended that they switch to 
goserelin for the duration of the trial, whenever possible. 

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs as defined below:
Women must remain abstinent or use non-hormonal contraceptive methods with a 
failure rate of 1% per year during the treatment period and for 90 days after the final 
dose of study treatment (or longer if required per the local prescribing information).
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 


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22/Protocol CO41012, Version 3
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations.
Examples of non-hormonal contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, and copper intrauterine devices.
Hormonal contraceptive methods may be used in accordance with specific country and 
local requirements for patients with breast cancer. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
contraceptive methods, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during 
the treatment period and for 6 months after the final dose of study treatment (or 
longer if required per the local prescribing information).  Men must refrain from 
donating sperm during this same period.
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period and for 90 days after the final dose of study treatment (or longer if 
required per the local prescribing information) to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure.  If required per local 
guidelines or regulations, locally recognized adequate methods of contraception and 
information about the reliability of abstinence will be described in the local Informed 
Consent Form.

Patients must have experienced radiologic/objective relapse during adjuvant endocrine 
therapy or radiologic/objective disease progression during the initial 12 months of first-line 
(1L) endocrine therapy in locally advanced unresectable or metastatic breast cancer 
Up to 20% of patients enrolled in the Phase III portion may have received a CDK4/6 
inhibitor as part of their neoadjuvant/adjuvant endocrine therapy.  
If a CDK4/6 inhibitor was included as part of a neoadjuvant/adjuvant therapy, relapse 
must be 12 months since completion of the CDK4/6 inhibitor portion of the 
neoadjuvant/adjuvant therapy.
Phase III portion only: Prior CDK4/6 inhibitor is not permitted for locally advanced 
unresectable or metastatic breast cancer.  
Phase Ib portion only: Prior CDK4/6 inhibitor is permitted and if previously treated 
with palbociclib, patient should have been on the 125-mg dose at the end of their 
palbociclib treatment period.

Radiologic/objective evidence of recurrence or progression to the most recent systemic 
therapy for breast cancer

Patients for whom endocrine-based therapy (e.g., palbociclib and 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.

At least one measurable lesion via RECIST v1.1 
Patients with bone only disease are not eligible even if a bone lesion qualifies as a 
measurable lesion. 


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Bone lesions are generally followed as non-target lesions.  However, lytic bone lesions 
or mixed lytic–blastic lesions (unless previously irradiated), with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
computed tomography (CT) or magnetic resonance imaging (MRI) may be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.  Blastic bone lesions, however, are non-measurable.
Previously irradiated lesions (other than bone) may be considered as measurable 
disease only if progressive disease has been unequivocally documented at that site 
since radiation.  

Have adequate organ and marrow function as defined below:
-
ANC 1500 cells/L
-
Hemoglobin 9 g/dL 
-
Platelet count 100,000/L
-
AST and ALT 2.5 upper limit of normal (ULN); with the following exception: 
Patients with liver or bone metastases may have AST and ALT 5 ULN.
-
Alkaline phosphatase 2 ULN (5 ULN if liver metastases present; 7 ULN if 
bone metastases present)
-
Total bilirubin 1.5 ULN (3 x ULN if hyperbilirubinemia is due to Gilbert’s syndrome)
-
Serum albumin 3.0 g/dL
-
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min as calculated using 
the method standard for the institution
-
Fasting glucose 150 mg/dL and hemoglobin A1c (HbA1c) 7.5%
-
PTT (or aPTT) and INR 1.5 ULN (except for patients receiving anticoagulation 
therapy)
Patients receiving heparin treatment should have a PTT (or aPTT) between 
1.5 and 2.5 ULN (or patient value before starting heparin treatment).  Patients 
receiving coumarin derivatives should have an INR between 2.0 and 3.0 assessed in 
two consecutive measurements 1 to 4 days apart.

Life expectancy 6 months

Resolved or stabilized toxicities resulting from previous therapy to grade 1
An ongoing Grade 2 non-hematologic toxicity related to the most recent treatment 
regimen may be permitted with approval from the Sponsor based on consultation with 
the Medical Monitor (ongoing toxicities alopecia, neuropathy, and hot flashes do not 
require Sponsor approval)

Phase III portion only:  Consent to provide tumor specimen from the most recently collected, 
available tumor tissue (formalin-fixed, paraffin-embedded [FFPE] block [preferred] or a 
minimum of 12 slides containing unstained, freshly cut, serial sections)
Cytologic or fine-needle aspiration samples and tumor tissue from bone metastases 
are not acceptable.  Alternatively, a newly collected tumor tissue sample may be 
provided.  

Phase III portion only: Valid Tri-AKT ctDNA test result by the central laboratory NGS assay 
within 6 weeks prior to enrollment

For patients enrolled in the China extension portion (if opened) of the Phase III:  current 
resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
90 days after the final dose of study treatment (or longer if required per the local prescribing 
information).


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Women of childbearing potential must have a negative serum pregnancy test result 
within 96 hours of first dose of study treatment. Alternatively, if a negative serum 
pregnancy test was obtained within 7 days of first dose of study treatment, it needs to 
be confirmed by a negative urine pregnancy test on the day of the first administration of 
study treatment prior to dosing.  

Prior treatment with fulvestrant or other SERDs, regardless of treatment setting

Prior treatment with PI3K inhibitor (such as alpelisib, taselisib, or buparlisib), mTOR inhibitor 
(such as everolimus) or AKT inhibitor (such as ipatasertib or capivasertib), regardless of 
treatment setting

Phase III portion only:  Prior treatment with CDK4/6 inhibitor for locally advanced 
unresectable or metastatic breast cancer

Concurrent hormone replacement therapy

Prior treatment with a cytotoxic chemotherapy regimen for metastatic breast cancer
Note: there is no restriction on the number of prior cytotoxic chemotherapy regimens in 
the neoadjuvant or adjuvant setting

Phase III portion only:  No more than one prior line of endocrine-based therapy for locally 
advanced unresectable or metastatic breast cancer 

Treatment with approved or investigational cancer therapy within 14 days prior to first dose 
of study treatment 
Local radiotherapy with palliative intent to non-target sites may be allowed within 
14 days prior to first dose of study treatment if not feasible earlier and if discussed with 
the Medical Monitor (however, once irradiated, bone lesions are generally no longer 
evaluable). 

History of or known presence of brain or spinal cord metastases 
Patients with leptomeningeal carcinomatosis will be excluded. 

Uncontrolled pleural effusion, pericardial effusion, or ascites, as judged by the investigator 

Uncontrolled tumor-related pain, as judged by the investigator 
Patients requiring narcotic pain medication must be on a relatively stable regimen at 
study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to first dose 
of study treatment. 
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to first dose of study treatment (however, once irradiated, lesions are 
generally no longer evaluable)

Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy 
Patients who are receiving bisphosphonate therapy specifically to prevent/treat skeletal 
events (e.g., bone metastasis, osteoporosis) and who do not have a history of clinically 
significant hypercalcemia are eligible. 

Nonstudy-related minor surgical procedures 5 days or major (invasive) surgical 
procedure 14 days prior to first dose of study treatment. 
Patient must have sufficiently recovered from surgery and be stable, and wound 
healing must have occurred.

History of Type I or Type II diabetes mellitus requiring insulin 
Patients who are on a stable dose of oral diabetes medication 2 weeks prior to 
initiation of study treatment are eligible for enrollment.  Patients must meet the 


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laboratory eligibility criteria for fasting blood glucose and HbA1c as outlined in the 
inclusion criteria.

History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis) 

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia

Patients with active (chronic or acute) hepatitis C virus (HCV) at screening
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
is negative for HCV RNA.
Patients receiving anti-viral therapy for HCV are not eligible

Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B 
surface antigen (HBsAg) test or a positive quantitative HBV DNA test at screening 
If a patient has a negative HBsAg test and a positive total hepatitis B core antibody 
(HBcAb) test, a quantitative HBV DNA test must be negative to be eligible.
Patients receiving anti-viral therapy for HBV are not eligible.

Known HIV infection

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
judgment

Active infection requiring systemic anti-microbial treatment (including antibiotics, 
anti-fungals, and anti-viral agents) 

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease 
or condition that contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment complications

History of malignancy other than breast cancer within 5 years prior to screening with the 
following exceptions:
-
Appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer, 
-
Other malignancies where the patient has undergone potentially curative therapy with no 
evidence of disease and are deemed by the treating physician to have a recurrence rate 
of 5% at 5 years.

History of clinically significant cardiovascular dysfunction, including the following:
-
History of stroke or transient ischemic attack within 6 months prior to first dose of study
treatment
-
History of myocardial infarction within 6 months prior to first dose of study treatment
-
New York Heart Association Class III or IV cardiac disease
-
Unstable arrhythmias, active ventricular arrhythmia requiring medication, or unstable
angina
-
Congenital long QT syndrome or screening QT interval corrected using Fridericia's 
formula (QTcF) 480 milliseconds based on the mean value of the triplicate ECGs
-
History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion (including complete left bundle branch block, second- or third-degree heart block, 
or evidence of prior myocardial infarction)

Presence of any other condition that may have increased the risk associated with study 
participation or may have interfered with the interpretation of study results, and, in the 
opinion of the investigator, would have made the patient inappropriate for entry into the 
study.


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
Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment

Malabsorption syndrome or other condition that would interfere with enteral absorption

Inability or unwillingness to swallow pills or receive intramuscular injections

Known or possible hypersensitivity to any of the study treatments, or to goserelin or 
alternative LHRH agonist (if applicable), including any excipients
End of Study
The end of this study is defined as the date when the last patient last visit occurs (i.e., the date 
at which the last data point required for statistical analysis or safety follow-up is received from 
the last patient, whichever occurs later).  In addition, the Sponsor may decide to terminate the 
study or OS follow-up at any time.
Length of Study
Provided the Phase III portion is initiated, the total length of the global study, from screening of 
the first patient to the end of the study, is expected to be approximately 64 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal products (IMPs) for this study are ipatasertib (RO5532961) or its 
placebo (in the randomized Phase III portion of the study), palbociclib, and fulvestrant.
Ipatasertib and Placebo
For patients enrolled in the Phase Ib portion only, 300 mg ipatasertib will be open label and will 
be administered PO QD in the clinic on Day -7 to Day -5, on Cycle 1 Day 1, on each 
subsequent cycle visit, and will be taken at home on non-clinic visit days based on the 21/7 dose 
schedule.  Ipatasertib will be administered approximately 6 hours prior to palbociclib and 
fulvestrant to enable collection of post-dose samples, that is, palbociclib and fulvestrant will be 
administered after the PK sampling of ipatasertib for Cycle 1, Day 1 is completed.  Starting from 
Cycle 1, Day 2, palbociclib will be given together with ipatasertib.  For the first cycle, ipatasertib 
will be administered continuously for 26 to 28 days given the Day -7 to Day -5 window for the 
start of the single-agent ipatasertib run-in; however, starting with Cycle 2, Day 1 ipatasertib will 
be taken orally once daily on Days 121 of each 28-day cycle.
In the randomized Phase III portion of the study, ipatasertib/placebo is given orally QD on 
Days 121 of each 28-day cycle at the dose confirmed in the Phase Ib portion.  
Ipatasertib/placebo will be administered in the clinic on Cycle 1 Day 1 and on each subsequent 
cycle visit; it will be taken at home on non-clinic visit days based on the 21/7 dose schedule. 
Palbociclib
In both open-label Phase Ib and the randomized Phase III portion of this study, palbociclib is 
given PO QD on Days 121 of each 28-day cycle.  Palbociclib will be administered in the clinic 
on Cycle 1 Day 1 and each subsequent cycle visit and will be taken at home on non-clinic visit 
days based on the 21/7 dose schedule.  Palbociclib should be taken at approximately the same 
time each day. Palbociclib capsules are taken with food to reduce the intersubject variability of 
palbociclib exposure (IBRANCE® U.S. Package Insert).  Palbociclib tablets, in contrast, may be 
taken with or without food (refer to the local prescribing information for additional details).
Fulvestrant
Fulvestrant 500 mg will be administered in the clinic as two intramuscular injections of 250 mg 
each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day cycle. Refer to the local 
prescribing information for more details.
For patients enrolled in the Phase Ib portion, it is recommended that fulvestrant be administered 
prior to the oral medications, ipatasertib and palbociclib, during all clinic visits following Cycle 1, 
Day 1. In contrast, on Cycle 1, Day 1, ipatasertib is administered first.  For patients enrolled in 


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the Phase III portion, it is recommended that fulvestrant be administered prior to the oral 
medications, ipatasertib/placebo and palbociclib, during all clinic visits.
Non-Investigational Medicinal Products
Goserelin is a non-IMP in this study for pre- or peri-menopausal women who must have started 
treatment with goserelin or an alternative LHRH agonist at least 14 days prior to first dose of 
study treatment. For men, treatment with goserelin or alternative LHRH agonist therapy is 
recommended beginning at least 14 days prior to first dose of study treatment and continuing 
for the duration of study treatment.  If patients have received an alternative LHRH agonist 
prior to study entry, it is recommended that they switch to goserelin for the duration of the trial, 
whenever possible.  Every effort should be made to administer goserelin or alternative LHRH 
agonist as applicable on site at the time of fulvestrant administration as applicable in order to 
minimize the number of clinic visits. Patients may self-administer goserelin or alternative LHRH 
agonist as applicable at home per local standard of care if the administration does not coincide 
with a clinic visit. In that case, patients will complete a diary.
Loperamide is a non-IMP in this study.  All patients should receive loperamide (2 mg PO twice a 
day [BID] or 4 mg QD) as prophylaxis for diarrhea upon start of study treatment through the first 
cycle if allowed by local guidance.  Investigators are encouraged to continue this dosing for the 
remainder of the study; the prophylaxis dose may be adjusted as necessary, using their 
discretion based on clinical judgment and per local guidance.
Statistical Methods
Primary Analysis
The primary analysis of co-primary endpoint of PFS will take place when approximately 98 PFS 
events have occurred in patients with Tri-AKT+ tumors, as defined by baseline ctDNA and 
approximately 180 PFS events have occurred in ITT patients, whichever occurs later, on the 
basis of the following assumptions:

1:1 randomization ratio

Two-sided significance level of 4% and at least 80% power for testing PFS in patients with 
Tri-AKT+ tumors, as defined by baseline ctDNA where median PFS is 10 months in the 
placebo palbociclib fulvestrant arm and 18 months in the 
ipatasertib palbociclib fulvestrant arm (hazard ratio 0.56)

Two-sided significance level of 1% and at least 80% power for testing PFS in ITT patients 
where median PFS is 12 months in the placebo palbociclib fulvestrant arm and 
20 months in the ipatasertib palbociclib fulvestrant arm (hazard ratio 0.60)  

An annual loss-to-follow-up rate of 5% for both arms

No interim analysis of PFS
The enrollment duration is projected to be approximately 14 months from the first patient 
enrolled in the randomized Phase III portion of the study.  With these assumptions, the analysis 
of the co-primary endpoint of PFS is projected to occur approximately 40 months after the first 
patient enrolled in the randomized Phase III portion of the study. In patients with Tri-AKT+ 
tumors, as defined by baseline ctDNA, it is projected that the largest HR deemed to be 
statistically significant at 4% level will be approximately 0.66 (with median PFS improvement 
from 10 months to 15.2 months). In ITT patients, it is predicted that there will be approximately 
201 PFS events which allows for approximately 85% power for testing the assumed median 
PFS improvement from 12 to 20 months, and the projected largest HR deemed to be 
statistically significant at 1% level will be approximately 0.70 (with median PFS improvement 
from 12 months to 17.2 months).
Determination of Sample Size  
This is a Phase III, randomized, multicenter, international, double blind, placebo controlled 
clinical study with an initial open-label Phase Ib portion. In the randomized portion of the study, 
approximately 340 patients will be enrolled and randomized in a 1:1 ratio to the experimental 
arm (ipatasertib palbociclib fulvestrant) and control arm (placebo palbociclib fulvestrant), 
including approximately 153 patients with Tri-AKT+ tumors, as defined by baseline ctDNA, 
assuming a prevalence rate of 45% for Tri-AKT+ status. 


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Interim Analyses
This study includes an initial open-label Phase Ib safety portion with internal Safety Review. 
An external iDMC will be formed to evaluate safety data during the randomized Phase III portion 
of the study approximately every 6 months from the first patient randomized until the time of the 
primary analysis of PFS.  The Sponsor will be blinded until the PFS primary analysis.
In the absence of extenuating circumstances, accrual will not be halted during the randomized 
Phase III portion of the study while the interim safety analysis is conducted. An iDCC will 
prepare all summaries and analyses for the iDMC’s review. The safety summaries will include 
but not limit to demographic data, adverse events, serious adverse events, and relevant 
laboratory data. Members of the iDMC will be external to the Sponsor and will follow a charter 
that outlines their roles and responsibilities. Any outcomes of the iDMC’s reviews on the safety 
and benefit-risk balance that affect study conduct will be communicated in a timely manner to 
the investigators for notification of IRB/ECs and competent authorities as required. A detailed 
plan will be included in the iDMC Charter.
Following the data review, the iDMC will provide a recommendation to the Sponsor whether to 
continue the study, amend the protocol, or stop the study. The final decision will rest with the 
Sponsor. In addition, the Sponsor may request ad-hoc meetings of the iDMC at any time during 
the study to review ongoing safety summary data.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
1L
first line
2L
second line
AESI
adverse event of special interest
AI
aromatase inhibitor
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AUC
area under the concentration-time curve
AUC0-t
AUC from hour 0 to the last measureable concentration
BID
twice daily
BPI-SF
Brief Pain Inventory-Short Form
CAP
College of American Pathologists
Cmax
maximum concentration
CBR
clinical benefit rate
CR
complete response
CRF
Case Report Form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DOR
duration of objective response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC 
QLQ-BR23
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire Breast Cancer Module 23
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire Core 30
EQ-5D-5L
European Quality of Life 5Dimension, 5-Level questionnaire
ER
estrogen receptor
ER+
estrogen receptor positive
ESMO
European Society of Medical Oncology
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
GHS
Global Health Status


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Abbreviation
Definition
HbA1c
glycosylated hemoglobin
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2-
human epidermal growth factor receptor 2 negative
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HR+
hormone receptor positive
ICH
International Council for Harmonisation
iDMC
Independent Data Monitoring Committee
iDCC
Independent Data Coordinating Center
IHC
immunohistochemistry
IM
intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
IxRS
interactive voice/web response system
LHRH
luteinizing hormone releasing hormone
mCRPC
metastatic castration-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
mPFS
median progression-free survival
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NGS
next-generation sequencing
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PF
physical functioning
PFS
progression-free survival
PK
pharmacokinetic
PO
orally


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Abbreviation
Definition
popPK
population PK
PR
partial response
PRO
patient-reported outcome
PTT
partial thromboplastin time
QD
once daily
RANKL
receptor activator of nuclear factor kappa-Β ligand
RBR
Research Biosample Repository
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
RF
role functioning
rPFS
radiographic progression-free survival
SAP
Statistical Analysis Plan
SERD
selective estrogen receptor down-regulator
SmPC
Summary of Product Characteristics
SOA
schedule of assessments
SOC
standard of care
SRE
skeletal-related event
tmax
time to Cmax
TNBC
triple negative breast cancer
TTD
time to deterioration
ULN
upper limit of normal
VAS
visual analog scale
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON HR+ BREAST CANCER
Breast cancer is the most frequent cancer diagnosed in women, with an estimated global 
incidence of 2.09 million new cases reported in 2018 (Bray et al. 2018).  Breast cancer 
accounts for approximately 7% (approximately 626,679 cases) of all cancer deaths.  
Breast cancer mortality rates differ by geographical region, with more favorable survival 
rates observed in more developed regions of the world (Bray et al. 2018).
Hormone receptorpositive (HR) human epidermal growth factor receptor 2 negative 
(HER2-) breast cancer accounts for approximately 70% of all breast cancer subtypes 
(Fedele et al. 2018).
Endocrine therapy, alone or in combination with targeted therapy, is recommended for 
HR+ HER2- advanced or metastatic breast cancer according to the European Society of 
Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and National 
Comprehensive Cancer Network guidelines, unless in visceral crisis when chemotherapy 
is indicated (Ngan 2018).  Monotherapy of selective estrogen receptor modulator, 
selective estrogen receptor down-regulator (SERD), or aromatase inhibitor (AI), or more 
recently their combination with targeted therapy, have been the mainstay treatment 
options as first-line (1L) therapy for most patients.  Mechanisms that can lead to primary 
and/or secondary endocrine resistance in HR+ breast cancer include a decrease or loss 
of hormone receptor expression, mutations in the gene that encodes estrogen receptor 
(ESR1), or an upregulation of growth factor signaling pathways, such as the epidermal 
growth factor receptor or HER2, the MAPK, or the PI3K/AKT/mTOR pathways (Johnston 
et al. 2009; Musgrove and Sutherland 2009; Robinson et al. 2013; Toy et al. 2013; 
Jeselsohn et al. 2014).
PIK3CA/AKT1/PTEN-altered tumors are frequently observed in breast cancer, and are 
reported in approximately 50% of HR+ HER2- breast cancers (Cancer Genome Atlas 
Network 2012).  Hyperactivation of the PI3K/AKT/mTOR signaling pathway was shown 
to promote both de novo and acquired resistance to hormone therapy in estrogen 
receptor (ER) positive (ER) breast cancer cell lines and xenograft models (Sabnis et al. 
2007). 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 provided support to the hypothesis that blocking 
PI3K/AKT/mTOR pathway signaling may have a therapeutic benefit in patients with ER+ 
HER2- breast cancer.
In the clinical setting, results from the BOLERO-2 trial, which investigated the 
combination of exemestane and everolimus, an mTOR inhibitor, led to regulatory 
approval of everolimus (Baselga et al. 2012).  This study compared everolimus and


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exemestane with placebo and exemestane in postmenopausal patients with ER
advanced breast cancer who had recurrence or progression of disease while receiving 
previous therapy with a nonsteroidal AI in the adjuvant setting and/or in advanced 
disease.  Median progression-free survival (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; p0.001.  
Furthermore, in the randomized, double-blind, placebo-controlled, Phase II study 
PrE0102 (Kornblum et al. 2018) in postmenopausal women with ER+ HER2-, 
AI-resistant, metastatic breast cancer, the addition of everolimus to fulvestrant improved 
the median PFS (mPFS) from 5.1 to 10.3 months (HR0.61, stratified log-rank p0.02).
Several PI3K inhibitors have been combined with fulvestrant showing promising activity 
in Phase III studies in patients with ER+ HER2- advanced breast cancer who had 
progressed on or after an AI.  In the Phase III BELLE-2 study, buparlisib (a pan-PI3K 
inhibitor) when combined with fulvestrant resulted in mPFS of 6.9 months versus 
5.0 months in the placebo group (HR 0.78; one-sided p0.00021) in unselected patients 
(Baselga et al. 2017). In an exploratory analysis of patients with PIK3CA-mutant tumor 
by circulating tumor DNA (ctDNA), mPFS was 7.0 months in the buparlisib group versus 
3.2 months in the placebo group (HR 0.58; one-sided p0.001).
In the Phase III study SANDPIPER, the addition of taselisib (a beta-sparing PI3K 
inhibitor) to fulvestrant showed a statistically significant improvement in 
investigator-assessed PFS in patients with PIK3CA-mutant tumors who comprised the 
primary endpoint population.  Median PFS increased from 5.4 months in the placebo 
arm to 7.4 months in the taselisib arm (HR0.70, p-value0.0037) (Baselga et al. 2018).  
The study also enrolled a smaller cohort of patients without detectable PIK3CA-mutant 
tumors for exploratory analyses of PFS.  Although the study was not powered to 
compare the two cohorts, the HR for PFS was similar in patients without detectable 
PIK3CA-mutant tumors and those with PIK3CA-mutant tumors based on an exploratory 
analysis.  Thus, a treatment effect of taselisib and fulvestrant in patients without 
detectable PIK3CA mutations could not be completely ruled out.
Recently, in the Phase III study SOLAR-1, the addition of alpelisib (an alpha selective 
PI3K inhibitor) to fulvestrant showed a statistically significant improvement in 
investigator-assessed PFS in patients with PIK3CA-mutant tumors.  Median PFS 
increased from 5.7 months in the placebo arm to 11 months in the alpelisib arm 
(HR0.65, p-value 0.00065) (André et al. 2018).  Based on the exploratory analysis, 
patients without detectable PIK3CA-mutant tumors did not seem to benefit from the 
addition of alpelisib to fulvestrant. 
Recently, an investigator-led, double-blind, placebo-controlled, randomized Phase II 
trial (FAKTION) evaluated the addition of the AKT inhibitor capivasertib to 
fulvestrant in postmenopausal women with ERHER2breast cancer after relapse or 


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disease progression on an AI (Jones et al. 2019). There were 140 patients randomized 
to fulvestrant plus capivasertib (n69) or fulvestrant plus placebo (n71). In the 
biomarker unselected intent-to-treat (ITT) population, median PFS was 10.3 months for 
patients in the capivasertib arm compared to 4.8 months in the placebo arm (adjusted 
HR 0.57, two-sided p0.0035). The HR for patients with or without PI3K/AKT 
pathway activation was similar. As seen with the mTOR inhibitor everolimus in the 
BOLERO-2 study, treatment benefit with an AKT inhibitor in combination with 
endocrine therapy seemed to also be independent of PI3K/AKT pathway activation.
Aside from everolimus and more recently alpelisib that have shown meaningful clinical 
activity when given in combination with endocrine therapy, CDK4/6 inhibitors have been 
approved as both 1L and second-line (2L) treatments in HR+ HER2- patients. Three 
CDK4/6 inhibitors are now in widespread clinical use: palbociclib, ribociclib, and 
abemaciclib.  They have been shown to significantly improve PFS over endocrine 
therapy alone (Finn et al. 2015; Cristofanilli et al. 2016; Hortobagyi et al. 2016; Sledge et 
al. 2017; Goetz et al. 2017) and have very similar therapeutic efficacy with slight 
differences in dosing schedule and toxicity (Spring et al, 2017; Petrelli et al. 2019). 
Aside from abemaciclib, these agents are approved for use only in combination with 
endocrine agents – typically with an AI in the first-line setting and fulvestrant in 
AI-resistant patients.  See Section 1.3 for additional details on palbociclib. Mechanisms 
of acquired resistance to CDK4/6 inhibitors are beginning to be elucidated (O’Leary et al. 
2018).  While the benefit of adding CDK4/6 inhibition to endocrine therapy is 
independent of PIK3CA mutation status, shorter survival has been observed in patients 
with PIK3CA mutations detectable in ctDNA (Turner et al. 2018).  Additional ctDNA 
analysis of the PALOMA-3 study showed a median PFS of 5.8 months (95% CI 5.3-9.5) 
in patients with detectable PIK3CA mutations versus patients with no detectable 
mutations at 9.2 months (95% CI 7.5-10.8) (Cristofanilli et al. 2016).
Despite the multiple advances in improving the clinical benefit of endocrine therapy, 
many patients have poor response to these combinations due to highly endocrine 
resistant or refractory disease.  These patients rapidly progress to require chemotherapy 
treatment and develop significant morbidity and mortality associated with treatment and 
progression of metastatic disease.
1.2
BACKGROUND ON IPATASERTIB 
Ipatasertib is a potent, highly selective, small-molecule inhibitor of all three isoforms of 
the serine/threonine kinase AKT.  Ipatasertib is being developed by Genentech/Roche 
as a single agent and in combination with other therapies for the treatment of cancers in 
which activation of the PI3K-AKT-mTOR pathway may be relevant for tumor growth or 
therapeutic resistance. 
In nonclinical models with high levels of phosphorylated AKT or PI3K-AKT pathway 
activity (i.e., PIK3CA mutation, PTEN alterations), sensitivity to ipatasertib has been 
observed across different tumor models, including breast cancers (Lin et al. 2013).  


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In vivo efficacy studies support the use of ipatasertib as a single agent or in combination 
with chemotherapeutic, hormonal, or targeted agents for the treatment of patients with 
advanced or metastatic solid tumors (Lin et al. 2013).
Clinical studies in a variety of tumor types have been conducted with ipatasertib both as 
monotherapy and in combination.  Combination partners have included hormonal 
therapies (i.e., abiraterone and enzalutamide), chemotherapy, and immunotherapy.  
Randomized studies with ipatasertib have been conducted in breast, prostate, and 
gastric cancer.  
In the Phase Ib study PAM4983g, 2 of 5 patients with HR+ breast cancer, who were 
treated with the combination of ipatasertib and paclitaxel, had confirmed partial 
responses. 
The randomized Phase Ib/II study GO27983 was conducted in patients with metastatic 
castration resistant prostate cancer (mCRPC) post-docetaxel.  Ipatasertib (400-mg dose) 
when added to hormonal therapy abiraterone and prednisone/prednisolone showed 
improved radiographic PFS (rPFS) benefit compared with abiraterone and 
prednisone/prednisolone in the all-comer population and in patients with PTEN-loss 
tumors (HR0.75 for all-comer; HR0.39 for PTEN-loss by Immunologic Constant of 
Rejection immunohistochemistry [IHC] assay).  There is an ongoing randomized 
Phase III study CO39303 evaluating 400 mg ipatasertib when added to abiraterone and 
prednisone/prednisolone compared to abiraterone and prednisone/prednisolone in 
front-line mCRPC.
The randomized Phase II study, GO29227, evaluated the addition of ipatasertib to 
paclitaxel in front-line metastatic triple-negative breast cancer (TNBC) patients and those 
with a PTEN loss (by IHC) and separately, patients with PIK3CA/AKT1/PTEN-altered 
tumors.  Results from this study showed improvement in mPFS in the ITT population 
(HR0.60; 6.2 months in the ipatasertib arm compared with 4.9 months in the control 
arm); and more pronouncedly in the pre-specified patient population with 
PIK3CA/AKT1/PTEN-altered tumors (HR0.44; 9 months vs. 4.9 months).  There is an 
ongoing randomized Phase III study CO40016 evaluating 400 mg ipatasertib when 
added to paclitaxel compared to paclitaxel in both first-line TNBC and HR+ HER2- breast 
cancer for patients with PIK3CA/AKT1/PTEN-altered tumors.  
Refer to the Ipatasertib Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
BACKGROUND ON PALBOCICLIB
Palbociclib is a CDK4/6 inhibitor indicated for the treatment of HRHER2- advanced or 
metastatic breast cancer in combination with an AI as initial endocrine based therapy in 
postmenopausal women; or in combination with fulvestrant in women with disease 
progression following endocrine therapy. The approval in combination with fulvestrant 


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was based on the Phase III PALOMA-3 study which showed that in women with HR
HER2- advanced or metastatic breast cancer who had disease progression following 
endocrine therapy, palbociclib-fulvestrant resulted in a mPFS of 9.2 months (95% CI, 7.5 
to not estimable) versus 3.8 months (95% CI, 3.5 to 5.5) with placebo–fulvestrant (HR 
0.42; 95% CI, 0.32 to 0.56; P0.001) (Turner et al. 2015). Updated PFS analysis data 
from the PALOMA-3 study demonstrated a median PFS of 11.2 months in the palbociclib 
arm versus 4.6 months in the placebo arm (HR 0.497) (Cristofanilli et al. 2018).
Refer to the local prescribing information for details on nonclinical and clinical studies.
1.4
BACKGROUND ON FULVESTRANT
Fulvestrant is a SERD indicated for the treatment of postmenopausal women with ER
advanced/metastatic breast cancer not previously treated with endocrine therapy, or with 
disease progression on antiestrogen therapy (Faslodex® package insert).  
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 (PFS 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).
The Phase III FALCON study investigated whether fulvestrant could improve PFS 
compared with anastrozole in postmenopausal patients with HR+ locally advanced or 
metastatic breast cancer who had not received previous endocrine therapy (Robertson 
et al., 2016).  The median PFS was 16.6 months in the fulvestrant group versus 
13.8 months in the anastrozole group (HR 0.797, p0.0486).
Fulvestrant has been successfully combined with CDK4/6 inhibitors, such as palbociclib 
(see Section 1.3).
Refer to the local prescribing information for details on nonclinical and clinical studies.
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Preclinical data suggests that an AKT inhibitor such as ipatasertib may be a good 
combination partner for a CDK4/6 inhibitor regimen. The combination of CDK4/6 
inhibitors and PI3K inhibitors, which act upstream of AKT, synergistically reduced the 
viability of cancer cells with otherwise reduced sensitivity to PI3K inhibitors (Vora et al. 
2014).  Additional data indicated that ERbreast cancer cells can adapt rapidly to 
CDK4/6 inhibition evading cytostasis and that a triplet combination of endocrine therapy, 
CDK4/6, and PI3K inhibition was more effective in patient-derived xenograft models than 
paired combinations (Herrera-Abreu et al. 2016). In another preclinical study, palbociclib 


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resistant ER+ breast cancer cells were shown to have a hyperactive PI3K/AKT/mTOR 
pathway and the mTOR inhibitor everolimus appeared to resensitize resistant cells to 
palbociclib (Chen et al. 2018). Importantly, fulvestrant/palbociclib double resistant cells 
maintained similar sensitivity to ipatasertib compared to parental cells (O’Brien et al. 
2017). 
Furthermore, exogenous expression of AKT1 in HR+ breast cancer cell lines in vitro 
conferred resistance to palbociclib, abemaciclib, and anti-estrogen therapy and acquired 
AKT1 alterations were identified in two patients with matched pre/post CDK4/6 inhibitor 
biopsy specimens (Wander et al. 2018). 
This study will enroll patients with locally advanced unresectable or metastatic HR+ 
HER2- breast cancer expected to have a poor prognosis to currently available endocrine 
therapy in that they relapsed during adjuvant endocrine therapy or progressed during the 
initial 12 months of first-line endocrine therapy in HR+ HER2-, unresectable, locally 
advanced or metastatic breast cancer (see Section 4.1.1 for more details). 
Although CDK4/6 inhibitor treatment regimens have resulted in considerable 
improvements in PFS in first- or second-line settings, limited data are available for 
patients with poorer prognosis who relapse or progress during endocrine therapy in the 
adjuvant or first-line metastatic setting. In addition, acquired resistance to CDK4/6 
inhibitors has emerged, highlighting the need for identifying new therapeutic agents to 
help delay acquired resistance and thus increase clinical benefit of CDK4/6 inhibitor 
regimens especially in patients with poor prognosis (Garrido-Castro et al. 2017; O’Leary 
et al. 2018; Ballinger et al. 2018; Robert et al. 2018). 
Despite the benefits from approved therapies, HR+ metastatic breast cancer remains an 
incurable disease and the majority of patients will eventually progress and subsequently 
die from the disease.  Given the remaining unmet clinical need, this population is 
considered appropriate for trials of novel therapeutic candidates to identify therapies that 
could further enhance CDK4/6 inhibitor treatment regimens.
As a novel target along the validated PI3K/AKT/mTOR pathway, ipatasertib has shown 
promising clinical activity so far in randomized Phase II studies in TNBC (GO29227) and 
mCRPC (see Section 1.2 for details).  In the Phase II study, GO27983, in mCRPC 
(de Bono et al. 2019), rPFS was prolonged in the ipatasertib cohort versus placebo with 
similar trends in overall survival and time-to-PSA progression. A larger rPFS 
prolongation for the combination was demonstrated in patients with tumor PTEN-loss 
versus those without (see Section 1.2 for details).  In addition, the clinical safety profile 
of ipatasertib as a single agent in the Phase Ia study (PAM4743g) and in combination 
with paclitaxel in the Phase Ib (PAM4983g) and Phase II studies (GO29227 and 
GO29505) supports continued development of ipatasertib in breast cancer.  Furthermore, 
in study GO27983 in prostate cancer the combination of ipatasertib with the endocrine 
agent abiraterone was well tolerated (de Bono et al. 2019). Consistent with 


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PI3K/mTOR/AKT pathway inhibition, ipatasertib has been associated with the risks 
presented in Section 5.1.1.  Refer to Section 5 and the Ipatasertib Investigator’s 
Brochure for further details.
There are limited overlapping toxicities and no expected drug-drug interactions between 
ipatasertib and fulvestrant (see Section 3.3.8).  There are also limiting overlapping 
toxicities between ipatasertib and palbociclib with palbociclib being associated primarily 
with hematologic toxicities. However, potential exacerbation of toxicities, such as rash, 
mucositis/stomatitis, pneumonitis, and diarrhea may exist (Verma et al. 2016; 
IBRANCE® U.S. Package Insert).  Therefore, patients will be monitored for these 
adverse events, and the potential for exacerbation of these toxicities is also being 
considered in the adverse event management guidelines (see Section 5.1). There are 
potential drug-drug interactions between ipatasertib and palbociclib (see Section 3.3.8). 
Therefore, the safety of combining ipatasertib with the labeled dose of palbociclib and 
fulvestrant will be assessed in the open-label Phase Ib portion to characterize the 
potential drug-drug interaction and identify the appropriate dose for the triplet 
combination (see Section 3.1.1).  
As part of risk mitigation, there will be additional clinic visits during the first two cycles.  
In the randomized Phase III portion of the study, an independent Data Monitoring 
Committee (iDMC) will review cumulative safety data regularly throughout the study as 
outlined in a separate charter (see further details in Section 3.1.6 and Section 6.8.1).  
Detailed management guidelines for treatment-related symptoms or potential risks are 
provided as outlined in Section 5.4.2.  To improve diarrhea management and patient 
experiences, anti-diarrhea prophylaxis (loperamide) will be mandated for the first cycle 
for all patients (where allowed by local guidance) and continued as clinically indicated 
(see Section 4.3.2.5). 
In summary, the Sponsor has assessed that the potential benefit-risk profile of 
ipatasertib in combination with palbociclib and fulvestrant justifies the present clinical 
study.  The anticipated or potential safety issues associated with the administration of 
ipatasertib in combination with palbociclib and 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.
2.
OBJECTIVES AND ENDPOINTS
The open-label Phase Ib portion of this study will evaluate the safety and 
pharmacokinetics of ipatasertib in combination with palbociclib and fulvestrant to identify 
a dose of ipatasertib that can be combined with palbociclib and fulvestrant in the 
Phase III portion. 
The randomized Phase III portion of this study will evaluate the efficacy, safety, and 
patient-reported outcome (PRO) objectives of ipatasertibpalbociclibfulvestrant 


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compared with placebopalbociclibfulvestrant in patients with HR+ HER2-, locally 
advanced unresectable or metastatic breast cancer who had relapsed during adjuvant 
endocrine therapy or progressed during the initial 12 months of first-line endocrine 
therapy in locally advanced unresectable or metastatic breast cancer.  Specific 
objectives and corresponding endpoints for the study are outlined in Section 2.
In this protocol, the term "study treatment" refers to the combination of treatments 
assigned to patients as part of this study (i.e., ipatasertib/placebo, palbociclib, and 
fulvestrant). Treatment with placebo only applies to the Phase III portion of this study.
In this study, when describing the different analysis populations and endpoints, Tri-AKT 
positive (Tri-AKT+) corresponds to the presence of PIK3CA/AKT1/PTEN alterations. 
2.1
EFFICACY OBJECTIVES
Efficacy objectives are applicable for only the randomized Phase III portion of this study 
as described below.
2.1.1
Primary Efficacy Objective
The primary efficacy objective for the randomized Phase III portion of this study is to 
evaluate the efficacy of ipatasertibpalbociclibfulvestrant compared with 
placebopalbociclibfulvestrant on the basis of the following co-primary endpoints:

Progression-free survival (PFS) in ITT patients, defined as the time from 
randomization to the first occurrence of disease progression as determined by the 
investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), or death from any cause, whichever occurs first 

Progression-free survival (PFS) in patients with Tri-AKT+ tumors, as defined by 
baseline ctDNA, defined as the time from randomization to the first occurrence of 
disease progression as determined by the investigator according to RECIST v1.1, or 
death from any cause, whichever occurs first
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for the randomized Phase III portion of this study is to 
evaluate the efficacy of ipatasertibpalbociclibfulvestrant compared with 
placebopalbociclibfulvestrant on the basis of the following endpoints both in the ITT 
population and in patients with Tri-AKT+ tumors, as defined by baseline ctDNA:

Objective response rate (ORR), defined as the proportion of patients with a 
complete response (CR) or partial response (PR) on two consecutive occasions 
4 weeks apart, as determined by the investigator according to RECIST v1.1

Duration of objective response (DOR), defined as the time from the first occurrence 
of a documented objective response to the first occurrence of disease progression 
as determined by the investigator according to RECIST v1.1, or death from any 
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
Clinical benefit rate (CBR), defined as the proportion of patients who have a CR or 
PR, or stable disease for at least 24 weeks, as determined by the investigator 
according to RECIST v1.1

Overall survival (OS), defined as the time from randomization to death from any 
cause

Time to deterioration (TTD) in severity of pain, defined as the time from 
randomization to the first documentation of a 2-point or more increase from baseline
on the “worst pain” item from the Brief Pain Inventory-Short Form (BPI-SF)

TTD in presence and interference of pain, defined as the time from randomization 
to the first documentation of a 10-point or more increase from baseline in the 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) pain scale (items 9 and 19)

TTD in physical functioning (PF), role functioning (RF), and Global Health Status
(GHS)/Quality of Life (QoL), defined as the time from randomization to the first 
documentation of a 10-point or more decrease from baseline in the following scales 
of the EORTC QLQ-C30: PF, RF, and GHS/QoL
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for the randomized Phase III portion of this study is to 
evaluate the efficacy of ipatasertibpalbociclibfulvestrant compared with 
placebopalbociclibfulvestrant on the basis of the following endpoints both in the ITT 
patients and patients with Tri-AKT+ tumors, as defined by baseline ctDNA:

Mean and mean changes from baseline scores in all functions (physical, role, 
cognitive, emotional, and social), GHS/QoL, and disease/ treatment-related 
symptoms, as measured by the scales of the EORTC QLQ-C30 and the EORTC 
Breast Cancer Module 23 Questionnaire (QLQ-BR23)

Health utility and visual analog score (VAS) of the European Quality of Life 
5-Dimension 5-Level (EQ-5D-5L) questionnaire for pharmacoeconomic modeling 

PFS2, defined as the time from randomization to second occurrence of objective 
disease progression through the use of RECIST v1.1, or death from any cause, 
whichever occurs first

Time to first skeletal–related event (SRE), defined as the time from randomization to 
the first occurrence of an SRE (an SRE is a pathologic fracture, radiation therapy to 
bone, surgery to bone, or spinal cord compression) 
In addition, this study will evaluate the efficacy of ipatasertibpalbociclibfulvestrant 
compared with placebopalbociclibfulvestrant on the basis of the following endpoints 
in patients with Tri-AKT+ tumor tissue and PTEN loss in tumor tissue:

PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by the investigator according to RECIST v1.1, or death 
from any cause, whichever occurs first


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2.2
SAFETY OBJECTIVES
Safety objectives are applicable for both the Phase Ib portion and the randomized 
Phase III portion of this study. The same endpoints as described below will be used for 
both portions.
2.2.1
Safety Objective
The safety objective for the Phase Ib portion of this study is to characterize the safety of 
combining ipatasertib with palbociclibfulvestrant using endpoints listed below for the 
Phase III portion. 
The safety objective for the randomized Phase III portion of this study is to evaluate the 
safety of ipatasertibpalbociclib fulvestrant compared with 
placebopalbociclibfulvestrant in all randomized patients as well as patients with 
Tri-AKT+ tumors, as defined by baseline ctDNA, who received at least one dose of study 
treatment on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
2.2.2
Exploratory Safety Objective
The exploratory safety objective for the randomized Phase III portion of this study is to 
evaluate patient-reported symptomatic adverse events of ipatasertibpalbociclib
fulvestrant compared with placebopalbociclibfulvestrant in all randomized patients 
who received at least one dose of study treatment, on the basis of the following 
endpoints:

Presence, frequency of occurrence, severity, and/or degree of interference with 
daily function of selected symptomatic treatment toxicities (i.e., diarrhea, nausea, 
vomiting, decreased appetite, fatigue, mouth sores, and rash symptoms and an 
additional item regarding the overall bother experienced due to side effects of 
treatment [see Appendix 13]), as measured by the NCI Patient-Reported Outcomes 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument

Change from baseline in symptomatic treatment toxicities, as measured by the 
PRO-CTCAE


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2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objectives are applicable for both the open-label Phase Ib 
portion and the randomized Phase III portion of this study, unless otherwise specified 
below.  The same endpoints, as described below, will be used for both portions, unless 
otherwise specified.  
The PK objective for the open-label Phase Ib portion is to evaluate the effect of 
palbociclib, a weak time-dependent inhibitor of CYP3A, on the PK profile of ipatasertib. 
The PK objective for the Phase III portion is to characterize the PK profiles of ipatasertib 
and its metabolite (G-037720) in combination with palbociclib and fulvestrant on the 
basis of the following endpoint:

Plasma concentration of ipatasertib and its metabolite, G-037720, at specified 
timepoints for analysis using population PK methodology
The exploratory PK objectives for this study are as follows:

To evaluate palbociclib trough concentrations and the effect of ipatasertib on 
palbociclib exposures in the open-label Phase Ib portion

To evaluate potential relationships between drug exposure and the efficacy and 
safety of ipatasertibpalbociclibfulvestrant in the randomized Phase III portion 
based on the following endpoints:
-
Relationship between plasma concentration or PK parameters for ipatasertib 
and efficacy endpoints
-
Relationship between plasma concentration or PK parameters for ipatasertib 
and safety endpoints
2.4
BIOMARKER OBJECTIVE
The exploratory biomarker objective for the open-label Phase Ib portion is to evaluate 
changes in plasma ctDNA levels.
The exploratory biomarker objectives for the randomized Phase III portion of this study 
are as follows:

Evaluate the effect of Tri-AKT status in tissue or plasma on treatment benefit to 
ipatasertibpalbociclib fulvestrant compared with placebopalbociclibfulvestrant 

Identify and evaluate predictive or prognostic biomarkers associated with disease 
activity status or response to treatment with ipatasertibpalbociclibfulvestrant 

Identify possible mechanisms of resistance to ipatasertibpalbociclibfulvestrant 
through the comparative analysis of potential biomarkers in pretreatment and 
post-progression biopsy tissue samples and in blood

Evaluate safety and pharmacodynamics biomarkers that may lead to improved 
monitoring and to provide evidence of activity of ipatasertibpalbociclibfulvestrant, 
respectively


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
Evaluate the relationship between tissue-based and blood-based biomarkers and 
patient clinical features (e.g., baseline features) and outcome (e.g., duration of PFS)

To increase the knowledge and understanding of disease biology and drug safety 
on the basis of the following endpoint: 

Relationship between biomarkers in blood and tumor tissue (listed in Section 4.5.8) 
and efficacy, safety, PK, or other biomarker endpoints including biomarker relevant 
therapies in development
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study CO41012 is a Phase III, randomized, multicenter, international, double-blind, 
placebo-controlled clinical study with an initial open-label, Phase Ib, safety portion.  The 
open-label Phase Ib portion is intended to evaluate the safety of the triplet combination 
and to further characterize the potential drug-drug interaction between ipatasertib and 
palbociclib and to determine the ipatasertib dose to be combined with palbociclib and 
fulvestrant.  The randomized Phase III portion is designed to compare the efficacy, as 
measured by PFS, and safety of ipatasertibpalbociclibfulvestrantwith that of 
placebopalbociclibfulvestrant in patients with HR+ HER2- locally advanced 
unresectable or metastatic breast cancer who relapsed during adjuvant endocrine 
therapy or progressed during the initial 12 months of first-line endocrine therapy in 
locally advanced unresectable or metastatic breast cancer.  Further details of the 
open-label Phase Ib and randomized Phase III portions are described below.  An 
overview of the study flow of the open-label Phase Ib portion (Figure 1) as well as the 
dose schedule for each study drug (Figure 2) are shown below.  The study schema for 
the Phase III portion (Figure 3) and the corresponding dose schedule for each study 
drug (Figure 4) are shown below.  
3.1.1
Open-label Phase Ib Portion
Patients in the open-label Phase Ib portion are required to fulfill the same eligibility 
criteria as those in the randomized Phase III portion unless otherwise indicated in 
Section 4.1.1 and Section 4.1.2.  Approximately 10 patients will initially be treated with a 
starting dose of 300 mg ipatasertib for 5-7 days as a single agent before palbociclib and 
fulvestrant will be started on Cycle 1, Day 1 (see additional details on the dose schedule 
below).  All patients will be followed to at least Cycle 2, Day 15 before the initial safety 
review will be triggered. PK samples will be collected up to Cycle 3, Day 15 (see
Appendix 4) and results will be included where available at the time of the safety review.  
If multiple patients come off prior to Cycle 2, Day 15 for reasons other than toxicity, the 
Sponsor may elect to replace the patients. The internal safety review will be conducted 
by the Sponsor and will include members of the study team including, but not limited to,
the study Medical Monitor, Safety Scientist, and Clinical Pharmacologist. Further 
enrollment will be halted until after the internal safety review has been completed and a 
recommendation has been made to either expand the original cohort or explore an 








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3.1.4
Key Study Parameters
Prior to enrollment but after signing the informed consent form, patients enrolled in the 
Phase III portion will have the Tri-AKT ctDNA test done by the central laboratory 
next-generation sequencing (NGS) assay within 6 weeks of first dose of study treatment.  
For patients enrolled in the Phase Ib portion, the test may be performed after enrollment. 
A valid result (Phase III only) will be required for patient stratification and therefore 
patients whose ctDNA samples have invalid test results will not be permitted to enroll in 
the Phase III portion of the study.  
Patients must have measurable disease per RECIST v1.1 (see Section 4.1 and 
Appendix 9).  
Primary endpoint is investigator-assessed PFS (Phase III).  Tumor assessments will be 
conducted as outlined in the schedule of assessments (Appendix 1 [Phase III schedule 
of assessments {SOA}] and Appendix 3 [Phase Ib SOA]) and Section 4.5.6.
3.1.5
Length of Treatment and Discontinuation
Study treatment will continue until disease progression, unacceptable toxicity, withdrawal
from study, or study completion or termination.  Upon treatment discontinuation, patients 
in the randomized Phase III portion will be followed for survival, PROs, and subsequent 
anti-cancer therapy (including outcome) as outlined in Section 4.6.1.  Patients enrolled in 
the randomized Phase III portion who discontinue treatment without evidence of disease 
progression per RECIST v1.1, will be followed every 8 weeks 7 days for tumor 
assessments until documented progression per RECIST v1.1.
Patients who need to discontinue any of the study drugs due to toxicity may continue on 
the other study drugs provided the toxicity is deemed unrelated to those:

Patients who need to permanently discontinue ipatasertib/placebo may stay on 
palbociclib and/or fulvestrant at the discretion of the investigator without medical 
monitor approval.

If patients need to permanently discontinue palbociclib and/or fulvestrant but not 
ipatasertib/placebo, medical monitor approval will be required to continue on 
ipatasertib/placebo alone or in combination with either palbociclib or fulvestrant. 
Crossover is not allowed.  See Section 4.6.2 for more details concerning patient 
discontinuations.
3.1.6
Independent Data Monitoring Committee
An iDMC will be used to evaluate safety during the randomized Phase III portion of the 
study as outlined in a separate charter and in Section 6.8.  However, no interim analysis 
of the primary efficacy endpoint PFS is planned.  
A schedule of study assessments is provided in Appendix 1 (Phase III SOA) and 
Appendix 3 (Phase Ib SOA).


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3.1.7
Potential China Extension Cohort
This study plans to enroll approximately 340 patients across all sites in the global 
enrollment phase of the randomized Phase III portion.  After completion of the global 
enrollment phase, additional patients may be enrolled in a China extension cohort at 
sites in mainland China, Hong Kong, and Taiwan (see Section 6.9 for details on the 
China subpopulation).  
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient last visit occurs 
(i.e., the date at which the last data point required for statistical analysis or safety 
follow-up is received from the last patient, whichever occurs later).  In addition, the 
Sponsor may decide to terminate the study or OS follow-up at any time (see 
Section 4.6.3). 
Provided the Phase III portion is initiated, the total length of the global study, from 
screening of the first patient to the end of the study, is expected to be approximately 
64 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Ipatasertib Dose and Schedule
For ipatasertib, the target starting dose of 400 mg QD on Days 121 of each 28-day 
cycle is consistent with the dose used in Phase II (GO29227) and Phase III (CO40016) 
breast cancer trials.  This dose is based on the safety and PK data from the combination 
treatment Arm C of Study PAM4983g and the combination treatment Arm 1 of 
Study GO29227 (Phase Ib and Phase II trials of ipatasertib combined with paclitaxel; 
refer to the Ipatasertib Investigator's Brochure for details).  The 400 mg ipatasertib was 
previously better tolerated than 600 mg ipatasertib (refer to Study PAM4743g in 
Ipatasertib Investigator’s Brochure for details).  Even though there is no safety data, yet, 
in combination with fulvestrant, there are no expected drug-drug interactions between 
ipatasertib and fulvestrant (see Section 3.3.8). However, given potential drug-drug 
interactions of ipatasertib with palbociclib that may result in an increase in ipatasertib 
exposure (see Section 3.3.8), the starting dose of ipatasertib of 300 mg was selected for 
the initial Phase Ib portion. Based on study GP30057 (Phase I study evaluating the 
effect of itraconazole on ipatasertib) and drug interactions of palbociclib (refer to 
palbociclib label), the sponsor believes that the 300-mg dose in the presence of 
palbociclib may result in ipatasertib exposure that is similar to the target 400-mg dose in 
the absence of palbociclib (see further details on the rationale for the target 400-mg 
dose below).  The Phase Ib portion of this study is intended to further characterize the 
drug-drug interaction and confirm the appropriate dose for the combination with 
palbociclib (see Section 3.1.1 for additional details on the open-label Phase Ib portion). 
Ipatasertib in combination with chemotherapy at the 400-mg dose has resulted in 
acceptable tolerability based on data from the randomized, placebo-controlled, Phase II 


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study (GO29227) in patients with locally advanced or metastatic TNBC.  In that study, 
the combination of ipatasertib 400 mg administered QD on Days 121 of each 28-day 
cycle and paclitaxel 80 mg/m2 administered weekly on Days 1, 8, and 15 of each 28-day 
cycle was generally well tolerated and showed an improvement in PFS (refer to 
Ipatasertib Investigator’s Brochure and Section 1.2).  The sparse sampling exposure 
results in this study were also consistent with the known PK profiles of ipatasertib (and 
its metabolite G-037720).
In addition, results of pretreatment and on-treatment biopsies indicated that ipatasertib, 
beginning at 100 mg, downregulated multiple AKT effectors, including pPRAS40, 
pGSK3β, pS6, and p4EBP (Saura et al. 2016) suggesting robust target inhibition at 
400 mg.
Overall, the PK data from the Phase I (PAM4743g, PK/pharmacodynamic analysis) as 
well as safety and efficacy data (including exploratory exposure-response analyses, data 
on file) from the randomized Phase II studies of ipatasertib (Study GO29227 in patients 
with locally advanced or metastatic TNBC and Study GO27983 in patients with mCRPC) 
support the starting dose of 400 mg ipatasertib for sufficient pathway inhibition and 
efficacy with a generally acceptable safety profile in combination regimens such as with 
chemotherapy (refer to the Ipatasertib Investigator's Brochure for details).  In the 
ipatasertibpaclitaxel combination arm of the GO29227 study, despite dose reduction of 
ipatasertib that occurred in 21% of patients due to adverse events, discontinuation of 
ipatasertib due to any adverse event was 7% (Kim et al. 2017).
A relative bioavailability and food-effect study (GO29868) was conducted in healthy 
volunteers.  The study confirmed that the Phase III tablet formulation of ipatasertib to be 
used in this study is anticipated to provide exposures similar to the exposures of
ipatasertib Powder-In-Capsule and Phase II tablet formulations used in the Phase I 
(PAM4743g, PAM4983g) and Phase II (GO29227) studies, respectively.
3.3.2
Rationale for Fulvestrant Dose and Schedule
The dose of fulvestrant of 500 mg administered by IM injection at Cycle 1, Days 1 and 
15, and then on Day 1 of each subsequent 28-day cycle was established in a 
randomized clinical study to be superior to the 250-mg dose (see Section 1.4) and was 
used in combination with palbociclib in the randomized clinical study PALOMA-3 that led 
to approval of palbociclib in combination with fulvestrant (see Section 1.3). 
3.3.3
Rationale for Palbociclib Dose and Schedule
The 125-mg palbociclib dose taken PO QD on Days 121 of each 28-day cycle 
beginning at Cycle 1, Day 1 in combination with fulvestrant was established in the 
Phase III PALOMA-3 study (see Section 1.3) and is the approved starting dose of 
palbociclib. 


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3.3.4
Rationale for Patient Population and Control Group
The population based on the proposed eligibility criteria (see Section 4.1) reflects 
patients for whom palbociclib and fulvestrant represents an appropriate treatment option. 
Palbociclib in combination with an AI or fulvestrant has been approved by health 
authorities in many regions, including the U.S. Food and Drug Administration (FDA) and 
the EMA for women with locally advanced unresectable or metastatic breast cancer (see 
Section 1.4).  Fulvestrant is not indicated for use in the adjuvant setting, whereas AIs are 
currently approved, thus switching patients who relapsed during adjuvant endocrine 
therapy (primarily AI based) or who progressed rapidly during front-line endocrine 
therapy to palbociclib and fulvestrant seems an appropriate treatment option. Despite 
recent PFS improvements with CDK4/6 inhibitors, the emergence of acquired resistance 
to CDK4/6 inhibitors highlights the continued unmet need to identify new treatment 
regimens including combination therapies for patients with HR+ breast cancer (O’Leary 
et al. 2016; O’Leary et al. 2018). Patients in this study are expected to have a poor 
prognosis and thus may benefit from the addition of new therapeutic agents such as an 
AKT inhibitor (see Section 1.5 for additional details).
Assumptions for the median PFS of the palbociclib and fulvestrant control arm in this trial 
are based on data from the two Phase III trials, PALOMA-3 (palbociclib and fulvestrant) 
and MONARCH-2 (abemaciclib and fulvestrant) and their subgroup analyses (Turner et 
al. 2015; Sledge et al 2017; Cristofanilli et al. 2018; Di Leo et al. 2018).  Neither of these 
clinical studies were restricted to only patients who relapsed during adjuvant endocrine 
therapy or who progressed during the initial 12 months of 1L endocrine therapy in locally 
advanced unresectable or metastatic breast cancer to be enrolled in this study. In 
addition, these trials included patients who could have progressed within 12 months of 
end of adjuvant endocrine therapy or who could have progressed anytime during 1L 
endocrine therapy for metastatic disease. While different CDK4/6 inhibitors have 
demonstrated comparable efficacy reflected in comparable HR of 0.497 in PALOMA-3 
(Cristofanilli et al. 2018) and HR of 0.553 in MONARCH-2 (Sledge et al. 2017), the trials 
enrolled slightly different patient populations, resulting in lower overall mPFS in the 
PALOMA-3 study in both treatment arms. In PALOMA-3 patients were allowed one prior 
chemotherapy in the metastatic setting and fewer patients presented with 1L metastatic 
disease compared to MONARCH-2. Based on PALOMA-3 subgroup analysis, mPFS of 
palbociclib and fulvestrant in patients with only one prior therapy was 13.3 months 
compared to 11.2 in the overall population (Cristofanilli et al. 2018). In contrast to 
PALOMA-3, this study will not allow prior chemotherapy in the metastatic setting, will 
only enroll patients with measurable disease and will exclude patients with bone-only 
disease.  In both PALOMA-3 and MONARCH-2, patients with bone-only disease 
experienced considerably longer mPFS (Cristofanilli et al. 2018; Di Leo et al. 2018).  


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Thus, overall, the assumptions for the palbociclib and fulvestrant arm in this study for the 
ITT population are expected to fall between the overall data from PALOMA-3 
(11.2 months) and MONARCH-2 (16.4 months), respectively (Cristofanilli et al. 2018; 
Sledge et al. 2017). The mPFS in patients with Tri-AKT+ tumors, as defined by baseline 
ctDNA, is expected to be lower given poorer prognosis observed in such patients (see 
Section 1.1). 
3.3.5
Rationale for Analysis Groups
This trial includes a co-primary endpoint of PFS in two analyses groups, the all-comer 
ITT population and patients with Tri-AKT+ tumors, as defined by baseline ctDNA (see 
Section 2).  The main rationale for the co-primary endpoint is that sponsor cannot rule 
out an all-comer benefit with ipatasertib especially in combination with palbociclib and 
fulvestrant. Although in nonclinical models sensitivity to ipatasertib seems enhanced 
with high levels of phosphorylated AKT or PI3K-AKT pathway activity (i.e., PIK3CA and 
PTEN alterations) (Lin et al. 2013), the all-comer benefit with the mTOR inhibitor 
everolimus e.g. in BOLERO-2 (Baselga et al. 2012; Moynahan et al, 2017), in contrast to 
the PI3K inhibitor alpelisib in SOLAR-1 (André et al. 2018) (see Section 1.1), suggests 
that targeting downstream of PI3K with an AKT inhibitor such as ipatasertib may provide 
benefit in unselected patients. Recent data from the randomized Phase II FAKTION 
study that demonstrated efficacy of the AKT inhibitor capivasertib in combination with 
endocrine therapy fulvestrant in unselected patients supports this assumption (see 
Section 1.1). In addition, in the Phase II GO29227 study in TNBC, the addition of 
ipatasertib to paclitaxel prolonged PFS in a biomarker unselected population with 
enhanced efficacy in patients with Tri-AKT+ tumors (see Section 1.2 for details). 
Therefore, the primary efficacy objective for this study is to evaluate the efficacy of 
ipatasertibpalbociclibfulvestrant compared with placebopalbociclibfulvestrant in 
both ITT and patients with Tri-AKT+ tumors, as defined by baseline ctDNA.
3.3.6
Rationale for Skeletal-Related Events Assessments 
Metastatic breast cancer is often associated with bone involvement, which may 
potentially lead to skeletal-related complications, possibly impacting a patient’s quality of 
life.  To describe the impact of bone involvement in breast cancer, SREs have previously 
been described as one or more of the following events (Coleman et al. 1985): 

Radiation to bone (for pain or impending fracture)

Pathological fracture

Spinal cord compression

Surgery to the bone
SREs will be measured as an exploratory endpoint in the Phase III randomized portion 
of the study to describe the incidence of these events and to determine the potential 


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impact of treatment with ipatasertib in the locally advanced or metastatic breast cancer 
setting (Hortobagyi et al. 1996).
3.3.7
Rationale for Biomarker Assessments
HR+ HER2- breast cancer is a heterogeneous disease, and PIK3CA/AKT1/PTEN 
alteration (Tri-AKT+) status has been shown to vary among patients (Cancer Genome 
Atlas Network 2012; Curtis et al. 2012).  In addition to the Tri-AKT 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 ipatasertib and/or palbociclib and 
fulvestrant.
3.3.7.1
Rationale for Using Circulating Tumor DNA (ctDNA) for 
Examining Tri-AKT Status
Activation of PI3K/AKT signaling frequently occurs in breast cancer through activating 
mutations in PIK3CA or AKT1 as well as through alterations in PTEN.  These alterations 
occur in approximately 45% of HR+ HER2- breast cancers (Pereira et al. 2016).  
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 
(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.  
Comparisons between plasma and tissue-based NGS showed that PIK3CA/AKT1
alterations detected in patients from the Phase II study GO29227 are largely concordant 
(Kim et al. 2017).  The use of ctDNA to identify the Tri-AKT status through NGS is a 
non-invasive and quantifiable method for patient stratification.
3.3.7.2
Rationale for the Collection of Tissue Samples 
To better understand the role of alterations detected in tissues, the use of archival tissue 
(i.e., sample from primary breast tumor) or a newly obtained biopsy at screening can be 
used to determine Tri-AKT status using NGS techniques, such as targeted sequencing.  
This approach offers a unique opportunity to further our understanding of breast cancer 
biology by molecular subtyping, as well as analyzing responses to agents targeting the 
PI3K/AKT/mTOR pathway, especially in the metastatic setting.  For example, 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 ipatasertib.
Tumor tissue may be collected at the time of disease 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 the 


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combination of ipatasertib plus palbociclib and fulvestrant is critical for the further 
development of agents in the PI3K/AKT pathway and may provide an opportunity to 
develop next-generation inhibitors to prevent resistance.
Progression biopsy tissue samples will aid in determining a resistance mechanism for 
the combination of ipatasertib plus palbociclib and fulvestrant, which may potentially 
influence future therapies for patients who progress on a PI3K/Akt inhibitor.  NGS will be 
performed by a clinical cancer genomic profiling laboratory (e.g., Foundation Medicine, 
Inc.).
See Section 4.5.8 for details on availability of results from the NGS testing. 
3.3.7.3
Rationale for Collection of DNA (Blood) for Exploratory Whole 
Genome Sequencing
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
Whole genome sequencing (WGS) provides a comprehensive characterization of the 
genome and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data may be analyzed in the 
context of this study but may also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For example, genetic variants of drug-metabolizing enzymes and transporters can alter 
the pharmacokinetics of drugs, affecting their safety and efficacy.  For example, patients 
who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1 (UGT1A1), which facilitates the metabolism and excretion 
of SN-38 (the active metabolite of irinotecan), are at higher risk for adverse events 
associated with the use of standard doses of irinotecan (O’Dwyer and Catalano 2006).  
Preliminary results from in vitro metabolism studies suggest that ipatasertib is primarily 
metabolized by the cytochrome P (CYP) 450 enzyme CYP3A, with a minor contribution 
by CYP2D6.  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, including differences in drug concentrations that the enzymes 
encounter in vitro and in vivo.  For this reason, a blood sample for DNA isolation will be 
collected from patients in this study (where approved locally) for potential 
pharmacogenetic analysis of genes or biomarkers that may affect the pharmacokinetics 
of ipatasertib in combination with palbociclib and fulvestrant.  The decision to analyze 
the samples will be based on a review of the PK data.  For example, if a patient in a 
given cohort has substantially higher ipatasertib plasma levels than other patients in that 
cohort, the patient may carry a defective allele of a gene important in the metabolism or 
transport of ipatasertib.  The genotyping efforts would be guided by results from in vitro 
metabolism studies and by results from ongoing clinical studies with ipatasertib.


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The pharmacogenetic analysis, if needed, will be performed on identifiable (referring to 
the blinded clinical trial number assigned to the patient at the time of randomization and 
not to the actual name or other protected health information of the patient) DNA samples, 
because it is necessary to link a patient’s PK data with genotype.  This analysis will be 
restricted to the evaluation of genes that may be involved in the pharmacokinetics of 
ipatasertib (e.g., drug metabolism, disposition, or elimination genes, or genes influencing 
these processes). 
In addition, tumor DNA can contain both reported and unreported chromosomal 
alterations resulting from the tumorigenesis process.  To help control for sequencing 
calls in previously unreported genomic alterations, the WGS blood sample will help 
determine whether an observed alteration identified in the tumor tissue is somatic 
throughout the evaluation of the DNA isolated in peripheral blood.  This sample for WGS 
will be collected if approved locally.
3.3.7.4
Rationale for Safety Biomarker Analysis
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
3.3.8
Rationale for the Pharmacokinetic Evaluation Schedule
In the Phase Ib portion, detailed sampling for PK characterization of ipatasertib and its 
metabolite G-037720, as well as palbociclib, is outlined in Appendix 4.  The sampling 
schedule is designed to enable the comparison of single-agent ipatasertib PK with 
ipatasertib PK in the presence of palbociclib to evaluate the effect of palbociclib on 
ipatasertib exposures. 
For the Phase III portion, a sparse sampling strategy will be applied to enable 
characterization of ipatasertib using population PK (popPK) methodology.  Samples for 
PK characterization of ipatasertib and its metabolite G-037720 as well as palbociclib will 
be collected as outlined in Appendix 2.
Palbociclib is metabolized, in part, by CYP3A and co-administration of itraconazole 
(a strong CYP3A inhibitor) increased the plasma exposure of palbociclib in healthy 
subjects by 87% (IBRANCE® U.S. Package Insert). Additionally, the clinical drug-drug 
interaction study with midazolam (a sensitive CYP3A substrate) showed a 2.2-fold 
increase in midazolam exposures in the presence of 600 mg ipatasertib 
(Study PAM4743g; see the Ipatasertib Investigator’s Brochure for details).  Therefore, as 
a mild-to-moderate inhibitor of CYP3A4, ipatasertib at 400 mg is not expected to change 
palbociclib exposures in a clinically meaningful way. However, palbociclib levels will 


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also be measured in both Phase Ib and Phase III as outlined in Appendix 4 and 
Appendix 2, respectively, to confirm. 
Ipatasertib is primarily metabolized by CYP3A (refer to Ipatasertib Investigator’s 
Brochure), and itraconazole, a strong CYP3A4 inhibitor, increased ipatasertib area under 
the concentration-time curve (AUC) and maximum concentration (Cmax) by approximately 
5-fold and 2-fold, respectively as observed in Study GP30057.  As a weak 
time-dependent inhibitor of CYP3A, palbociclib can potentially increase the plasma 
exposure of ipatasertib (refer to the local prescribing information for additional details for 
palbociclib) which has been taken into consideration in selecting the starting dose of 
ipatasertib in the Phase Ib portion (see Section 3.1.1). 
Although fulvestrant is a CYP3A4 substrate, strong CYP3A inhibitors and inducers did 
not have clinically relevant effect on fulvestrant disposition (Faslodex® package insert).  
Based on this, although ipatasertib is a mild-to-moderate inhibitor of CYP3A4 
(Study PAM4743g; see the Ipatasertib Investigator’s Brochure for details), ipatasertib is 
not expected to alter the exposure of fulvestrant in a clinical meaningful way.  
Fulvestrant is not an inhibitor or inducer of CYP3A (Faslodex® package insert), and 
therefore, it is not expected to alter plasma exposure of ipatasertib. Based upon the 
labeling, an analysis of fulvestrant pharmacokinetics does not seem warranted for this 
study, however PK of fulvestrant may be analyzed using remaining samples, if needed. 
Any PK samples that remain after the above evaluations have been completed may be 
used for exploratory evaluation of other analytes related to the administered drugs or 
biomarkers affecting their disposition and safety.  
3.3.9
Rationale for Patient-Reported Outcome Assessments
As metastatic breast cancer is not curable with currently approved and available 
therapies, the primary focus for patients is on living as long as possible and delaying the 
progression of cancer while maintaining their quality of life and the ability to carry out 
daily activities (Cardoso et al. 2012).  Research indicates that a higher proportion of HR+ 
patients have bone metastases compared to other subtypes which is often associated 
with pain (Irvin et al. 2011; Wood et al. 2016); thus, disease and treatment-related pain 
may be important components of the patient’s treatment experience.  Limited data are 
available characterizing the clinical presentation of disease in this population; however, it 
is hypothesized that progression of disease would be associated with an increase in pain 
symptoms.  Examining and measuring patients’ disease-related pain, treatment-related 
symptoms, and their interference with daily life is important to capture and will be 
assessed using validated PRO assessments in patients enrolled in the Phase III portion.
The “worst pain” item from the BPI-SF (Section 4.5.10.1 and Appendix 10) will be used 
to gain further insight into increase in pain severity. The EORTC QLQ-C30 will be 
administered to patients to assess disease symptoms including pain presence and 
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(see Section 4.5.10.2 and Appendix 11). The EORTC QLQ-BR23 will provide an 
additional assessment of treatment-related symptoms and symptoms that may occur 
with advanced disease (Section 4.5.10.3 and Appendix 12). As the EORTC QLQ-BR23 
was not developed or tested and validated with men, male patients in this study will 
not complete the QLQ-BR23 measure. In addition, selected symptomatic adverse event 
items from the Patient-Reported Outcomes Version of the Common Terminology Criteria 
for Adverse Events (PRO-CTCAE) and an additional item regarding bother due to side 
effects of treatment will be assessed (see Section 4.5.10.4 and Appendix 13).  The 
EQ-5D-5L (see Section 4.5.10.5 and Appendix 14) will also be collected and utilized to 
derive health states for use in economic models, and therefore the results will not be 
reported in the CSR (see Appendix 1 Phase III SOA for further administration details).
The BPI-SF worst pain item, EORTC QLQ-C30, EORTC QLQ-BR23, selected items 
from the PRO-CTCAE, and EQ-5D-5L will be completed in this order as applicable: 
BPI-SF first, followed by the EORTC-QLQ-C30 second, followed by the EORTC QLQ-
BR23 third, followed by the PRO-CTCAE fourth, and the EQ-5D-5L last. After 
treatment discontinuation, to minimize burden to patients and support market access 
requirements, the EORTC QLQ-C30 and EORTC QLQ-BR23 will be administered over 
the phone or in-clinic only once during the follow-up period at 3 months, while the 
BPI-SF and EQ-5D-5L will be administered over the phone or in-clinic at separate time 
points during the follow-up period of every 6 months for a duration of one year (see 
Appendix 1 [Phase III SOA]).
3.3.10
Rationale for Potential China Extension Cohort
To characterize the efficacy and safety profile of ipatasertib in combination with 
palbociclib and fulvestrant in a Chinese population to support a regulatory submission in 
China, a China extension phase may be included in the study.  See Section 6.9 for 
additional details.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 370 patients with HR+ HER2- locally advanced unresectable or 
metastatic breast cancer will be enrolled overall in this study in both the Phase Ib and 
the global enrollment portion of the Phase III.  After completion of the global enrollment 
phase, additional patients may be enrolled in an extended China enrollment phase.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment


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
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see 
Appendix 5)

Histologically documented HR+ HER2- adenocarcinoma of the breast that is locally 
advanced or metastatic and is not amenable to surgical or local therapy with 
curative intent

Documented ER and/or progesterone receptor positivity defined as 1% of tumor 
cell nuclei immunoreactive to the respective hormonal receptor based on most 
recent evaluable tumor biopsy as assessed locally (see Appendix 6 for additional 
information)

Documented HER2- as assessed locally based on most recent evaluable tumor 
biopsy defined as immunohistochemistry (IHC) score 0/1+, or an IHC score of 2
accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization 
test (FISH/CISH/SISH) indicating the absence of HER2 gene amplification, or a 
HER2/CEP17 ratio of 2.0 (see Appendix 7 for additional information)

Either male 
OR

Postmenopausal, defined as:
-
Age 60 years -OR-
-
Age 60 years AND have undergone bilateral oophorectomy, medically 
confirmed ovarian failure -OR-
-
Age 60 years AND have had cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause 
and have serum levels of estradiol and follicle-stimulating hormone within the 
laboratory’s reference range for postmenopausal females
OR 

Pre- or peri-menopausal and amenable to being treated with the LHRH agonist 
goserelin 
Patients must have started treatment with goserelin or an alternative LHRH 
agonist at least 14 days prior to first dose of study treatment.  If patients have 
received an alternative LHRH agonist prior to study entry, it is recommended 
that they switch to goserelin for the duration of the trial, whenever possible. See 
Section 3.1.3 for recommendations for male patients.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from
donating eggs as defined below:
Women must remain abstinent or use non-hormonal contraceptive methods 
with a failure rate of 1% per year during the treatment period and for 90 days 
after the final dose of study treatment (or longer if required per the local 
prescribing information).
Women must refrain from donating eggs during this same period.


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A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of non-hormonal contraceptive methods with a failure rate of 
1% per year include bilateral tubal ligation, male sterilization, and copper 
intrauterine devices.
Hormonal contraceptive methods may be used in accordance with specific 
country and local requirements for patients with breast cancer. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below:
With a female partner of childbearing potential who is not pregnant, men who 
are not surgically sterile must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of 1% 
per year during the treatment period and for 6 months after the final dose of 
study treatment (or longer if required per the local prescribing information).  
Men must refrain from donating sperm during this same period.
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 90 days after the final dose of study 
treatment (or longer if required per the local prescribing information) to avoid 
exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, locally recognized 
adequate methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form.

Patients must have experienced radiologic/objective relapse during adjuvant 
endocrine therapy or radiologic/objective disease progression during the initial 
12 months of 1L endocrine therapy in locally advanced unresectable or metastatic 
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Up to 20% of patients enrolled in the Phase III portion may have received a 
CDK4/6 inhibitor as part of their neoadjuvant/adjuvant endocrine therapy.
If a CDK4/6 inhibitor was included as part of a neoadjuvant/adjuvant
therapy, relapse must be 12 months since completion of the CDK4/6 
inhibitor portion of the neoadjuvant/adjuvant therapy.
Phase III portion only: Prior CDK4/6 inhibitor is not permitted for locally 
advanced unresectable or metastatic breast cancer (see Section 4.1.2).  
Phase Ib portion only: Prior CDK4/6 inhibitor is permitted and if previously 
treated with palbociclib, patient should have been on the 125-mg dose at the 
end of their palbociclib treatment period.

Radiologic/objective evidence of recurrence or progression to the most recent 
systemic therapy for breast cancer

Patients for whom endocrine-based therapy (e.g., palbociclib and 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.

At least one measurable lesion via RECIST v1.1 (see Appendix 9 for details)
Patients with bone only disease are not eligible even if a bone lesion qualifies 
as a measurable lesion. 
Bone lesions are generally followed as non-target lesions.  However, lytic bone 
lesions or mixed lytic–blastic lesions (unless previously irradiated), with 
identifiable soft tissue components, that can be evaluated by cross-sectional 
imaging techniques such as computed tomography (CT) or magnetic resonance 
imaging (MRI) may be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above.  Blastic bone 
lesions, however, are non-measurable.
Previously irradiated lesions (other than bone) may be considered as 
measurable disease only if progressive disease has been unequivocally 
documented at that site since radiation.  

Have adequate organ and marrow function as defined below:
-
ANC 1500 cells/L
-
Hemoglobin 9 g/dL 
-
Platelet count 100,000/L
-
AST and ALT 2.5upper limit of normal (ULN); with the following exception: 
Patients with liver or bone metastases may have AST and ALT 5ULN.
-
Alkaline phosphatase 2ULN (5ULN if liver metastases present; 7ULN 
if bone metastases present)
-
Total bilirubin 1.5ULN (3x ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome)
-
Serum albumin 3.0 g/dL


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-
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min as calculated 
using the method standard for the institution
-
Fasting glucose 150 mg/dL and hemoglobin A1c (HbA1c) 7.5%
-
PTT (or activated PTT [aPTT]) and INR 1.5ULN (except for patients 
receiving anticoagulation therapy)
Patients receiving heparin treatment should have a PTT (or aPTT) 
between 1.5 and 2.5ULN (or patient value before starting heparin 
treatment).  Patients receiving coumarin derivatives should have an INR 
between 2.0 and 3.0 assessed in two consecutive measurements 
1 to 4 days apart.

Life expectancy 6 months

Resolved or stabilized toxicities resulting from previous therapy to Grade 1
An ongoing Grade 2 non-hematologic toxicity related to the most recent 
treatment regimen may be permitted with approval from the Sponsor based on 
consultation with the Medical Monitor (ongoing toxicities alopecia, neuropathy, 
and hot flashes do not require Sponsor approval)

Phase III portion only:  Consent to provide tumor specimen from the most recently 
collected, available tumor tissue (formalin-fixed, paraffin-embedded [FFPE] block 
[preferred] or a minimum of 12 slides containing unstained, freshly cut, serial 
sections)
Cytologic or fine- needle aspiration samples and tumor tissue from bone 
metastases are not acceptable.  Alternatively, a newly collected tumor 
tissue sample may be provided.  

Phase III portion only: Valid Tri-AKT ctDNA test result by the central laboratory NGS
assay within 6 weeks prior to enrollment

For patients enrolled in the China extension portion (if opened) of the Phase III:  
current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 90 days after the final dose of study treatment (or longer if required per the 
local prescribing information).
Women of childbearing potential must have a negative serum pregnancy test 
result within 96 hours of first dose of study treatment. Alternatively, if a 
negative serum pregnancy test was obtained within 7 days of first dose of study 
treatment, it needs to be confirmed by a negative urine pregnancy test on the 
day of the first administration of study treatment prior to dosing.  

Prior treatment with fulvestrant or other SERDs, regardless of treatment setting


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
Prior treatment with PI3K inhibitor (such as alpelisib, taselisib, or buparlisib), mTOR 
inhibitor (such as everolimus) or AKT inhibitor (such as ipatasertib or capivasertib), 
regardless of treatment setting

Phase III portion only: Prior treatment with CDK4/6 inhibitor for locally advanced 
unresectable or metastatic breast cancer (see Section 4.1.1 for details on prior 
treatment of CDK4/6 inhibitor in the neoadjuvant/adjuvant setting)

Concurrent hormone replacement therapy

Prior treatment with a cytotoxic chemotherapy regimen for metastatic breast cancer
Note: there is no restriction on the number of prior cytotoxic chemotherapy 
regimens in the neoadjuvant or adjuvant setting

Phase III portion only: No more than one prior line of endocrine-based therapy for 
locally advanced unresectable or metastatic breast cancer 

Treatment with approved or investigational cancer therapy within 14 days prior to 
first dose of study treatment 
Local radiotherapy with palliative intent to non-target sites may be allowed 
within 14 days prior to first dose of study treatment if not feasible earlier and if 
discussed with the Medical Monitor (however, once irradiated, bone lesions are 
generally no longer evaluable). 

History of or known presence of brain or spinal cord metastases 
Patients with leptomeningeal carcinomatosis will be excluded. 

Uncontrolled pleural effusion, pericardial effusion, or ascites, as judged by the 
investigator

Uncontrolled tumor-related pain, as judged by the investigator 
Patients requiring narcotic pain medication must be on a relatively stable 
regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to first 
dose of study treatment.
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to first dose of study treatment 
(however, once irradiated, lesions are generally no longer evaluable)

Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use 
of bisphosphonate therapy 
Patients who are receiving bisphosphonate therapy specifically to prevent/treat 
skeletal events (e.g., bone metastasis, osteoporosis) and who do not have a 
history of clinically significant hypercalcemia are eligible. 

Nonstudy-related minor surgical procedures 5 days or major (invasive) surgical 
procedure 14 days prior to first dose of study treatment. 


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Patient must have sufficiently recovered from surgery and be stable, and wound 
healing must have occurred.

History of Type I or Type II diabetes mellitus requiring insulin 
Patients who are on a stable dose of oral diabetes medication 2 weeks prior to 
initiation of study treatment are eligible for enrollment.  Patients must meet the 
laboratory eligibility criteria for fasting blood glucose and HbA1c as outlined in 
the inclusion criteria.

History of or active inflammatory bowel disease (e.g., Crohn's disease and 
ulcerative colitis) or active bowel inflammation (e.g., diverticulitis) 

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, 
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia

Patients with active (chronic or acute) hepatitis C virus (HCV) at screening
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA.
Patients receiving anti-viral therapy for HCV are not eligible

Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test or a positive quantitative HBV DNA test at 
screening 
If a patient has a negative HBsAg test and a positive total hepatitis B core 
antibody (HBcAb) test, a quantitative HBV DNA test must be negative to be 
eligible.
Patients receiving anti-viral therapy for HBV are not eligible.

Known HIV infection

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
judgment

Active infection requiring systemic anti-microbial treatment (including antibiotics, 
anti-fungals, and anti-viral agents) 

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug or that 
may affect the interpretation of the results or render the patient at high risk from 
treatment complications

History of malignancy other than breast cancer within 5 years prior to screening with 
the following exceptions:
-
Appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, or Stage I uterine cancer


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-
Other malignancies where the patient has undergone potentially curative 
therapy with no evidence of disease and are deemed by the treating physician 
to have a recurrence rate of 5% at 5 years.

History of clinically significant cardiovascular dysfunction, including the following:
-
History of stroke or transient ischemic attack within 6 months prior to first dose 
of study treatment
-
History of myocardial infarction within 6 months prior to first dose of study 
treatment
-
New York Heart Association Class III or IV cardiac disease
-
Unstable arrhythmias, active ventricular arrhythmia requiring medication, or 
unstable angina
-
Congenital long QT syndrome or screening QT interval corrected using 
Fridericia's formula (QTcF) 480 milliseconds based on the mean value of the 
triplicate ECGs
-
History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion (including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction)

Presence of any other condition that may have increased the risk associated with 
study participation or may have interfered with the interpretation of study results, 
and, in the opinion of the investigator, would have made the patient inappropriate for 
entry into the study.

Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants 
for a chronic disease

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment 
(see Appendix 8 for examples of strong CYP3A inducers and inhibitors)

Malabsorption syndrome or other condition that would interfere with 
enteral absorption

Inability or unwillingness to swallow pills or receive intramuscular injections

Known or possible hypersensitivity to any of the study treatments, or to goserelin or 
alternative LHRH agonist (if applicable), including excipients


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This study includes an initial open-label Phase Ib safety portion and a randomized, 
double-blind, placebo-controlled Phase III portion. 
After written informed consent has been obtained, eligibility has been established and 
patient has been approved (Phase Ib only), the study site will obtain the patient’s 
identification number and treatment assignment (randomized Phase III portion, only) 
from the interactive voice/Web response system (IxRS). 
For patients in the randomized Phase III portion of the study, randomization will occur in 
a 1:1 ratio using a permuted-block randomization method.  Patients will be randomized
to one of two treatment arms.  The randomization scheme is designed to ensure that an 
approximately equal number of patients will be enrolled in each treatment arm within the 
stratum determined by the following stratification factors at baseline:

Relapse 2 vs 2 years during adjuvant endocrine therapy (Y/N/NA) 

Tri-AKT status by ctDNA (positive/negative)

Baseline liver metastasis (Y/N)

Geographic region 
–
Western Europe, United States, Canada, Australia
–
Asia
–
Rest of World (remaining countries) 
Study site personnel and patients will be blinded to treatment assignment during the 
randomized Phase III portion of the study.  The Sponsor and its agents will also be 
blinded to treatment assignment, with the exception of individuals who require access to 
patient treatment assignments to fulfill their job roles during a clinical trial. These roles 
include the unblinding group responsible, clinical supply chain managers, sample 
handling staff, operational assay group personnel, IxRS service provider, the 
Independent Data Coordinating Center (iDCC) facilitating the iDMC meetings, and iDMC 
members. 
While 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 the Phase III portion 
of this study.  Laboratories responsible for performing study drug PK assays for the 
Phase III portion will be unblinded to patients' treatment assignments to identify 
appropriate samples to be analyzed.  PK samples from patients assigned to the 
comparator arm will not be analyzed for study drug PK concentration except by request 
(e.g., to evaluate a possible error in dosing). 
If unblinding is necessary for a patient enrolled in the Phase III portion for a medical 
emergency (e.g., in the case of a serious adverse event for which patient management 
might be affected by knowledge of treatment assignment), the investigator will be able to 


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break the treatment code by contacting IxRS.  The investigator is not required to contact 
the Medical Monitor prior to breaking the treatment code; however, the treatment code 
should not be broken except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  Provided 
the patient progressed on this study or had to permanently discontinue study treatment 
due to unacceptable toxicity, unblinding may be permitted if an investigator is deciding 
whether a patient should initiate treatment with a proven therapy or alternatively may 
participate in a clinical trial where blinded treatment would be exclusionary but patient 
fulfills all remaining eligibility criteria after having been enrolled in this study.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  The investigator will be able to break the treatment code by contacting the 
IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are ipatasertib (RO5532961) 
or its placebo (in the randomized Phase III portion of the study), palbociclib, and 
fulvestrant. A pharmacy manual with additional details on IMP storage, handling, and 
administration will be provided by the Sponsor.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Ipatasertib and Placebo
Ipatasertib will be supplied by the Sponsor as 100-mg and 200-mg tablets in packaged 
bottles.  The ipatasertib placebo tablets (Phase III only) have been manufactured to 
match the size, shape, and color of the ipatasertib active tablets (100 and 200 mg) and 
are indistinguishable in appearance from the active ipatasertib tablets.  For information 
on the formulation and handling of ipatasertib/placebo, see the Ipatasertib Investigator’s 
Brochure and/or pharmacy manual as appropriate.
4.3.1.2
Palbociclib
Palbociclib will be supplied by the Sponsor as 125-mg, 100-mg, and 75-mg capsules
and as 125-mg, 100-mg, and 75-mg tablets once tablet supply can be provided by the 
Sponsor; therefore, palbociclib is being referred to as capsule/tablet. For information on 


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the formulation, packaging, and handling of palbociclib as well as the safety profile, refer 
to the local prescribing information and/or pharmacy manual as appropriate.
4.3.1.3
Fulvestrant
Fulvestrant will be supplied by the Sponsor in all participating countries, except the 
countries where procurement will be reimbursed.  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 information on the formulation, 
packaging, and handling of fulvestrant as well as the safety profile, refer to the local 
prescribing information and/or pharmacy manual as appropriate.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1 and Section 3.1.2.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.4.
4.3.2.1
Ipatasertib and Placebo
For patients enrolled in the Phase Ib portion only, ipatasertib will be open label and will 
be administered orally in the clinic on Day -7 to Day -5, on Cycle 1 Day 1 and on each 
subsequent cycle visit and will be taken at home on non-clinic visit days based on the 
21/7 dose schedule (see Figure 2).  Ipatasertib is initially given orally for 5-7 days as a 
single agent prior to Cycle 1, Day 1.  On Cycle 1, Day 1, ipatasertib will be administered 
approximately 6 hours prior to palbociclib and fulvestrant to enable collection of 
post-dose samples (see Appendix 4), that is, palbociclib and fulvestrant will be 
administered after the PK sampling of ipatasertib for Cycle 1, Day 1 is completed.  
Starting from Cycle 1, Day 2, palbociclib will be given together with ipatasertib.  For the 
first cycle, ipatasertib will be administered continuously for 26 to 28 days given the 
Day -7 to Day -5 window for the start of the single-agent ipatasertib run-in; however, 
starting with Cycle 2, Day 1 ipatasertib will be taken orally once daily on Days 121 of 
each 28-day cycle (see Figure 2).
In the randomized Phase III portion of the study, ipatasertib/placebo is given orally once 
daily on Days 121 of each 28-day cycle.  Ipatasertib/placebo will be administered in the 
clinic on Cycle 1 Day 1 and on each subsequent cycle visit; it will be taken at home on 
non-clinic visit days based on the 21/7 dose schedule.
Ipatasertib/placebo may be taken with or without food.  If a dose is missed (i.e., not 
taken within approximately 8 hours after the scheduled dosing time), the patient should 


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resume dosing with the next scheduled dose.  Missed or vomited doses will not be made 
up.  If ipatasertib/placebo cannot be safely administered during any of the Days 121 of 
any 28-day cycle, it is permitted to make up for the missed doses on any of the Days 
2228, if safe to do so.  
On study days requiring a predose blood draw for PK sampling, patients will be 
instructed to take their daily oral dose of ipatasertib/placebo in the clinic after completion 
of the pretreatment assessments (see Appendix 1 [Phase III SOA] and Appendix 3
[Phase Ib SOA]).  Ipatasertib/placebo should be taken at approximately the same time 
each day, and ideally, the time of dosing outside the clinic should be the same as the 
time of dosing during the clinic visit. Time of dose administration will be collected on the 
PK sampling day and for prior doses administered, for up to 2 days before a PK 
sampling visit. Importantly, the dosing time should be the same or similar on the 3 days 
prior to and on the day of the PK visit. Any incidence of vomiting within 3 hours post 
drug administration should also be recorded for the day of PK sampling. 
A sufficient amount of ipatasertib/placebo should be provided to the patient to last one 
treatment cycle. Notably, there is one extra dose of ipatasertib/placebo in each bottle.
This may be explained to the patient to minimize the risk that the patient mistakenly 
takes the extra dose. Patients will be instructed to bring their bottles of 
ipatasertib/placebo and their medication diaries to each study visit. Patients should use 
their medication diary to record daily ipatasertib/placebo dosing taken as applicable. 
4.3.2.2
Palbociclib
In both open-label Phase Ib and the randomized Phase III portion of this study, 
palbociclib is given PO QD on Days 121 of each 28-day cycle.  Palbociclib will be 
administered in the clinic on Cycle 1 Day 1 and each subsequent cycle visit and will be 
taken at home on non-clinic visit days based on the 21/7 dose schedule.  Palbociclib 
should be taken at approximately the same time each day. Palbociclib capsules are 
taken with food to reduce the intersubject variability of palbociclib exposure (IBRANCE®
U.S. Package Insert). Palbociclib tablets, in contrast, may be taken with or without 
food (refer to the local prescribing information for additional details). If the patient 
vomits or misses a dose, an additional dose should not be taken. The next prescribed 
dose should be taken at the usual time. Palbociclib capsules/tablets should be 
swallowed whole (they should not be chewed, crushed, or opened/split prior to 
swallowing). Capsules/tablets should not be ingested if they are broken, cracked, or 
otherwise not intact. Patients will be instructed to bring their bottles/blister cards (as 
applicable) of palbociclib and their medication diaries to each study visit. Patients 
should use their medication diary to record daily palbociclib dosing taken as applicable.
Refer to the local prescribing information for more details.


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4.3.2.3
Fulvestrant
Fulvestrant 500 mg will be administered in the clinic as two intramuscular injections of 
250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day cycle. 
Refer to the local prescribing information for more details.
For patients enrolled in the Phase Ib portion, it is recommended that fulvestrant be 
administered prior to the oral medications, ipatasertib and palbociclib, during all clinic 
visits following Cycle 1, Day 1. In contrast, on Cycle 1, Day 1, ipatasertib is 
administered first (see Section 4.3.2.1).  For patients enrolled in the Phase III portion, it 
is recommended that fulvestrant be administered prior to the oral medications, 
ipatasertib/placebo and palbociclib, during all clinic visits.
4.3.2.4
Goserelin
Goserelin is a non-IMP in this study for pre- or peri-menopausal women who must have 
started treatment with goserelin or an alternative LHRH agonist at least 14 days prior to 
first dose of study treatment. For men, treatment with goserelin or alternative LHRH 
agonist therapy is recommended beginning at least 14 days prior to first dose of study 
treatment and continuing for the duration of study treatment. If patients have received 
an alternative LHRH agonist prior to study entry, it is recommended that they switch to 
goserelin for the duration of the trial, whenever possible.  Every effort should be made to 
administer goserelin or alternative LHRH agonist as applicable on site at the time of 
fulvestrant administration as applicable in order to minimize the number of clinic visits. 
Patients may self-administer goserelin or alternative LHRH agonist as applicable at 
home per local standard of care if the administration does not coincide with a clinic visit. 
In that case, patients will complete a diary.
Refer to the local prescribing information for more details.
4.3.2.5
Loperamide
Loperamide is a non-IMP in this study.  All patients should receive loperamide (2 mg PO 
twice a day [BID] or 4 mg QD) as prophylaxis for diarrhea upon start of study treatment 
through the first cycle if allowed by local guidance.  Investigators are encouraged to 
continue this dosing for the remainder of the study; the prophylaxis dose may be 
adjusted as necessary, using their discretion based on clinical judgment and per local 
guidance.  Patients should use their medication diary to record loperamide dosing taken 
as applicable.
See Section 5.1.4.5.1 for additional details on loperamide use for treatment emergent 
diarrhea.
Refer to the local prescribing information for more details.


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4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (i.e., ipatasertib or its placebo, palbociclib 
and fulvestrant) will be provided by the Sponsor where required by local health authority 
regulations.  The study site will acknowledge receipt of IMPs supplied by the Sponsor, 
using the IxRS.  Any damaged shipments will be replaced, if needed.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Ipatasertib
Currently, the Sponsor does not have any plans to provide the Roche IMP (ipatasertib) 
or any other study treatments or interventions to patients who have completed the study.  
The Sponsor may evaluate whether to continue providing ipatasertib in accordance with 
the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
However, patients may be eligible to receive ipatasertib as part of an extension study if 
the Sponsor elects to initiate an extension study while this study is ongoing.  
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug to the study completion/discontinuation visit or up to 
30 days after last dose if medication was given for an Adverse Event, whichever is 
longer.  All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF (see Section 4.5.2 for additional information for specific 
concomitant medications).
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Loperamide as prophylaxis for diarrhea (racecadotril as used in Europe)


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See Section 4.3.2.5 for further details. Patients who experience diarrhea should 
be on treatment doses of loperamide per the management guidelines (see 
Section 5.1.4.5.1).

Goserelin or alternative LHRH agonist (as applicable for pre- or peri-menopausal 
women and men, see Section 4.3.2.4 and Section 4.1.1) 

Bisphosphonate therapy or receptor activator of nuclear factor kappa-Β ligand 
(RANKL) inhibitor therapy
Bisphosphonate therapy (e.g., zoledronic acid) or RANKL inhibitor therapy 
(e.g., denosumab) used specifically to prevent skeletal events (e.g., bone 
metastasis, osteoporosis) are allowed.
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
at the discretion of the investigator. Antihistamine prophylaxis for potential adverse 
event of rash may be considered for the first cycle and as clinically indicated for 
subsequent cycles. Note that primary prophylactic use of hematopoietic growth factors 
(e.g., erythropoietins, granulocyte colony-stimulating factor [G-CSF], and GM-CSF) is 
not permitted. However, they may be used to treat treatment-emergent neutropenia or 
anemia or as secondary prophylaxis if dose reduction or delay is not considered a 
reasonable alternative. The Medical Monitor may be consulted for further clarification.
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  
4.4.2
Cautionary Therapy
Palliative radiotherapy is permitted for the treatment of known bony metastases or 
symptomatic relief of pain provided it does not interfere with the assessment of tumor 
target lesions (e.g., the lesion to be irradiated must not be a site of measurable disease).
For patients who require radiation or surgery as part of medical treatment in the absence 
of radiographic disease progression, investigators must exercise caution.  
Ipatasertib/placebo should be temporarily held for at least 7 days before, if feasible, and 
7 days after the procedure.  For minor surgery or single-day radiotherapy, the 
ipatasertib/placebo hold may be shorter, if approved by the Medical Monitor.  After the 
temporary treatment hold is complete, ipatasertib/placebo may be re-initiated when the 
patient has sufficiently recovered.  Fulvestrant should not be administered on the day of 
surgery or radiation therapy, but otherwise, dosing does not generally need to be 
interrupted. Surgery should be performed after neutropenia and/or thrombocytopenia 
has been resolved whenever possible.  Palbociclib may be held temporarily per 
investigator judgment. 
Live vaccines should be used with caution and preferably only administered in patients 
not experiencing neutropenia or once neutropenia has resolved to Grade 1 or below. 


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Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events (see Section 5 for details).  Ipatasertib/placebo 
should be temporarily held during systemic corticosteroid treatment.
4.4.2.1
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
In vitro data suggest that ipatasertib is metabolized by CYP3A and may be a 
time-dependent inhibitor of CYP3A.  A clinical drugdrug interaction study with 
midazolam (a sensitive CYP3A substrate) showed a 2.2-fold increase in midazolam 
exposures in presence of steady-state ipatasertib dosed at 600 mg QD.  
Given that ipatasertib is primarily metabolized by CYP3A, there is a high potential for 
drugdrug interactions of ipatasertib with any medication that strongly inhibits or induces 
CYP3A.  Data from clinical studies showed that ipatasertib exposures were reduced by 
~50% when co-administered with enzalutamide, a strong CYP3A inducer and a strong 
CYP3A inhibitor itraconazole increased ipatasertib exposures by 5-fold.  
In vitro data indicate that CYP3A and SULT2A1 are mainly involved in the metabolism of 
palbociclib and palbociclib is a weak time-dependent inhibitor of CYP3A. 
Co-administration of midazolam with multiple doses of palbociclib increased the 
midazolam exposure by 61%. Palbociclib exposures decreased by 85% with 
co-administration of rifampin, a strong CYP3A inducer. Co-administration of 
itraconazole with palbociclib increased palbociclib exposures by approximately 87%.
Therefore, the following drugs, and those listed in Appendix 8, should be used with 
caution when palbociclib and ipatasertib/placebo are given: 

Drugs that are strong CYP3A inhibitors, strong CYP3A inducers, and sensitive 
CYP3A substrates with narrow therapeutic window should be used with caution 
when these drugs need to be given intermittently for medical treatment.  
Ipatasertib/placebo should be temporarily held until at least 7 days after the last 
dose of strong CYP3A inhibitors and sensitive CYP3A substrates with a narrow 
therapeutic window. Avoid concurrent use of palbociclib with strong CYP3A 
inducers and with strong CYP3A inhibitors. If patients must be co-administered a 
strong CYP3A inhibitor, refer to the local prescribing information for guidance on the 
palbociclib dose.  See Section 4.4.3 for further details on chronic use of strong 
CYP3A inhibitors, strong CYP3A inducers, and sensitive CYP3A substrates.

Drugs that are moderate CYP3A inhibitors should be used with caution 

Since palbociclib and ipatasertib have overlapping CYP3A interactions, please refer 
to the ipatasertib Investigator’s Brochure and to the local prescribing information for 
palbociclib for concomitant medication use for CYP3A inhibitors, CYP3A inducers, 
and sensitive CYP3A substrates with narrow therapeutic window.


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Patients should be closely monitored.  Refer to the following information for further 
guidance on CYP450 -drug interactions and a list of common substrates, inhibitors, and 
inducers:
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors, and Inducers 
(U.S. FDA):
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm
The lists of medications (see Appendix 8 and link above) are not necessarily 
comprehensive.  The investigator should consult the prescribing information when 
determining whether a concomitant medication can be safely administered with study 
treatment.  In addition, the investigator should contact the Medical Monitor if questions 
arise regarding medications not listed above.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer may be 
used during the study at the discretion of the investigator.  Herbal therapies that require 
caution or are prohibited due to CYP interactions, such as St. John’s wort, are described 
in Section 4.4.2.1 and Section 4.4.3, respectively.
4.4.3
Prohibited Therapy, Foods, and Supplements
Use of the following concomitant therapies is prohibited as described below:

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 14 days prior to initiation of study treatment and during study treatment.

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy [other than study treatment fulvestrant as well 
as goserelin for pre- and peri-menopausal women], immunotherapy, radiotherapy, 
and herbal therapy) is prohibited for various time periods prior to starting study 
treatment, depending on the agent (see Section 4.1.2), and during study treatment, 
until disease progression is documented and the patient has discontinued study 
treatment, with the exception of palliative radiotherapy and local therapy under 
certain circumstances (see Section 4.1.2 for details).

Chronic use of strong CYP3A inhibitors, strong CYP3A inducers (see Appendix 8 for 
examples), or sensitive CYP3A substrates with narrow therapeutic window (refer to 
drug label) is prohibited within 14 days (or 5 drug-elimination half-lives, whichever is 
longer) prior to and during the study treatment period and for 7 days after the last 
dose of study treatment.  Grapefruit juice, a potent CYP3A inhibitor, and St. John’s 
wort, a potent CYP3A inducer, are also prohibited for similar duration.

Primary prophylactic use of hematopoietic growth factors (e.g., erythropoietins, 
granulocyte colony-stimulating factor [G-CSF], and GM-CSF) is not permitted 
(see Section 4.4.1 for use for treatment-emergent events or secondary prophylaxis).


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4.4.4
Additional Restrictions
No food or fluids other than water will be allowed for 8 hours prior to each study visit until 
after study laboratory samples for fasting glucose and fasting lipid profile, as applicable, 
are obtained.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1
(Phase III SOA) and Appendix 3 (Phase Ib SOA).  All activities should be performed and 
documented for each patient.
Patients will be closely monitored for safety and tolerability throughout 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-related procedures (including screening evaluations) and may be 
obtained more than 6 weeks before initiation of study treatment.  Informed Consent 
Forms for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. Patient re-screening may be considered under certain 
circumstances, after approval by the sponsor based on consultation with the Medical 
Monitor, as needed.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and reproductive status, will be 
recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
In addition, to assess the actual use of analgesic (Phase III only), and anti-diarrheal 
medications outside of the clinic/hospital setting, patients will complete a medication 
diary.  Patients will receive the diary at the start of the ipatasertib run-in period (Phase 
Ib only) and on the first day of each cycle, with site staff completing relevant information 
on any prescribed analgesic or anti-diarrheal medications, including the recommended 
dosage and route of administration.  The intake of analgesic medication (Phase III only), 


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and loperamide (or other anti-diarrheal) medication will be reported in the corresponding 
eCRFs.
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
will be captured to assess if any differences in safety exist based on this entry.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, as 
specified in Appendix 1 (Phase III SOA) and Appendix 3 (Phase Ib SOA), should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature as 
specified in Appendix 1 (Phase III SOA) and Appendix 3 (Phase Ib SOA).
4.5.5
ECOG Performance Status
Performance status will be completed at screening and as specified in the SOA (see 
Appendix 1 [Phase III SOA] and Appendix 3 [Phase Ib SOA]) using the ECOG 
performance status scale (see Appendix 5) and recorded on the eCRF.
4.5.6
Tumor and Response Evaluations
All known sites of disease must be documented at screening (baseline) and re-assessed 
at each subsequent tumor evaluation, post-baseline.  Post-baseline tumor assessments 
should be performed every 8 weeks 7 days from Cycle 1 Day 1 regardless of dose 
delay, treatment interruption, or early treatment discontinuation until disease progression.


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Screening (baseline) tumor assessments should include CT scans of the chest, 
abdomen, and pelvis and be performed 28 days before Cycle 1, Day 1 (or first dose of 
study treatment for Phase Ib patients).  CT scans of the neck and brain imaging should 
be included if clinically indicated.  Screening (or documented standard of care [SOC]) 
bone scans (technetium) should be performed within 6 weeks before Cycle 1, Day 1 (or 
first dose of study treatment for Phase Ib patients).  A documented standard-of-care 
tumor assessment performed within 28 days before Cycle 1, Day 1 (or first dose of study 
treatment for Phase Ib) may be used for the screening assessment, provided it meets 
the following requirements that apply to all study specific tumor assessments: 

CT scans are the preferred imaging modality for tumor assessments.  Tumor 
assessments should include a diagnostic quality, contrast-enhanced CT scan of the 
chest, abdomen, and pelvis.  To be suitable for RECIST assessments, CT scans 
should have a maximum slice thickness/interval of 5 mm and no gaps.

In patients for whom a CT scan is contraindicated because of an allergy to 
intravenous (IV) radiographic contrast both a CT scan of the chest without contrast 
and an MRI scan of the abdomen and pelvis with contrast are recommended.

MRI scans may be performed in lieu of CT scans.  However, an MRI scan of the 
chest may be performed only with the approval from the Sponsor based on 
consultation with the Medical Monitor.
For patients with bone metastases, subsequent post-baseline bone scans should be 
performed with every other tumor assessment starting from Week 16 (7 days), unless 
the bone lesions are followed via CT scan or other imaging modality (MRI or X-ray) 
during the regular tumor assessments every 8 weeks (7 days), in which case additional 
post-baseline bone scans are only needed as clinically indicated.  Bone disease and any 
changes in bone imaging should be evaluated radiographically by CT scan, MRI, or 
X-ray to verify the presence of bone destruction versus a healing reaction.  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. 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]).
Response assessments will be made by the investigator on the basis of physical 
examinations and imaging (CT, MRI, and bone scans) through use of RECIST v1.1 
criteria (see Appendix 9).
To ensure a valid comparison of tumor data and uniformity in the assessment of tumor 
response during the study, the following procedures should be implemented at the study 
site:

All lesions identified at baseline (target and non-target) will be reassessed using the 
same imaging method throughout the course of the study.  The same radiographic 
procedure used to assess disease sites at screening should be used throughout the 


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study (e.g., the same contrast protocol for CT scans).  Assessments should be 
performed by the same evaluator to ensure internal consistency across visits.  

All CT scans and other relevant imaging, such as 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 patients with bone metastases should also be 
reviewed similarly.

For patients in the Phase III portion only:  All radiological data (e.g., CT scan, MRI, 
bone scan) and photos for skin lesions obtained at baseline, during the treatment 
period, and the follow-up period should be sent to a central imaging vendor 
contracted by the Sponsor within 2 weeks of imaging to enable retrospective blinded 
independent central review when needed.  Additional details will be outlined in the 
statistical analysis plan and 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.

Confirmation of an objective response is only valid when the repeat assessments 
are performed 4 weeks after initial documentation.
At the investigator’s discretion, and if clinically indicated, tumor assessments may be 
repeated at any time if progressive disease is suspected.  For symptomatic deterioration 
attributed to disease progression (clinical progression), every effort should be made to 
document progression through use of objective criteria per RECIST v1.1.  
Note:  Pathologic fracture, new compression fracture, or bone metastases complications 
will not be considered generally as evidence of disease progression unless there is 
radiographic progression per RECIST v1.1.  See Section 4.5.7 for the assessment of 
SREs.  Patients with symptoms of rapidly progressing disease without radiographic (or 
photographic) 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 9.
Patients in the randomized Phase III portion who discontinue study treatment for any 
reason other than radiographic disease progression per RECIST v1.1, will be followed 
every 8 weeks 7 days for tumor assessments until documented progression per 
RECIST v1.1 or death, whichever occurs first.
After the primary PFS analysis has been completed, tumor assessments may be done 
per local SOC. 
Patients who are enrolled in the Phase Ib portion of the study may have post-baseline
tumor assessments done per local SOC as the efficacy data will not be part of the 
primary PFS analysis. 


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4.5.7
Skeletal-Related Events Assessment
For this study, an SRE is defined as a pathologic fracture, radiation therapy to the bone, 
surgery to the bone, or a spinal cord compression.  The investigator assessment for 
each adverse event, radiation or surgery relating to the bone or spinal cord, should be 
reported in the patient chart and in the corresponding eCRF.  Patients in the Phase III 
portion should be monitored for any SREs during the study treatment and adverse event 
follow-up period of the study (see Appendix 1 [Phase III SOA], and Section 5.5).
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Laboratory samples should be drawn according to the schedule of activities (see 
Appendix 1 [Phase III SOA] and Appendix 3 [Phase Ib SOA]).  Results of the following 
assessments should be available for review at each clinic visit (as required per SOA) 
prior to dosing to inform dosing decisions:  complete blood count, fasting glucose, 
bilirubin, total ALP, AST, and ALT.
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  RBC count, hemoglobin, hematocrit, WBC count with differential (i.e., 
must be sufficient for the determination of ANCs, lymphocytes), and platelet count

Fasting serum chemistry:  glucose (following 8-hour fast, plasma glucose is also 
acceptable per local practice), BUN (or urea), bicarbonate (or total carbon dioxide), 
creatinine, sodium, potassium, magnesium, calcium, phosphorus, albumin, total 
bilirubin, ALP (total ALP), AST, and ALT
For investigational sites in countries where bicarbonate (or total carbon dioxide) 
may not be collected as part of the standard chemistry panel, bicarbonate (or 
total carbon dioxide) will not be measured.

Home glucose monitoring:  for any patients who initiate home glucose monitoring as 
a result of treatment emergent hyperglycemia (see Section 5.1.4.5.2 for 
management guidelines of fasting hyperglycemia), a glucose log will be made 
available for capturing these results.

Glycosylated hemoglobin (HbA1c)

Amylase and lipase

Fasting lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, 
triglycerides) performed following a 8 hour fast

Urinalysis (dipstick allowed): pH, specific gravity, glucose, protein, ketones, and 
blood; microscopic examination if clinically indicated 

Screening viral serology:  HBsAg, total HBcAb, HCV antibody
Additional tests for HBV DNA or HCV RNA may be required to confirm eligibility 
(see Section 4.1.2).

HIV serology: as per local standard, after any applicable local consenting 
requirements

Coagulation:  PTT (or aPTT) and INR


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
Pregnancy test (see Section 4.1.2 regarding eligibility requirements)
The following samples will be sent to the Sponsor or a designee for analysis:

Plasma samples for PK analysis of ipatasertib, G-037720, palbociclib and possibly 
fulvestrant (see Appendix 2 and Appendix 4 for details) 

Optional tumor biopsy (see Appendix 1 [Phase III SOA] and Appendix 3 [Phase Ib 
SOA])

Blood samples for WGS (if approved locally)
If approved by the local regulatory authority, gene mutations will be assayed by 
WGS or other acceptable methodology such as multiplex PCR or allele-specific 
PCR.  Results may be correlated to ipatasertib exposure or other clinical 
measures to better understand the impact of genetic variants on drug 
metabolism, exposure, adverse events, and/or response (see Section 4.5.11 for 
more details).

Biomarker assays in blood, tissue, and plasma
–
Blood samples acquired from all patients at screening will be processed to 
obtain plasma for the determination of Tri-AKT tumor status, as defined by 
baseline ctDNA. For patients in the Phase III portion a valid test result will be 
required for patient stratification.
–
Plasma samples will be collected at predefined timepoints during treatment 
(see Appendix 1 [Phase III SOA] and Appendix 3 [Phase Ib SOA]), and at the 
time of disease progression for the determination of changes in blood-based 
biomarkers (e.g. ctDNA).
–
Tissue biopsies (tissue blocks or unstained slides) may be processed for 
protein marker analysis (IHC) or for their derivatives (e.g. RNA, DNA, protein).

For patients in the Phase III portion only: Archival or newly collected tumor tissue 
sample obtained at baseline for determination of PIK3CA/AKT1/PTEN status and for 
exploratory research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at 
minimum of 12 slides containing unstained, freshly cut, serial sections must be 
submitted along with an associated pathology report prior to study enrollment.  
If only 10 slides are available, the patient may still be eligible for the study, after 
Sponsor approval has been obtained.  Sponsor may consider approving up to 
15 patients with fewer than 10 slides, thus sites may contact Sponsor if fewer 
than 10 but at least 8 slides are available.  
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Samples collected via resection, core-needle biopsy (at least three cores, 
embedded in a single paraffin block), or excisional, incisional, punch, or forceps 
biopsy are acceptable.  Fine-needle aspiration (defined as samples that do not 
preserve tissue architecture and yield cell suspension and/or smears), brushing, 


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cell pellets from pleural effusion, and lavage samples are not acceptable.  
Tumor tissue from bone metastases that have been decalcified is not 
acceptable.
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required. 
Exploratory biomarker research methods on the above biomarker samples may include, 
but will not be limited to, NGS, PCR, RNASeq, IHC, and proteomics-based approaches.  
These methods will be used to identify somatic mutations or signatures of mutations that 
are predictive of response to study drug, are associated with disease progression, are 
associated with acquired resistance to the study medications, or that can increase the 
knowledge and understanding of disease biology.  NGS methods will not include WGS. 
NGS may be performed by Foundation Medicine, Inc. or other central laboratory
selected by the Sponsor. Depending on the central laboratory performing the test, the 
investigator may obtain results from these analyses by requesting an NGS report upon 
patient’s screen failure or progression of disease.  If allowed by local laws, the 
investigator may share and discuss the results with the patient, unless the patient 
chooses otherwise.  The NGS report is generated for research purposes and is not 
provided for the purpose of guiding future treatment decisions.  Results may not be 
available for samples that do not meet criteria for testing.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.13), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Plasma samples collected for PK analysis may be needed for additional PK 
characterization and assay development and validation; therefore, these samples 
will be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Blood, plasma and tissue samples collected for biomarker research will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
Institutional Review Board/Ethics Committee (IRB/EC) approved Informed Consent 
Form and applicable laws (e.g., health authority requirements).

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination.


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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from the central 
laboratory which may be requested at screen failure or progression of disease).  The 
aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication.
4.5.9
Electrocardiograms
Triplicate ECG recordings will be obtained at baseline to determine eligibility (see 
Section 4.1.2).  Additional single ECG recordings will be obtained as outlined in the 
schedule of activities (see Appendix 1 [Phase III SOA] and Appendix 3 [Phase Ib SOA]). 
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.
4.5.10
Patient-Reported Outcomes
PROs will be collected to more fully characterize ipatasertib in combination with 
palbociclib and fulvestrant compared with placebopalbociclibfulvestrant in patients 
enrolled in the randomized Phase III portion of the study.  PRO data will be collected via 
paper questionnaires at the clinic sites using the following instruments: BPI-SF “worst 
pain” item, EORTC QLQ-C30, EORTC QLQ-BR23, select items of the PRO-CTCAE, 
and the EQ-5D-5L.  The questionnaires, translated into the local language as 
appropriate, will be distributed by the site staff and completed in their entirety by the 
patient at baseline (Cycle 1, Day 1) and at subsequent timepoints as noted in the 
schedule of assessments (see Appendix 1 [Phase III SOA]).  To minimize burden to 
patients and support market access requirements, after treatment discontinuation, the 


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EORTC QLQ-C30 and EORTC QLQ-BR23 will be administered over the phone or in-
clinic only once during the follow-up period at 3 months, and the BPI-SF and EQ-5D-
5L will be administered over the phone or in-clinic every 6 months for a duration of 1 
year.  To ensure instrument validity and that data standards meet health authority 
requirements, questionnaires will be self-administered or interviewer-administered (as 
appropriate; see below) before the patient receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of 
study treatment, unless otherwise specified.
It is common for patients to complete laboratory assessments before a scheduled clinic 
visit.  Completion of PROs after laboratory tests is permitted so long as there is no prior 
discussion of the patients’ laboratory results or health record with clinic staff and that the 
PROs are completed before drug administration. 
For patients who are unable to complete the measures on their own, interviewer 
assessment is allowed but can only be conducted by a member of the clinic staff who 
reads the questionnaire items to the patient verbatim; no interpretation, rephrasing, or 
rewording of the questions is allowed during interview-assisted completion. 
Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site and should ask the patient to rectify any response that is 
not clearly marked in the appropriate location.  If a response is missing, site staff should 
ask the patient to complete the item or confirm that the item was intentionally left blank.
Hard copy originals of the questionnaires must be maintained as part of the patient’s 
medical record at the site for source data verification.  These originals should have the 
respondent’s initials, study patient number and date, and time of completion recorded in 
compliance with good clinical practice.  Sites will enter patient responses to the PRO 
questionnaires into the electronic data capture (EDC) system.
4.5.10.1
BPI-SF “Worst Pain” Item
The BPI-SF (see Appendix 10) is a widely used patient-reported outcome measure for 
assessing pain, and the “worst pain” item is frequently recommended for evaluating 
increases in the severity of pain (Cleeland, 2009; Shi et al., 2009). The item asks 
patients to rate their pain at its worst in the last week on a scale from 0 to 10. The 
BPI-SF worst pain item takes approximately 1 minute to complete.
4.5.10.2
EORTC QLQ-C30
The EORTC QLQ-C30 (see Appendix  is a validated and reliable self-reported measure 
(Aaronson et al. 1993; Sprangers et al. 1996; Fitzsimmons et al. 1999).  It consists of 30 
questions that assess 5 aspects of patient functioning (physical, emotional, role, 
cognitive, and social), eight symptom scales (fatigue, nausea and vomiting, pain, 
dyspnea, insomnia, appetite loss, constipation, and diarrhea), financial difficulties, and 
GHS/QoL with a recall period of the previous week.


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The EORTC QLQ-C30 data will be scored according to the EORTC scoring manual 
(Fayers et al. 2001).  Scale scores will be obtained for each of the multi-item and 
single-items scales by using a linear transformation for standardization of the calculated 
raw score.  The EORTC QLQ-C30 takes approximately 10 minutes to complete.
4.5.10.3
EORTC QLQ-BR23
The EORTC QLQ-BR23 (see Appendix 12) breast cancer module is meant for use 
among women diagnosed with breast cancer (Sprangers et al. 1996). The breast cancer 
module incorporates five, multiple-item scales to assess systemic therapy side effects, 
arm symptoms, breast symptoms, body image, and sexual functioning. In addition, 
single items assess sexual enjoyment, hair loss, and future perspective. The EORTC 
QLQ-BR23 takes approximately 10 minutes to complete. Because the QLQ-BR23 was 
not developed or tested and validated with men, male patients in this study will not 
complete the QLQ-BR23 measure.
4.5.10.4
PRO-CTCAE
The PRO-CTCAE (see Appendix 13) is an item bank reflecting 78 symptomatic adverse 
events rated according to their severity, interference with daily function, frequency, 
and/or occurrence.  The item bank was designed and validated as a repository of 
standalone items (Basch et al. 2014).  PRO-CTCAE will be completed per the Schedule 
of Activities (see Appendix 1 [Phase III SOA]), if available in the patient’s preferred 
language.
Only adverse events that are patient self-reportable (Basch et al. 2014) were selected 
for assessment in this study.  Adverse events of which assessments rely on laboratory 
testing (e.g., neutropenia) that are presented as being primarily asymptomatic or with 
nonspecific signs and symptoms were disregarded.  Adverse events that did not have an 
identifiable symptom equivalent in the PRO-CTCAE were also excluded.  Based on the 
above criteria, 7 symptomatic adverse events that have been associated with ipatasertib 
or palbociclib and fulvestrant treatment were selected from the PRO-CTCAE item bank:  
diarrhea, nausea, vomiting, decreased appetite, fatigue, mouth sores, and rash 
symptoms. An additional question from the PRO-CTCAE providing an overall 
assessment of the burden of side effects will also be collected. The PRO-CTCAE takes 
approximately 5 minutes to complete.
4.5.10.5
EQ-5D-5L
The EQ-5D-5L (see Appendix 14) is a validated self-report health status questionnaire 
that is used to calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There 
are two components to the EQ-5D-5L:  a five-item health state profile that assesses 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a 
VAS that measures health state.  Published weighting systems allow for creation of a 
single composite score of the patient's health status.  The EQ-5D-5L takes 


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approximately 3 minutes to complete. The EQ-5D-5L will be collected to inform 
pharmacoeconomic modeling and will not be included in the Clinical Study Report.
4.5.11
Samples for Whole Genome Sequencing 
At participating sites (where approved locally), blood samples will be collected for DNA 
extraction to enable WGS or alternative technology to identify mutations that are 
predictive of response to study drug, are associated with progression to a more severe 
disease state, are associated with acquired resistance to study drug, are associated with 
susceptibility to developing adverse events, can lead to improved adverse event 
monitoring or investigation, or can increase the knowledge and understanding of disease 
biology and drug safety.  Research may aim to distinguish germline mutations from 
somatic mutations.  The samples may be sent to one or more laboratories for analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research by each site's IRB/EC and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for WGS sampling, this section 
of the protocol (see Section 4.5.11) will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Patient medical information associated with WGS samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 


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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.12
Optional Tumor Biopsies
Consenting patients will undergo optional tumor biopsies at baseline and/or at disease 
progression (if deemed clinically feasible by the investigator).  Samples collected via 
resection, core-needle biopsy (at least three cores preferred), or excisional, incisional, 
punch, or forceps biopsy are preferred.  For sampling procedures, storage conditions, 
and shipment instructions, see the laboratory manual.  
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF.
Samples may be used for exploratory biomarker research as described in Section 4.5.8.  
Refer to Section 4.5.13.3 for details on sample storage, use of samples after patient 
withdrawal, confidentiality standards for data, and availability of data from biomarker 
analyses. 
4.5.13
Optional Samples for Research Biosample Repository
4.5.13.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety


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
To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.13.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (see Section 4.5.13) 
will not be applicable at that site.
4.5.13.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to ipatasertib or the 
PI3K/Akt/mTOR pathway, diseases, or drug safety:

If patient provides consent, any leftover samples, such as blood, serum, plasma, 
and tumor tissue samples (with the exception of remaining archival tissue blocks, 
which will be returned to sites), and any derivatives thereof (e.g., DNA, RNA, 
proteins, peptides), including leftover tissue samples from medically indicated 
procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, colonoscopy) 
performed at the investigator's discretion during the course of the study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via WGS, whole exome sequencing (WES), or other genomic 
analysis methods. Genomics is increasingly informing researcher's understanding of 
disease pathobiology.  WGS and WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or predicting which patients are more likely to 
respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).


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4.5.13.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.13.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.13.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 


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Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.13.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy 

Use of an anticancer therapy not required per protocol

Disease progression per investigator assessment according to RECISTv1.1 (see 
Appendix 9).  
-
Symptomatic deterioration (clinical progression) in the absence of radiographic 
disease progression does not require treatment discontinuation
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.


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Patients will return to the clinic for a treatment discontinuation visit within approximately 
30 days after the final dose of study drug (ipatasertib/placebo or palbociclib or fulvestrant, 
whichever is discontinued last).  See Appendix 1 (Phase III SOA) and Appendix 3
(Phase Ib SOA) for additional details.
Patients in the randomized Phase III portion who discontinue study treatment for any 
reason other than radiographic disease progression per RECIST v1.1 will be followed 
every 8 weeks 7 days for tumor assessments until documented progression per 
RECIST v1.1 or death, whichever occurs first.
For patients in the randomized Phase III portion of the study, after treatment 
discontinuation, information on survival follow-up and new anti-cancer therapy (including 
outcome) will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study or the survival follow-up).  See Appendix 1 (Phase III SOA) 
for additional details.
Additional PRO assessments for patients in the randomized Phase III portion of the 
study will also be completed at 3, 6, and 12 months after treatment discontinuation
unless the patient withdraws consent or the Sponsor terminates the study or the PRO 
follow-up.  See Appendix 1 (Phase III SOA) for additional details.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  Patients who withdraw from the 
study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Ipatasertib is not currently approved for any indication, and clinical development is 
ongoing.  Palbociclib and fulvestrant have been approved for the treatment of HR
HER2-advanced or metastatic breast cancer in women with disease progression 
following endocrine therapy (see Section 1.3). 
The safety plan for patients in this study is based on clinical experience with ipatasertib 
in completed and ongoing studies as well as clinical experience with combined 
palbociclib and fulvestrant and fulvestrant alone or fulvestrant in combination with PI3K 
pathway inhibitors.
The anticipated important safety risks and management plan for ipatasertib plus 
palbociclib and fulvestrant are outlined below.  Refer to the Ipatasertib Investigator’s 
Brochure for a complete summary of safety information. Refer to the local prescribing 
information for a complete summary of safety information for fulvestrant and palbociclib 
(including in combination with fulvestrant), respectively.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events. An initial open-label Phase Ib portion 
will investigate the tolerability and potential drug-drug interaction of combining ipatasertib 


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in combination with palbociclib and fulvestrant (see Section 3.1.1 for further details).  In 
the randomized Phase III portion, an iDMC will review unblinded safety data regularly 
throughout the study (see Section 6.8 for further details). Furthermore, guidelines for 
managing adverse events, including criteria for dosage modification and treatment 
interruption or discontinuation, are provided below. These guidelines apply to both the 
open-label Phase Ib portion as well as the blinded Phase III portion. In addition to these 
guidelines, more conservative dose modifications of any study treatment for the 
management of adverse events are permitted at the discretion of the investigator when 
deemed to be in the best interest of the patient.
5.1.1
Risks Associated with Ipatasertib
Ipatasertib has been associated with identified risks including the following: nausea, 
vomiting, diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, 
erythema multiforme, and rash.  Ipatasertib's potential risks include hematologic or 
immunosuppressant effects, hyperlipidemia, hepatotoxicity, pneumonitis, colitis, and 
developmental toxicity. 
Refer to Section 6 of the ipatasertib Investigator's Brochure for a detailed description of 
anticipated safety risks for ipatasertib.
5.1.2
Risks Associated with Palbociclib
Palbociclib has been associated with adverse events such as the following: neutropenia, 
febrile neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, ILD (interstitial 
lung disease)/pneumonitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, 
decreased appetite, asthenia, and pyrexia as well as dysgeusia, vision blurred, 
lacrimation increased, dry eye, epistaxis, dry skin, and ALT and AST increases.  
Palbociclib has been associated with embryo-fetal toxicity and can cause fetal harm.
For additional information on the safety profile of palbociclib, refer to the local prescribing 
information.
5.1.3
Risks Associated with Fulvestrant
Fulvestrant has been associated with risks such as the following: hypersensitivity 
reactions, hot flushes, nausea, elevated hepatic enzymes (ALT, AST, ALP), rash, joint 
and musculoskeletal pain, asthenia, injection site reactions, urinary tract infection, 
reduced platelet count, anorexia, headache, venous thromboembolism, vomiting, 
diarrhea, elevated bilirubin, back pain, vaginal hemorrhage, neuropathy peripheral, and 
sciatica. Uncommon risks include anaphylactic reactions, hepatic failure, hepatitis, 
elevated gamma-glutamyl transferase, vaginal moniliasis, leucorrhea, injection site 
hemorrhage, injection site hematoma, and neuralgia (Summary of Product 
Characteristics [SmPC]).
For additional information on the safety profile of fulvestrant, refer to the local prescribing 
information.


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5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
Dose Modification for Ipatasertib
Management of some adverse reactions may require temporary dose 
interruptions/delays, and/or dose reductions, or permanent discontinuation of ipatasertib 
as per dose reduction schedules provided in Table 1 and Section 5.1.4.5. 
If the patient does not tolerate the QD dosing of the ipatasertib/placebo, dosing with food 
may be used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or 
diarrhea.  No more than two dose reductions of ipatasertib/placebo per patient will be 
allowed (see Table 1 exemplified by the starting dose of 300 mg). If the starting dose for 
the Phase III portion is determined to be 400 mg, two dose reductions are allowed, the 
first to 300 mg and the second down to the 200 mg.  If the starting dose is determined to 
be 200 mg, only one dose reduction to 100 mg will be allowed. Dose re-escalation is not 
permitted for ipatasertib/placebo, regardless of the dose level.
Table 1
Dose Reductions for Ipatasertib/Placebo (Exemplified by the 
Starting Dose of 300 mg)
Dose Level a
Ipatasertib/Placebo
Starting dose
300 mg
First dose reduction
200 mg
Second dose reduction
100 mg
Third dose reduction
Not permitted  
a If the patient continues to experience specified drug-related adverse events after the second 
reduction, ipatasertib/placebo should be discontinued.
5.1.4.2
Dose Modification for Palbociclib
Management of some adverse reactions may require temporary dose 
interruptions/delays, and/or dose reductions, or permanent discontinuation of palbociclib 
as per dose reduction schedules provided in Table 2 and Section 5.1.4.5. In general, the 
investigator may consider continuing palbociclib if the observed adverse event is not 
thought to be palbociclib related. See Section 3.1.5 for additional details on conditions 
for permanent discontinuation of palbociclib. Dose re-escalation of palbociclib is not 
permitted, regardless of the dose level.
Table 2
Dose Reductions for Palbociclib
Dose Level 
Palbociclib
Starting dose
125 mg
First dose reduction
100 mg
Second dose reduction
75 mg
Third dose reduction
Not permitted  


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5.1.4.3
Dose Modification for Fulvestrant
The fulvestrant dose level should generally not be modified unless required in 
accordance with the label as determined by the investigator.  In general, the investigator 
may consider continuing fulvestrant if the observed adverse event is not thought to be 
fulvestrant related.  See Section 3.1.5 for additional details on conditions for permanent 
discontinuation of fulvestrant. 
5.1.4.4
Treatment Interruption
Ipatasertib/placebo and/or palbociclib and/or fulvestrant treatment may be temporarily 
interrupted in patients who experience toxicity considered to be related to study drug. If 
corticosteroids are initiated for treatment of the toxicity, they must be tapered to 
10 mg/day oral prednisone or equivalent before ipatasertib/placebo can be resumed, if 
clinically appropriate.  If ipatasertib/placebo has been withheld for 60 consecutive days 
because of treatment-related toxicity, the patient should be permanently discontinued 
from ipatasertib/placebo.  See Section 3.1.5 for further details on considerations for 
palbociclib and fulvestrant once ipatasertib/placebo is permanently discontinued.  If, in 
the judgment of the investigator, the patient is likely to derive clinical benefit from 
resuming ipatasertib/placebo after a hold of 60 consecutive days, study drug may be 
restarted with the approval from the Sponsor based on consultation with the Medical 
Monitor.  Ipatasertib/placebo and/or palbociclib and/or fulvestrant treatment may be 
temporarily interrupted for reasons other than toxicity (e.g., surgical procedures) with 
approval from the sponsor based on consultation with the Medical Monitor.
If a scheduled fulvestrant dose coincides with a holiday or inclement weather or other 
conditions that preclude dosing, dosing should commence on the nearest following date, 
and subsequent dosing can continue on a new 28-day schedule on the basis of the new 
IM injection date.
5.1.4.5
Adverse Event Management Guidelines 
Guidelines for management of specific adverse events are provided in the subsections 
below.  Educational materials related to diarrhea management will be provided to 
investigators and patients.  Additional guidelines may be provided as needed.
5.1.4.5.1
Diarrhea Management Guidelines
Specific guidelines for managing diarrhea including treatment modifications to improve 
safety and tolerability are provided in Table 3 and should be instituted as early as 
possible once diarrhea of any grade occurs. Patients should be monitored closely and all 
events of diarrhea should be evaluated thoroughly for more common etiologies other 
than drug-induced effects, such as infectious etiology.
For diarrhea that persists for more than 5 days, despite treatment with anti-diarrheal 
agent(s) and/or withholding dosing of ipatasertib/placebo, gastroenterologists should be 
consulted to rule out the risk of colitis and infection (e.g., obtaining CT images or a stool 
culture for infectious workup [Clostridium difficile, enteric bacteria, cytomegalovirus]).  
Patients should be educated on the symptoms and importance of early reporting of 


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diarrhea to receive instructions of treatment and prevention of dehydration so that 
patients can be promptly and appropriately managed. 
The palbociclib dose may be adjusted at the discretion of the investigator as clinically 
indicated unless otherwise specified below or unless required by the local prescribing 
information.  See Table 2 for dose reductions with palbociclib.  For additional 
information, refer to the local prescribing information for dose modifications of palbociclib.


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Table 3
Diarrhea Management Guidelines
Severity of Diarrhea a
Management Guideline
Prevention

All patients should receive loperamide (2 mg BID or 4 mg QD) as 
prophylaxis for diarrhea upon start of study treatment through the 
first cycle (if allowed by local guidance), except when the Medical 
Monitor approves omission, for example if there are clinical 
concerns that preclude the use of loperamide prophylaxis in the 
first cycle.  Loperamide dose adjustments may be made per 
investigator discretion after discussion with the Medical Monitor.

After the first cycle, investigators are encouraged to continue this 
dosing for the remainder of the study using their discretion as 
clinically indicated.
Grade 1
Increase of 4 stools per 
day over baseline; mild 
increase in ostomy 
output compared to 
baseline

Continue study drugs at the current dose level.

Manage with loperamide 4 mg initially and then 2 mg every 
4 hours or after every unformed stool until after 12-hour 
diarrhea-free interval.

Dietary modifications, such as avoiding any lactose-containing 
foods and eating small meals.

Hydration with 810 glasses per day (~12 oz/glass) of clear liquid, 
such as broth or low-calorie drinks with electrolytes.

Upon resolution, loperamide prophylaxis can be considered and 
continues as clinically indicated, if allowed by local guidance. 
Please note, loperamide prophylaxis is to be taken throughout at 
least the first cycle. 
Grade 2
Increase of 46 stools 
per day over baseline; 
moderate increase in 
ostomy output 
compared to baseline; 
limiting instrumental 
ADL

Rule out infectious etiology.

Manage with loperamide as early as possible 4 mg initially and 
then 2 mg every 4 hours or after every unformed stool until after
12-hour diarrhea free interval.

Dietary modifications, such as avoiding any lactose-containing 
foods and eating small meals. 

Hydration with 810 glasses per day (~12 oz/glass) of clear liquid, 
such as broth or low-calorie drinks with electrolytes.

For non-infectious diarrhea lasting more than 48 hours despite 
optimal loperamide treatment, manage with second-line 
anti-diarrheal agents, including, but not limited to Lomotil®, 
codeine, or octreotide, or as per institutional guidelines.

Interrupt ipatasertib/placebo until diarrhea improves to Grade 1 or 
better.  Ipatasertib/placebo can be resumed at the same dose or 
one dose lower per investigator's evaluation upon improvement to 
Grade 1 or better.

Reduce ipatasertib/placebo by one (or one additional) dose level 
(see Section 5.1.4.1 for further details) for recurrent Grade 2 
diarrhea.

When ipatasertib, or its placebo, is resumed, loperamide 
prophylaxis should also be resumed and continued as clinically 
indicated, if allowed by local guidance. Please note, loperamide 
prophylaxis is to be taken throughout at least the first cycle.


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Table 3
Diarrhea Management Guidelines (cont.)
Severity of Diarrhea a
Management Guideline
Grade 3
Increase of 7 stools 
per day over baseline; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting 
self-care ADL

Rule out infectious etiology.

Treat per Grade 2 management guidelines and supportive care.

Interrupt ipatasertib/placebo until diarrhea improves to Grade 1 or 
better.  Consider interrupting palbociclib. Ipatasertib/placebo 
should be reduced by one dose level (see Section 5.1.4.1 for 
further details) when treatment is restarted. 

For recurrent Grade 3 diarrhea, interrupt as above and reduce 
ipatasertib/placebo dose by one additional dose level when 
treatment is restarted (see Section 5.1.4.1 for further details).  
Consider interrupting palbociclib and resuming at the reduced 
dose when palbociclib is restarted (see Section 5.1.4.2).

When ipatasertib, or its placebo, is resumed, loperamide 
prophylaxis should also be resumed and continues as clinically 
indicated, if allowed by local guidance. Please note, loperamide 
prophylaxis is to be taken throughout at least the first cycle.
Grade 4
Life-threatening 
consequences; urgent 
intervention indicated

Rule out infectious etiology.

Treat per Grade 2 management guidelines and supportive care.

Permanently discontinue ipatasertib/placebo. 

If after permanent discontinuation of ipatasertib/placebo diarrhea 
persists, permanently discontinue palbociclib and fulvestrant.
ADLactivities of daily living; BIDtwice a day; NCI CTCAE v5.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0; QD once a day.
a Diarrhea, as defined by NCI CTCAE v5.0, a disorder characterized by an increase in frequency 
and/or loose or watery bowel movements.
5.1.4.5.2
Fasting Hyperglycemia
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours. 
Guidelines for fasting hyperglycemia attributable to ipatasertib/placebo are outlined 
below (see Table 4) based on fasting glucose measurements assessed in the clinic, 
unless otherwise specified below.  This table is not meant to inform grading of adverse 
events, which should be conducted per NCI CTCAE v5.0.
All events of hyperglycemia should be thoroughly evaluated for more common etiologies 
other than drug-induced effects.  As clinically indicated, the work-up should include 
confirmation of fasting blood glucose, urinary glucose and ketones, arterial blood gas, 
serum bicarbonate, and hemoglobin A1C.
Hyperglycemia should be treated per institutional guidelines.  
Home glucose measurements, where indicated based on the below management 
guidelines, may be used to trigger contact between patient and investigative site team 
and may lead to an unscheduled clinic visit to assess fasting glucose.  Guidance for 


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when to call the investigator/site staff (or designated endocrinologist, if applicable) 
should be provided to patients for hypoglycemia (e.g., glucose value under 70 mg/dL) 
and hyperglycemia (e.g., glucose value over 300 mg/dL).  Alternative thresholds may be 
selected as clinically indicated per investigator discretion or institutional guidance and 
noted in the source documents. For any patients performing home glucose monitoring, 
the blood glucose log should be reviewed at each clinic visit (and source data retained), 
entry of results into the patient’s eCRF will be limited to values which result in 
intervention.  
In the event of ipatasertib/placebo interruption, anti-diabetic medications may need to be 
held or reduced (per investigator judgment) and glucose should be monitored closely to 
minimize the risk of hypoglycemia.
Table 4
Fasting Hyperglycemia Management Guidelines
Severity of Fasting 
Hyperglycemia
Management Guideline
Fasting glucose value 
ULN to 160 mg/dL 
(8.9 mmol/L)

Continue ipatasertib/placebo.

Provide patient with education on a diabetic diet and consider home 
glucose monitoring.

Consider oral anti-diabetic medications (e.g., metformin).
Fasting glucose value 
160 to 250 mg/dL 
(8.913.9 mmol/L)

Interruption of ipatasertib/placebo until fasting glucose values return 
to 160 mg/dL (8.9 mmol/L)

Encourage a diabetic diet and initiate home glucose monitoring.

Start oral anti-diabetic medications (e.g., metformin).

If patient is already on an oral anti-diabetic medication, the dose of 
ipatasertib/placebo should be reduced by one dose level (see 
Section 5.1.4.1 for further details).

If the patient previously has not been receiving any oral antidiabetic 
medication, ipatasertib/placebo may be resumed at the previous dose 
level with initiation of oral anti-diabetic medication.
Fasting (or non-
fasting) glucose value 
250 to 500 mg/dL 
(13.927.8 mmol/L)

Interrupt ipatasertib/placebo until fasting glucose values return to 
160 mg/dL (8.9 mmol/L)

Encourage a diabetic diet and initiate home glucose monitoring.

Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used. 

Start (or increase dose of) oral anti-diabetic medications 
(e.g., metformin). 

If the patient is already on an oral anti-diabetic medication, 
ipatasertib/placebo should be reduced by one dose level when 
treatment is restarted.

If previously, the patient has not been receiving any oral anti-diabetic 
medication, ipatasertib/placebo may be resumed at the previous dose 
level with initiation of oral anti-diabetic medication.


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Table 4
Fasting Hyperglycemia Management Guidelines (cont.)
If fasting glucose value exceeds 250 mg/dL (13.9 mmol/L) again, the dose 
of ipatasertib/placebo should be reduced by one dose level when 
treatment is restarted (see Section 5.1.4.1 for further details).
Fasting (or non
-fasting) glucose 
value 500 mg/dL 
(27.8 mmol/L); Life
-threatening 
consequences; urgent 
intervention indicated
Interrupt ipatasertib/placebo until fasting glucose values return to 
160 mg/dL (8.9 mmol/L).
Encourage a diabetic diet and initiate home glucose monitoring.
Treat hyperglycemia per standard of care, noting risk of hypoglycemia if 
insulin is used.
Start (or increase dose of) oral anti-diabetic medications (e.g., metformin).
Assess for volume depletion and appropriate intravenous or oral 
hydration.
Reduce ipatasertib/placebo by one dose level when treatment is restarted 
(see Section 5.1.4.1 for further details).
If fasting (or non-fasting) glucose value exceeds 500 mg/dL (27.8 
mmol/L) again, permanently discontinue ipatasertib/placebo.
ULNupper limit of normal.  
Note:  For all grades, the patient should receive education on a diabetic diet.
5.1.4.5.3
Nausea and/or Vomiting
Dose reductions for nausea and/or vomiting should occur only if the symptoms persist 
despite a minimum of two treatments with adequate (combination) anti-emetic 
treatment(s), including ondansetron and other anti-emetics (i.e., prochlorperazine or 
metoclopramide per institutional guidelines; see Table 5).  For persistent nausea and/or 
vomiting attributable to ipatasertib/placebo, dosage modification guidelines are outlined 
in Section 5.1.4.1 and Table 5). 
The palbociclib dose may be adjusted at the discretion of the investigator as clinically 
indicated unless required by the local prescribing information. For additional
information, refer to the local prescribing information for dose modifications of palbociclib 
for non-hematologic toxicities.
Table 5
Nausea and Vomiting Management Guidelines
Severity of Nausea 
and /or Vomiting
Management Guideline
Grade 1

Provide supportive care as needed.
Grade 2

Provide maximum supportive care as needed per local guidelines, 
with a minimum of two anti-emetics, including ondansetron.
Grade 3

Interrupt ipatasertib/placebo until nausea or vomiting resolves to 
Grade 2 or better. 

Provide maximum supportive care per local guidelines, with a 
minimum of two anti-emetics, including ondansetron.

If Grade 3 nausea or vomiting recurs, ipatasertib/placebo should be 
reduced by one dose level (see Section 5.1.4.1 for further details) 
when treatment is restarted.  


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5.1.4.5.4
Rash
Ipatasertib/placebo and palbociclib should be permanently discontinued for rash 
associated with Stevens-Johnson syndrome, toxic epidermal necrolysis, or other 
suspected severe hypersensitivity or allergic reaction.  Dosage modification and 
symptom management guidelines for skin toxicity attributable to study treatment are 
shown in Table 6.
The palbociclib dose may be adjusted at the discretion of the investigator as clinically 
indicated unless otherwise specified below or unless required by the local prescribing 
information. For additional information, refer to the local prescribing information for 
dose modifications of palbociclib for non-hematologic toxicities.
Table 6
Rash Management Guidelines
Severity of Rash
Management Guideline
Grade 1

Continue study drugs. 

Consider topical corticosteroids.

Consider antihistamine prophylaxis for the first cycle and as clinically 
indicated for subsequent cycles a
Grade 2

Interrupt ipatasertib/placebo treatment until resolution to Grade1 or better 
or the toxicity is no longer clinically significant. Consider interrupting 
palbociclib.

Treat rash with topical corticosteroids.

Consider treatment of rash with oral corticosteroids.
Grade 3

Interrupt ipatasertib/placebo and palbociclib treatment until resolution to 
Grade1 or better or the toxicity is no longer clinically significant. 

Treat rash with topical and systemic corticosteroids.

Consider dermatological consultation.

If the skin toxicity resolves to Grade1 or better or is no longer clinically 
significant following completion of the steroid taper, ipatasertib/placebo 
may be resumed at one dose level below the previous dose (see 
Section 5.1.4.1 for further details). Palbociclib may be resumed once skin 
toxicity resolves to Grade 1 even if corticosteroid taper has not been 
completed.

If skin toxicity remains clinically significant continuously for 4 weeks, or 
Grade 3 rash recurs, permanently discontinue ipatasertib/placebo and 
palbociclib and fulvestrant.
Grade 4

Administration of systemic steroids (oral or intravenous) is recommended.  
Consider dermatological consultation and skin biopsy. 

Ipatasertib/placebo plus palbociclib and fulvestrant should be permanently 
discontinued.
a Sponsor will closely monitor the incidence of rash in this study and may advise investigators 
to consider antihistamine prophylaxis if warranted by the data.


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5.1.4.5.5
Pneumonitis
Pneumonitis has been observed with palbociclib and also with drugs that target pathways
similar to ipatasertib.  Every effort should be made to determine the etiology of dyspnea
and changes in pulmonary function (see Table 7).
Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated 
with palbociclib when it is taken in combination with endocrine therapy. In clinical trials 
(PALOMA-1, PALOMA-2, PALOMA-3), any grade and Grade 3 ILD/pneumonitis was 
reported in 1.0% and 0.1% of patients treated with palbociclib, respectively. Although no 
fatal cases were reported in these studies, additional cases of ILD/pneumonitis with 
fatalities have been observed in the post-marketing setting.
Patients should be closely monitored for pulmonary symptoms indicative of 
ILD/pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or 
interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and 
other causes have been excluded. In patients who have new or worsening respiratory 
symptoms who are suspected to have developed ILD/pneumonitis, interrupt palbociclib 
immediately and evaluate the patient. Permanently discontinue palbociclib in patients 
with severe ILD or pneumonitis.  See Table 7 for detailed guidance, including 
ipatasertib/placebo dose modifications and discontinuation. 


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Table 7
Interstitial Lung Disease/Pneumonitis Management Guidelines
Severity of ILD/
Pneumonitis
Management Guideline
Grade 1

Interrupt palbociclib until the event resolves to baseline and continue 
the other study drugs.

Consider pulmonary consult.

Consider infectious work-up. a

Perform CT scan and PFTs. Repeat CT scan every 8 weeks until a 
return to baseline.
Grade 2

Perform infectious work-up. a  

If infectious etiology is ruled out or if improvement is not evident with 
broad spectrum antibiotics, prescribe corticosteroids as clinically 
indicated.

Interrupt palbociclib and ipatasertib/placebo.

Consult with a pulmonologist and with the Medical Monitor.

Start treatment for ILD/pneumonitis as per pulmonologist guidance.

Perform CT scan and PFTs. Repeat CT scan every 4 weeks until a 
return to baseline.

Interrupt ipatasertib/placebo treatment until improvement to Grade 1 or 
better. Consider resuming ipatasertib/placebo at same dose level or 
one dose level below (see Section 5.1.4.1 for further details) per 
investigator's assessment, but interrupt palbociclib until the event 
resolves to baseline.

For recurrent Grade 2 ILD/pneumonitis, palbociclib should be 
discontinued and ipatasertib/placebo must be resumed at one dose 
level below the previous dose (see Section 5.1.4.1 for further details).
Grade 3

Perform infectious work-up. a   

If infectious etiology is ruled out or if improvement is not evident with 
broad-spectrum antibiotics, prescribe corticosteroids as clinically 
indicated.

Discontinue palbociclib and interrupt ipatasertib/placebo.

Consult with a pulmonologist and the Medical Monitor.

Perform CT scan and PFTs. Repeat CT scan every 4 weeks until a 
return to baseline. Bronchoscopy is recommended.

Start treatment for ILD/pneumonitis as per pulmonologist guidance.

If permitted by the Medical Monitor, resume ipatasertib/placebo 
treatment once improved to Grade 1 or better at one dose level below
(see Section 5.1.4.1 for further details) per investigator's assessment.

For recurrent non-infectious Grade 3 ILD/pneumonitis events,
ipatasertib/placebo should be permanently discontinued.
Grade 4

Perform infectious work-up. a  

If infectious etiology is ruled out or if improvement is not evident with 
broad-spectrum antibiotics, prescribe corticosteroids as clinically 
indicated.

Permanently discontinue ipatasertib/placebo and palbociclib.

Consult with a pulmonologist and the Medical Monitor.

Start treatment for ILD/pneumonitis as per pulmonologist guidance.

Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a 
return to baseline.  Bronchoscopy is recommended.
CTcomputed tomography; PFT pulmonary function test.
a Such as for bacterial, viral, or fungal pneumonia (e.g., Pneumocystis jiroveci pneumonia or 
pneumonia aspergillus).


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5.1.4.5.6
Mucositis
Mouthwash such as magic mouthwash (if inaccessible, warm salt or bicarbonate water) 
should be used as supportive care per institution guidelines.  Brushing teeth after meals, 
keeping lips moisturized with non-Vaselineproducts, and avoiding alcohol, spicy food, 
and smoking have all been shown to reduce pain and infection related to mucositis.  
Ranitidine or omeprazole may be helpful if patients have epigastric pain.  Dosage 
modification guidelines for mucositis attributable to study treatment are outlined in
Table 8.
The palbociclib dose may be adjusted at the discretion of the investigator as clinically 
indicated unless otherwise specified below or unless required by the local prescribing 
information. For additional information, refer to the local prescribing information for 
dose modifications of palbociclib for non-hematologic toxicities.
Table 8
Mucositis Management Guidelines
Severity of 
Mucositis
Management Guidelines
Grade 1 or 2

Manage with maximum supportive care.  

If Grade 2 mucositis recurs in subsequent 4 week cycles, despite 
maximal supportive care, the dose of ipatasertib/placebo should be 
reduced by one dose level (see Section 5.1.4.1 for further details).  
Grade 3

Interrupt ipatasertib/placebo until recovery to Grade 2 or better.  If the 
mucositis resolves to Grade 2 or better, the dose of ipatasertib/placebo 
should be reduced by one dose level (see Section 5.1.4.1). Consider 
interrupting palbociclib. However, if mucositis persists despite optimal 
medical management, interrupt palbociclib until recovery to Grade 2 or 
better and resume at the reduced dose level. 
5.1.4.5.7
Hematologic Toxicities
Palbociclib is associated with hematologic toxicities, in particular neutropenia. Monitor 
complete blood count per schedule in Appendix 1 (Phase III SOA) and Appendix 3
(Phase Ib SOA) and as clinically indicated.  Refer to the local prescribing information for 
further details.  Potential risks associated with ipatasertib include hematologic effects 
(see Section 5.1.1).
Dosage modification (for palbociclib as well as ipatasertib/placebo) and symptom 
management guidelines are shown in Table 9.


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Table 9
Management of Hematologic Toxicities
Severity of Hematologic 
Toxicity
Management Guidelines a
Grade 1 or 2

Continue study drugs.
Grade 3
Day 1 of cycle:

Interrupt palbociclib and ipatasertib/placebo, repeat complete 
blood count monitoring within 1 week. When recovered to 
Grade 2, start the next cycle at the same dose.
Day 15 of first 2 cycles:

If Grade 3 on Day 15, continue palbociclib and 
ipatasertib/placebo at current dose to complete cycle and repeat 
complete blood count on Day 22.

If Grade 4 on Day 22, see Grade 4 dose modification guidelines 
below.

Consider palbociclib dose reduction in cases of prolonged 
(1 week) recovery from Grade 3 neutropenia or recurrent 
Grade 3 neutropenia on Day 1 of subsequent cycles.
Grade 3 neutropeniab
with fever 38.5 ºC and/or 
infection
At any time:

Interrupt palbociclib and ipatasertib/placebo until recovery to 
Grade 2, then resume palbociclib at the next lower dose and 
ipatasertib/placebo at the same dose level.

For recurrent Grade 3 event, resume both palbociclib and 
ipatasertib/placebo at the next lower dose level once recovery to 
Grade 2.
Grade 4
At any time:

Interrupt palbociclib and ipatasertib/placebo until recovery to 
Grade 2, then resume palbociclib at the next lower dose and 
ipatasertib/placebo at the next lower dose level if patient was 
previously at the full dose level. If ipatasertib/placebo was 
previously reduced, resume at the same ipatasertib/placebo dose 
level.

If recurrent Grade 4 event, permanently discontinue palbociclib 
and ipatasertib/placebo.
LLNlower limit of normal.
See Sections 5.1.4.1 and 5.1.4.2 for further details on allowed dose modifications with 
ipatasertib/placebo and palbociclib, respectively.
a Table applies to all hematologic adverse reactions except lymphopenia, unless associated with 
clinical events (e.g., opportunistic infections).
b ANC: Grade 1: ANC LLN 1500/mm3; Grade 2: ANC 10001500/mm3; 
Grade 3: ANC 5001000/mm3; Grade 4: ANC 500/mm3.
5.1.4.5.8
Hepatotoxicity
Elevations in liver enzyme concentrations have been associated with ipatasertib, 
palbociclib, and fulvestrant administration and specific management guidelines are 
outlined in Table 10.


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Permanently discontinue ipatasertib/placebo, palbociclib, and fulvestrant for any patients 
who develop a concurrent elevation of ALT and/or AST greater than 3baseline and
total bilirubin greater than 2ULN and/or clinical jaundice in the absence of biliary 
obstruction or other causes responsible for the concurrent elevation, including patients 
having abnormal liver function tests that meet Hy’s law criteria (see Section 5.3.5.7).
The palbociclib dose may be adjusted at the discretion of the investigator as clinically 
indicated unless otherwise specified below or unless required by the local prescribing 
information. For additional information, refer to the local prescribing information for 
dose modifications of palbociclib for non-hematologic toxicities.


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Table 10 Hepatotoxicity Management Guidelines
Severity of LFT Elevation
Management Guideline
Grade 1 
AST or ALT ULN3.0ULN if baseline 
was normal; 1.53.0baseline if baseline 
was abnormal 
or 
Total bilirubin ULN1.5ULN if 
baseline was normal; 1.01.5baseline 
if baseline was abnormal

Continue study drugs.

Monitor LFTs until values resolve to baseline 
values.
Grade 2 
AST or ALT 3.05.0ULN if baseline 
was normal; 3.05.0baseline if 
baseline was abnormal
or
Total bilirubin 1.53.0ULN if baseline 
was normal; 1.53.0baseline if 
baseline was abnormal

Continue study drugs. 

The frequency of liver function test monitoring 
should be increased as clinically indicated if the 
investigator judges that the laboratory 
abnormalities are potentially related to study 
medication.
Grade 3 
AST or ALT 5.020.0ULN if baseline 
was normal; 5.020.0baseline if 
baseline was abnormal 
or
Total bilirubin 3.0 - 10.0ULN if 
baseline was normal; 
3.010.0baseline if baseline was 
abnormal

Interrupt ipatasertib/placebo, palbociclib and 
fulvestrant until improvement of AST/ALT to 
Grade 2 at which point treatment may be 
resumed at the previous dose level.

Consider hepatology consult

Following treatment resumption, monitor serum 
transaminases and bilirubin at a minimum every 
2 weeks for 3 months and monthly thereafter.

If another Grade 3 event occurs, interrupt 
ipatasertib/placebo, palbociclib and fulvestrant.  
On return of LFTs to Grade 2 resume 
ipatasertib/placebo reducing the dose by one 
level.  Palbociclib and fulvestrant may be resumed 
at the original dose.

Permanently discontinue treatment with 
ipatasertib/placebo, palbociclib, and fulvestrant for 
further Grade 3 occurrences.
Grade 4
AST or ALT 20.0ULN if baseline was 
normal; 20.0baseline if baseline was 
abnormal 
or
Total bilirubin 10.0ULN if baseline 
was normal; 10.0baseline if baseline 
was abnormal

Permanently discontinue treatment with 
ipatasertib/placebo, palbociclib, and fulvestrant.
LFTliver function test; QD once daily; ULNupper limit of normal.
See Section 5.1.4.1 for further details on dose modifications of ipatasertib/placebo.


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5.1.4.5.9
Hypersensitivity 
If a hypersensitivity reaction due to injection of fulvestrant develops in patients, treatment 
for the hypersensitivity reaction, including the possibility of rechallenging with the 
attributable agent, should be administered as per institutional guidelines or at the 
discretion of the investigator.  The patient may continue the other study treatment 
components not associated with the toxicity (i.e., palbociclib or ipatasertib/placebo).
5.1.4.5.10
Management of Other Clinically Significant Adverse Events
If other Grade 3 toxicities not described above develop in patients, any study treatment 
may be held, depending on the attribution of the toxicity, at the discretion of the 
investigator.  During this time, treatment may continue with the other non-attributable 
treatment agent (i.e., either ipatasertib/placebo or palbociclib or fulvestrant).  Grade 3 
clinically significant toxicity should be monitored at least weekly.
If the toxicity resolves to Grade 1 or better treatment may resume with the attributable 
agent.
If the toxicity is deemed related to ipatasertib/placebo and resolves to Grade 1 or better 
in 24 weeks, the dose of ipatasertib/placebo should be reduced by one level per the 
suggested guidelines in Table 1. 
For Grade 3 toxicities associated primarily with laboratory abnormalities only (e.g.,
increases in lipase, or amylase, or decreases in phosphorus without clinical or other 
evidence of pancreatitis), study treatment may continue without interruption and/or dose 
reduction (in case of ipatasertib/placebo) at the discretion of the investigator per 
institutional practice.
See Section 5.1.4.4 for further details on the allowed duration of treatment interruptions. 
Refer to the local prescribing information for additional details on dose modifications with 
palbociclib and/or fulvestrant.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 and 
Section 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
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 
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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

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 5.3.5.7)

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 fasting hyperglycemia 

Grade 3 hepatotoxicity

Grade 3 ALT/AST elevations

Grade 2 colitis/enterocolitis

Grade 3 diarrhea

Grade 3 rash

Grade 2 pneumonitis

Grade 4 neutropenia (including febrile neutropenia)

Erythema multiforme


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5, 
Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 30 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 11 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 11 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 12):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 12 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
Adverse events that occur during or within 24 hours after fulvestrant injection should be 
captured as individual signs and symptoms on the Adverse Event eCRF rather than an 
overall diagnosis (e.g., record dyspnea and hypotension as separate events rather than 
a diagnosis of injection-related reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection reactions (see Section 5.3.5.1), 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.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
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 patients enrolled in the Phase Ib portion only, additional details regarding any 
increases in severity will be captured on the Adverse Event Intensity or Grade Changes 
eCRF). If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated by 
changing the event from "non-serious" to "serious," 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.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms


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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.


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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
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 the underlying breast cancer should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other deaths that 
occur during the adverse event reporting period, regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2).  An iDMC will monitor the frequency of deaths from all causes
during the Phase III portion.
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").


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Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
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").
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, qualifies as an adverse event of special interest (AESI) or is a 
pregnancy, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4).  For ipatasertib/placebo, adverse 
events associated with special situations should be recorded as described below for 
each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.


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
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with ipatasertib/placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.


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As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events.
5.3.5.14
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

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 for All Sites
Medical Monitor:
 M.D. (Primary) 
Mobile Telephone No.:
Backup Medical Monitor:
 M.D., Ph.D.
(Secondary)
Mobile Telephone No.:
Backup Medical Monitor:
 M.D.                   
(Tertiary)
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 30 days after the final 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 
EDC system.  A report will be generated and sent to Roche Safety Risk Management by 
the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 


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than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 30 days after the final dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 90 days after the final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
6 months after the final dose of any study drug.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
drug.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
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5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.


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5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 30 days after the final 
dose of study drug), all deaths, regardless of cause, should be reported through use of 
the Long-Term Survival Follow-Up eCRF for patients in the Phase III portion
(see Section 4.6.1). Patients in the Phase Ib portion will not be followed for long-term 
survival. 
For all patients, if the investigator becomes aware of a serious adverse event that is 
believed to be related to prior exposure to study drug, the event should be reported 
through use of the Adverse Event eCRF.  However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Ipatasertib Investigator's Brochure

Palbociclib EU SmPC

Fulvestrant EU 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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Unless otherwise specified, statistical considerations and analysis plan in this section will 
only focus on the randomized Phase III portion of the study for the global population, and 
further analysis details will be documented in the Statistical Analysis Plan. 


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Separate analyses will be performed for the global population and the potential China 
subpopulation (see Section 6.9).
6.1
DETERMINATION OF SAMPLE SIZE
This is a Phase III, randomized, multicenter, international, double blind, placebo 
controlled clinical study with an initial open-label Phase Ib portion. In the randomized 
portion of the study, approximately 340 patients will be enrolled and randomized in a 
1:1 ratio to the experimental arm (ipatasertibpalbociclibfulvestrant) and control arm 
(placebo palbociclibfulvestrant), including approximately 153 patients with Tri-AKT+ 
tumors, as defined by baseline ctDNA, assuming a prevalence rate of 45% for Tri-AKT+ 
status. 
6.1.1
Type I Error Control
The Type I error (α) for this study is 0.05 (two-sided). The overall type I error () for this 
study is 0.05 (two sided) and is split between the following two co-primary efficacy 
endpoints of PFS in ITT patients (of 0.01) and PFS in patients with Tri-AKT+ tumors, 
as defined by baseline ctDNA (of 0.04). PFS testing for both ITT and patients with 
Tri-AKT+ tumors, as defined by baseline ctDNA will be performed independently at the 
same time.
6.1.2
Co-Primary Endpoint: Progression-Free Survival
The primary analysis of co-primary endpoint of PFS will take place when approximately 
98 PFS events have occurred in patients with Tri-AKT+ tumors, as defined by baseline 
ctDNA and approximately 180 PFS events have occurred in ITT patients, whichever
occurs later, on the basis of the following assumptions:

1:1 randomization ratio

Two-sided significance level of 4% and at least 80% power for testing PFS in 
patients with Tri-AKT+ tumors, as defined by baseline ctDNA where median PFS is 
10 months in the placebopalbociclibfulvestrant arm and 18 months in the 
ipatasertibpalbociclibfulvestrant arm (hazard ratio0.56)

Two-sided significance level of 1% and at least 80% power for testing PFS in ITT 
patients where median PFS is 12 months in the placebopalbociclibfulvestrant 
arm and 20 months in the ipatasertibpalbociclibfulvestrant arm (hazard 
ratio0.60)  

An annual loss-to-follow-up rate of 5% for both arms

No interim analysis of PFS
The enrollment duration is projected to be approximately 14 months from the first patient 
enrolled in the randomized Phase III portion of the study.  With these assumptions, the 
analysis of the co-primary endpoint of PFS is projected to occur approximately 
40 months after the first patient enrolled in the randomized Phase III portion of the study. 
In patients with Tri-AKT+ tumors, as defined by baseline ctDNA, it is projected that the 
largest HR deemed to be statistically significant at 4% level will be approximately 0.66 


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(with median PFS improvement from 10 months to 15.2 months). In ITT patients, it is 
predicted that there will be approximately 201 PFS events which allows for 
approximately 85% power for testing the assumed median PFS improvement from 12 to 
20 months, and the projected largest HR deemed to be statistically significant at 1% 
level will be approximately 0.70 (with median PFS improvement from 12 months to 
17.2 months).
6.2
SUMMARIES OF CONDUCT OF STUDY
Study enrollment and duration, study drug discontinuation, study discontinuation, 
reasons for study drug discontinuation and study discontinuation will be summarized by 
treatment arm. Major protocol deviations, including major deviations of 
inclusion/exclusion criteria, will be reported and summarized by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
The evaluation of treatment group comparability between the two treatment arms will 
include demographics summaries, stratification factors, patient treatment history, and 
other baseline disease characteristics.
Continuous data will be summarized with means, standard deviations, and medians and 
ranges.  Categorical data will be summarized by counts and proportions.
6.4
EFFICACY ANALYSES
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization.
6.4.1
Co-Primary Efficacy Endpoint
The co-primary efficacy endpoints are as follows:

PFS in ITT patients, defined as the time from randomization to the first occurrence 
of disease progression as determined by the investigator according to RECIST v1.1, 
or death from any cause, whichever occurs first. 

PFS in patients with Tri-AKT+ tumors, as defined by baseline ctDNA, defined as the 
time from randomization to the first occurrence of disease progression as 
determined by the investigator according to RECIST v1.1, or death from any cause, 
whichever occurs first.
Data for patients without the recurrence 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 plus 1 day if no tumor assessment was performed after the baseline 
visit). 
PFS will be compared between treatment arms using the stratified log-rank test.  The HR 
will be estimated using a stratified Cox proportional hazards model.  The 95% CI for the 
HR will be provided.  The stratification factors to be used will be the same as the 
randomization stratification factors, except for geographic region.  Results from an 
unstratified analysis will also be provided.  Kaplan-Meier methodology will be used to 


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estimate the mPFS for each treatment arm, and Kaplan-Meier curves will be produced.  
The Brookmeyer-Crowley method will be used to construct the 95% CI for the mPFS for 
each treatment arm (Brookmeyer and Crowley 1982).
6.4.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints will also be evaluated separately in both ITT patients and 
patients with Tri-AKT+ tumors, as defined by baseline ctDNA, unless specified otherwise. 
6.4.2.1
Objective Response Rate
An objective response is defined as response (CR or PR) on two consecutive occasions 
4 weeks apart, as determined by the investigator using RECIST v1.1.  Patients not 
meeting these criteria, including patients without any post-baseline tumor assessment, 
will be considered non-responders. ORR is defined as the proportion of patients who 
had an objective response.  The analysis population for ORR will be ITT patients with 
measurable disease at baseline.
An estimate of ORR and its 95% CI will be calculated using the Clopper Pearson method 
for each treatment arm.  Response rates in the treatment arms will be compared using 
the stratified Mantel-Haenszel test. The stratification factors to be used will be the same 
as those used for the investigator-assessed PFS analysis. The difference in ORR 
between treatment arms will be calculated, and its 95% CI will be calculated using the 
normal approximation to the binomial distribution.
6.4.2.2
Duration of Response
DOR will be assessed in patients who had an objective response as determined by the 
investigator using RECIST v1.1. DOR is defined as the time from the first occurrence of 
a documented objective response (CR or PR, whichever status is recorded first) until the 
first occurrence of progressive disease, as determined by the investigator according to 
RECIST v1.1, or death, whichever occurs first.  Patients who have not progressed and 
who have not died at the time of analysis will be censored at the time of last tumor 
assessment date.  DOR is based on a non-randomized subset of patients (specifically, 
patients who achieved an objective response); therefore, formal hypothesis testing will 
not be performed for this endpoint.  Comparisons between treatment arms will be made 
for descriptive purposes.  The methodologies detailed for the investigator-assessed PFS 
analysis will be used for the DOR analysis.
6.4.2.3
Clinical Benefit Rate
CBR is defined as the proportion of patients who have a CR, PR or stable disease for at 
least 24 weeks, as determined by the investigator using RECIST v1.1. CBR will be 
analyzed using methods similar to those used for ORR.
6.4.2.4
Overall Survival
OS is defined as the time from randomization to death from any cause.  Data for patients 
who have not died as of the clinical data cutoff date will be censored at the date when 


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they are known to be alive. Data for patients who do not have post-baseline information 
will be censored at the time of randomization plus 1 day.  The methodologies detailed for 
the investigator-assessed PFS analysis will be used for the OS analysis.
6.4.2.5
Patient- Reported Outcomes (TTD of Pain; TTD of PF, RF, and 
GHS/QoL)
To evaluate TTD in severity of pain, the “worst pain” item from the BPI-SF will be 
assessed. TTD is defined as the time from randomization to the first documentation of a 
2-point increase from baseline in “worst pain”. A 2-point change is defined as clinically 
meaningful (Mathias et al. 2010). 
To evaluate TTD in presence and interference of pain, changes in the pain scale (items 
9 and 19) of the EORTC QLQ-C30 will be assessed. TTD is defined as the time from 
randomization to the first documentation of a 10-point increase from baseline on the 
pain scale. A 10-point change is defined as clinically meaningful (Osoba et al. 1998).
To evaluate TTD of PF, RF, and GHS/QoL, changes in the PF, RF, GHS/QoL scales of 
the EORTC QLQ-C30 will be assessed.  TTD of PF, RF, and GHS/QoL is defined as the 
time from randomization to the first documentation of a 10-point or more decrease from 
baseline on the functioning and GHS/QoL scales. A 10 point change is defined as a 
clinically meaningful difference (Osoba et al. 1998) on all scales of the EORTC QLQ 
C30; additional sensitivity analyses using different thresholds will be conducted.  
Patients who do not have an observed deterioration at the time of clinical data cut-off will 
be censored at the last non-missing assessment date.  Patients without a post-baseline 
assessment will be censored at the time of randomization plus 1 day.
6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy will be evaluated separately in both ITT patients and patients 
with Tri-AKT+ tumors, as defined by baseline ctDNA, unless otherwise specified.  
p-values will be reported for descriptive purposes only.
6.4.3.1
Progression-Free Survival 2
PFS2 is defined as the time from randomization to second occurrence of objective 
disease progression through the use of RECIST v1.1, or death from any cause, 
whichever occurs first.  Patients alive and for whom a second objective disease 
progression has not been observed will be censored at the last time known to be alive 
and without second objective disease progression.  This analysis will be performed as 
data allows.
6.4.3.2
Time to First Skeletal-Related Event 
Time to first SRE is defined as the time from randomization to the first occurrence of an 
SRE.  An SRE is a pathologic fracture, radiation therapy to bone, surgery to bone, or 
spinal cord compression.  Patients for whom an SRE has not been observed will be 


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censored at the last time known to be alive and without an SRE.  This analysis will be 
performed as data allow.
6.4.3.3
Exploratory Patient-Reported Outcome Analyses 
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) for each 
assessment timepoint will be reported for the “worst pain” item of the BPI-SF as well as 
for linearly transformed scores of all scales (symptoms, functional domains, and 
GHS/QoL) of the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires according 
to the EORTC scoring manual guidelines (Fayers et al. 2001).  The mean change of the 
linearly transformed scores from baseline (and 95% CI using the normal approximation) 
will also be reported independently for each treatment arm.  Line charts depicting the 
mean and mean changes from the baseline assessment (and 95% confidence intervals) 
of items and scales over time will be provided for each treatment arm.  In the event of 
incomplete data, for all questionnaire scales, if more than 50% of the constituent items 
are completed, a prorated score will be computed consistent with the scoring manuals 
and validation papers.  For scales with less than 50% of the items completed, the scale 
will be considered as missing.
PRO completion, compliance rates, and reasons for missing data will be summarized at 
each timepoint by treatment arm for each measure in ITT patients.  The compliance rate 
will be based on the total number of patients expected to complete the questionnaire at a 
particular timepoint.
The EQ-5D-5L (Appendix 14) will be scored according to its manual, and results will be 
reported separately from the clinical study report.
6.4.3.4
Investigator-Assessed PFS in Patients with Tri-AKT+ Tumor 
Tissue and PTEN Loss in Tumor Tissue
The methodologies detailed for the investigator-assessed PFS analysis will be used to 
analyze PFS in patients with Tri-AKT+ tumor tissue and PTEN loss in tumor tissue.


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6.5
SAFETY ANALYSES
6.5.1
Analyses of Exposure, Adverse Event, Laboratory, and Vital 
Sign Data
Safety analyses for the Phase Ib portion will be conducted and reported separately from 
the Phase III analyses but will include similar analyses as those listed below for Phase III. 
Safety analyses for the Phase III portion will be performed on the safety-evaluable 
population, including all randomized patients who received any amount of study 
treatment (i.e., ipatasertib, placebo, palbociclib, or fulvestrant). In addition, key safety 
analyses will also be performed for patients with Tri-AKT+ tumors, as defined by 
baseline ctDNA, in both treatment arms. For all safety analyses, patients will be 
grouped according to whether any amount of ipatasertib was received, including the 
case when ipatasertib was received in error.
Frequency, nature, and severity of treatment-emergent adverse events, adverse events 
leading to death, adverse events leading to study drug discontinuation and dose 
modification, serious adverse events, and adverse events of special interest will be 
summarized.  All deaths will be summarized. Laboratory measurements outside of the 
normal range will be identified.  Selected laboratory data will be summarized by 
treatment received and grade compared with baseline.  Relevant vital signs will be 
presented using summary statistics by treatment received and visit.  Drug exposure will 
be summarized as well, including duration of treatment, cumulative dose, and dose 
intensity.
Treatment-emergent adverse events are defined as adverse events that occur after the 
first dose of study treatment. Adverse events will be summarized by mapped Medical 
Dictionary for Regulatory Activities (MedDRA) preferred terms and appropriate MedDRA 
hierarchy.  Adverse event severity will be graded according to NCI CTCAE v5.0.  
Multiple occurrences of the same event will be counted once at the maximum severity. 
6.5.2
Exploratory Safety Analysis of Patient-Reported Symptomatic 
Adverse Events:  PRO CTCAE Data
PRO-CTCAE analyses will be primarily descriptive, with a focus on characterizing the 
pattern of patient-reported symptomatic adverse event occurrence over the course of the 
trial.  Results from these analyses will be presented separately from the safety analyses.  
PRO-CTCAE data will be analyzed at the item level in line with current NCI 
recommendations for data handling (Basch et al. 2014).  
PRO-CTCAE data will be summarized over time.  The proportion of missing data at each 
assessment timepoint will also be summarized to facilitate interpretation of data. The 
number and percentage of patients reporting each symptom, including overall side effect 
bother, and the change from baseline by category (frequency of occurrence, severity, 
interference) will be summarized at each assessment timepoint by treatment arm.  For 
items that are rated on a 5-point Likert scale, the maximum post-baseline score and 


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change from baseline will be summarized by treatment arm. Graphical representation of 
PRO-CTCAE data over time will also be provided.
6.6
PHARMACOKINETIC ANALYSES
Ipatasertib concentrations will be measured as outlined in Appendix 4 (Phase Ib) and
Appendix 2 (Phase III), respectively. For Phase Ib, the following PK parameters will be 
derived from the plasma concentrations of ipatasertib and its metabolite G-037720 using 
the noncompartmental methods, when appropriate as data allow:

Maximum observed concentration (Cmax)

Time to maximum observed concentration (tmax)

AUC from hour 0 to the last measurable concentration (AUC0-t)
Additional PK analyses will be conducted as appropriate.
Appropriate PK parameters from Day 1 and Day 15 will be compared to assess the 
effect of palbociclib on the PK profile of ipatasertib.
For the randomized Phase III portion, ipatasertib plasma concentration versus time data, 
together with information on dosing and patient characteristics, will be pooled and 
analyzed using a popPK analysis approach and reported separately.  Nonlinear 
mixed-effect modeling will be used for the estimation of popPK parameters for 
ipatasertib.  Covariates such as patient demographics (e.g., age and body size), serum 
albumin, liver function tests (e.g., AST, ALT, alkaline phosphatase), and serum 
creatinine will be tested for significance on PK parameters of interest.
Palbociclib levels will be measured as outlined in Appendix 4 (Phase Ib) and Appendix 2
(Phase III), respectively. Plasma concentrations of palbociclib will be compared to 
available historical and/or literature values.
The PK data will be combined with the safety and efficacy (e.g., PFS) data for 
exposureresponse modeling as data permit.  PK and PK/pharmacodynamic analyses 
may be reported in separate stand-alone reports.  Additional analyses may be explored 
as warranted by the data.
6.7
EXPLORATORY 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
INTERIM ANALYSES
6.8.1
Planned Interim Safety Analyses
This study includes an initial open-label Phase Ib safety portion with internal Safety 
Review (see further details in Section 3.1.1). 


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An external iDMC will be formed to evaluate safety data during the randomized Phase III 
portion of the study approximately every 6 months from the first patient randomized until 
the time of the primary analysis of PFS (see Section 6.4.1).  The Sponsor will be blinded 
until the PFS primary analysis.
In the absence of extenuating circumstances, accrual will not be halted during the 
randomized Phase III portion of the study while the interim safety analysis is conducted. 
An iDCC will prepare all summaries and analyses for the iDMC’s review. The safety 
summaries will include but not limit to demographic data, adverse events, serious 
adverse events, and relevant laboratory data. Members of the iDMC will be external to 
the Sponsor and will follow a charter that outlines their roles and responsibilities. Any
outcomes of the iDMC’s reviews on the safety and benefit-risk balance that affect study 
conduct will be communicated in a timely manner to the investigators for notification of 
IRB/ECs and competent authorities as required. A detailed plan will be included in the 
iDMC Charter.
Following the data review, the iDMC will provide a recommendation to the Sponsor 
whether to continue the study, amend the protocol, or stop the study. The final decision 
will rest with the Sponsor. In addition, the Sponsor may request ad-hoc meetings of the 
iDMC at any time during the study to review ongoing safety summary data.
6.8.2
Planned Interim Efficacy Analyses
No interim efficacy analyses are planned for the co-primary endpoint of PFS.
6.8.3
Optional Interim Analysis
To adapt to information that may emerge during the study, the Sponsor may choose to 
conduct an optional interim efficacy analysis, prior to the time of the primary analysis for 
PFS.  For example, availability of clinical trial results for a specific external competitor 
molecule during this study might (depending on the data) trigger an interim analysis, or 
the existence of an internal competitor molecule might necessitate an interim analysis to 
enable decision-making regarding continued development of the study drug ipatasertib.  
Below are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed.
The interim analysis will be conducted by an iDCC and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
Charter.
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the Statistical Analysis Plan 
(SAP), and the SAP will be submitted to relevant health authorities at least 2 months 
prior to the conduct of the interim analysis.  The iDMC charter will be updated to 
document potential recommendations the iDMC can make to the Sponsor as a result of 


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the analysis (e.g., stop the study for positive efficacy, stop the study for futility), and the 
iDMC charter will also be made available to relevant health authorities.
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Specifically, the Lan-DeMets -spending function that approximates the 
O'Brien-Fleming boundary will be applied on the primary endpoint of PFS to determine 
the critical value for stopping for positive efficacy at the interim analysis (DeMets and 
Lan 1994). Additional criteria for recommending that the study be stopped for positive 
efficacy may be added to the iDMC charter.  If the study continues beyond the interim 
analysis, the critical value at the final analysis would be adjusted accordingly to maintain 
the protocol-specified overall type I error rate, per standard Lan-DeMets methodology.
6.9
CHINA SUBPOPULATION ANALYSES (AS APPLICABLE)
After the enrollment of patients in the global phase of this study is complete, additional 
Chinese patients may be recruited into the China extension cohort. The analysis 
population for China subpopulation analyses includes Chinese patients recruited in the
global study population and China extension cohort combined. The total number of 
patients in the China subpopulation is aimed to show treatment benefit consistency 
between the global population and the China subpopulation. A pre-specified clinical 
data cutoff for the China subgroup analysis will be planned before the PFS primary 
analysis.
China subpopulation analyses will be performed and summarized in a separate study
report. Further details will be provided in the SAP.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.


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PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.


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7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 


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will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
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 utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.


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8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on germline mutations for patients in the 
randomized portion of the study, may be submitted to government or other health 


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research databases or shared with researchers, government agencies, companies, or 
other groups that are not participating in this study.  These data may be combined with 
or linked to other data and used for research purposes, to advance science and public 
health, or for analysis, development, and commercialization of products to treat and 
diagnose disease.  In addition, redacted Clinical Study Reports and other summary 
reports will be provided upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data 
and will implement plans for evaluating and controlling these risks.  Risk evaluation 
and control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 


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parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and 
monitoring of quality tolerance limits will be provided in a Quality Tolerance Limit 
Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 145 sites globally will participate to enroll approximately 370 patients in 
both Phase Ib and Phase III portions of the protocol.  Enrollment will occur through an 
IxRS.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
An iDMC will be employed to monitor and evaluate patient safety throughout the 
Phase III portion of the study.  
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 


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the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Ipatasertib—F. Hoffmann-La Roche Ltd 
14/Protocol CO41012, Version 3 
Appendix 1  
Schedule of Activities (Phase III Portion) 
 
Screening a 
Cycle 1 
Cycle 2 
Cycles  3 
Tx 
DC b 
Long-Term 
FU c 
Day
(Window) -42 to -29
-28 to -1
1 
8 
( 1) 
15 
(+2) 
1 
(2) 
15 
( 2) 
1 
( 3) 
15 
( 3) d
 
 
Informed consent 
x e 
 
 
 
 
 
 
 
 
 
Whole Blood Sample: somatic tumor mutations 
x f 
 
 
 
 
 
 
 
 
 
Archival tumor tissue for biomarker analysis 
x 
 
 
 
 
 
 
 
 
 
Demographics, medical history/baseline conditions, 
prior cancer treatment 
 
x 
 
 
 
 
 
 
 
 
 
Vital signs g 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Weight 
 
x 
x 
 
 
x 
 
x 
 
x 
 
Height 
 
x 
 
 
 
 
 
 
 
 
 
Complete physical examination h 
 
x 
 
 
 
 
 
 
 
x 
 
Limited physical examination i  
 
 
x j 
 
x 
x 
x 
x 
 
 
 
ECOG Performance Status 
 
x 
x k 
 
 
x 
 
x 
 
x 
 
12-Lead electrocardiogram (ECG) l 
 
x 
As clinically indicated 
x 
 
Pregnancy test m 
 
x 
x 
 
 
x 
 
x 
 
x 
 
Viral serology (hepatitis) n 
 
x 
 
 
 
 
 
 
 
 
 
Hematology o 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
INR and PTT (or aPTT) 
 
x 
 
 
 
 
 
 
 
x 
 
Fasting serum chemistry p 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Fasting lipid profile, amylase, lipase q 
 
x 
 
 
 
 
 
x q 
 
x 
 
HbA1c 
 
x 
 
 
 
 
 
x q 
 
x 
 


Appendix 1: Schedule of Activities (Phase III Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
146/Protocol CO41012, Version 3
Screening a
Cycle 1
Cycle 2
Cycles 3
Tx 
DC b
Long-Term 
FU c
Day
(Window) -42 to -29
-28 to -1
1
8
(1)
15 
(+2)
1
(2)
15
(2)
1
(3)
15
(3) d
Urinalysis r
x
As clinically indicated
x
Anti-diarrheal prophylaxis s
See Section 4.3.2.5 (prophylaxis)/
Table 3 (management)
In clinic palbociclib administration (otherwise taken 
at home based on QD dosing Days 121 of each 
cycle)
x t
x
x
x
x
x
In clinic ipatasertib/placebo administration (otherwise 
taken at home based on QD dosing Days 121 of 
each cycle)
x t
x
x
x
x
x
Ipatasertib/placebo dispensing and drug 
accountability as applicable
x
x
x
x
Palbociclib dispensing and drug accountability as 
applicable
x
x
x
x
Medication Diary (palbociclib, ipatasertib or placebo, 
loperamide or other anti-diarrheal; as well as 
analgesic medication and goserelin or alternative 
LHRH agonist as applicable)
Complete at home and as applicable during clinic 
visits when medication is taken as instructed in 
the diary
Fulvestrant administration u
x t
x
x
x
For pre-/peri-menopausal women and recommended 
for men: Goserelin administration v
Switch to goserelin 
(if needed)
Administer at time of fulvestrant administration 
whenever possible (as applicable); may be 
self-administered at home per local standard of 
care if the administration does not coincide with a 
clinic visit.


Appendix 1: Schedule of Activities (Phase III Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
147/Protocol CO41012, Version 3
Screening a
Cycle 1
Cycle 2
Cycles 3
Tx 
DC b
Long-Term 
FU c
Day
(Window) -42 to -29
-28 to -1
1
8
(1)
15 
(+2)
1
(2)
15
(2)
1
(3)
15
(3) d
BPI-SF “worst pain” item, EORTC QLQ-C30, and 
EQ-5D-5L w
x
x
x
x
x x
EORTC QLQ-BR23 w
x
x w
x
x x
NCI PRO-CTCAE w
x
x
x
x
Tumor assessments y
x
Every 8 weeks (7 days) from Cycle 1 Day 1 
regardless of dose modifications (see Section 4.5.6
for more details)
Bone scan z
x
Every 16 weeks (7 days) from Cycle 1 Day 1 
regardless of dose modifications (see Section 4.5.6
for more details)
Concomitant medications aa
x
x
x
x
x
x
x
x d
x
Adverse events bb, cc
x
x
x
x
x
x
x
x d
x
Mid-cycle phone visit d
x d
Record cancer-related radiotherapy/surgical 
procedures cc
x
As clinically indicated (see Section 4.5.7)
Survival/anti-cancer therapy follow-up
x
Plasma sample: somatic tumor mutations
x
x
x
Optional tumor biopsy dd
x
x
Blood sample for WGS if approved locally ee
x
Plasma PK sample
See Appendix 2


Appendix 1: Schedule of Activities (Phase III Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
148/Protocol CO41012, Version 3
aPTTactivated PTT; BIDtwice a day; BPI-SFBrief Pain Inventory- Short Form; CT computed tomography; ctDNAcirculating tumor DNA; 
eCRFelectronic Case Report Form; ECOG Eastern Cooperative Oncology Group; EORTC BR23European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module 23; EORTC QLQ-C30European Organisation for Research and 
Treatment of Cancer Quality-of-Life Questionnaire Core 30; EQ-5D-5LEuropean Quality of Life 5-Dimension, 5-Level questionnaire; FUFollow 
Up; HbA1c glycosylated hemoglobin; HBcAbhepatitis B core antibody; HBsAg hepatitis B surface antigen; HBVhepatitis B virus; 
HCVhepatitis C virus; LHRHluteinizing hormone releasing hormone; INR international normalized ratio; MRImagnetic resonance imaging; 
NGSnext generation sequencing; PKpharmacokinetic; PRO-CTCAEPatient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events; PO by mouth; QDonce daily; RBRResearch Biosample Repository; SOC standard of care; SREskeletal-related event; 
PTT partial thromboplastin time; Tx DCTreatment Discontinuation; WGSwhole genome sequencing.
Notes:  All assessments should be performed within 2 days of the scheduled visit, unless otherwise specified.  On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified. Additional assessments may also be done at unplanned visits if clinically indicated. 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days before Cycle 1 Day 1 may be 
used (for bone scans, standard-of-care scans within 6 weeks before Cycle 1 Day 1 may be used, see Section 4.5.6 for details); such tests do not 
need to be repeated for screening.  Unless otherwise stated, screening assessments that are done within 2 days prior to Cycle 1 Day 1 do not 
need to be repeated on Cycle 1 Day 1.
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit within approximately 30 days after their final dose 
of study drug (ipatasertib/placebo, palbociclib or fulvestrant, whichever is discontinued last).  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.
c Required follow-up information will be collected via telephone calls and/or clinic visits approximately every 3 months until death, loss to follow-up, 
or study termination or termination of follow-up by the Sponsor.
d Mid-cycle phone call starting at Cycle 3 Day 15 from the site to the patient to assess adverse events as well as concomitant medications.  This 
will allow site staff to implement adequate adverse event management in a timely manner once clinic visits occur every 28 days.
e Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 6 weeks 
before initiation of study treatment.
f
Valid Tri-AKT ctDNA test result by the central laboratory NGS assay within 6 weeks prior to enrollment required for stratification.
g Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure, while the patient is in a seated position, and temperature. 
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.


Appendix 1: Schedule of Activities (Phase III Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
149/Protocol CO41012, Version 3
h Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General 
Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse 
Event eCRF. 
i
Perform a limited, symptom-directed physical examination at specified timepoints and as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
j
If the complete physical examination required at screening was done within 4 days of Cycle 1 Day 1, a limited physical examination is no longer 
required 
k If ECOG Performance status completed at screening was done within 4 days of Cycle 1 Day 1, a Cycle 1 Day 1 assessment is no longer 
required
l
Triplicate ECG recordings will be obtained at baseline to determine eligibility (see Section 4.1.2), otherwise single ECG recordings are sufficient. 
See Section 4.5.9 for more details. 
m Women of childbearing potential must have a negative serum pregnancy test result within 96 hours of first dose of study treatment. Alternatively, 
if a negative serum pregnancy test was obtained within 7 days of first dose of study treatment, it needs to be confirmed by a negative urine 
pregnancy test on the day of the first administration of study treatment prior to dosing.   Urine/serum pregnancy tests will be performed at the 
specified subsequent visits (or within 96 hours of the visit).  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
For all other women, documentation must be present in medical history confirming that patient is not of childbearing potential.  
n HBsAg, total HBcAb, and HCV antibody; additional tests for HBV DNA or HCV RNA may be required to confirm eligibility (see Section 4.1.2).
o Hematology includes RBC count, hemoglobin, hematocrit, WBC count with differential (i.e., must be sufficient for the determination of absolute 
neutrophil counts, lymphocytes) and platelet count. Laboratory samples should be drawn within 48 hours prior to study drug administration 
at the clinic; results should be available to assess prior to dosing for complete blood count as indicated in Section 4.5.8.  
p Fasting serum chemistry panel includes glucose (following 8-hour fast, plasma glucose is also acceptable per local practice), BUN (or urea), 
bicarbonate (or total carbon dioxide if considered standard of care for the region), creatinine, sodium, potassium, magnesium, calcium, 
phosphorus, albumin, total bilirubin, ALP (total ALP), AST, and ALT.  Laboratory samples should be drawn within 48 hours prior to study drug 
administration at the clinic; results should be available to assess prior to dosing for fasting glucose, bilirubin, total ALP, AST, and ALT, as 
indicated in Section 4.5.8.
q Fasting lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides following a 8 hour fast), amylase, lipase, and 
HbA1c will be assessed at screening, every 3 cycles starting on Day 1 of Cycle 3, and at SDDV visit. Laboratory samples should be drawn 
within 48 hours prior to study drug administration at the clinic.


Appendix 1: Schedule of Activities (Phase III Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
150/Protocol CO41012, Version 3
r
Urinalysis (dipstick allowed):  pH, specific gravity, glucose, protein, ketones, and blood; microscopic examination if clinically indicated (sediment, 
RBCs, WBCs, casts, crystals, epithelial cells, bacteria). Laboratory samples should be taken within 48 hours prior to study drug 
administration at the clinic.
s Anti-diarrheal prophylaxis:  All patients should receive loperamide (2 mg PO twice a day [BID] or 4 mg QD) as prophylaxis for diarrhea in the first 
cycle if allowed by local guidance.  Investigators are encouraged to continue this dosing for the remainder of the study; the prophylaxis dose may 
be adjusted as necessary, using their discretion based on clinical judgment and per local guidance. If diarrhea occurs, it should be managed per 
guidelines in Table 3.
t
Patients should receive their first dose of study drug on the day of randomization, if possible.  If this is not possible, the first dose should occur no 
later than 4 days after randomization.
u It is recommended to administer fulvestrant prior to the oral medications (i.e., ipatasertib/placebo and palbociclib) during all clinic visits (see 
Section 4.3.2.1).
v Pre- or peri-menopausal women must have started treatment with goserelin or an alternative LHRH agonist at least 14 days prior to first dose of 
study treatment (for men this is recommended). If patients have received an alternative LHRH agonist prior to study entry, it is recommended 
that they switch to goserelin for the duration of the trial, whenever possible.  Every effort should be made to administer goserelin or alternative 
LHRH agonist as applicable on site at the time of fulvestrant administration as applicable in order to minimize the number of clinic visits. Patients 
may self-administer goserelin or alternative LHRH agonist as applicable at home per local standard of care if the administration does not 
coincide with a clinic visit. In that case, patients will complete a diary.
w Patient-reported outcomes:  The BPI-SF worst pain item (Appendix 10), EORTC QLQ-C30, (Appendix 11), PRO-CTCAE, (Appendix 13), and 
EQ-5D-5L (Appendix 14) questionnaires will be completed on paper starting on Cycle 1 Day 1, and Day 1 of every cycle, thereafter, as well as
at the Tx DC visit. The EORTC QLQ-BR23 (Appendix 12) will be completed on paper starting on Cycle 1 Day 1, Cycle 3 Day 1, and Day 1 of 
every third cycle, thereafter (i.e., Cycles 6, 9, 12, 15, etc.), as well as at the Tx DC visit. The BPI-SF worst pain item, EORTC QLQ-C30, 
EORTC QLQ-BR23, PRO-CTCAE, and EQ-5D-5L should be completed in this order, as applicable. Male patients will not complete the QLQ-
BR23, as this measure has not been validated in men. All PRO questionnaires scheduled for administration during a clinic visit are required to be 
completed by the patient at the investigational site at the start of the clinic visit before discussion of the patient's health state, laboratory results or 
health record, before administration of study treatment, and/or prior to any other study assessment(s) that could bias patients’ responses to 
ensure that the validity of the instrument is not compromised and that data quality meets regulatory requirements.  Study personnel should 
review all questionnaires for completeness before the patient leaves the investigational site. 
x During long-term follow-up, the EORTC QLQ-C30 and EORTC QLQ-BR23 will be completed either in-clinic or over the phone only once at 3 
months after the Tx DC visit. The BPI-SF worst pain item and the EQ-5D-5L questionnaire will be completed every 6 months for a duration of 
1 year, unless the patient withdraws consent or the Sponsor terminates the study or the PRO follow-up.  PRO questionnaires during the 
long-term follow-up period may be completed at the investigational site should the patient come in for a clinic visit or be administered via 
telephone calls.


Appendix 1: Schedule of Activities (Phase III Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
151/Protocol CO41012, Version 3
y Tumor assessments performed according to RECIST v1.1.  Post-baseline tumor assessments should be performed every 8 weeks 7 days from 
Cycle 1 Day 1 regardless of dose delay, treatment interruption or early treatment discontinuation until disease progression.  The method used for 
a patient (CT or MRI scan or photographic measurements) must be the same throughout the study.  A missed tumor assessment should be 
rescheduled as soon as possible.  See Section 4.5.6 for more details.
z A screening (or documented SOC) technetium bone scan should be performed within 6 weeks before Cycle 1, Day 1.  For patients with known or 
suspected bone metastasis, subsequent post-baseline bone scans should be performed with every other tumor assessment starting from Week 
16 (7 days), unless the bone lesions are followed via CT scan or other imaging modality (MRI or X-ray) during the regular tumor assessments 
every 8 weeks (7 days), in which case additional post-baseline bone scans are only needed as clinically indicated.  Bone disease and any 
changes in bone imaging should be evaluated radiographically by CT scan, MRI, or X-ray to ascertain the presence of bone destruction versus a 
healing reaction.  See Section 4.5.6 for more details.
aa Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 30 days after the final dose of study drug.
bb 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 30 days after the final dose of study drug.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).
cc An SRE is defined as either a pathologic fracture, radiation therapy to the bone, surgery to the bone, or spinal cord compression.  Any 
cancer-related radiation or surgery to the bone (on–study treatment and during the adverse event follow-up), or adverse events with diagnosis of 
pathologic fracture or spinal cord compression, should be assessed according to the SRE criteria and reported with this assessment on the 
relevant eCRF page.
dd Optional fresh biopsy at screening and at disease progression prior to start of next cancer therapy (can be collected anytime at or after 
progression), see Section 4.5.8. For patients without adequate tumor specimen per Section 4.1.1, alternatively, a newly collected tumor 
tissue sample may be provided at screening.
ee Blood sample collection on Cycle 1 Day 1 for WGS unless prohibited by local regulations (see details in Section 4.5.11).


Ipatasertib—F. Hoffmann-La Roche Ltd
152/Protocol CO41012, Version 3
Appendix 2
Schedule of Pharmacokinetic Samples (Phase III portion)
Visit
Timepoint
Sample Type
Cycle 1, Day 1
24 hours after ipatasertib 
or its placebo
Plasma sample for ipatasertib or 
its placebo and G-037720
Cycle 1, Day 15 a
Predose b
Plasma sample for ipatasertib or 
its placebo and G-037720 and 
palbociclib
Cycle 1, Day 15 a
24 hours after ipatasertib 
or its placebo
Plasma sample for ipatasertib or 
its placebo and G-037720
Cycle 2, Day 15 a
Predose b
Plasma sample for ipatasertib or 
its placebo and G-037720 and 
palbociclib
Cycle 2, Day 15 a
24 hours after ipatasertib 
or its placebo
Plasma sample for ipatasertib or 
its placebo and G-037720
PKpharmacokinetic.
Notes:  Study assessments may be delayed or moved ahead of the window to 
accommodate holidays, vacations, and unforeseen delays.

Dose time on the day before and day of PK sampling should be accurately 
reported.

Any incidence of vomiting within 3 hours post drug administration should also 
be recorded for the day of PK sampling.
PK sampling timepoint should be accurately reported.  
a Other than the Cycle 1, Day 1 visit, if 3 or more consecutive doses of 
ipatasertib/placebo were withheld immediately prior to the PK sample collection 
(including the day of PK collection visit), the sample collection may be delayed 
to another day after at least 3 consecutive days of ipatasertib/placebo dosing 
have been administered (including the day of PK collection visit).  The sampling 
can be done any day after Day 12 of the relevant cycle corresponding with a 
planned ipatasertib/placebo dosing day.
b Predose0 to 3 hours prior to dosing with ipatasertib/placebo on the day of 
the visit.


Ipatasertib—F. Hoffmann-La Roche Ltd
153/Protocol CO41012, Version 3
Appendix 3
Schedule of Activities (Phase Ib Portion)
Screening a
Start of Ipatasertib 
Only Run In
Cycle 1
Cycle 2
Cycle 3
Cycles 4
Tx 
DC b
Day
(Window)
-49 
to -36
-35
to -8
-7 to -5
1
8
(1)
15 
(2)
1
(2)
15
(2)
1
(3)
15
(3)
1
(3)
15
(3) v
Informed consent
x c
Whole Blood Sample: somatic tumor mutations
x d
Demographics, medical history/baseline conditions, 
prior cancer treatment
x
Vital signs e
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
Height
x
Complete physical examination f
x
x
Limited physical examination g
x h
x
x
x
x
x
ECOG Performance Status
x
x i
x
x
x
x
12-Lead electrocardiogram (ECG) j
x
As clinically indicated
x
Pregnancy test k
x
x
x
x
x
x
Viral serology (hepatitis) l
x
Hematology m
x
x
x
x
x
x
x
x
x
x
x
INR and PTT (or aPTT)
x
x
Fasting serum chemistry n
x
x
x
x
x
x
x
x
x
x
x
Fasting lipid profile, amylase, lipase o
x
x o
x o
x
HbA1c
x
x o
x o
x
Urinalysis p
x
As clinically indicated
x


Appendix 3: Schedule of Activities (Phase Ib Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
154/Protocol CO41012, Version 3
Screening a
Start of Ipatasertib 
Only Run In
Cycle 1
Cycle 2
Cycle 3
Cycles 4
Tx 
DC b
Day
(Window)
-49 
to -36
-35
to -8
-7 to -5
1
8
(1)
15 
(2)
1
(2)
15
(2)
1
(3)
15
(3)
1
(3)
15
(3) v
Anti-diarrheal prophylaxis q
See Section 4.3.2.5 (prophylaxis)/Table 3 (management)
In clinic palbociclib administration (otherwise taken 
at home based on QD dosing Days 121 of each 
cycle)
x
x
x
x
x
x
x
x
In clinic ipatasertib administration (otherwise taken 
at home based on QD dosing during the initial 5-7 
day single-agent run-in and on Days 121 of each 
cycle)
x r, s
x 
x
x
x
x
x
x
x
Ipatasertib dispensing and drug accountability as 
applicable
x r
x
x
x
x
x
Palbociclib dispensing and drug accountability as 
applicable
x
x
x
x
x
Medication Diary (palbociclib, ipatasertib, 
loperamide or other anti-diarrheal, as well as 
goserelin or alternative LHRH agonist if applicable 
as applicable)
Complete at home and as applicable during clinic visits when 
medication is taken as instructed in the diary
Fulvestrant administration z
x
x
x
x
x
For pre-/peri-menopausal women and recommended 
for men: Goserelin administration t
Switch to 
goserelin 
(if needed)
Administer at time of fulvestrant administration whenever possible (as 
applicable); may be self-administered at home per local standard of care 
if the administration does not coincide with a clinic visit.
Tumor Assessments
x
Post-baseline tumor assessments may be 
performed per local SOC
Bone scan 
x
Post-baseline tumor assessments may be 


Appendix 3: Schedule of Activities (Phase Ib Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
155/Protocol CO41012, Version 3
Screening a
Start of Ipatasertib 
Only Run In
Cycle 1
Cycle 2
Cycle 3
Cycles 4
Tx 
DC b
Day
(Window)
-49 
to -36
-35
to -8
-7 to -5
1
8
(1)
15 
(2)
1
(2)
15
(2)
1
(3)
15
(3)
1
(3)
15
(3) v
performed per local SOC
Concomitant medications u
x
x
x
x
x
x
x
x
x
x
xv
x
Adverse events w
x
x
x
x
x
x
x
x
x
x
xv
x
Mid-cycle phone visit v
xv
Optional tumor biopsy x
x
x
Blood sample for WGS if approved locally y
x
Plasma sample: somatic tumor mutations
x
x
Plasma PK sample
See Appendix 4
aPTTactivated PTT; BIDtwice a day; ctDNAcirculating tumor DNA; eCRF electronic Case Report Form; ECOG Eastern Cooperative 
Oncology Group; HbA1c glycosylated hemoglobin; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B 
virus; HCVhepatitis C virus; LHRHluteinizing hormone releasing hormone; INR international normalized ratio; NGSnext generation 
sequencing; PKpharmacokinetic; POby mouth; QD once daily; SOCstandard of care; PTTpartial thromboplastin time; Tx DCTreatment 
Discontinuation; WGSwhole genome sequencing.
Notes:  All assessments should be performed within 2 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. Additional assessments may also be done at unplanned visits if 
clinically indicated.
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days before first dose of study 
treatment may be used (for bone scans, standard-of-care scans within 6 weeks before first dose of study treatment may be used, see 
Section 4.5.6 for details); such tests do not need to be repeated for screening.  Unless otherwise stated, screening assessments that are done 
within 2 days prior to first dose of study treatment do not need to be repeated on the Day -7 to Day -5 clinic visit.


Appendix 3: Schedule of Activities (Phase Ib Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
156/Protocol CO41012, Version 3
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit within approximately 30 days after their final 
dose of study drug (ipatasertib/placebo, palbociclib or fulvestrant, whichever is discontinued last).  The visit at which response assessment 
shows progressive disease may be used as the treatment discontinuation visit. 
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 6 weeks 
before initiation of study treatment.
d Sample should be collected during screening and immediately submitted for testing but a valid ctDNA test result for Tri-AKT status by the
central laboratory NGS assay is not required prior to enrollment.
e Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure, while the patient is in a seated position, and temperature.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new 
or worsened clinically significant abnormalities on the Adverse Event eCRF.
f
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
g Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
h If the complete physical examination required at screening was done within 4 days of first dose of study treatment, a limited physical 
examination is no longer required at the Day -7 to Day -5 clinic visit.
i
If the ECOG performance status completed at screening was done within 4 days of first dose of study treatment, the assessment is no longer 
required at the Day -7 to Day -5 clinic visit. 
j
Triplicate ECG recordings will be obtained at baseline to determine eligibility (see Section 4.1.2), otherwise single ECG recordings are 
sufficient. See Section 4.5.9 for more details. 
k All women of childbearing potential will have a serum pregnancy test within 96 hours of first dose of study treatment.  Alternatively, if a 
negative serum pregnancy test was obtained within 7 days of first dose of study treatment, it needs to be confirmed by a negative urine 
pregnancy test on the day of the first administration of study treatment prior to dosing.  Urine/serum pregnancy tests will be performed at the 
specified subsequent visits (or within 96 hours of the visit).  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test. For all other women, documentation must be present in medical history confirming that patient is not of childbearing potential.  
l
HBsAg, total HBcAb, and HCV antibody; additional tests for HBV DNA or HCV RNA may be required to confirm eligibility (see Section 4.1.2).
m Hematology includes RBC count, hemoglobin, hematocrit, WBC count with differential (i.e., must be sufficient for the determination of absolute 
neutrophil counts, lymphocytes) and platelet count. Laboratory samples should be drawn within 48 hours prior to study drug administration 
at the clinic; results should be available to assess prior to dosing for complete blood count as indicated in Section 4.5.8.  


Appendix 3: Schedule of Activities (Phase Ib Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
157/Protocol CO41012, Version 3
n Fasting serum chemistry panel includes glucose (following 8-hour fast, plasma glucose is also acceptable per local practice), BUN or urea, 
bicarbonate or total carbon dioxide (if considered standard of care for the region), creatinine, sodium, potassium, magnesium, calcium, 
phosphorus, albumin, total bilirubin, ALP (total ALP), ALT, and AST.  Laboratory samples should be drawn within 48 hours prior to study drug 
administration at the clinic; results should be available to assess prior to dosing for fasting glucose, bilirubin, total ALP, AST, and ALT, as 
indicated in Section 4.5.8.
o Fasting lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides following a 8 hour fast), amylase, lipase, 
and HbA1c will be assessed at screening, every 3 cycles starting on Day 1 of Cycle 3, and at SDDV visit. Laboratory samples should be 
drawn within 48 hours prior to study drug administration at the clinic.
p Urinalysis (dipstick allowed):  pH, specific gravity, glucose, protein, ketones, and blood; microscopic examination if clinically indicated 
(sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria). Laboratory samples should be taken within 48 hours prior to study drug 
administration at the clinic.
q Anti-diarrheal prophylaxis:  All patients should receive loperamide (2 mg PO BID or 4 mg QD) as prophylaxis for diarrhea once ipatasertib 
study treatment is started and in the first cycle if allowed by local guidance.  Investigators are encouraged to continue this dosing for the 
remainder of the study; the prophylaxis dose may be adjusted as necessary, using their discretion based on clinical judgment and per local 
guidance. If diarrhea occurs, it should be managed per guidelines in Table 3; anti-diarrheal prophylaxis with loperamide should also be 
resumed as needed.
r
Start of ipatasertib only Run In:  On clinic visit Day -7 to -5, patients are to start ipatasertib as a single agent for 5-7 days prior to Cycle 1, 
Day 1.
s Patients should receive their first dose of ipatasertib (given first as a single agent for 5-7 days) on the day of enrollment, if possible.  If this is 
not possible, the first dose should occur no later than 4 days after. Note that patients should be on a minimum of 5 days of single-agent 
ipatasertib before the Cycle 1, Day 1 visit. On Cycle 1, Day 1, palbociclib and fulvestrant should be administered after PK sampling is 
completed (see Section 4.3.2.1); thereafter, ipatasertib and palbociclib are to be administered at the same time.
t
Pre- or peri-menopausal women must have started treatment with goserelin or an alternative LHRH agonist at least 14 days prior to first dose 
of study treatment (for men this is recommended). If patients have received an alternative LHRH agonist prior to study entry, it is 
recommended that they switch to goserelin for the duration of the trial, whenever possible.  Every effort should be made to administer 
goserelin or alternative LHRH agonist as applicable on site at the time of fulvestrant administration as applicable in order to minimize the 
number of clinic visits. Patients may self-administer goserelin or alternative LHRH agonist as applicable at home per local standard of care if 
the administration does not coincide with a clinic visit. In that case, patients will complete a diary.
u
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 30 days after the final dose of study drug.


Appendix 3: Schedule of Activities (Phase Ib Portion)
Ipatasertib—F. Hoffmann-La Roche Ltd
158/Protocol CO41012, Version 3
v
Mid-cycle phone calls from the site to the patient to assess adverse events as well as concomitant medications will start at Cycle 4, Day 15.  
This will allow site staff to implement adequate adverse event management in a timely manner once clinic visits occur every 28 days.
w 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 30 days after the final dose of study 
drug.  After that point patients in the Phase Ib will permanently discontinue from the study as they do not undergo any long-term follow-up.  
The Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study 
drug treatment (see Section 5.6).
x
Optional fresh biopsy at screening and at disease progression prior to start of next cancer therapy (can be collected anytime at or after 
progression), see Section 4.5.8.
y
Blood sample collection on first dose of study treatment for WGS unless prohibited by local regulations (see details in Section 4.5.11).
z
It is recommended that fulvestrant be administered prior to the oral medications, ipatasertib and palbociclib, during all clinic visits following 
Cycle 1, Day 1. In contrast, on Cycle 1, Day 1, ipatasertib is administered first (see Section 4.3.2.1).


Ipatasertib—F. Hoffmann-La Roche Ltd
159/Protocol CO41012, Version 3
Appendix 4
Schedule of Pharmacokinetic Samples (Phase Ib portion)
Visit a
Timepoint
Sample Type
Cycle 1, Day 1
15 min pre-dose (10 
min)
Plasma sample for ipatasertib and G-037720
0.5 hr post-dose (5 min)
Plasma sample for ipatasertib and G-037720
1 hr post-dose (5 min)
Plasma sample for ipatasertib and G-037720
2 hr post-dose (10 min)
Plasma sample for ipatasertib and G-037720
3 hr post-dose (10 min)
Plasma sample for ipatasertib and G-037720
4 hr post-dose (15 min)
Plasma sample for ipatasertib and G-037720
6 hr post-dose (15 min)
Plasma sample for ipatasertib and G-037720
Cycle 1, 
Day 15 b
15min pre-dose
(10 min)
Plasma sample for ipatasertib and G-037720 and 
palbociclib
0.5 hr post-dose (5 min)
Plasma sample for ipatasertib and G-037720
1 hr post-dose (5 min)
Plasma sample for ipatasertib and G-037720
2 hr post-dose (10 min)
Plasma sample for ipatasertib and G-037720
3 hr post-dose (10 min)
Plasma sample for ipatasertib and G-037720
4 hr post-dose (15 min)
Plasma sample for ipatasertib and G-037720
6 hr post-dose (15 min)
Plasma sample for ipatasertib and G-037720
Cycle 2, Day 15
c
15 min pre-dose (10 
min)
Plasma sample for ipatasertib and G-037720 and 
palbociclib
Cycle 3, Day 15
c
15 min pre-dose (10 
min)
Plasma sample for ipatasertib and G-037720 and 
palbociclib
2 hr post-dose (10 min)
Plasma sample for ipatasertib and G-037720 
hrhour; minminute; PKpharmacokinetic.
Notes: Timepoints listed are for the pre-dose and post-dose of ipatasertib. The actual PK 
sampling times need to be recorded, including samples collected outside of the sampling window. 
a With exception to Cycle 1 Day 1, sampling can be done any day after Day 12 of the relevant 
cycle corresponding with a planned ipatasertib dosing day (i.e., Days 12–21).
b If 3 or more consecutive doses of ipatasertib were withheld immediately prior to the PK 
sample collection (including the day of PK collection visit), the sample collection may be 
delayed to another day after at least 12 consecutive days of ipatasertib and palbociclib 
dosing have been administered (including the day of PK collection visit).
c If 3 or more consecutive doses of ipatasertib were withheld immediately prior to the PK 
sample collection (including the day of PK collection visit), the sample collection may be 
delayed to another day after at least 3 consecutive days of ipatasertib and palbociclib 
dosing have been administered (including the day of PK collection visit).


Ipatasertib—F. Hoffmann-La Roche Ltd
160/Protocol CO41012, Version 3
Appendix 5
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale
Grade
Description
0
Fully active, able to carry on all predisease 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


Ipatasertib—F. Hoffmann-La Roche Ltd
161/Protocol CO41012, Version 3
Appendix 6
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations
Additional details and the most current version of the guideline recommendations can 
be found at the URL below: 
https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-guidelines/guideline-
recommendations-for-immunohistochemical-testing-of-estrogen-and-progesterone-receptors-in-
breast-cancer


Appendix 6: ASCO/CAP Estrogen Receptor and Progesterone Receptor Guideline 
Recommendations
Ipatasertib—F. Hoffmann-La Roche Ltd
162/Protocol CO41012, Version 3


Ipatasertib—F. Hoffmann-La Roche Ltd
163/Protocol CO41012, Version 3
Appendix 7
ASCO/CAP HER2 Test Guideline Recommendations 
Updates to the ASCO/CAP HER2 Test Guideline Recommendations are summarized 
below as found in the following article:
Wolff AC, Hammond ME, Hicks DG, et al. Human Epidermal Growth Factor 
Receptor 2 Testing in Breast Cancer: American Society of Clinical 
Oncology/College of American Pathologists Clinical Practice Guideline 
Focused Update. J Clin Oncol 2018;36(20):2105-2122.
The complete guidelines can also be accessed at the following website URL:
https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-
guidelines/recommendations-for-human-epidermal-growth-factor-2-testing-in-breast-
cancer


Appendix 7: ASCO/CAP HER2 Test Guideline Recommendations
Ipatasertib—F. Hoffmann-La Roche Ltd
164/Protocol CO41012, Version 3


Appendix 7: ASCO/CAP HER2 Test Guideline Recommendations
Ipatasertib—F. Hoffmann-La Roche Ltd
165/Protocol CO41012, Version 3


Appendix 7: ASCO/CAP HER2 Test Guideline Recommendations
Ipatasertib—F. Hoffmann-La Roche Ltd
166/Protocol CO41012, Version 3


Ipatasertib—F. Hoffmann-La Roche Ltd
167/Protocol CO41012, Version 3
Appendix 8
Examples of Strong and Moderate CYP3A Inhibitors and Strong 
CYP3A Inducers
This table is to provide examples and is not intended to be a complete list; names may 
vary in different locations.
Strong CYP3A inhibitors
Moderate CYP3A inhibitors
Strong CYP3A inducers
VIEKIRA PAK1*
erythromycin*
rifampin*
indinavir* 
fluconazole*
mitotane*
tipranavir*
darunavir
avasimibe
ritonavir*
dronedarone*
rifapentine
cobicistat*
crizotinib*
apalutamide
ketoconazole*
atazanavir
phenytoin*
idelalisib*
letermovir
carbamazepine*
troleandomycin*
GSK2647544
enzalutamide*
telaprevir*
aprepitant*
St John's Wort3*
danoprevir*
casopitant
lumacaftor
elvitegravir* 
amprenavir
rifabutin
lopinavir* 
faldaprevir
phenobarbital
itraconazole*
imatinib*
voriconazole*
verapamil*
mibefradil
netupitant
LCL161
nilotinib
clarithromycin*
grapefruit juice2
posaconazole*
tofisopam*
telithromycin
cyclosporine*
grapefruit juice2* 
ACT-178882
conivaptan*
ciprofloxacin*
nefazodone*
magnolia vine (Schisandra sphenanthera)
nelfinavir*
isavuconazole
saquinavir*
cimetidine*
ribociclib
FK1706
diltiazem*
clotrimazole*
boceprevir*
fluvoxamine*
Source:  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664.htm
This table is prepared to provide examples of clinical inhibitors and inducers of CYP3A.  Data 
were collected based on a search of the University of Washington Drug Interaction Database 
1 VIEKIRA PAK paritaprevir/ritonavir ombitasvir dasabuvir 
2 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent.  Studies have shown that it can be classified as a “strong CYP3A 
inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a 
“moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength)
3 The effect of St. John’s wort varies widely and is preparation-dependent.
* Drugs listed in FDA website


Ipatasertib—F. Hoffmann-La Roche Ltd
168/Protocol CO41012, Version 3
Appendix 9
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST), (Eisenhauer et al. 2009) are presented below, with slight modifications from 
the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below. All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints. Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE 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 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 5 mm).  At baseline and at follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
                                           
1 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 9: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
Ipatasertib—F. Hoffmann-La Roche Ltd
169/Protocol CO41012, Version 3
DEFINITION OF 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 
nonmeasurable 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:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and 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 
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


Appendix 9: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
Ipatasertib—F. Hoffmann-La Roche Ltd
170/Protocol CO41012, Version 3
METHODS FOR ASSESSING 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. 
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 AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness 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 and interpretation of 


Appendix 9: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
Ipatasertib—F. Hoffmann-La Roche Ltd
171/Protocol CO41012, Version 3
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
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.
IDENTIFICATION 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 considered non-target lesions.
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. Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node that is reported as being 20 mm 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis 


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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. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline. Measurements are not required. 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"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non-lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to < 10 mm during the study. Thus, when 
lymph nodes are included as target lesions, the sum of diameters 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. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non-lymph node) 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 measurement 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 "too small to measure" should be 
ticked. (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 


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assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When non-lymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters. 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 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short 
axis. Non-target lesions should be noted at baseline and should be identified as
"present" or "absent" and (in rare cases) may be noted as "indicative of progression" at 
subsequent evaluations. In addition, if a lymph node lesion shrinks to a non-malignant 
size (short axis 10 mm), this should be captured on the CRF as part of the assessment 
of non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 

Complete response (CR): Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to 10 mm. 

Partial response (PR): At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 

Progressive disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm. 

Stable disease (SD): Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 


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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below. 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 schedule of activities. 

CR: Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size (10 mm short axis). 

Non-CR/Non-PD: Persistence of one or more non-target lesions and/or (if 
applicable) maintenance of tumor marker level above the normal limits 

PD: Unequivocal progression of existing non-target lesions 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, 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 lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
Patients with Non-Measurable Disease Only
For patients with non-measurable disease only, the same general concepts apply 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-measurable 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. If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to 


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have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions). This is particularly important when the patient’s baseline lesions show PR or 
CR. 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, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1  provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 


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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.
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 measurements are made on only a subset of target 
lesions at a timepoint, 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 
lesions 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.


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SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as
having "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 lesions as shown in Table 1 and Table 2. 
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. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.




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Appendix 11
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30)


Appendix 11: European Organisation for Research and Treatment of Cancer Quality-of-Life 
Questionnaire Core 30 (EORTC QLQ-C30)
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Appendix 12
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire Breast Cancer Module 23
(EORTC QLQ-BR23)


Appendix 12:European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Breast Cancer Module 23 (EORTC QLQ BR23)
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Appendix 13
National Cancer Institute Patient-Reported Outcomes Version of 
the Common Terminology Criteria for Adverse Events (NCI 
PRO-CTCAE) Items


Appendix 13:National Cancer Institute Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events (NCI PRO-CTCAE) Items
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Appendix 14
European Quality of Life 5Dimension, 5-Level questionnaire
(EQ-5D-5L) Health Questionnaire
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group