Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 579
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy of ipatasertib + paclitaxel versus placebo + paclitaxel in participants with histologically confirmed, locally advanced or metastatic triple-negative breast cancer (TNBC) and in participants with locally advanced or metastatic hormone receptor positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2-) breast adenocarcinoma who are not suitable for endocrine therapy.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Ipatasertib intervention 2: Paclitaxel intervention 3: Placebo
Intervention descriptions: intervention 1: Ipatasertib, 400 milligrams (mg), administered orally once a day (QD) on Days 1-21 of each 28-day cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. intervention 2: Paclitaxel, 80 mg/square meter (m\^2), administered intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. intervention 3: Matching placebo, administered orally QD on Days 1-21 of each 28-day cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Protocol document:
Prot_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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 CO40016, Version 11 (Cohort C)
PROTOCOL
TITLE:
A DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED PHASE III STUDY OF IPATASERTIB IN 
COMBINATION WITH PACLITAXEL AS A TREATMENT 
FOR PATIENTS WITH PIK3CA/AKT1/PTEN-ALTERED, 
LOCALLY ADVANCED OR METASTATIC, 
TRIPLE-NEGATIVE BREAST CANCER OR HORMONE 
RECEPTOR–POSITIVE, HER2-NEGATIVE BREAST 
CANCER
PROTOCOL NUMBER:
CO40016
VERSION NUMBER:
11 (Cohort C)
EUDRACT NUMBER:
2017-001548-36
IND NUMBER:
133823
NCT NUMBER
NCT03337724
TEST PRODUCTS:
Ipatasertib (RO5532961, GDC-0068)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
17-Feb-2022 21:49:01


Ipatasertib—F. Hoffmann-La Roche Ltd
2/Protocol CO40016, Version 11 (Cohort C)
PROTOCOL HISTORY
Protocol
Version
Date Final
11 (Cohort C)
see electronic date stamp on title page
10 (Cohort C)
9 February 2021
9 (Cohort C)
20 September 2019
8 (Australia, Brazil, France, South Korea, Peru, 
Poland, Singapore, Taiwan, Ukraine, United 
Kingdom, United States)
27 March 2019
7 (Australia, Brazil, France, South Korea, 
Singapore, United Kingdom, United States)
4 October 2018
6
16 August 2018
5
15 June 2018
4 (Germany)
11 May 2018
3
16 February 2018
2
23 June 2017
1
4 May 2017


Ipatasertib—F. Hoffmann-La Roche Ltd
3/Protocol CO40016, Version 11 (Cohort C)
PROTOCOL AMENDMENT, VERSION 11 (COHORT C)
RATIONALE
Protocol CO40016, Version 11 (Cohort C) has primarily been amended to align the 
protocol with the most recent Investigator’s Brochures for Ipatasertib (Version 13) and 
Atezolizumab (Version 18).  Changes to the protocol, along with a rationale for each 
change, are summarized below:

Language for atezolizumab and accelerated approval in the United States for the 
treatment of patients with PD-L1positive locally advanced or metastatic 
triple-negative breast cancer (mTNBC) has been removed (Section 1.3) due to the 
withdrawal of the Tecentriq label in PD-L1-positive mTNBC in the United States.

Language added to allow Tumor Assessments to be performed per standard of care, 
(Section 3.1.1, Section 4.5.5, Appendix 1, Appendix 2) to reduce burden on patients.

In Section 5.1.1 (Risks associated with ipatasertib in combination with paclitaxel), 
added that Investigators should refer to Section 6 of the ipatasertib Investigator's 
Brochure for a detailed description of anticipated safety risks for ipatasertib. 

The Medical Monitor information has been updated (Section 5.4.1).

The medical term “primary biliary cirrhosis” has been replaced by the term “primary 
biliary cholangitis” to align with the updated preferred term in MedDRA
(Appendix 11).

Hepatoxicity management guidelines for ipatasertib added to align with ipatasertib
Investigator’s Brochure Version 13 (Appendix 13).

Updates have been made to the management guidelines for atezolizumab for the 
following immune-mediated risks (Appendix 14, Appendix 15): 
–
Pulmonary Events
–
Hepatic Events
–
Endocrine Events
–
Infusion-Related Reactions and Cytokine-Release Syndrome
–
Neurologic Disorders
–
Renal Events
–
Myositis
–
Dermatologic Events

The footnotes of extended treatment interruption and rechallenging patients with 
atezolizumab after treatment discontinuation in all AE management tables updated 
to remove the requirement of the Medical Monitor (MM) approval.  Instead, the role 
of the MM for safety-related issues has been updated to being available for advice 
(Appendix 14, Appendix 15).
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.




Ipatasertib—F. Hoffmann-La Roche Ltd
5/Protocol CO40016, Version 11 (Cohort C)
3.3.7.3
Rationale for Collection of DNA (Blood) for 
Exploratory Whole Genome Sequencing............................... 68
3.3.7.4
Rationale for Optional Collection of New Tumor 
Biopsies at Disease Progression for 
Exploratory Purposes ............................................................ 70
3.3.8
Rationale for the Pharmacokinetic Evaluation 
Schedule................................................................................ 70
3.3.9
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 71
3.3.10
Rationale for Skeletal-Related Events 
Assessments ......................................................................... 72
4.
MATERIALS AND METHODS .................................................................... 72
4.1
Patients.................................................................................. 72
4.1.1
Inclusion Criteria.................................................................... 72
4.1.2
Exclusion Criteria................................................................... 77
4.2
Method of Treatment Assignment and Blinding..................... 82
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 83
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 84
4.3.1.1
Ipatasertib and Placebo......................................................... 84
4.3.1.2
Atezolizumab......................................................................... 84
4.3.1.3
Paclitaxel ............................................................................... 84
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 84
4.3.2.1
Ipatasertib and Placebo......................................................... 84
4.3.2.2
Atezolizumab......................................................................... 85
4.3.2.3
Paclitaxel ............................................................................... 86
4.3.3
Other Treatments: Premedications and 
Prophylactic Treatment.......................................................... 87
4.3.4
Investigational Medicinal Product Accountability ................... 87
4.3.5
Continued Access to Ipatasertib and 
Atezolizumab......................................................................... 88
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 89
4.4.1
Permitted Therapy................................................................. 89


Ipatasertib—F. Hoffmann-La Roche Ltd
6/Protocol CO40016, Version 11 (Cohort C)
4.4.2
Cautionary Therapy ............................................................... 90
4.4.2.1
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 91
4.4.2.2
Herbal Therapies................................................................... 92
4.4.3
Prohibited Therapy ................................................................ 92
4.4.4
Prohibited Food ..................................................................... 93
4.4.5
Additional Restrictions ........................................................... 93
4.5
Study Assessments ............................................................... 93
4.5.1
Informed Consent Forms and Screening Log........................ 93
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 94
4.5.3
Physical Examinations........................................................... 94
4.5.4
Vital Signs.............................................................................. 95
4.5.5
Tumor and Response Evaluations......................................... 95
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 97
4.5.7
Electrocardiograms and Cardiac Function 
Assessment......................................................................... 100
4.5.8
Patient-Reported Outcomes ................................................ 101
4.5.8.1
EORTC QLQ-C30................................................................ 102
4.5.8.2
PRO-CTCAE ....................................................................... 102
4.5.8.3
EQ-5D-5L ............................................................................ 103
4.5.9
Skeletal-Related Events Assessment.................................. 103
4.5.10
Mandatory Samples for Whole Genome 
Sequencing.......................................................................... 103
4.5.11
Post-Treatment Follow-Up................................................... 104
4.5.12
Optional Samples for Research Biosample 
Repository ........................................................................... 104
4.5.12.1
Overview of the Research Biosample Repository................ 104
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 105
4.5.12.3
Sample Collection................................................................ 105
4.5.12.4
Confidentiality...................................................................... 106
4.5.12.5
Consent to Participate in the Research 
Biosample Repository.......................................................... 106


Ipatasertib—F. Hoffmann-La Roche Ltd
7/Protocol CO40016, Version 11 (Cohort C)
4.5.12.6
Withdrawal from the Research Biosample 
Repository ........................................................................... 107
4.5.12.7
Monitoring and Oversight..................................................... 107
4.6
Treatment, Patient, Study, and Site 
Discontinuation.................................................................... 108
4.6.1
Study Treatment Discontinuation......................................... 108
4.6.2
Patient Discontinuation from Study...................................... 108
4.6.3
Study Discontinuation.......................................................... 109
4.6.4
Site Discontinuation............................................................. 109
5.
ASSESSMENT OF SAFETY..................................................................... 109
5.1
Safety Plan .......................................................................... 109
5.1.1
Risks Associated with Ipatasertib in Combination 
with Paclitaxel...................................................................... 110
5.1.2
Risks Associated with Atezolizumab ................................... 111
5.1.3
Risks Associated with Combination Use of 
Atezolizumab and Ipatasertib .............................................. 111
5.1.4
Risks Associated with Paclitaxel.......................................... 111
5.1.5
Management of Patients Who Experience 
Specific Adverse Events...................................................... 112
5.1.5.1
Dose Modifications .............................................................. 112
5.1.5.2
General Guidelines.............................................................. 112
5.1.5.3
Dosage Modification for Ipatasertib/Placebo and 
Paclitaxel ............................................................................. 114
5.1.5.4
Treatment Interruption ......................................................... 115
5.1.5.5
Adverse Event Management Guidelines.............................. 116
5.2
Safety Parameters and Definitions ...................................... 116
5.2.1
Adverse Events ................................................................... 116
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 117
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 118
5.2.4
Selected Adverse Events..................................................... 119
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 120
5.3.1
Adverse Event Reporting Period ......................................... 120


Ipatasertib—F. Hoffmann-La Roche Ltd
8/Protocol CO40016, Version 11 (Cohort C)
5.3.2
Eliciting Adverse Event Information..................................... 120
5.3.3
Assessment of Severity of Adverse Events ......................... 121
5.3.4
Assessment of Causality of Adverse Events ....................... 121
5.3.5
Procedures for Recording Adverse Events.......................... 122
5.3.5.1
Infusion-Related Reactions.................................................. 123
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 123
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 123
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 124
5.3.5.5
Abnormal Laboratory Values ............................................... 124
5.3.5.6
Abnormal Vital Sign Values ................................................. 125
5.3.5.7
Abnormal Liver Function Tests............................................ 126
5.3.5.8
Deaths ................................................................................. 126
5.3.5.9
Preexisting Medical Conditions............................................ 126
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer ................. 127
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 127
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse ........................................................ 128
5.3.5.13
Patient-Reported Outcome Data ......................................... 130
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 130
5.4.1
Emergency Medical Contacts.............................................. 131
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 131
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 131
5.4.2.2
Events That Occur after Study Drug Initiation...................... 131
5.4.3
Reporting Requirements for Pregnancies............................ 132
5.4.3.1
Pregnancies in Female Patients.......................................... 132
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 132
5.4.3.3
Abortions ............................................................................. 133
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 133
5.5
Follow-Up of Patients after Adverse Events ........................ 133
5.5.1
Investigator Follow-Up......................................................... 133
5.5.2
Sponsor Follow-Up .............................................................. 134


Ipatasertib—F. Hoffmann-La Roche Ltd
9/Protocol CO40016, Version 11 (Cohort C)
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 134
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 134
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 135
6.1
Determination of Sample Size ............................................. 135
6.2
Summaries of Conduct of Study.......................................... 137
6.3
Summaries of Treatment Group Comparability ................... 138
6.4
Efficacy Analyses ................................................................ 138
6.4.1
Primary Efficacy Endpoint.................................................... 138
6.4.2
Secondary Efficacy Endpoints............................................. 139
6.4.2.1
Objective Response Rate with Duration of 
Response ............................................................................ 139
6.4.2.2
Clinical Benefit Rate ............................................................ 139
6.4.2.3
Overall Survival ................................................................... 139
6.4.2.4
(Cohort C only) 1-Year PFS and 1-Year OS Rate ............... 140
6.4.3
Exploratory Efficacy Endpoints............................................ 140
6.4.3.1
Progression-Free Survival 2 (PFS2).................................... 140
6.4.3.2
Patient Subgroup Analysis in Cohort A................................ 140
6.4.4
Time to First Skeletal-Related Event ................................... 140
6.4.5
Patient-Reported Outcome Analyses .................................. 140
6.4.5.1
Secondary Patient-Reported Outcome Endpoints............... 140
6.4.5.2
Exploratory Patient-Reported Outcome Analyses ............... 141
6.5
Safety Analyses................................................................... 141
6.5.1
Exploratory Safety Analysis................................................. 142
6.6
Pharmacokinetic Analyses................................................... 142
6.7
Biomarker Analyses............................................................. 143
6.8
Interim Analyses .................................................................. 143
6.8.1
Planned Interim Safety Analyses......................................... 143
6.8.2
Safety monitoring will be performed on a 
continual basis by the Sponsor for Cohort C.  
Planned Interim OS Analysis at PFS Primary 
Analysis ............................................................................... 143
6.8.3
Optional Interim Analyses.................................................... 144


Ipatasertib—F. Hoffmann-La Roche Ltd
10/Protocol CO40016, Version 11 (Cohort C)
6.9
China Subgroup Analyses ................................................... 145
7.
DATA COLLECTION AND MANAGEMENT ............................................. 146
7.1
Data Quality Assurance....................................................... 146
7.2
Electronic Case Report Forms............................................. 146
7.3
Source Data Documentation................................................ 146
7.4
Use of Computerized Systems ............................................ 147
7.5
Retention of Records........................................................... 147
8.
ETHICAL CONSIDERATIONS.................................................................. 148
8.1
Compliance with Laws and Regulations .............................. 148
8.2
Informed Consent................................................................ 148
8.3
Institutional Review Board or Ethics Committee.................. 149
8.4
Confidentiality...................................................................... 149
8.5
Financial Disclosure ............................................................ 150
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 150
9.1
Study Documentation .......................................................... 150
9.2
Protocol Deviations.............................................................. 150
9.3
Site Inspections ................................................................... 151
9.4
Administrative Structure....................................................... 151
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 151
9.6
Protocol Amendments ......................................................... 152
10. REFERENCES ......................................................................................... 153
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints (Applicable for 
Both Cohort A and Cohort B, Unless Otherwise Stated)............. 48
Table 2
Objectives and Corresponding Endpoints (Cohort C) ................. 51
Table 3
Administration of First and Subsequent Infusions of 
Atezolizumab .............................................................................. 86
Table 4
Dose Reductions for Ipatasertib/Placebo.................................. 115
Table 5
Dose Reductions for Paclitaxel ................................................. 115
Table 6
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 121


Ipatasertib—F. Hoffmann-La Roche Ltd
11/Protocol CO40016, Version 11 (Cohort C)
Table 7
Causal Attribution Guidance ..................................................... 122
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 58
LIST OF APPENDICES
Appendix 1
Schedule of Activities: Cohorts A and B................................... 161
Appendix 2
Schedule of Activities:  Cohort C.............................................. 169
Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Samples: 
Cohorts A and B........................................................................ 176
Appendix 4
Schedule of Pharmacokinetic and Immunogenicity, Samples:  
Cohort C.................................................................................... 177
Appendix 5
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations.................................................... 178
Appendix 6
ASCO/CAP HER2 Test Guideline Recommendations............. 180
Appendix 7
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-
C30).......................................................................................... 188
Appendix 8
EuroQol 5-Dimension Questionnaire,  Five-Level Version 
(EQ-5D-5L) ............................................................................... 190
Appendix 9
Selected items from the Patient-Reported Outcomes version 
of the Common Terminology Criteria for Adverse Events  
(PRO-CTCAE) .......................................................................... 192
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication ............................... 194
Appendix 11
Preexisting Autoimmune Diseases and Immune Deficiencies . 205
Appendix 12
Anaphylaxis Precautions.......................................................... 206
Appendix 13
Guidelines for Management of Adverse Events for Patients 
in Cohorts A and B.................................................................... 207
Appendix 14
Adverse Event Management Guidelines for Patients in 
Cohort C (Ipatasertib Plus Atezolizumab Plus Paclitaxel)......... 220
Appendix 15
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 245


Ipatasertib—F. Hoffmann-La Roche Ltd
12/Protocol CO40016, Version 11 (Cohort C)
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED PHASE III STUDY OF IPATASERTIB 
IN COMBINATION WITH PACLITAXEL AS A 
TREATMENT FOR PATIENTS WITH
PIK3CA/AKT1/PTEN-ALTERED, LOCALLY 
ADVANCED OR METASTATIC, TRIPLE-NEGATIVE 
BREAST CANCER OR HORMONE RECEPTOR–
POSITIVE, HER2-NEGATIVE BREAST CANCER
PROTOCOL NUMBER:
CO40016
VERSION NUMBER:
11 (Cohort C)
EUDRACT NUMBER:
2017-001548-36
IND NUMBER:
133823
NCT NUMBER
NCT03337724
TEST PRODUCTS:
Ipatasertib (RO5532961, GDC-0068)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
 M.D
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files.


Ipatasertib—F. Hoffmann-La Roche Ltd
13/Protocol CO40016, Version 11 (Cohort C)
PROTOCOL SYNOPSIS
TITLE:
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED 
PHASE III STUDY OF IPATASERTIB IN COMBINATION WITH 
PACLITAXEL AS A TREATMENT FOR PATIENTS WITH
PIK3CA/AKT1/PTEN-ALTERED, LOCALLY ADVANCED OR 
METASTATIC, TRIPLE-NEGATIVE BREAST CANCER OR 
HORMONE RECEPTOR–POSITIVE, HER2-NEGATIVE BREAST 
CANCER
PROTOCOL NUMBER:
CO40016
VERSION NUMBER:
11 (Cohort C)
EUDRACT NUMBER:
2017-001548-36
IND NUMBER:
133823
NCT NUMBER
NCT03337724
TEST PRODUCTS:
Ipatasertib (RO5532961, GDC-0068)
Atezolizumab (RO5541267)
PHASE:
III
INDICATION:
Locally advanced unresectable or metastatic triple-negative breast 
cancer with PIK3CA/AKT1/PTEN-altered tumor and no prior 
chemotherapy in the advanced setting
Locally advanced or metastatic hormone receptor–positive, 
HER2-negative breast cancer with PIK3CA/AKT1/PTEN-altered 
tumor and no prior chemotherapy in the advanced setting
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
Cohorts A and B will independently evaluate the safety, efficacy, and pharmacokinetics of 
ipatasertib in combination with paclitaxel (ipatasertib + paclitaxel) compared with placebo plus 
paclitaxel (placebo + paclitaxel) in patients with PIK3CA/AKT1/PTEN-altered tumors.  Cohort A 
will evaluate first-line treatment in patients with locally advanced unresectable or metastatic 
triple-negative breast cancer (TNBC), and Cohort B will evaluate first-chemotherapy treatment 
in patients with advanced hormone receptor–positive, HER2-negative (HR/HER2) breast 
cancer who are not appropriate candidates for endocrine therapy (as defined by the Sponsor).  
Patients will be enrolled based on central or local/commercial determination of 
PIK3CA/AKT1/PTEN-altered status, with central assessment of PIK3CA/AKT1/PTEN-altered 
status in tumor tissue performed in any patients enrolled using alternative methods and will be 
allocated to one of the cohorts based on hormone-receptor status.  Patients with HER2-positive 
breast cancer are not eligible.  The reason that the Cohorts A and B will be evaluated 
separately is that TNBC and HR/HER2breast cancers have different biologies that manifest 
clinically in different prognoses and response to treatment, and molecularly with distinctly 
different molecular profiles with dissimilar oncogenic drivers.  The patients in Cohorts A and B 
have different prevalences and progression-free survival (PFS) and overall survival (OS) 
expectations, and thus different enrollment and analysis timelines. 
Patients who initially screen for Cohort A (with TNBC) but do not qualify (i.e., lack of 
PIK3CA/AKT1/PTEN alteration validated by central tumor tissue testing using the FMI CTA) 


Ipatasertib—F. Hoffmann-La Roche Ltd
14/Protocol CO40016, Version 11 (Cohort C)
may be eligible for Cohort C.  Cohort C is an open-label, non-randomized cohort for patients 
with locally advanced unresectable or metastatic TNBC that will assess the safety, efficacy, and 
pharmacokinetics of ipatasertib in combination with paclitaxel and atezolizumab.  Due to the 
differences in mechanism of action and evaluation of clinical benefit following cancer 
immunotherapy treatments, as well as delayed opening of Cohort C, this cohort will be 
evaluated separately from Cohorts A and B.
The target patient populations for this study are premenopausal and postmenopausal female 
and male patients with measurable, locally advanced unresectable or metastatic TNBC and 
HR/HER2breast cancer who have not received chemotherapy in either of these settings.  
Patients must be appropriate candidates for taxane monotherapy.  In particular, patients with 
HR/HER2breast cancer should be suitable for treatment with chemotherapy (e.g., 
demonstrated insensitivity to endocrine therapy; reference eligibility criteria for Sponsor 
definition of endocrine-insensitivity).  Prior adjuvant or neoadjuvant chemotherapy is allowed, 
provided it has been concluded at least 12 months before recurrence of (locally advanced 
unresectable or metastatic) disease.
Patients with PIK3CA/AKT1/PTEN-altered tumors will be assigned to Cohort A (TNBC) or 
Cohort B (HR/HER2breast cancer) based on their hormone receptor status (as evaluated 
locally, or on study, only if local evaluation is not available, with additional slides submitted for 
this purpose) and randomized with a 2:1 ratio to the experimental versus control arm.  Patients 
with TNBC who are biomarker-negative (i.e., lack of PIK3CA/AKT1/PTEN alteration validated by 
central tumor tissue testing using the FMI CTA) but otherwise eligible will be assigned to 
Cohort C to receive ipatasertib in combination with atezolizumab and paclitaxel until this cohort 
is fully accrued.  All primary, secondary, exploratory, and safety objectives will be assessed 
independently for each cohort (i.e., Cohort A:  patients with TNBC with 
PIK3CA/AKT1/PTEN-altered tumors, Cohort B:  patients with HR/HER2breast cancer with 
PIK3CA/AKT1/PTEN-altered tumors and Cohort C: patients with TNBC whose tumors lack 
PIK3CA/AKT1/PTEN alteration validated by central tumor tissue testing using the Foundation 
Medicine Clinical Trial Algorithm).
The primary endpoint is PFS for all cohorts.  The primary analysis for each cohort will be 
independent and triggered by cohort-specific events and will also be independent of the readout 
of the other cohort.  The secondary endpoints for Cohorts A and B will be tested if the primary 
analysis of the respective PFS reaches statistical significance at the level of 5%.
Specific objectives and corresponding endpoints for each cohort will be analyzed independently 
following cohort-specific statistical analysis plans, and are outlined in the tables below.


Ipatasertib—F. Hoffmann-La Roche Ltd
15/Protocol CO40016, Version 11 (Cohort C)
Table 1
Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated)
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of 
ipatasertib paclitaxel compared with 
placebo paclitaxel  
PFS, defined as the time from randomization to 
the first occurrence of disease progression, as 
determined locally by the investigator through 
the use of RECIST v1.1, or death from any 
cause, whichever occurs first
Secondary Efficacy Objectives:
To evaluate the efficacy of 
ipatasertib paclitaxel compared with 
placebo paclitaxel 
Objective response rate, defined as a CR or 
PR on two consecutive occasions 4 weeks 
apart, as determined locally by the investigator 
through the use of RECIST v1.1
Duration of response, defined as the time from 
the first occurrence of a documented objective 
response to disease progression, as 
determined locally by the investigator through 
use of RECIST v1.1, or death from any cause, 
whichever occurs first
Clinical benefit rate, defined as an objective 
response (CR or PR), or stable disease for at 
least 24 weeks, as determined locally by the 
investigator through the use of RECIST v1.1
OS, defined as the time from randomization to 
death from any cause


Ipatasertib—F. Hoffmann-La Roche Ltd
16/Protocol CO40016, Version 11 (Cohort C)
Table 1 Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Secondary Efficacy Objectives (cont.):
To evaluate PROs of GHS/HRQoL associated 
with ipatasertib paclitaxel compared with 
placebo paclitaxel  
Mean and mean changes from baseline 
GHS/HRQoL score as measured by the 
GHS/HRQoL scale (Questions 29 and 30) of 
the EORTC QLQ-C30, by cycle
To evaluate PROs of disease-related pain of 
ipatasertib paclitaxel compared with 
placebo paclitaxel (Cohort B only) 
Time to deterioration in pain, defined as the 
first minimally important increase of ≥11 points 
from the baseline pain scale score (Questions 
9 and 19) of the EORTC QLQ-C30
Exploratory Efficacy Objectives:
To evaluate the efficacy of 
ipatasertib paclitaxel compared with 
placebo paclitaxel in TNBC (Cohort A only) 
patients with tumors that have the following:
-
PIK3CA/AKT1-activating mutations 
-
PTEN alterations (and no 
PIK3CA/AKT1-activating mutations) 
PFS
Objective response rate
Duration of response
Clinical benefit rate
OS 
To evaluate PROs of function and 
disease/treatment-related symptoms 
associated with ipatasertib + paclitaxel 
compared with placebo + paclitaxel 
Mean and mean changes from baseline scores 
in functional (i.e., role, physical, cognitive,
emotional, and social) and 
disease/treatment-related symptoms by cycle 
as assessed by the functional and symptom 
scales of the EORTC QLQ-C30
To collect utilities for pharmacoeconomic 
modeling 
Health states for utility assessment and the VAS 
as measured by the EQ-5D-5L questionnaire for 
modeling
To evaluate the clinical benefit
PFS2, defined as the time from randomization 
to first objective disease progression on 
next-line treatment, or death from any cause, 
whichever occurs first
Time to first skeletal–related event (SRE), 
defined as the time from randomization to the 
occurrence of an SRE.  An SRE is either 
a pathologic fracture, radiation therapy to the 
bone, surgery to the bone, or spinal cord 
compression.


Ipatasertib—F. Hoffmann-La Roche Ltd
17/Protocol CO40016, Version 11 (Cohort C)
Table 1 Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Exploratory Efficacy Objectives (cont.):
To evaluate analgesic use in ipatasertib + 
paclitaxel and placebo + paclitaxel treatment 
arms (Cohort B only)
Change in use of opioid and non-opioid 
analgesics during treatment, as measured by 
the intake of analgesic treatments
Safety Objective:
To evaluate the safety of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel 
Incidence of adverse events as assessed by the 
investigator, with severity determined through 
the use of NCI CTCAE v4.0 
Incidence of prespecified adverse events 
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Exploratory Safety Objective:
To collect PROs regarding key symptomatic 
adverse events of ipatasertib paclitaxel 
compared with placebo paclitaxel 
Selected items from the PRO-CTCAE capturing 
patients' rating of the presence, severity, 
frequency, and/or interference of diarrhea, 
nausea, vomiting, decreased appetite, fatigue, 
neuropathy, mouth sores, and rash symptoms 
and an additional item regarding bother due to 
side effects of treatment
Pharmacokinetic Objective:
To characterize the pharmacokinetics of 
ipatasertib and its metabolite (G-037720) 
when administered in combination with 
paclitaxel
Plasma concentration of ipatasertib and 
G-037720 at specified timepoints for analysis 
using population PK methodology
Exploratory Pharmacokinetic Objective:
To evaluate potential relationships between 
ipatasertib exposure, efficacy, and safety of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel 
Relationship between ipatasertib PK and 
efficacy endpoints 
Relationship between ipatasertib PK and safety 
endpoints 


Ipatasertib—F. Hoffmann-La Roche Ltd
18/Protocol CO40016, Version 11 (Cohort C)
Table 1 Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated) (cont.)
Exploratory Biomarker Objectives:
To evaluate predictive or prognostic 
biomarkers (plasma or tissue) associated 
with disease activity status or response to 
treatment 
To identify possible mechanisms of 
resistance to study treatments through the 
comparative analysis of potential biomarkers 
in pretreatment and post-progression biopsy 
tissue samples and in blood 
To evaluate alternative diagnostics testing 
methods for PIK3CA/AKT1/PTEN-altered 
status
Relationship between tissue- and blood-based 
biomarkers and patient clinical features (e.g., 
baseline features) and outcome (e.g., duration 
of PFS)
Change in mutation and copy number in 
oncogenes, tumor suppressors, and/or other 
genes associated with disease progression by 
DNA sequencing 
Change in levels of tumor suppressors, 
immune checkpoints, mitotic index, apoptotic 
index, and/or immune-cell infiltration by 
immunohistochemistry
Associations of breast cancer subtypes 
defined by molecular signatures with patient 
outcomes
Association of BRCA1/2 genetic alterations 
and homologous repair deficiency with patient 
outcomes
BRCAbreast and ovarian cancer susceptibility gene; CR complete response; 
EORTC European Organisation for Research and Treatment of Cancer; GHSglobal health 
status; HRQoLhealth-related quality of life; NCI CTCAE v4.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; OSoverall survival; 
PKpharmacokinetics; PFSprogression-free survival; PRpartial response; PRO patient-
reported outcome; PRO-CTCAEPatient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events; RECIST v1.1 Response Evaluation Criteria in Solid 
Tumors, Version 1.1; TNBCtriple-negative breast cancer; VASvisual analog scale.


Ipatasertib—F. Hoffmann-La Roche Ltd
19/Protocol CO40016, Version 11 (Cohort C)
Table 2 Objectives and Corresponding Endpoints (Cohort C)
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of 
ipatasertib paclitaxel atezolizumab 
PFS, defined as the time from enrollment to the 
first occurrence of disease progression, as 
determined locally by the investigator through 
the use of RECIST v1.1, or death from any 
cause, whichever occurs first
Secondary Efficacy Objectives:
To evaluate the efficacy of 
ipatasertib paclitaxel atezolizumab
Objective response rate, defined as a CR or 
PR on two consecutive occasions 4 weeks 
apart, as determined locally by the investigator 
through the use of RECIST v1.1
Duration of response, defined as the time from 
the first occurrence of a documented objective 
response to disease progression, as 
determined locally by the investigator through 
use of RECIST v1.1, or death from any cause, 
whichever occurs first
Clinical benefit rate, defined as an objective 
response (CR or PR), or stable disease for at 
least 24 weeks, as determined locally by the 
investigator through the use of RECIST v1.1
OS, defined as the time from enrollment to 
death from any cause
1year PFS defined as progression-free 
survival probabilities at 1 year.
1year OS defined as overall survival 
probabilities at 1 year.
To evaluate PROs of GHS/HRQoL associated 
with ipatasertib paclitaxel atezolizumab
Mean and mean changes from baseline 
GHS/HRQoL score as measured by the 
GHS/HRQoL scale (Questions 29 and 30) of 
the EORTC QLQ-C30, by cycle
To evaluate PROs of disease-related pain of 
ipatasertib paclitaxel atezolizumab
Time to deterioration in pain, defined as the 
first minimally important increase of 10 points 
from the baseline pain scale score (Questions 
9 and 19) of the EORTC QLQ-C30


Ipatasertib—F. Hoffmann-La Roche Ltd
20/Protocol CO40016, Version 11 (Cohort C)
Table 2
Objectives and Corresponding Endpoints (Cohort C) (cont.)
Objectives
Corresponding Endpoints
Exploratory Efficacy Objectives: (cont.)
To evaluate PROs of function and 
disease/treatment-related symptoms 
associated with 
ipatasertib paclitaxel atezolizumab
Mean and mean changes from baseline scores 
in functional (i.e., role, physical, emotional, 
cognitive, and social) and 
disease/treatment-related symptoms by cycle 
as assessed by the functional and symptom 
scales of the EORTC QLQ-C30
To collect utilities for pharmacoeconomic 
modeling 
Health states for utility assessment and the VAS 
as measured by the EQ-5D-5L questionnaire for 
modeling
To evaluate the clinical benefit
PFS2, defined as the time from enrollment to 
first objective disease progression on next-line 
treatment, or death from any cause, whichever 
occurs first
Time to first skeletal–related event (SRE), 
defined as the time from treatment assignment 
to the occurrence of an SRE.  An SRE is either 
a pathologic fracture, radiation therapy to the 
bone, surgery to the bone, or spinal cord 
compression.
Safety Objective:
To evaluate the safety of 
ipatasertib paclitaxel atezolizumab 
Incidence of adverse events as assessed by the 
investigator, with severity determined through 
the use of NCI CTCAE v4.0 
Incidence of prespecified adverse events 
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Exploratory Safety Objective:
To collect PROs regarding key symptomatic 
adverse events of 
ipatasertib paclitaxel atezolizumab 
Selected items from the PRO-CTCAE capturing 
patients' rating of the presence, severity, 
frequency, and/or interference of diarrhea, 
nausea, vomiting, decreased appetite, fatigue, 
neuropathy, mouth sores, and rash symptoms 
and an additional item regarding bother due to 
side effects of treatment


Ipatasertib—F. Hoffmann-La Roche Ltd
21/Protocol CO40016, Version 11 (Cohort C)
Table 2
Objectives and Corresponding Endpoints (Cohort C) (cont.)
Objectives
Corresponding Endpoints
Pharmacokinetic Objective:
To characterize the pharmacokinetics of 
atezolizumab, ipatasertib and its metabolite 
(G-037720) when administered in 
combination with paclitaxel 
Plasma concentration of ipatasertib and its 
metabolite, G-037720 at specified timepoints for 
analysis using population PK methodology
Serum concentration of atezolizumab at 
specified timepoints
Exploratory Pharmacokinetic Objective:
To evaluate potential relationships between 
ipatasertib  and/or atezolizumab exposure, 
efficacy, and safety of 
ipatasertib paclitaxel atezolizumab
Relationship between ipatasertib and/or 
atezolizumab PK and efficacy endpoints 
Relationship between ipatasertib and/or 
atezolizumab PK and safety endpoints 
Immunogenicity Objective:
To evaluate the immune response to 
atezolizumab
Incidence of ADAs to atezolizumab during the 
study relative to the prevalence of ADAs at 
baseline
Exploratory Immunogenicity Objective:
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Biomarker Objectives:
To evaluate predictive or prognostic 
biomarkers (plasma or tissue) associated 
with disease activity status or response to 
treatment 
To identify possible mechanisms of 
resistance to study treatments through the 
comparative analysis of potential biomarkers 
in pretreatment and post-progression biopsy 
tissue samples and in blood 
To evaluate alternative diagnostics testing 
methods for PIK3CA/AKT1/PTEN-altered 
status
Relationship between tissue- and blood-based 
biomarkers and patient clinical features (e.g., 
baseline features) and outcome (e.g., duration 
of PFS)
Change in mutation and copy number in 
oncogenes, tumor suppressors, and/or other 
genes associated with disease progression by 
DNA sequencing 
Change in levels of tumor suppressors, 
immune checkpoints, mitotic index, apoptotic 
index, and/or immune-cell infiltration by 
immunohistochemistry
Associations of breast cancer subtypes 
defined by molecular signatures with patient 
outcomes
Association of BRCA1/2 genetic alterations 
and homologous repair deficiency with patient 
outcomes
ADAanti-drug antibody; BRCAbreast and ovarian cancer susceptibility gene; CR complete 
response; EORTCEuropean Organisation for Research and Treatment of Cancer; 
GHSglobal health status; HRQoLhealth-related quality of life; NCI CTCAE v4.0 National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0; OSoverall 
survival; PKpharmacokinetics; PFSprogression-free survival; PRpartial response; 
PROpatient-reported outcome; PRO-CTCAEPatient-Reported Outcomes Version of the 
Common Terminology Criteria for Adverse Events; RECIST v1.1Response Evaluation Criteria 
in Solid Tumors, Version 1.1; TNBCtriple-negative breast cancer; VASvisual analog scale.


Ipatasertib—F. Hoffmann-La Roche Ltd
22/Protocol CO40016, Version 11 (Cohort C)
Study Design
Description of Study
The two-cohort (Cohorts A and B), randomized, double-blind, placebo-controlled portion of this 
Phase III study is designed to evaluate the efficacy of ipatasertib + paclitaxel versus 
placebopaclitaxel in patients with histologically confirmed, locally advanced unresectable or 
metastatic TNBC and in patients with locally advanced unresectable or metastatic 
HR/HER2-breast adenocarcinoma who are not suitable for endocrine therapy (as defined by 
Sponsor; see eligibility criteria).   Each cohort will be independent with separate analyses, but 
with a single screening process to identify, allocate, and subsequently stratify on the basis of 
histologic and diagnostic status.  Patients must have measurable disease as defined by 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) and a 
PIK3CA/AKT1/PTEN-altered tumor as determined either centrally or using local/commercial 
molecular testing, by a clinical cancer genomic profiling laboratory (e.g., Foundation Medicine, 
Inc. [FMI]) or a CLIA [or equivalently accredited] diagnostic laboratory).  Tumor 
PIK3CA/AKT1/PTEN-altered status is defined as the presence of PTEN alterations or 
PIK3CA/AKT1-activating mutations as determined by any blood- or tissue-based molecular 
assay (see Disease-Specific Inclusion Criteria for further details).  Pathological determination of 
estrogen receptor (ER), progesterone receptor (PgR), and HER2 status based on local 
assessment according to American Society of Clinical Oncology (ASCO) and College of 
American Pathologists (CAP) guidelines will be applied for cohort assignment by an interactive 
voice or Web-based response system (IxRS), with subsequent randomization within each 
cohort based on the appropriate stratification factors for the different cohorts.  Patients who 
have unknown tumor ER, PgR, HER2, or PIK3CA/AKT1/PTEN-altered status and for whom 
determination of status is not possible are not eligible for this study.
If a patient will screen for biomarker eligibility with the tissue-based FMI CTA, time for tumor 
tissue retrieval, shipping, and turnaround of eligibility results should be taken into account when 
screening patients (and submitted sample should be sufficient per protocol requirements to 
have maximum likelihood that a valid result can be obtained).
As the FoundationACT™ (FACT) assay is not able to detect all qualifying alterations that may 
be identified using the FMI CTA, tissue submission should not be delayed as patients may 
qualify by the latter, rather than by FACT.  FACT testing at FMI may not necessarily be faster 
than the FMI CTA and, therefore, should only be performed when it is anticipated that there will 
be a significant delay to acquisition of existing tumor tissue.
If local/commercial testing is available, demonstrating a qualifying alteration, or if this result is 
obtained, these results may be used to determine biomarker eligibility.  However, please note, 
for patients not enrolled on the basis of the FMI tissue-based CTA (e.g., local/commercial tests 
or blood-based FACT assay), submission of tumor tissue is still required, but randomization 
should proceed based on the local result with no requirement to wait for central assessment of 
biomarker eligibility.
Treatment benefit in patients with PIK3CA/AKT1/PTEN-altered tumors will be independently 
compared in patients with triple-negative receptor status and in patients with HR/HER2status.
Approximately 349 patients with TNBC (249 biomarker-positive patients and 100 
biomarker negative patients), and 201 biomarker-positive patients with HR/HER2breast 
cancer will be enrolled at approximately 165195 centers worldwide during the global 
enrollment phase.  Patients will be assigned to either Cohort A (TNBC biomarker-positive), 
Cohort B (HR/HER2-biomarker-positive breast cancer), or Cohort C (TNBC biomarker-
negative) according to the most recent locally assessed pathologically documented receptor 
status and PIK3CA/AKT1/PTEN alteration status.  Receptor status should be assessed in their 
recurrent or metastatic tumor where applicable and if safely accessible, per ASCO/CAP 
guidelines.  Patients in Cohorts A and B will be randomly assigned in a 2:1 ratio to the 
experimental arm (ipatasertib 400 mg + paclitaxel) or control arm (placebo + paclitaxel).  
Approximately 100 patients with TNBC who screen for Cohort A who are shown not to have 
a PIK3CA/AKT1/PTEN-altered tumor by centrally tested FMI CTA may be assigned to Cohort C 
to receive ipatasertib in combination with atezolizumab and paclitaxel, unless the cohort is 
completely accrued.  
Randomization for patients in Cohort A and B will be stratified by the following factors:  prior 
adjuvant/neoadjuvant chemotherapy (yes vs. no), region (Asia-Pacific vs. Europe vs. North 


Ipatasertib—F. Hoffmann-La Roche Ltd
23/Protocol CO40016, Version 11 (Cohort C)
America vs. rest of the world), tumor PIK3CA/AKT1/PTEN-alteration status 
(PIK3CA/AKT1-activating mutations vs. PTEN alterations with no PIK3CA/AKT1-activating 
mutations; Cohort A only), and prior therapy with a phosphoinositide 3-kinase (PI3K) or mTOR 
inhibitor (yes vs. no; Cohort B only).
All patients must have a validated PIK3CA/AKT1/PTEN-alteration status using a blood- or 
tissue-based molecular assay and must have consented to provide sufficient archival tissue or 
newly obtained tumor biopsy tissue for central molecular evaluation to be eligible for enrollment.  
If the patient already has PIK3CA/AKT1/PTEN alteration results available from the FMI 
commercial tissue-based NGS assay known as FoundationONE CDx, then the FMI CTA does 
not need to be re-run; in this situation the lesser amount of tissue specified within the protocol is 
acceptable for other protocol-mandated secondary and exploratory assessments, upon 
approval of the Medical Monitor.  Given the probability of PIK3CA/AKT1/PTEN non-altered 
status (approximately 80%85% for TNBC and 50%60% for HR positive by blood-based NGS 
assay, such as FACT, and 55%65% by tissue-based NGS, such as FMI CTA), it remains an 
option to use the biomarker-specific ICF/screening process first, prior to other study screening 
procedures for those patients who require central testing of biomarker status.  It is advised that 
even if the patient will be screened for biomarker eligibility on the basis of the FACT (or other 
blood-based) NGS assay, that tissue be submitted as quickly.  In blood, the fraction of available 
circulating tumor DNA (ctDNA) to sequence is less than that in tumor tissue, and because of 
this biology, it is expected that the FACT assay will not detect all alterations that can be 
identified using tissue-based NGS; i.e., even if there is biomarker ineligibility based on the 
blood-based assay, the patient may still qualify on the basis of the tissue-based assay.
All patients in Cohorts A and B will receive paclitaxel chemotherapy (80 mg/m2 IV) on Days 1, 8, 
and 15 of each 28-day cycle and either ipatasertib at a dose of 400 mg administered orally once 
a day (QD) on Days 121 of each 28-day cycle (experimental arm) or placebo orally QD on 
Days 121 of each 28-day cycle (control arm).  In Cohort C, patients will receive paclitaxel 
chemotherapy (80 mg/m2 IV) on Days 1, 8, and 15 of each 28-day cycle, ipatasertib at a dose of 
400 mg administered orally once a day (QD) on Days 121 of each 28-day cycle, and 
atezolizumab 840 mg IV on Days 1 and 15 of each 28-day cycle.  Study treatment will continue 
until disease progression, intolerable toxicity, elective withdrawal from the study, or study 
completion or termination.  Upon treatment discontinuation, patients will be followed every 
3 months for survival, PROs, and new anti-cancer therapy and outcome (therapy/procedures, 
doses, start and stop date, best responses, most recent tumor assessment date, and 
progression date).  As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up 
assessments are no longer required.
As of Protocol CO40016 Version 11 (Cohort C), tumor measurement for disease evaluation 
will be performed per standard of care, regardless of whether patients receive study treatment 
during the treatment cycle.  For estimation of PFS, objective response rate (ORR), and duration 
of response (DOR), tumor response will be based on RECIST v1.1.  For patients who 
discontinue treatment without evidence of disease progression per RECIST v1.1, in addition to 
post-treatment follow-up, patients will be followed every 812 weeks for tumor assessments 
until documented progression per RECIST v1.1, elective withdrawal from the study, or study 
completion or termination (as of Protocol CO40016 Version 11 [Cohort C] this is no longer 
required).  Images for tumor assessments for all patients will be prospectively collected to 
enable retrospective blinded independent central review when needed.  As of protocol 
CO40016 Version 10 (Cohort C), images for tumor assessments will no longer be collected for 
blinded independent central review.
The pharmacokinetics of ipatasertib and its metabolite G-037720 will be assessed in all patients 
receiving ipatasertib.  Safety will be evaluated on an ongoing basis in this study through the 
monitoring of all serious and non-serious adverse events and will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 
(NCI CTCAE v4.0).
An independent Data Monitoring Committee (iDMC) will periodically evaluate the safety of 
ipatasertib or placebo combined with paclitaxel (Cohorts A and B).  The analysis supporting 
iDMC review will be conducted by an independent Data Coordinating Center (iDCC) and 
provided to the iDMC.  Interactions between the iDMC and Sponsor will be carried out as 
specified in the iDMC Charter. Safety monitoring will be performed on a continual basis by the 
Sponsor for Cohort C.


Ipatasertib—F. Hoffmann-La Roche Ltd
24/Protocol CO40016, Version 11 (Cohort C)
No interim analysis of the primary efficacy endpoint PFS is planned.  One interim OS analysis 
(at the time of the primary analysis for PFS) for each cohort is planned.   
Analysis of safety and efficacy for each cohort will be performed independently.
Crossover is not allowed (Cohorts A and B).
Potential China Extension Phase for Cohorts A and B
After completion of the global enrollment phase, as needed, additional patients may be enrolled 
at China Food and Drug Administration (CFDA)-recognized sites in an extended enrollment 
phase to ensure a total of up to 90 patients with TNBC and up to 120 patients with 
HR/HER2breast cancer, constituting the analysis population of a China subgroup.  For each 
of Cohort A and Cohort B, patients from the China extension phase will be randomized in a 2:1 
ratio to the two treatment arms, the same as during the global enrollment phase.  Any Chinese 
patients enrolled in the China extension phase will undergo the same schedule of assessments 
and will receive study treatment as in the global study cohorts. 
The China subgroup includes all Chinese patients enrolled in the global study cohorts and the 
China extension phase.  The China subgroup analysis will be performed and summarized 
separately.  The Chinese patients enrolled in the global study cohorts will be analyzed together 
with all other patients enrolled in the global study, and will be reported in the global study clinical 
study report.
Number of Patients
Approximately 450 patients with PIK3CA/AKT1/PTEN-altered tumors are expected to be 
enrolled in this study (~249 patients with TNBC in Cohort A and ~201 patients with 
HR/HER2-breast cancer in Cohort B) during the global enrollment phase. Among the 
~249 patients in Cohort A, at least 150 patients with a valid alteration as measured by central 
FMI testing is required. Additionally, approximately 100 patients with TNBC without 
PIK3CA/AKT1/PTEN-altered tumors are expected to be enrolled in Cohort C.
After the global enrollment phase is completed, additional Chinese patients may be enrolled in 
the China extension phase for up to a total of 90 Chinese patients with TNBC in Cohort A and 
up to a total of 120 Chinese patients with HR+/HER2breast cancer in Cohort B.
Target Population
Inclusion Criteria
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent Form(s) 

Woman or man age18 years at the time of signing the Informed Consent Form

Eastern Cooperative Oncology Group Performance Status of 0 or 1 

Adequate hematologic and organ function within 14 days before the first study treatment on 
Day 1 of Cycle 1, defined by the following:
Neutrophils (ANC 1500/L)
Hemoglobin 9 g/dL
Platelet count 100,000/L
Serum albumin 3 g/dL
Total bilirubin 1.5 the upper limit of normal (ULN), with the following exception:
–
Patients with known Gilbert syndrome who have serum bilirubin 3 ULN may 
be enrolled.
AST and ALT 2.5 ULN, with the following exception:
–
Patients with documented liver or bone metastases may have AST and ALT 
5 ULN.
ALP 2 ULN, with the following exceptions: 
–
Patients with known liver involvement may have ALP 5 ULN
–
Patients with known bone involvement may have ALP 7 ULN


Ipatasertib—F. Hoffmann-La Roche Ltd
25/Protocol CO40016, Version 11 (Cohort C)
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.  Patients should 
be on a stable anticoagulant regimen.
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min based on 
Cockcroft−Gault glomerular filtration rate estimation:
(140 − age) (weight in kg) 0.85 (if female)
72 (serum creatinine in mg/dL)
Fasting total glucose 150 mg/dL and HbA1C 7.5%

Life expectancy of at least 6 months

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year 
during the treatment period and for at least 28 days after the last dose of 
ipatasertib/placebo, 5 months after the last dose of atezolizumab,  and 6 months after the 
last dose of paclitaxel, whichever occurs later, and agreement to refrain from donating eggs 
during this same period
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year, when used 
consistently and correctly, include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion, 
male sterilization, intrauterine hormone-releasing system, copper interuterine device, 
and sexual abstinence.
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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men 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 28 days after the last dose of 
ipatasertib or 6 months after the last dose of paclitaxel, whichever occurs later.  Men 
must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for 28 days after the last dose of ipatasertib or 6 months after 
the last dose of paclitaxel, whichever occurs later, to avoid exposing the embryo.
Examples of contraceptive methods with a failure rate of 1% per year, when used 
consistently and correctly, include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion, 
male sterilization, intrauterine hormone-releasing system, copper interuterine device, 
and sexual abstinence.


Ipatasertib—F. Hoffmann-La Roche Ltd
26/Protocol CO40016, Version 11 (Cohort C)
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.

For any patients enrolled in the extended enrollment phase (i.e., China extension phase):  
patient is a current resident of mainland China, Hong Kong, or Taiwan, and of Chinese 
ancestry.
Disease-Specific Inclusion Criteria
Patients must meet the following disease-specific criteria for study entry:

Histologically documented TNBC or HR/HER2– adenocarcinoma of the breast that is 
locally advanced or metastatic and is not amenable to resection with curative intent
Receptor status at study entry should correspond to the evaluation of the most recent 
biopsy (i.e., recurrent or metastatic tissue where applicable and if safely accessible, 
and nonfine-needle aspiration [FNA] sample), as assessed locally (or on-study, if not 
available locally) according to the ASCO/CAP guidelines:  
HER2is defined as one of the following:  immunohistochemistry 3or in situ 
hybridization positive  
ER or PgR positivity is defined as 1% of tumor cell nuclei immunoreactive to the 
respective hormonal receptor
TNBC is defined as HER2–, ER–, and PgR– (required for eligibility for Cohort A)
HR/HER2– is defined as HER2– and ERand/or PgR(required for eligibility for 
Cohort B)

Measurable disease according to RECIST v1.1

Eligible for taxane monotherapy, as per local investigator assessment (e.g., absence of 
rapid clinical progression, life-threatening visceral metastases, or the need for rapid 
symptom and/or disease control which may require combination chemotherapy)

HR+/HER2– breast cancer that is not considered appropriate for endocrine-based therapy 
and that meets one of the following inclusion criteria:

Patient has recurrent disease (locoregional or metastatic) during adjuvant endocrine 
therapy (i.e., ≤5 years of being on therapy).

If patient has de novo metastatic disease, patient has progressive disease within 
6 months of being on first-line endocrine treatment of metastatic disease.
Note that prior treatment with CDK4/6 inhibitors or mTOR inhibitors is allowed.

Submission of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or a minimum 
of 20 freshly cut unstained, serial tumor slides from the most recently collected tumor tissue 
for central molecular analysis (mandatory NGS testing [PIK3CA/AKT1/PTEN-altered status] 
and for other protocol-mandated secondary and exploratory assessments).  Cytologic or 
FNA samples are not acceptable.  Tumor tissue from bone metastases that is subject to 
decalcification is not acceptable.
If a newer specimen is either insufficient or unavailable, the patient may still be eligible 
if the patient can provide a tissue block (preferred) or a minimum of 20 unstained 
serial slides from an older archival tumor tissue or is willing to consent to and undergo 
an additional pretreatment core or excisional biopsy of the non-target lesion (if it is 
assessable and the biopsy can be safely obtained).  In general, a minimum of three 
core biopsies for NGS testing are required.
If the patient already has PIK3CA/AKT1/PTEN alteration results available from the 
FMI commercial tissue-based NGS assay known as FoundationONE CDx, then the 
FMI clinical trial assay (CTA) does not need to be rerun; in this situation 
formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or 10 freshly 
cut unstained, serial tumor slides from the most recently collected tumor tissue is 


Ipatasertib—F. Hoffmann-La Roche Ltd
27/Protocol CO40016, Version 11 (Cohort C)
acceptable for other protocol-mandated secondary and exploratory assessments, 
upon approval by the Medical Monitor.
Please note, this tumor tissue sample is required to be submitted as described above 
for all patients (i.e., if local assessment of PIK3CA/AKT1/PTEN alteration status or 
central ctDNA is used to assess biomarker eligibility (see below), tumor tissue is still 
required to assess alteration status centrally.)

Confirmation of biomarker eligibility, i.e., valid results from either central testing (in tumor 
tissue as detailed above or blood [using FACT assay]tested at FMI) or local/commercial 
testing of tumor tissue or blood (using an appropriately validated molecular assay at a 
diagnostic laboratory [full laboratory report must be available and captured within the 
patient’s source documents to support eligibility]) demonstrating 
PIK3CA/AKT1/PTEN-altered status defined as the presence of one or more of the following:
AKT1 missense mutations that result in amino acid substitution at the following 
residues E17, L52, or Q79
PIK3CA missense mutations that result in amino acid substitution at the following 
residues R88, G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, 
H1047, or G1049
PTEN alterations that meet any of the following criteria:
Homozygous deletion (copy number of 0)
Dominant negative short variant (e.g., C124S, G129E, R130X)
Loss of heterozygosity (LOH) with copy number of 1 without concomitant single-
nucleotide variants
One deleterious short variant (including insertions and deletions; classification criteria 
provided below) with a concomitant loss of the non-mutant PTEN allele defined by 
LOH with copy number of 1 or LOH with copy number 1.  
o
Any protein truncating mutations, including nonsense mutations and frameshift 
indels
o
Any mutations in the consensus splice donor and acceptor sequence that 
disrupts the consensus, including insertions and deletions
o
Any missense or non-frameshift mutation that has been confirmed somatic as 
described in the COSMIC database
o
If there are two or more deleterious short variants under LOH, the patient will 
not be eligible for the study.
Please note, for local/commercial testing using tumor tissue or blood, a valid result 
from the most recently collected tumor tissue/blood is preferred, however, the patient 
would still be eligible if a valid result is obtained from older archival tissue/blood 
sample.  
Exclusion Criteria
General Exclusion Criteria
Patients who meet any of the following general criteria will be excluded from study entry:

Inability to comply with study and follow-up procedures

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills 

Active infection requiring systemic anti-microbial treatment (including antibiotics, 
anti-fungals, and anti-viral agents)

Known HIV infection 

Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] 
or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis 


Ipatasertib—F. Hoffmann-La Roche Ltd
28/Protocol CO40016, Version 11 (Cohort C)
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive hepatitis B core antibody [HBcAb] test, 
accompanied by a negative HBV DNA test) are eligible.
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
is negative for HCV RNA. 

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
Day 1 of Cycle 1 or anticipation of need for a major surgical procedure during the course of 
the study 
Placement of a vascular access device is not considered major surgery. 

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
28 days after the last dose of ipatasertib/placebo and within 6 months after the last dose of 
paclitaxel, whichever occurs later 
Women of childbearing potential (who are not postmenopausal with 12 months of 
non-therapy induced amenorrhea nor surgically sterile) must have a negative serum 
pregnancy test result either within 96 hours prior to initiation of study drug, or within 
7 days of Day 1, Cycle 1 (in this case, confirmed by a negative urine pregnancy test 
result on Day 1 of Cycle 1 prior to dosing). 

New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction 
50%; or active ventricular arrhythmia requiring medication

Current unstable angina or history of myocardial infarction within 6 months prior to Day 1 of 
Cycle 1

Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF) 480 milliseconds 

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)

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
For Cohort C, no chronic corticosteroid use is permitted at baseline with rare 
exceptions.  Refer to Atezolizumab-Specific Exclusion Criteria.

Treatment with approved or investigational cancer therapy within 14 days prior to Day 1 of 
Cycle 1 

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 
Disease-Specific Exclusion Criteria
Patients who meet any of the following disease-specific criteria will be excluded from study 
entry:

History of or known presence of brain or spinal cord metastases, as determined by 
computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during 
screening or prior radiographic assessments  
Patients with leptomeningeal carcinomatosis will be excluded.

Any previous chemotherapy for inoperable locally advanced or metastatic TNBC or 
HR/HER2– adenocarcinoma of the breast 
Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or 
radiation treatment for breast adenocarcinoma, provided all chemotherapy was 
completed 12 months prior to recurrence.


Ipatasertib—F. Hoffmann-La Roche Ltd
29/Protocol CO40016, Version 11 (Cohort C)
Patients with TNBC must not have received any previous systemic therapy for 
inoperable locally advanced or metastatic TNBC, including chemotherapy, immune 
checkpoint inhibitors, or targeted agents.
Chemotherapy does not include HER2-targeted therapy, such as trastuzumab, 
pertuzumab, or neratinib (for cases in which patients had early stage HER2+ breast 
cancer and are entering the study with HER2advanced breast cancer).  The 
minimum 12-month, disease-free inclusion requirement begins with the last 
administration of chemotherapy in the early breast cancer setting.

Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 
peripheral neuropathy 

Patients who have received palliative radiation treatment to peripheral sites (e.g., bone 
metastases) for pain control and whose last treatment was completed 14 days prior to Day 
1 of Cycle 1 may be enrolled in the study if they have recovered from all acute, reversible 
effects (e.g., to Grade 1 or resolved by enrollment)

Uncontrolled pleural effusion, pericardial effusion, or ascites
Patients with indwelling catheters (e.g., PleurX) are allowed. 

Uncontrolled tumor-related pain 
Patients requiring narcotic pain medication must be on a 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 
randomization.  Patients should be recovered (e.g., to Grade 1 or resolved) from the 
effects of radiation prior to study enrollment.  There is no required minimum recovery 
period beyond the 14 days required for radiation therapy.
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 randomization. 

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium, 12 mg/dL calcium, or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy 
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events (e.g., bone metastasis, osteoporosis) and who do not have a history of 
clinically significant hypercalcemia are eligible. 

Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer
For other cancers considered to have a low risk of recurrence, discussion with the 
Medical Monitor is required.
In cases where there is a history of early-stage breast cancer with ER/PR/HER2 
status differing from the advanced breast cancer for which the patient is entering the 
study, the above language still applies (i.e., any breast cancer within the 5 years prior 
to consent is permitted, provided there is no controversy as to the current 
ER/PR/HER2 status.)
Ipatasertib-Specific Exclusion Criteria
Patients who meet any of the following ipatasertib-specific criteria will be excluded from study 
entry:

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.

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia


Ipatasertib—F. Hoffmann-La Roche Ltd
30/Protocol CO40016, Version 11 (Cohort C)

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)

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

Prior treatment with an Akt inhibitor
Note that prior PI3K or mTOR inhibitors are allowed.
Paclitaxel-Specific Exclusion Criteria
Patients who meet any of the following paclitaxel-specific criteria will be excluded from study 
entry:

Known hypersensitivity or contraindication to any component of the study treatments, 
including the paclitaxel excipient macrogolglycerol ricinoleate

Grade 2 peripheral neuropathy
Atezolizumab-Specific Exclusion Criteria (Cohort C Only)
Patients who meet any of the following atezolizumab-specific criteria will be excluded from study 
entry:

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple 
sclerosis (see the protocol for a more comprehensive list of autoimmune diseases and 
immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid-replacement hormone are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of the following conditions are met:
o
Rash must cover 10% of body surface area.
o
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids.
o
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the previous 12 months.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan

History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, 
or anticipation of need for such a vaccine during treatment with atezolizumab or within 
5 months after the last dose of atezolizumab

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins


Ipatasertib—F. Hoffmann-La Roche Ltd
31/Protocol CO40016, Version 11 (Cohort C)

Known hypersensitivity to Chinese hamster ovary cell products or recombinant human 
antibodies

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to 
initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during the course of the 
study, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant medication or 
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study.
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later.
Length of Study
The total length of the study, from screening of the first patient to the end of the study (excluding 
the potential China extension phase), is expected to be approximately 53 months.
In addition, the Sponsor may decide to terminate a cohort or the study at any time.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal products (IMPs) for this study are ipatasertib, matching placebo,
atezolizumab, and, dependent on local regulations, paclitaxel.  Paclitaxel is an approved 
treatment for breast cancer and is considered standard of care in some countries.  Loperamide 
(racecadotril as used in Europe) is a non-IMP in the study.  The sequence of drug 
administration is ipatasertib/placebo, then atezolizumab (only for patients in Cohort C), and then 
paclitaxel.  On non-atezolizumab administration days, the sequence of drug administration is 
ipatasertib/placebo and then paclitaxel.
Each dose of ipatasertib should be taken with a minimum of 3 ounces (90 mL) of fluid.  
Ipatasertib may be taken with or without food.  If a dose is missed (not taken within 8 hours after 
the scheduled dosing time), the patient should resume dosing with the next scheduled dose.  
Missed or vomited doses will not be made up.
Patients will receive atezolizumab 840 mg administered by IV infusion Q2W (on Days 1 and 
15 [3] days) of each 28-day cycle.  Administration of atezolizumab will be performed in 
a monitored setting where there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
and 15 of each 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can be given on 
Day 22.  Calculation of body surface area for the purposes of dosing of paclitaxel should be 
made according to the prescribing information.  If the patient's weight changes by 10% during 
the study, the body surface area and drug doses should be recalculated.  
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per institutional 
guidelines and administered after the oral dose of ipatasertib/placebo.  
Because of the known potential for allergic reactions to paclitaxel and/or the 
Cremophorvehicle, precautions must be taken to decrease the risk of anaphylaxis.  Patients 


Ipatasertib—F. Hoffmann-La Roche Ltd
32/Protocol CO40016, Version 11 (Cohort C)
must be premedicated prior to paclitaxel with dexamethasone, diphenhydramine, and an 
H2-receptor blocker (i.e., ranitidine or famotidine) or per institutional practice.  H2-receptor 
antagonists, such as cimetidine, which are known to inhibit cytochrome P450, are excluded.
Comparator
The ipatasertib placebo tablets 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.  Placebo will be administered at the starting dose of 400 mg orally QD, 
beginning on Cycle 1, on Days 121 of each 28-day cycle until the patient experiences disease 
progression, intolerable toxicity, or withdraws consent.  Patients will receive placebo prior to the 
IV infusion of paclitaxel.
Each dose of placebo should be taken with a minimum of 3 ounces (90 mL) of fluid.  Placebo 
may be taken with or without food.  If a dose is missed (not taken within 8 hours after the 
scheduled dosing time), the patient should resume dosing with the next scheduled dose.  
Missed or vomited doses will not be made up.
Non-Investigational Medicinal Products
Loperamide is a non-investigational medicinal product (non-IMP) in the study.  All patients 
should receive loperamide (2 mg oral twice a day or 4 mg once a day) 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, and the prophylaxis dose may be adjusted as 
necessary, using their discretion based on clinical judgment and per local guidance.
Statistical Methods
The three cohorts, Cohort A (TNBC biomarker-positive), Cohort B (HR+/HER2–
biomarker-positive breast cancer), and Cohort C (TNBC biomarker-negative) are three 
independent cohorts and will be analyzed separately for the following reasons:

The three patient populations are distinct patient populations and are expected to have 
different prevalence and PFS and OS expectations, and thus different enrollment and 
analysis timelines. 

The readout from one cohort is independent of the readout of the other cohorts. 

This study is essentially three independent trials running under one protocol for operational 
efficiency.
Therefore, for all analyses described below, these three cohorts will be analyzed separately.
The global population will include all patients enrolled during the global enrollment phase 
(including patients enrolled at CFDA-recognized sites during that phase), and the China 
subgroup will include all patients enrolled at CFDA-recognized sites (i.e., during both the global 
enrollment phase and the extended China enrollment phase).  Separate analyses will be 
performed for the global population and the China subgroup.
Primary Analysis
The primary efficacy endpoint is investigator-assessed PFS, defined as the time from 
randomization (Cohorts A and B) or enrollment (Cohort C) to the first occurrence of disease 
progression, as determined by the investigator using RECIST v1.1, or death from any cause, 
whichever occurs first.  Data for patients who do not experience disease progression or death 
will be censored at the last date of evaluable tumor assessment.  For patients who do not have 
an evaluable tumor assessment after randomization/enrollment, the data will be censored at the 
date of randomization plus 1 day.
For Cohort A and Cohort B, PFS will be compared between treatment arms using the stratified 
log-rank test.  The hazard ratio will be estimated using a stratified Cox proportional hazards 
model.  The 95% CI for the hazard ratio will be provided.  The stratification factors to be used 
will be the same as the randomization stratification factors.  Results from an unstratified 
analysis will also be provided.  Sensitivity analyses will be conducted to compare PFS between 
the treatment arms in patients with PIK3CA/AKT1/PTEN-altered tumors as centrally determined 
by the FMI CTA. 


Ipatasertib—F. Hoffmann-La Roche Ltd
33/Protocol CO40016, Version 11 (Cohort C)
For each treatment arm in each cohort, Kaplan-Meier methodology will be used to estimate the 
median PFS, and the Brookmeyer-Crowley method will be used to construct the 95% CI for the 
median PFS (Brookmeyer and Crowley 1982).  Kaplan-Meier curves will be produced as well.
Determination of Sample Size
As described earlier, Cohort A (TNBC biomarker-positive), Cohort B (HR+/HER2–
biomarker-positive breast cancer), and Cohort C (TNBC biomarker-negative) are three 
independent cohorts and will be analyzed separately.  Cohort A and Cohort B will be tested 
independently with 5% type I error control each.   Cohort C is a single-arm cohort with no 
statistical hypothesis testing and will be reported descriptively only.  
For unblinding of Cohort A and Cohort B, in the event that the primary PFS analysis timelines 
for the Cohort A and Cohort B are far apart, after the iDMC's review, the treatment codes of the 
cohort whose PFS data are mature earlier will be sent to the Sponsor to unblind only that cohort 
for the primary analysis of PFS.  The Sponsor will remain blinded to the treatment assignments 
of the other cohort. Data from any additional patients enrolled within the China extension phase 
will not be included in the analysis of the global study.
Global Study
For Cohort A, approximately 249 patients with TNBC with PIK3CA/AKT1/PTEN-altered tumors 
will be enrolled and randomized in a 2:1 ratio to the experimental arm (ipatasertib 
400 mg paclitaxel) and control arm (placebo + paclitaxel).  The sample size of 249 patients is 
determined on the basis of the power calculation for the PFS and OS endpoints. 
For Cohort B, approximately 201 HR+/HER2– patients with PIK3CA/AKT1/PTEN-altered 
tumors will be enrolled and randomized in a 2:1 ratio to the experimental arm (ipatasertib 
400 mg + paclitaxel) and control arm (placebo + paclitaxel).  The sample size of 201 patients is 
determined on the basis of the power calculation for the primary endpoint, PFS. 
For Cohort C, approximately 100 patients with TNBC lacking PIK3CA/AKT1/PTEN-altered 
tumors will be enrolled and assigned to a single arm of ipatasertib plus atezolizumab plus 
paclitaxel.  The sample size of 100 patients is determined on the basis of having a sufficient 
number of patients for efficacy signal seeking, as well as adding to current knowledge on the 
safety profile of this combination, and not delaying the enrollment of patients with TNBC for 
Cohorts A and C.  
Potential China Extension 
For the potential China extension phase, if at least 1 patient is enrolled into Cohorts A or B in 
mainland China, Hong Kong, or Taiwan during the global enrollment phase, additional patients 
may be enrolled at CFDA-recognized sites in an extended enrollment phase for up to a total of 
90 Chinese patients with TNBC with PIK3CA/AKT1/PTEN-altered tumors and up to a total of 
120 Chinese patients with HR/HER2breast cancer with PIK3CA/AKT1/PTEN-altered tumors; 
these patients will constitute an analysis population of a China subgroup.  The sample size of 
this China subgroup is determined on the basis of showing consistency in the China subgroup 
for the primary endpoint and PFS with the global cohort.
Planned Interim Safety Analysis
An external iDMC will be set up to evaluate safety data in Cohorts A and B on a periodic basis.  
All summaries/analyses by treatment arm for the iDMC's review will be prepared by an external 
iDCC.  Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  Any outcomes of these safety reviews that affect study 
conduct will be communicated in a timely manner to the investigators for notification of the 
IRB/EC.  A detailed plan will be included in the iDMC Charter.


Ipatasertib—F. Hoffmann-La Roche Ltd
34/Protocol CO40016, Version 11 (Cohort C)
The iDMC will convene a review of summaries of the safety data by cohort and by treatment 
arm after approximately 50 patients (in total from both cohorts) have competed 1 treatment 
cycle and approximately every 6 months thereafter until the time of the analysis of the primary 
efficacy endpoint for both cohorts are complete.  In the absence of extenuating circumstances, 
accrual will not be halted while the safety analysis is conducted.  The iDMC will review the 
available data to make a recommendation as to the following: to continue without changes to 
the protocol, to modify the safety monitoring and/or eligibility criteria, to add additional safety 
reviews to address emerging safety issues, or to terminate the study.  In addition, the Sponsor 
may request ad hoc meetings of the iDMC at any time during the study to review ongoing safety 
summary data.
Safety monitoring will be performed on a continual basis by the Sponsor for Cohort C.
Planned Interim OS Analysis at PFS Primary Analysis
For Cohort A, interim OS will be analyzed at the time of the primary analysis for PFS, and final 
OS will be analyzed at the time that approximately 188 OS events occur or around after 
a minimum follow-up of 36 months after the last patient has been enrolled, whichever is earlier.  
The Lan-DeMets -spending function with an O’Brien-Fleming boundary will be used to control
the type I error accounting for OS interim and final analyses.  With a sample size of 249 patients 
in Cohort A, it is estimated that there will be approximately 75 OS events at the time of PFS 
primary analysis, and approximately 188 OS events at the final OS analysis, with corresponding 
p-value boundaries of (0.000774, 0.049737).  The corresponding hazard ratio boundaries are 
0.44 and 0.74 at interim and final analysis, respectively. The actual alpha-spending will be 
adjusted and determined based on the actual information fraction at the interim analysis.
For Cohort B, interim OS will be analyzed at the time of the primary analysis for PFS, and final 
OS will be at the time that approximately 148 OS events occur or around 5 years after the last 
patient has been enrolled.  The Lan-DeMets -spending function with an O’Brien-Fleming 
boundary will be used to control the type I error accounting for OS interim and final analyses.  
For Cohort B, it is estimated that there will be approximately 81 OS events at the time of PFS 
primary analysis, and approximately 148 OS events at the final OS analysis, with corresponding 
p-value boundaries of (0.00489, 0.04842).  The corresponding hazard ratio boundaries are 0.52 
and 0.71 at interim and final analysis, respectively.  The actual alpha-spending will be adjusted 
and determined based on the actual information fraction at the interim analysis.
Further details can be found in the SAP.
Optional Interim Analyses
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct an optional interim efficacy analysis, prior to the time of the primary analysis 
for PFS, with each cohort considered independently.  For example, availability of clinical trial 
results for a specific external competitor molecule during the course of 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 two molecules.  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 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 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 the primary endpoint of PFS to determine the critical value for stopping 
for positive efficacy at the interim analysis.  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 


Ipatasertib—F. Hoffmann-La Roche Ltd
35/Protocol CO40016, Version 11 (Cohort C)
to maintain the protocol-specified overall type I error rate, per standard Lan-DeMets 
methodology.
After the primary analysis for PFS, additional OS interim analyses may be conducted to provide 
additional OS data, per the recommendation from health authorities.  If conducted, the 
Lan-DeMets -spending function with an O’Brien-Fleming boundary will be used to control the 
overall type I error for OS accounting for the additional OS interim analyses.


Ipatasertib—F. Hoffmann-La Roche Ltd
36/Protocol CO40016, Version 11 (Cohort C)
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ASCO
American Society of Clinical Oncology
BRCA
breast and ovarian cancer susceptibility gene
CAP
College of American Pathologists
CFDA
China Food and Drug Administration
CIT
Cancer immunotherapy
CR
complete response
CT
computed tomography
CTA
clinical trial assay
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
DOR
duration of response
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of 
Cancer 
ER
estrogen receptor
ESMO
European Society for Medical Oncology
FACT
FoundationACT
FDA
Food and Drug Administration
FFPE
formalin fixed, paraffin embedded
FMI
Foundation Medicine, Inc.
FNA
fine-needle aspiration
GHS
global health status
HBcAg
hepatitis B core antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HLH
hemophagocytic lymphohistiocytosis
HR
hormone receptor
HRQoL
health-related quality of life
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (application)


Ipatasertib—F. Hoffmann-La Roche Ltd
37/Protocol CO40016, Version 11 (Cohort C)
Abbreviation
Definition
IRB
Institutional Review Board
ITT
intent-to-treat
IxRS
interactive voice or Web-based response system
LOH
loss of heterozygosity
MAS
macrophage activation syndrome
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NSCLC
non-small cell lung cancer
NGS
next-generation sequencing
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD-L1
programmed death-ligand 1
PFS
progression-free survival
PgR
progesterone receptor
PI3K
phosphoinositide 3-kinase
PIK3CA
phosphatidylinositol-4, 5bisphosphate 3-kinase, 
catalytic subunit, alpha
PK
pharmacokinetic
popPK
population pharmacokinetics
PR
partial response
PRO
patient-reported outcome
PRO-CTCAE
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events
PTEN
phosphatase and tensin homolog
QD
once a day
QoL
quality of life
QTcF
QT interval corrected using Fridericia’s formula
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
statistical analysis plan
TNBC
triple-negative breast cancer
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


Ipatasertib—F. Hoffmann-La Roche Ltd
38/Protocol CO40016, Version 11 (Cohort C)
1.
BACKGROUND
1.1
BACKGROUND ON TRIPLE-NEGATIVE AND HORMONE-
RECEPTOR–POSITIVE BREAST CANCER 
Globally, breast cancer is the second most common invasive malignancy and the most 
common cause of cancer-related mortality in women, with a 5-year survival rate 
following metastatic diagnosis of approximately 15% (Jemal et al. 2011; 
Ferlay et al. 2015).
Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast 
cancers and is defined by the absence of immunostaining (<1%) for estrogen receptor 
(ER), progesterone receptor (PgR), and non-amplified human epidermal growth factor 
receptor 2 (HER2) expression per American Society of Clinical Oncology (ASCO) and 
College of American Pathologists (CAP) guidelines (ASCO/CAP 2010, 2013).  Patients 
with metastatic TNBC exhibit a particularly poor clinical outcome, generally with rapid 
progression and a median overall survival (OS) rate of approximately 16 months (Rodler 
et al. 2010; Miles et al. 2013).  Although TNBC may respond to chemotherapy, including 
taxanes, there are no approved first-line regimens or targeted therapies for patients with 
this specific subtype of breast cancer. Because of an increase in toxicity and little 
survival benefit with combination chemotherapy, treatment with sequential single agents 
is generally preferred (Cardoso et al. 2017; NCCN 2017).  Paclitaxel is considered an 
appropriate first-line regimen, with a median progression-free survival (PFS) of
approximately 6 months in patients with TNBC (Miles et al. 2013; Miles et al. 2017).
There is a pressing need for clinically active agents for the triple-negative subtype of 
metastatic breast cancer.
Hormone receptorpositive, HER2-negative breast cancer (hereafter referred to as 
HR/HER2breast cancer) accounts for over 70% of all breast cancers. Patients with 
metastatic HR/HER2breast cancer are treated with endocrine therapy;
premenopausal patients often undergo additional ovarian ablation/suppression.  
Chemotherapy is indicated in patients with symptomatic visceral disease (visceral crisis) 
or in patients with disease progression after demonstration of endocrine resistance 
(Cardoso et al. 2017; NCCN 2017).  Patients with visceral disease requiring 
chemotherapy often exhibit symptoms associated with visceral disease burden, such as 
dyspnea and pain, and have a median OS of approximately 1824 months (Harb 2015). 
Patients with HR/HER2breast cancer receiving first-line chemotherapy with paclitaxel 
have a median PFS of approximately 78 months in recent studies (RIBBON-1, Robert 
et al. 2011; PEGGY, Vuylsteke et al. 2016). As with TNBC, there is no clear standard or 
defined treatment regimen for patients with metastatic HR/HER2breast cancer who 
have progressed after endocrine therapy; in particular, effective treatment is needed for 
patients when continued endocrine therapy is not indicated. 


Ipatasertib—F. Hoffmann-La Roche Ltd
39/Protocol CO40016, Version 11 (Cohort C)
PI3K/Akt Pathway in Breast Cancer
The phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway is more frequently 
activated by genomic aberrations than any other signaling pathway in cancer (LoRusso 
2016).  The most common genetic alterations in this pathway are activating mutations of 
phosphatidylinositol-4, 5bisphosphate 3-kinase, catalytic subunit, alpha (PIK3CA), 
loss-of-function alterations of the tumor suppressor phosphatase and tensin homolog 
(PTEN), deregulation of receptor tyrosine kinase signaling, and amplification and 
mutations of receptor tyrosine kinases (Cancer Genome Atlas Network 2012; Millis et al. 
2015).  Alterations in Akt itself, including amplification and overexpression of individual 
Akt isoforms, as well as activating mutations in Akt, have been identified in a subset of 
human cancers (Bellacosa et al. 2005; Brugge et al. 2007; Tokunaga et al. 2008). All of 
these mechanisms of pathway activation ultimately funnel through Akt as the central 
node that drives cell survival, growth, proliferation, angiogenesis, metabolism, and 
migration (Manning and Cantley 2007). 
Large-scale comprehensive genomic analyses have characterized the heterogeneous 
nature of TNBC, including a subgroup with a PI3K/Akt pathway activation signature 
characterized by PIK3CA or AKT1 activating mutations and PTEN alterations (Cancer 
Genome Atlas Network 2012).  Overall, PIK3CA/AKT1/PTEN-altered tumors are 
frequently observed in breast cancer, and are reported in approximately 35% of patients 
with TNBC and in approximately 50% of HR/HER2breast cancers (Cancer Genome 
Atlas Network 2012).  
To date, the relationship between PI3K/Akt pathway activation and prognosis in early 
breast cancer is mixed, with some data demonstrating association with favorable 
outcomes, some data with poor prognosis, and a number of studies showing insignificant 
results (Yang et al. 2016). Information demonstrating significant differences in the 
prevalence of these gene alterations between primary and metastatic tumor tissues is
limited, while enrichment in metastatic patients is probable (Millis et al. 2015).
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 binds to the activated conformation of Akt and 
is ATP competitive.  Ipatasertib binding inhibits the kinase activity of Akt and suppresses 
the phosphorylation of its direct substrates, including PRAS40, and additional 
downstream targets, such as S6 ribosomal protein (S6RP), resulting in G1 arrest and/or 
apoptosis in human cancer cells (Lin et al. 2012). In clinical tumor samples, robust 
Akt pathway inhibition by ipatasertib can be achieved at clinically relevant doses 
(Yan et al. 2013).
Upregulation of Akt signaling (whether intrinsic or induced following chemotherapy) 
represents a potentially important survival pathway in response to genotoxic/mitotic 
stress (Xu et al. 2012). Activation of Akt signaling following chemotherapy (including 
taxanes) may promote cell survival and chemoresistance across several cancer models,


Ipatasertib—F. Hoffmann-La Roche Ltd
40/Protocol CO40016, Version 11 (Cohort C)
including breast cancer (Clark et al. 2002). Conversely, inhibition of the PI3K/Akt 
pathway in diverse cancers leads to radiosensitization and/or chemosensitization 
(Brognard et al. 2001; Solit et al. 2003; Wallin et al. 2010).
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).  Additionally, 
ipatasertib plus microtubule inhibitors or DNA-damaging chemotherapeutic agents 
showed a clear advantage over respective single-agent treatment in preclinical models 
(refer to the Ipatasertib Investigator’s Brochure for further information).  
Based on the scientific rationale that PI3K/Akt blockade attenuates survival signals 
associated with mitotic stress from treatment with microtubule inhibitors and the high 
prevalence of PI3K/Akt pathway activation signatures in TNBC and in HR/HER2-tumors 
(Cancer Genome Atlas Network, 2012), clinical trials evaluating the preliminary safety 
and efficacy of the combination of ipatasertib and paclitaxel in patients with breast 
cancer have been conducted. These trials include a Phase Ib study with an expansion 
cohort of patients with HER2breast cancer (Study PAM4983g, Arm C) and a 
randomized Phase II Study (GO29227, LOTUS) comparing ipatasertibpaclitaxel versus 
placebopaclitaxel as first-line treatment for patients with inoperable locally advanced or 
metastatic TNBC. 
In the Phase Ib Study PAM4983g, 3 of the 15 patients (20%) with breast cancer 
remained progression-free for 6 months (HR/HER2: n2; TNBC: n1), and 4 partial 
responses included patients who had prior exposure to paclitaxel or investigational 
PI3K inhibitors (HR/HER2: n2; TNBC: n2).
In the randomized Phase II Study GO29227, one of the objectives was to investigate the 
added benefit of ipatasertib to paclitaxel in the subgroup of patients with
PIK3CA/AKT1/PTEN-altered tumors.  Results from this study showed improvement in
median PFS in the intent-to-treat (ITT) population (hazard ratio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 (hazard 
ratio0.44; 9 months vs. 4.9 months).
Refer to the Ipatasertib Investigator's Brochure for details on nonclinical and clinical 
studies, including single-agent activities in the Phase I study (PAM4743g).
1.3
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized Ig G1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 


Ipatasertib—F. Hoffmann-La Roche Ltd
41/Protocol CO40016, Version 11 (Cohort C)
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy (CIT).
Atezolizumab is approved in numerous countries for the treatment of several types of 
solid tumors, including urothelial carcinoma, nonsmall cell lung cancer, small-cell lung 
cancer, and PD-L1positive TNBC.  
In metastatic TNBC, the Phase III IMpassion130 (WO29522) study met its co-primary 
endpoint, PFS, as assessed by investigator in the ITT population (hazard ratio for 
progression or death, 0.80; 95% CI: 0.69% to 0.92%; p0.002) and PD-L1selected 
population (hazard ratio: 0.62; 95% CI: 0.49 to 0.78; p 0.001). In the ITT analysis, 
median PFS was 7.2 months with atezolizumab plus nab-paclitaxel compared with 
5.5 months with placebo plus nab-paclitaxel; among patients with PD-L1–positive tumors, 
the median PFS was 7.5 months and 5.0 months, respectively.  Clinically meaningful OS 
benefit was seen at interim OS analysis in PD-L1positive patients. In the ITT analysis, 
median OS was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months 
with placebo plus nab-paclitaxel (hazard ratio for death: 0.84; 95% CI: 0.69 to 1.02; 
p 0.08); among patients with PD-L1–positive tumors, median OS was 25.0 months and 
15.5 months, respectively (hazard ratio: 0.62; 95% CI: 0.45 to 0.86) (Schmid et al. 
2018b). No new safety signals were identified.
In IMpassion130, the most common adverse events (occurring in20% of patients) in 
the atezolizumab arm were alopecia, fatigue, nausea, diarrhea, anemia, constipation, 
cough, headache, peripheral neuropathy, neutropenia, and decreased appetite.  Serious 
adverse events occurred in 22.8% of patients in the experimental arm compared with 
18.3% in the control arm.  Fatal adverse events occurred in 1.3% of patients in the 
experimental arm and 0.7% in the control arm.  Grade 3 or 4 adverse events occurred in 
48.7% of patients in the experimental arm relative to 42.2% in the control arm.  All-grade 
adverse events that occurred with 5% higher incidence in the experimental arm 
included nausea, cough, neutropenia, pyrexia, and hypothyroidism and the only Grade 3 
or 4 adverse event with2% higher incidence in the experimental arm was peripheral 
neuropathy.  Adverse events of special interest (predefined to detect adverse events
suggestive of a potential immune-mediated cause) occurred in 57.3% of patients in the 
experimental arm and 41.8% in the control arm. Grade 3 or 4 adverse events of special 
interest occurred in 7.5% of patients in the experimental arm versus 4.3% in the control 
arm.  Adverse events led to discontinuation of (any) study treatment in 15.9% of patients 
in the experimental arm relative to 8.2% of patients in the control arm (Schmid et al. 


Ipatasertib—F. Hoffmann-La Roche Ltd
42/Protocol CO40016, Version 11 (Cohort C)
2018b). Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.4
BACKGROUND ON STUDIES IN TNBC COMBINING
IPATASERTIB AND ATEZOLIZUMAB
Study CO40151 is a Phase Ib study currently evaluating the safety and efficacy of the 
combination of ipatasertib and atezolizumab with either paclitaxel or nab-paclitaxel in 
a population of patients with diagnostically unselected first-line advanced TNBC.  To 
date, an early safety analysis has been completed on the initial two safety run-in arms 
enrolled (n 6 in one arm using paclitaxelipatasertibatezolizumab; n6 in one arm 
using nab-paclitaxelipatasertibatezolizumab) in Cohort 1, and enrollment continues 
into the remaining arms in Cohort 1 with continuous safety and efficacy monitoring.  The 
toxicity profile in this study, paired with the very early but promising response rate that 
does not seem to be dependent on presence of a PIK3CA/AKT1/PTEN-alteration, 
suggests that this is a reasonable combination to be used for Cohort C study treatment 
in the current study.  The CO40151 Study Team, including the Study Medical Monitor 
and Safety Scientist, monitors patient safety throughout the study.  In addition to the 
ongoing assessment of the incidence, nature and severity of adverse events, serious 
adverse events, deaths, and laboratory abnormalities performed by the investigators and 
the Medical Monitor, the Study Team reviews all necessary cumulative data at regular 
intervals (i.e., approximately three times a year) during the study.  Assessment of safety 
for the safety-run-in cohorts is performed by the Study Team and communicated to 
investigators prior to opening enrollment for the expansion cohorts.
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Metastatic breast cancer remains an incurable disease.  For patients with locally 
advanced and metastatic TNBC, clinical outcome is particularly poor, generally with 
rapid progression and a median OS of approximately 16 months (Rodler et al. 2010; 
Miles et al. 2013). For patients with HR/HER2breast cancer who are not appropriate 
candidates for endocrine therapy, OS with first-line chemotherapy with weekly 
single-agent paclitaxel is approximately 28 months (Miles et al. 2013; Miles et al. 2017). 
Results of the Phase II randomized Study GO29227 demonstrated that adding 
ipatasertib to paclitaxel as first-line therapy for inoperable locally advanced or metastatic 
TNBC improves PFS in the ITT and in PTEN-low populations; the PFS improvement was 
more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors identified with the 
FoundationOne next-generation sequencing (NGS) assay (representing approximately 
40% of the randomized patients in this setting). The use of
PIK3CA/AKT1/PTEN-alteration status as a predictive biomarker for response to the 
combination of ipatasertib and paclitaxel in metastatic TNBC is further supported by the 
pronounced PFS improvement over the complementary population of patients with
PIK3CA/AKT1/PTEN non-altered tumors.


Ipatasertib—F. Hoffmann-La Roche Ltd
43/Protocol CO40016, Version 11 (Cohort C)
Nonclinical and preliminary clinical data also support use of the same biomarker 
selection to identify patients who may derive greater benefit from ipatasertib and 
paclitaxel in HR/HER2breast cancer. Future studies to evaluate ipatasertib 
combination therapy in cancers being driven by PI3K/Akt pathway activation are 
warranted.
This study protocol incorporates two parallel Phase III (Cohorts A and B), multicenter, 
randomized, double-blind, placebo-controlled trials designed to evaluate ipatasertib in 
combination with paclitaxel in a biomarker-selected patient population with TNBC and in 
a biomarker-selected patient population with HR/HER2breast cancer. Patients must 
have PIK3CA/AKT1/PTEN-altered tumors as determined by local/commercial or central 
laboratory blood- or tissue-based molecular assay (e.g., Foundation Medicine, Inc. [FMI]
FoundationOne, FoundationONE CDx, Foundation ACT, or PCR, etc.) and have not 
received prior chemotherapy in the advanced disease setting.  Regardless of the 
biomarker assay performed to confirm eligibility, it remains an eligibility requirement to 
submit a tumor tissue block or 20 unstained slides for central testing of the
PIK3CA/AKT1/PTEN alteration, which may be reduced only in the case of subjects 
meeting biomarker eligibility on the basis of FoundationONE CDx.  If the patient 
already has PIK3CA/AKT1/PTEN alteration results available from the FMI commercial 
tissue-based NGS assay known as FoundationONE CDx, then the FMI clinical trial 
assay (CTA) does not need to be re-run; in this situation the lesser amount of tissue 
specified within the eligibility is acceptable for other protocol-mandated secondary and 
exploratory assessments, upon approval by the Medical Monitor.  Because the biology
and natural treatment history of these two subtypes of breast cancers are distinct and 
heterogeneous, independent stratification and analyses will be conducted.  Eligible 
patients will be assigned to Cohort A (TNBC) or Cohort B (HR/HER2breast cancer) 
according to tumor hormone receptor status.  
In addition, Cohort C with an open-label, non-randomized treatment regimen within this 
study investigates the combination of atezolizumab, ipatasertib, and paclitaxel in 
approximately 100 patients with TNBC who are screened for Cohort A but who do not 
qualify (i.e., lack of PIK3CA/AKT1/PTEN alteration validated by central tumor tissue 
testing using the Foundation Medicine (FMI) clinical trial algorithm [CTA]). 
For each cohort, the primary endpoint is investigator-assessed PFS; secondary 
endpoints include OS, objective response rate (ORR), duration of response (DOR), and 
clinical benefit rate.  In addition, 1-year landmark PFS and OS will be analyzed in
Cohort C. Patient-reported outcomes (PROs) will be both secondary and exploratory 
endpoints, and, along with the other secondary endpoints, may be supportive of the 
primary PFS endpoint.
CIT has demonstrated significant survival benefits over standard treatment, observed 
across multiple advanced malignancies.  Currently, the prevailing CIT approach is to 
circumvent immune evasion mechanisms and reinvigorate anti-tumor responses by 


Ipatasertib—F. Hoffmann-La Roche Ltd
44/Protocol CO40016, Version 11 (Cohort C)
identifying and targeting T-cell co-inhibitory surface receptors such as cytotoxic 
T-lymphocyte-associated protein 4 (CTLA-4) and PD-L1/PD-1.  While these targets have 
resulted in remarkable clinical therapeutic success for various cancer indications, 
ongoing research indicates a series of stepwise events necessary for the generation of 
a continuous anti-tumor immune response (Chen and Mellman 2013).  Each event is 
critical for an effective response, and each is also susceptible to several tumor immune 
evasion mechanisms.  Thus, the need to identify and circumvent the various factors 
involved in tumor immune evasion will be critical for propagating the anti-tumor immune 
response and advancing the field of CIT, most likely through combined targeted therapy 
regimens.
Recently, nonclinical and clinical data have indicated a correlation between PTEN loss 
and impaired anti-tumor immune responses, including reduced CD8 T-cell infiltration and 
reduced efficacy of anti-PD1 therapy in melanoma patients.  Furthermore, nonclinical 
studies reveal synergistic anti-tumor responses when combining PI3K-Akt pathway 
inhibition and PD-L1/PD-1 axis blockade (Peng et al. 2016).  In addition, Akt inhibitors 
may restore and enhance physiological functionalities of T cells in the tumor 
microenvironment and enhance expansion of tumor-specific lymphocytes with memory 
cell phenotype (Crompton et al. 2015).  Concurrent treatment with ipatasertib may 
enhance checkpoint inhibitor efficacy by driving development of memory T-cells over 
effector T-cells, thereby enabling a long-term response in patients (Gubser et al. 2013; 
Xue et al. 2015).  On the basis of these results as well as the tolerability and limited 
overlapping toxicity of atezolizumab, ipatasertib, and paclitaxel, combination treatment 
with these agents appears to have promising therapeutic potential in solid tumors such 
as TNBC.  
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 (GO29227) studies supports continued development in metastatic breast 
cancer. As a single agent, ipatasertib has a predictable pharmacokinetic (PK) profile 
with a half-life of approximately 48 hours and significantly downregulates the PI3K/Akt 
pathway at doses 200 mg. In Study GO29227, the adverse effects of ipatasertib plus 
paclitaxel in metastatic TNBC were consistent with previous experiences of ipatasertib 
and of paclitaxel, most notably ipatasertib-related gastrointestinal toxicities that are 
manageable and reversible. Common adverse events with a 10% higher incidence in 
the ipatasertib arm than in the placebo arm were diarrhea, nausea, asthenia, and 
peripheral sensory neuropathy.  Common Grade 3 adverse events included diarrhea, 
neutropenia, neutrophil count decreased, and fatigue. When grouping the adverse event 
preferred terms with similar medical concepts, asthenia/fatigue and peripheral 
neuropathy were not significantly different between the two arms (refer to the Ipatasertib 
Investigator’s Brochure and Section 3.3.3 for detailed safety information).
In Study GO29227, diarrhea was more common in the ipatasertib arm compared with 
the placebo arm (93% vs. 19%); however, the majority of cases were low grade. The 


Ipatasertib—F. Hoffmann-La Roche Ltd
45/Protocol CO40016, Version 11 (Cohort C)
onset of diarrhea was most common within the first cycle; late onset diarrhea was rare, 
and no cases of colitis were reported.  Diarrhea generally responded to loperamide 
treatment and to ipatasertib dose holds and dose reductions when resuming treatment; 
limited (only 3%) discontinuation of ipatasertib treatment due to diarrhea was reported.
Despite the high frequency of diarrhea in the ipatasertib arm, the median relative dose 
intensity of both ipatasertib and paclitaxel approached 100% and was comparable in the 
ipatasertib and placebo arms.
In this current study, 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 implemented subsequently as clinically indicated. 
Patients will be monitored for early signs of diarrhea symptoms, and investigators will be 
provided with comprehensive management guidelines for study treatmentrelated 
symptoms or potential risks.  If there are clinical concerns that preclude the use of 
loperamide prophylaxis in Cycle 1, discussion with the Medical Monitor is required.
The adverse events observed with atezolizumab in combination with chemotherapy 
and/or targeted therapies are consistent with the known risks of each study treatment.  
The most commonly reported adverse events with single-agent atezolizumab include 
fatigue, nausea, decreased appetite, diarrhea, constipation, and cough.  
Immune-mediated adverse events are consistent with the role of the PD-L1/PD-1 
pathway in regulating peripheral tolerance.  Given the mechanism of action of 
atezolizumab, events associated with inflammation and/or immune-mediated adverse 
events will be closely monitored in this study.  Immune-mediated adverse events 
associated with atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré 
syndrome, myasthenic syndrome/myasthenia gravis, hypophysitis, myocarditis, 
meningoencephalitis, nephritis, and myositis.  Immune-mediated reactions may involve 
any organ system and may lead to hemophagocytic lymphohistiocytosis and 
macrophage activation syndrome. Guidance regarding the management of 
immune-mediated adverse events is provided in Appendix 15 of the protocol and in 
Section 6 of the Atezolizumab Investigator’s Brochure.
Adverse events of special interest, in addition to overall safety, will be monitored as 
outlined in this protocol.
In summary, the two study populations eligible for this trial (TNBC and HR+/HER2-) both 
require chemotherapy for the first time in the advanced setting and are appropriate for 
receiving paclitaxel monotherapy.  Prior Phase II data in patients with advanced TNBC 
support the addition of ipatasertib to paclitaxel treatment with enhanced benefit in those
patients with PIK3CA/AKT1/PTEN-altered tumors, as demonstrated by a pronounced 
improvement in PFS compared to treatment with paclitaxel alone.  Preclinical and
preliminary clinical data also support the addition of ipatasertib to paclitaxel using the 
same biomarker selection in patients with HR/HER2breast cancer. Similarly, 


Ipatasertib—F. Hoffmann-La Roche Ltd
46/Protocol CO40016, Version 11 (Cohort C)
preclinical and preliminary clinical data support the addition of atezolizumab to the
combination of ipatasertib and paclitaxel in patients with TNBC independent of
PIK3CA/AKT1/PTEN alteration status.  As described in more detail above, the 
combination of ipatasertib and paclitaxel (and atezolizumab) has been generally well 
tolerated, with comprehensive guidelines for management of anticipated treatment-
related symptoms incorporated into this protocol.  On the basis of the data available to 
date, the benefit-risk assessment for administration of ipatasertib alongside paclitaxel is 
considered positive in both locally advanced unresectable or metastatic TNBC and 
HR/HER2breast cancer patient populations.  In addition, benefit-risk of the triplet 
combination of ipatasertib alongside paclitaxel and atezolizumab is supported by 
preliminary Phase Ib safety and response data in Study CO40151.
2.
OBJECTIVES AND ENDPOINTS
Cohorts A and B will independently evaluate the safety, efficacy, and pharmacokinetics 
of ipatasertib in combination with paclitaxel (ipatasertibpaclitaxel) compared with
placebo plus paclitaxel (placebopaclitaxel) in patients with
PIK3CA/AKT1/PTEN-altered tumors.  Cohort A will evaluate first-line treatment in 
patients with locally advanced unresectable or metastatic TNBC, and Cohort B will 
evaluate first-chemotherapy treatment in patients with advanced HR/HER2breast 
cancer who are not appropriate candidates for endocrine therapy (as defined by the 
Sponsor; see Section 4.1).  Patients will be enrolled based on central or 
local/commercial determination of PIK3CA/AKT1/PTEN-altered status, with central 
assessment of PIK3CA/AKT1/PTEN-altered status in tumor tissue performed in any 
patients enrolled using alternative methods and will be allocated to one of the cohorts 
based on hormone-receptor status.  Patients with HER2-positive breast cancer are not 
eligible. The reason that the Cohorts A and B will be evaluated separately is that TNBC 
and HR/HER2breast cancers have different biologies that manifest clinically in 
different prognoses and response to treatment, and molecularly with distinctly different 
molecular profiles with dissimilar oncogenic drivers. The patients in Cohorts A and B
have different prevalences and PFS and OS expectations, and thus different enrollment 
and analysis timelines.
Patients who initially screen for Cohort A (with TNBC) but do not qualify (i.e., lack of
PIK3CA/AKT1/PTEN alteration validated by central tumor tissue testing using the FMI 
CTA) may be eligible for Cohort C.  Cohort C is an open-label, non-randomized cohort 
for patients with locally advanced unresectable or metastatic TNBC that will assess the 
safety, efficacy, and pharmacokinetics of ipatasertib in combination with paclitaxel and 
atezolizumab.  Due to the differences in mechanism of action and evaluation of clinical 
benefit following cancer immunotherapy treatments, as well as delayed opening of 
Cohort C, this cohort will be evaluated separately from Cohorts A and B.
The target patient populations for this study are premenopausal and postmenopausal 
female and male patients with measurable, locally advanced unresectable or metastatic 


Ipatasertib—F. Hoffmann-La Roche Ltd
47/Protocol CO40016, Version 11 (Cohort C)
TNBC and HR/HER2breast cancer who have not received chemotherapy in either of 
these settings.  Patients must be appropriate candidates for taxane monotherapy. In 
particular, patients with HR/HER2breast cancer should be suitable for treatment with 
chemotherapy (e.g., demonstrated insensitivity to endocrine therapy; reference eligibility
criteria for Sponsor definition of endocrine-insensitivity).  Prior adjuvant or neoadjuvant 
chemotherapy is allowed, provided it has been concluded at least 12 months before
recurrence of (locally advanced unresectable or metastatic) disease.
Patients with PIK3CA/AKT1/PTEN-altered tumors (as defined in Section 3.1.1 and
Section 4.1.1) will be assigned to Cohort A (TNBC) or Cohort B (HR/HER2breast 
cancer) based on their hormone receptor status (as evaluated locally, or on study, only if 
local evaluation is not available, with additional slides submitted for this purpose) and 
randomized with a 2:1 ratio to the experimental versus control arm. Patients with TNBC
who are biomarker-negative (i.e., lack of PIK3CA/AKT1/PTEN alteration validated by 
central tumor tissue testing using the FMI CTA) but otherwise eligible will be assigned to 
Cohort C to receive ipatasertib in combination with atezolizumab and paclitaxel until this 
cohort is fully accrued. All primary, secondary, exploratory, and safety objectives will be 
assessed independently for each cohort (i.e., Cohort A:  patients with TNBC with
PIK3CA/AKT1/PTEN-altered tumors, Cohort B:  patients with HR/HER2breast cancer 
with PIK3CA/AKT1/PTEN-altered tumors and Cohort C: patients with TNBC whose 
tumors lack PIK3CA/AKT1/PTEN alteration validated by central tumor tissue testing 
using the FMI CTA).
The primary endpoint is PFS for all cohorts. The primary analysis for each cohort will be 
independent and triggered by cohort-specific events and will also be independent of the 
readout of the other cohort (refer to Section 6). The secondary endpoints for Cohorts A 
and B will be tested if the primary analysis of the respective PFS reaches statistical 
significance at the level of 5%.  
Specific objectives and corresponding endpoints for each cohort will be analyzed 
independently following cohort-specific statistical analysis plans, and are outlined in
Table 1 and Table 2.


Ipatasertib—F. Hoffmann-La Roche Ltd
48/Protocol CO40016, Version 11 (Cohort C)
Table 1
Objectives and Corresponding Endpoints (Applicable for Both 
Cohort A and Cohort B, Unless Otherwise Stated)
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of
ipatasertib + paclitaxel compared with placebo 
+ paclitaxel  
PFS, defined as the time from randomization to 
the first occurrence of disease progression, as 
determined locally by the investigator through 
the use of RECIST v1.1, or death from any 
cause, whichever occurs first
Secondary Efficacy Objectives:
To evaluate the efficacy of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel 
Objective response rate, defined as a CR or 
PR on two consecutive occasions 4 weeks 
apart, as determined locally by the investigator
through the use of RECIST v1.1
Duration of response, defined as the time from 
the first occurrence of a documented objective 
response to disease progression, as 
determined locally by the investigator through 
use of RECIST v1.1, or death from any cause, 
whichever occurs first
Clinical benefit rate, defined as an objective 
response (CR or PR), or stable disease for at 
least 24 weeks, as determined locally by the 
investigator through the use of RECIST v1.1
OS, defined as the time from randomization to 
death from any cause
To evaluate PROs of GHS/HRQoL associated 
with ipatasertib paclitaxel compared with 
placebo paclitaxel  
Mean and mean changes from baseline 
GHS/HRQoL score as measured by the 
GHS/HRQoL scale (Questions 29 and 30) of 
the EORTC QLQ-C30, by cycle
To evaluate PROs of disease-related pain of 
ipatasertib paclitaxel compared with 
placebo paclitaxel (Cohort B only) 
Time to deterioration in pain, defined as the first 
minimally important increase of ≥11 points from 
the baseline pain scale score (Questions 9 and 
19) of the EORTC QLQ-C30
Exploratory Efficacy Objectives:
To evaluate the efficacy of 
ipatasertib paclitaxel compared with placebo 
+ paclitaxel in TNBC (Cohort A only) patients 
with tumors that have the following:
-
PIK3CA/AKT1-activating mutations 
-
PTEN alterations (and no 
PIK3CA/AKT1-activating mutations) 
PFS
Objective response rate
Duration of response
Clinical benefit rate
OS 


Ipatasertib—F. Hoffmann-La Roche Ltd
49/Protocol CO40016, Version 11 (Cohort C)
Table 1
Objectives and Corresponding Endpoints (Applicable for Both 
Cohort A and Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Exploratory Efficacy Objectives: (cont.)
To evaluate PROs of function and 
disease/treatment-related symptoms 
associated with ipatasertib paclitaxel 
compared with placebo paclitaxel 
Mean and mean changes from baseline scores 
in functional (i.e., role, physical, cognitive, 
emotional, and social) and 
disease/treatment-related symptoms by cycle as 
assessed by the functional and symptom scales 
of the EORTC QLQ-C30
To collect utilities for pharmacoeconomic 
modeling
Health states for utility assessment and the VAS 
as measured by the EQ-5D-5L questionnaire for 
modeling
To evaluate the clinical benefit
PFS2, defined as the time from randomization to
first objective disease progression on next-line 
treatment, or death from any cause, whichever 
occurs first
Time to first skeletal–related event (SRE),
defined as the time from randomization to the 
occurrence of an SRE. An SRE is either a 
pathologic fracture, radiation therapy to the 
bone, surgery to the bone, or spinal cord 
compression.
To evaluate analgesic use in 
ipatasertibpaclitaxel and placebopaclitaxel 
treatment arms (Cohort B only)
Change in use of opioid and non-opioid 
analgesics during treatment, as measured by
the intake of analgesic treatments
Safety Objective:
To evaluate the safety of 
ipatasertibpaclitaxel compared with 
placebopaclitaxel 
Incidence of adverse events as assessed by the 
investigator, with severity determined through 
the use of NCI CTCAE v4.0 
Incidence of prespecified adverse events 
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Exploratory Safety Objective:
To collect PROs regarding key symptomatic 
adverse events of ipatasertibpaclitaxel 
compared with placebopaclitaxel 
Selected items from the PRO-CTCAE capturing 
patients' rating of the presence, severity, 
frequency, and/or interference of diarrhea, 
nausea, vomiting, decreased appetite, fatigue, 
neuropathy, mouth sores, and rash symptoms 
and an additional item regarding bother due to 
side effects of treatment


Ipatasertib—F. Hoffmann-La Roche Ltd
50/Protocol CO40016, Version 11 (Cohort C)
Table 1
Objectives and Corresponding Endpoints (Applicable for Both 
Cohort A and Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Pharmacokinetic Objective:
To characterize the pharmacokinetics of 
ipatasertib and its metabolite (G-037720) 
when administered in combination with 
paclitaxel
Plasma concentration of ipatasertib and 
G-037720 at specified timepoints for analysis 
using population PK methodology
Exploratory Pharmacokinetic Objective:
To evaluate potential relationships between 
ipatasertib exposure, efficacy, and safety of 
ipatasertib paclitaxel compared with 
placebo paclitaxel 
Relationship between ipatasertib PK and 
efficacy endpoints
Relationship between ipatasertib PK and safety 
endpoints
Exploratory Biomarker Objectives:
To evaluate predictive or prognostic 
biomarkers (plasma or tissue) associated 
with disease activity status or response to 
treatment 
To identify possible mechanisms of 
resistance to study treatments through the 
comparative analysis of potential biomarkers 
in pretreatment and post-progression biopsy 
tissue samples and in blood 
To evaluate alternative diagnostics testing 
methods for PIK3CA/AKT1/PTEN-altered 
status
Relationship between tissue- and blood-based 
biomarkers and patient clinical features (e.g., 
baseline features) and outcome (e.g., duration 
of PFS)
Change in mutation and copy number in 
oncogenes, tumor suppressors, and/or other 
genes associated with disease progression by 
DNA sequencing
Change in levels of tumor suppressors, 
immune checkpoints, mitotic index, apoptotic 
index, and/or immune-cell infiltration by 
immunohistochemistry
Associations of breast cancer subtypes 
defined by molecular signatures with patient 
outcomes
Association of BRCA1/2 genetic alterations
and homologous repair deficiency with patient 
outcomes
BRCAbreast and ovarian cancer susceptibility gene; CR complete response; 
EORTCEuropean Organisation for Research and Treatment of Cancer; GHSglobal health 
status; HRQoLhealth-related quality of life; NCI CTCAE v4.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; OSoverall survival; 
PKpharmacokinetics; PFSprogression-free survival; PRpartial response; PRO patient-
reported outcome; PRO-CTCAEPatient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events; RECIST v1.1 Response Evaluation Criteria in Solid 
Tumors, Version 1.1; TNBCtriple-negative breast cancer; VASvisual analog scale. 


Ipatasertib—F. Hoffmann-La Roche Ltd
51/Protocol CO40016, Version 11 (Cohort C)
Table 2
Objectives and Corresponding Endpoints (Cohort C)
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of 
ipatasertibpaclitaxelatezolizumab 
PFS, defined as the time from enrollment to the 
first occurrence of disease progression, as 
determined locally by the investigator through 
the use of RECIST v1.1, or death from any 
cause, whichever occurs first
Secondary Efficacy Objectives:
To evaluate the efficacy of 
ipatasertibpaclitaxelatezolizumab
Objective response rate, defined as a CR or 
PR on two consecutive occasions 4 weeks 
apart, as determined locally by the investigator 
through the use of RECIST v1.1
Duration of response, defined as the time from 
the first occurrence of a documented objective 
response to disease progression, as 
determined locally by the investigator through 
use of RECIST v1.1, or death from any cause, 
whichever occurs first
Clinical benefit rate, defined as an objective 
response (CR or PR), or stable disease for at 
least 24 weeks, as determined locally by the 
investigator through the use of RECIST v1.1
OS, defined as the time from enrollment to 
death from any cause
1year PFS, defined as progression-free 
survival probabilities at 1 year.
1year OS, defined as overall survival 
probabilities at 1 year.
To evaluate PROs of GHS/HRQoL associated 
with ipatasertib paclitaxel atezolizumab
Mean and mean changes from baseline 
GHS/HRQoL score as measured by the 
GHS/HRQoL scale (Questions 29 and 30) of 
the EORTC QLQ-C30, by cycle


Ipatasertib—F. Hoffmann-La Roche Ltd
52/Protocol CO40016, Version 11 (Cohort C)
Table 2
Objectives and Corresponding Endpoints (Cohort C) (cont.)
Objectives
Corresponding Endpoints
Exploratory Efficacy Objectives: (cont.)
To evaluate PROs of function and 
disease/treatment-related symptoms 
associated with 
ipatasertibpaclitaxelatezolizumab
Mean and mean changes from baseline scores 
in functional (i.e., role, physical, cognitive, 
emotional, and social) and 
disease/treatment-related symptoms by cycle as 
assessed by the functional and symptom scales 
of the EORTC QLQ-C30
To collect utilities for pharmacoeconomic 
modeling 
Health states for utility assessment and the VAS 
as measured by the EQ-5D-5L questionnaire for 
modeling
To evaluate the clinical benefit
PFS2, defined as the time from enrollment to 
first objective disease progression on next-line 
treatment, or death from any cause, whichever 
occurs first
Time to first skeletal–related event (SRE), 
defined as the time from treatment assignment 
to the occurrence of an SRE.  An SRE is either 
a pathologic fracture, radiation therapy to the 
bone, surgery to the bone, or spinal cord 
compression.  
Safety Objective:
To evaluate the safety of 
ipatasertibpaclitaxelatezolizumab 
Incidence of adverse events as assessed by the 
investigator, with severity determined through 
the use of NCI CTCAE v4.0 
Incidence of prespecified adverse events 
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Exploratory Safety Objective:
To collect PROs regarding key symptomatic 
adverse events of 
ipatasertibpaclitaxelatezolizumab 
Selected items from the PRO-CTCAE capturing 
patients' rating of the presence, severity, 
frequency, and/or interference of diarrhea, 
nausea, vomiting, decreased appetite, fatigue, 
neuropathy, mouth sores, and rash symptoms 
and an additional item regarding bother due to 
side effects of treatment


Ipatasertib—F. Hoffmann-La Roche Ltd
53/Protocol CO40016, Version 11 (Cohort C)
Table 2
Objectives and Corresponding Endpoints (Cohort C) (cont.)
Objectives
Corresponding Endpoints
Pharmacokinetic Objective:
To characterize the pharmacokinetics of 
atezolizumab, ipatasertib and its metabolite 
(G-037720) when administered in combination 
with paclitaxel 
Plasma concentration of ipatasertib and its 
metabolite, G-037720 at specified timepoints for 
analysis using population PK methodology
Serum concentration of atezolizumab at 
specified timepoints
Exploratory Pharmacokinetic Objective:
To evaluate potential relationships between 
ipatasertib and/or atezolizumab exposure, 
efficacy, and safety of 
ipatasertibpaclitaxelatezolizumab
Relationship between ipatasertib and/or 
atezolizumab PK and efficacy endpoints 
Relationship between ipatasertib and/or 
atezolizumab PK and safety endpoints 
Immunogenicity Objective:
To evaluate the immune response to 
atezolizumab
Incidence of ADAs to atezolizumab during the 
study relative to the prevalence of ADAs at 
baseline
Exploratory Immunogenicity Objective:
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Biomarker Objectives:
To evaluate predictive or prognostic 
biomarkers (plasma or tissue) associated 
with disease activity status or response to 
treatment 
To identify possible mechanisms of 
resistance to study treatments through the 
comparative analysis of potential biomarkers 
in pretreatment and post-progression biopsy 
tissue samples and in blood 
To evaluate alternative diagnostics testing 
methods for PIK3CA/AKT1/PTEN-altered 
status
Relationship between tissue- and blood-based 
biomarkers and patient clinical features (e.g., 
baseline features) and outcome (e.g., duration 
of PFS)
Change in mutation and copy number in 
oncogenes, tumor suppressors, and/or other 
genes associated with disease progression by 
DNA sequencing 
Change in levels of tumor suppressors, 
immune checkpoints, mitotic index, apoptotic 
index, and/or immune-cell infiltration by 
immunohistochemistry
Associations of breast cancer subtypes 
defined by molecular signatures with patient 
outcomes
Association of BRCA1/2 genetic alterations 
and homologous repair deficiency with patient 
outcomes
BRCAbreast and ovarian cancer susceptibility gene; CR complete response; 
EORTCEuropean Organisation for Research and Treatment of Cancer; GHSglobal health 
status; HRQoLhealth-related quality of life; NCI CTCAE v4.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; OSoverall survival; 
PKpharmacokinetics; PFSprogression-free survival; PRpartial response; 
PROpatient-reported outcome; PRO-CTCAEPatient-Reported Outcomes Version of the 
Common Terminology Criteria for Adverse Events; RECIST v1.1Response Evaluation Criteria 
in Solid Tumors, Version 1.1; TNBCtriple-negative breast cancer; VASvisual analog scale. 


Ipatasertib—F. Hoffmann-La Roche Ltd
54/Protocol CO40016, Version 11 (Cohort C)
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
The two-cohort (Cohorts A and B), randomized, double-blind, placebo-controlled portion 
of this Phase III study is designed to evaluate the efficacy of ipatasertibpaclitaxel 
versus placebopaclitaxel in patients with histologically confirmed, locally advanced 
unresectable or metastatic TNBC and in patients with locally advanced unresectable or 
metastatic HR/HER2breast adenocarcinoma who are not suitable for endocrine 
therapy (as defined by Sponsor; see eligibility criteria).  Each cohort will be independent 
with separate analyses, but with a single screening process to identify, allocate, and 
subsequently stratify on the basis of histologic and diagnostic status.  Patients must 
have measurable disease as defined by Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) and a PIK3CA/AKT1/PTEN-altered tumor as determined by 
any blood- or tissue-based molecular diagnostic assay (using a CLIA or equivalently 
accredited diagnostic laboratory).  Tumor PIK3CA/AKT1/PTEN-altered status is defined 
as the presence of PTEN alterations or PIK3CA/AKT1-activating mutations (see
Section 4.1.1, Disease-Specific Inclusion Criteria).  Pathological determination of ER, 
PgR, and HER2 status based on local assessment according to ASCO and CAP 
guidelines (see Appendix 5 and Appendix 6) will be applied for cohort assignment by an 
interactive voice or Web-based response system (IxRS), with subsequent randomization 
within each cohort based on the appropriate stratification factors for the different cohorts.  
Patients who have unknown tumor ER, PgR, HER2, or PIK3CA/AKT1/PTEN-altered 
status and for whom determination of status is not possible are not eligible for this study.
If a patient will screen for biomarker eligibility with the tissue-based FMI CTA, time for 
tumor tissue retrieval, shipping, and turnaround of eligibility results should be taken into 
account when screening patients (and submitted sample should be sufficient per 
protocol requirements to have maximum likelihood that a valid result can be obtained).
As the FoundationACT™(FACT) assay is not able to detect all qualifying alterations that 
may be identified using the FMI CTA, tissue submission should not be delayed as 
patients may qualify by the latter, rather than by FACT. FACT testing at FMI may not 
necessarily be faster than the FMI CTA and, therefore, should only be performed when it 
is anticipated that there will be a significant delay to acquisition of existing tumor tissue.
If local/commercial testing is available, demonstrating a qualifying alteration, or if this 
result is obtained, these results may be used to determine biomarker eligibility.  However, 
please note, for patients not enrolled on the basis of the FMI tissue-based CTA 
(e.g., local/commercial tests or blood-based FACT assay), submission of tumor tissue is 
still required, but randomization should proceed based on the local result with no 
requirement to wait for central assessment of biomarker eligibility.  Treatment benefit in 
patients with PIK3CA/AKT1/PTEN-altered tumors will be independently compared in 
patients with triple-negative receptor status and in patients with HR/HER2status. 


Ipatasertib—F. Hoffmann-La Roche Ltd
55/Protocol CO40016, Version 11 (Cohort C)
Approximately 349 patients with TNBC (249 biomarker-positive patients and 
100 biomarker-negative patients), and 201 biomarker-positive patients with 
HR/HER2breast cancer will be enrolled at approximately 165195 centers worldwide
during the global enrollment phase.  Patients will be assigned to either Cohort A (TNBC
biomarker-positive), Cohort B (HR/HER2biomarker-positive breast cancer), or 
Cohort C (TNBC biomarker-negative) according to the most recent locally assessed 
pathologically documented receptor status and PIK3CA/AKT1/PTEN alteration status.  
Receptor status should be assessed in their recurrent or metastatic tumor where 
applicable and if safely accessible, per ASCO/CAP guidelines (see Appendix 5 and 
Appendix 6 for the 2013 guidelines [includes recent HER2 testing update [Wolff et al. 
2018]). Patients in Cohorts A and B will be randomly assigned in a 2:1 ratio to the 
experimental arm (ipatasertib 400 mgpaclitaxel) or control arm (placebopaclitaxel).  
Approximately 100 patients with TNBC who screen for Cohort A who are shown not to 
have a PIK3CA/AKT1/PTEN-altered tumor by centrally tested FMI CTA may be assigned 
to Cohort C to receive ipatasertib in combination with atezolizumab and paclitaxel, 
unless the cohort is completely accrued. The study schema is shown in Figure 1. 
Randomization for patients in Cohort A and B will be stratified by the following factors:  
prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region (Asia-Pacific vs. Europe 
vs. North America vs. rest of the world), tumor PIK3CA/AKT1/PTEN-alteration status 
(PIK3CA/AKT1-activating mutations vs. PTEN alterations with no 
PIK3CA/AKT1-activating mutations; Cohort A only), and prior therapy with a PI3K or 
mTOR inhibitor (yes vs. no; Cohort B only).
All patients must have a validated PIK3CA/AKT1/PTEN-alteration status using a 
blood- or tissue-based molecular assay and must have consented to provide sufficient 
archival tissue or newly obtained tumor biopsy tissue for central molecular evaluation to 
be eligible for enrollment.  If the patient already has PIK3CA/AKT1/PTEN alteration 
results available from the FMI commercial tissue-based NGS assay known as 
FoundationONE CDx, then the FMI CTA does not need to be re-run; in this situation 
the lesser amount of tissue specified within Section 4.1.1 is acceptable for other 
protocol-mandated secondary and exploratory assessments, upon approval of the 
Medical Monitor.  Given the probability of PIK3CA/AKT1/PTEN non-altered status 
(approximately 80%85% for TNBC and 50%60% for HR positive by blood-based NGS 
assay, such as FACT, and 55%65% by tissue-based NGS, such as FMI CTA), it 
remains an option to use the biomarker-specific ICF/screening process first, prior to 
other study screening procedures for those patients who require central testing of 
biomarker status. It is advised that even if the patient will be screened for biomarker 
eligibility on the basis of the FACT (or other blood-based) NGS assay, that tissue be 
submitted as quickly.  In blood, the fraction of available circulating tumor DNA (ctDNA) to 
sequence is less than that in tumor tissue, and because of this biology, it is expected 
that the FACT assay will not detect all alterations that can be identified using 
tissue-based NGS; i.e., even if there is biomarker ineligibility based on the blood-based 
assay, the patient may still qualify on the basis of the tissue-based assay.


Ipatasertib—F. Hoffmann-La Roche Ltd
56/Protocol CO40016, Version 11 (Cohort C)
All patients in Cohorts A and B will receive paclitaxel chemotherapy (80 mg/m2 IV) on 
Days 1, 8, and 15 of each 28-day cycle and either ipatasertib at a dose of 400 mg
administered orally once a day (QD) on Days 121 of each 28-day cycle (experimental 
arm) or placebo orally QD on Days 121 of each 28-day cycle (control arm).  In Cohort C,
patients will receive paclitaxel chemotherapy (80 mg/m2 IV) on Days 1, 8, and 15 of each 
28-day cycle, ipatasertib at a dose of 400 mg administered orally once a day (QD) on 
Days 121 of each 28-day cycle, and atezolizumab 840 mg IV on Days 1 and 15 of each 
28-day cycle.  Study treatment will continue until disease progression, intolerable toxicity, 
elective withdrawal from the study, or study completion or termination. Upon treatment 
discontinuation, patients will be followed every 3 months for survival, PROs (see
Section 4.5.8), and new anti-cancer therapy and outcome (therapy/procedures, doses, 
start and stop date, best responses, most recent tumor assessment date, and 
progression date). As of Protocol CO40016 Version 11 (Cohort C), these long-term
follow-up assessments are no longer required.
As of Protocol CO40016 Version 11 (Cohort C), tumor measurement for disease 
evaluation will be performed per standard of care, regardless of whether patients receive 
study treatment during the treatment cycle.  For estimation of PFS, ORR, and DOR, 
tumor response will be based on RECIST v1.1.  For patients who discontinue treatment 
without evidence of disease progression per RECIST v1.1, in addition to post-treatment 
follow-up, patients will be followed every 812 weeks for tumor assessments until 
documented progression per RECIST v1.1, elective withdrawal from the study, or study 
completion or termination (as of Protocol CO40016 Version 11 [Cohort C] this is no 
longer required).  Images for tumor assessments for all patients will be prospectively 
collected to enable retrospective blinded independent central review when needed.  As 
of protocol CO40016 Version 10 (Cohort C), images for tumor assessments will no 
longer be collected for blinded independent central review.
Patients will also be given the option of providing a tissue biopsy sample obtained at 
disease progression for exploratory analyses; this decision will not affect overall study 
eligibility.  Patients who are not randomized in the study may receive a copy of the FMI 
NGS (and FACT assay report if performed) research report (if available) for their tumor 
upon request, unless the patient is enrolled onto Cohort C.  A copy of this report(s) may 
also be available upon request by the investigator for all patients, at the time they 
discontinue all study treatment or following end of the study, whichever occurs earlier, 
unless required by law.  The research report(s) may be obtained by the investigator, via 
the Sponsor study team, and will describe results from investigational tests that are not 
intended to be used to guide future treatment decisions. 


Ipatasertib—F. Hoffmann-La Roche Ltd
57/Protocol CO40016, Version 11 (Cohort C)
The pharmacokinetics of ipatasertib and its metabolite G-037720 will be assessed in all 
patients receiving ipatasertib.  Safety will be evaluated on an ongoing basis in this study 
through the monitoring of all serious and non-serious adverse events and will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.0 (NCI CTCAE v4.0).
An independent Data Monitoring Committee (iDMC) will periodically evaluate the safety 
of ipatasertib or placebo combined with paclitaxel (Cohorts A and B).  The analysis 
supporting iDMC review will be conducted by an independent Data Coordinating Center 
(iDCC) and provided to the iDMC.  Interactions between the iDMC and Sponsor will be 
carried out as specified in the iDMC Charter. Safety monitoring will be performed on 
a continual basis by the Sponsor for Cohort C.
No interim analysis of the primary efficacy endpoint PFS is planned.  One interim OS 
analysis (at the time of the primary analysis for PFS) for each cohort is planned as
described in Section 6.8.2.
Analysis of safety and efficacy for each cohort will be performed independently.
Crossover is not allowed (Cohorts A and B).
A schedule of study assessments is provided in Appendix 1, Appendix 2, Appendix 3, 
and Appendix 4.
Potential China Extension Phase for Cohorts A and B
After completion of the global enrollment phase, as needed, additional patients may be 
enrolled at China Food and Drug Administration (CFDA)-recognized sites in an extended 
enrollment phase to ensure a total of up to 90 patients with TNBC and up to 120 patients 
with HR/HER2breast cancer, constituting the analysis population of a China subgroup.  
For each of Cohort A and Cohort B, patients from the China extension phase will be 
randomized in a 2:1 ratio to the two treatment arms, the same as during the global 
enrollment phase.  Any Chinese patients enrolled in the China extension phase will 
undergo the same schedule of assessments and will receive study treatment as in the 
global study cohorts. 
The China subgroup includes all Chinese patients enrolled in the global study cohorts 
and the China extension phase.  The China subgroup analysis will be performed and 
summarized separately.  The Chinese patients enrolled in the global study cohorts will 
be analyzed together with all other patients enrolled in the global study, and will be 
reported in the global study clinical study report.


Ipatasertib—F. Hoffmann-La Roche Ltd
58/Protocol CO40016, Version 11 (Cohort C)
Figure 1
Study Schema


Ipatasertib—F. Hoffmann-La Roche Ltd
59/Protocol CO40016, Version 11 (Cohort C)
Figure 1
Study Schema (cont.)
BCbreast cancer; Dday; EUEurope; HER2human epidermal growth factor receptor 2; HRhormone receptor; LAlocally advanced 
unresectable; MBCmetastatic breast cancer; NA= North America; POby mouth; Rrandomization; RoWRest of the World; 
TNBCtriple-negative breast cancer; Y/Nyes or no.
Note:  If allowed locally, prophylaxis loperamide is mandated in Cycle 1, dose adjustment is as necessary, and continuation is per investigator 
judgment.
a PIK3CA/AKT1 mutant versus PTEN-altered (and non-PIK3CA/AKT1 mutant).
b If applicable, patients will return to the clinic every 812 weeks for tumor assessments (disease follow-up visit) until disease progression, elective 
withdrawal from study, or study completion or termination. As of Protocol CO40016 Version 11 (Cohort C), follow-up tumor assessments are 
no longer required.
c As needed to potentially support a regulatory submission in China, additional Chinese patients may be subsequently enrolled at 
CFDA-recognized sites in an extended enrollment phase (China extension phase), for up to a total of 90 Chinese patients with TNBC with
PIK3CA/AKT1/PTEN-altered tumors and up to 120 Chinese patients with HR/HER2breast cancer with PIK3CA/AKT1/PTEN-altered tumors,
constituting the analysis population of the China subgroup (including Chinese patients enrolled in the global enrollment phase).
d A lower number of slides may be required if FoundationONE CDxis commercially already run and used for biomarker qualification.
e Patients with HR+/HER2breast cancer who are not suitable candidates for endocrine therapy (as defined by Sponsor; see eligibility criteria) 
and who meet one of the following criteria: the patient has recurrent disease (locoregional or metastatic) during adjuvant endocrine therapy (i.e.,
≤5 years of being on therapy), or if the patient has de novo metastatic disease, patient has progressive disease within 6 months of being on 
first-line endocrine treatment of metastatic disease.


Ipatasertib—F. Hoffmann-La Roche Ltd
60/Protocol CO40016, Version 11 (Cohort C)
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is
received from the last patient, whichever occurs later.
The total length of the study, from screening of the first patient to the end of the study
(excluding the potential China extension phase), is expected to be approximately 
53 months.
In addition, the Sponsor may decide to terminate a cohort or the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
Despite multiple treatment options, advanced breast cancer remains an incurable 
disease.  Although chemotherapy is a mainstay treatment, resistance inevitably 
develops and benefit is often short-lived.  This study evaluates the benefit of the addition 
of ipatasertib to chemotherapy in two distinct populations that require chemotherapy: 
1) locally advanced unresectable or metastatic TNBC with no previous systemic 
treatment in the advanced setting; and 2) advanced HR/HER2breast cancer requiring 
chemotherapy for the first time in the advanced setting, after development of endocrine 
resistance (as defined by the Sponsor; see eligibility criteria).  
In Study GO29227, patients with TNBC in the ipatasertib + paclitaxel arm showed 
a more pronounced improvement in PFS in the pre-specified patient population with
PIK3CA/AKT1/PTEN-altered tumors (hazard ratio0.44, 9.0 months vs. 4.9 months)
compared with PIK3CA/AKT1/PTEN non-altered tumors (hazard ratio0.76, 5.3 months 
vs. 3.7 months) or unselected ITT patients (hazard ratio0.60, 6.2 months vs. 
4.9 months). Similarly, improvements in PFS in the biomarker-selected patients were 
observed for ipatasertibabiraterone in patients with metastatic castration-resistant 
prostate cancer in the Phase II study GO27983 (refer to the Ipatasertib Investigator’s 
Brochure for details). To prospectively evaluate a clinically meaningful delay in disease 
progression in patients for whom add-on treatment of ipatasertib to paclitaxel is 
appropriate, this study will enroll patients with PIK3CA/AKT1/PTEN-altered tumors, who 
are likely to derive greater benefit from the addition of ipatasertib compared with
unselected patient populations.
Ipatasertib with paclitaxel has shown encouraging clinical benefit for TNBC from the 
randomized Phase II study (GO29227 or LOTUS).  In addition, CIT has shown promising 
preliminary clinical data in the treatment of TNBC (Nanda et al. 2016; Schmid et al. 
2017), and it has changed the standard of care for other cancers.  For those TNBC 
patients without PIK3CA/AKT1/PTEN-altered tumors Cohort C provides patients with the 
possibility of receiving the combination of ipatasertib with atezolizumab and taxane.


Ipatasertib—F. Hoffmann-La Roche Ltd
61/Protocol CO40016, Version 11 (Cohort C)
Taxanes, in particular paclitaxel or docetaxel, are increasingly used for adjuvant 
treatment of HER2breast cancers worldwide. Many patients are expected to have 
received adjuvant chemotherapy, including taxanes, leading to a concern regarding 
rechallenge with taxane treatment at recurrence when patients first relapse in the 
advanced setting. Although there has been no specific prospective trial to evaluate the 
efficacy of rechallenge with paclitaxel in the metastatic setting after prior adjuvant taxane 
exposure, guidelines support the re-use of a taxane in the metastatic setting, particularly 
if there has been at least 1 year of disease-free survival since its use in the adjuvant 
setting (Cardoso et al. 2017).  In this study, patients who relapsed within 12 months of 
completing neoadjuvant/adjuvant chemotherapy treatment (including taxane) will be 
excluded, thus selecting for patients who are likely to retain sensitivity to paclitaxel in the 
metastatic setting.  
For patients with metastatic HR/HER2breast cancer, approved therapy during the
endocrine-sensitive phase includes CDK4/6 inhibitors and PI3K/Akt pathway inhibitors
such as everolimus. Preliminary data from the Phase Ib study PAM4983g suggest that 
HR/HER2patients may still respond to the combination of ipatasertib + paclitaxel after 
prior exposure to PI3K/Akt pathway inhibitors (e.g., PI3K inhibitors) (Isakoff et al. 2014);
therefore, patients previously treated with a PI3K/mTOR inhibitor will be allowed and 
stratified at enrollment for Cohort B. However, patients who had received prior 
investigational Akt inhibitors will be excluded, due to the similarity in the mechanism of 
action with ipatasertib. The efficacy of ipatasertib for patients previously treated with 
CDK4/6 inhibitors is unknown, but these patients are not excluded from participation in 
this study.
Recently, the TNT study demonstrated superiority of carboplatin over docetaxel for the 
treatment of patients with breast and ovarian cancer susceptibility gene (BRCA)
mutation-positive breast cancer (Tutt et al. 2015). Thus, in patients with 
BRCA-associated TNBC or endocrine-resistant metastatic breast cancer, a platinum 
regimen may be a preferred option, if not previously administered (Cardoso et al. 2017). 
The efficacy of ipatasertib in combination with paclitaxel for patients with homologous 
recombination repair deficiency (e.g., BRCA1/2 germline mutationpositive patients)
is unknown.  More recently, the Phase III OlympIAD trial led to the first approval of 
a PARP-inhibitor (olaparib) for patients with deleterious or suspected deleterious 
germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer.  In this 
study patients previously exposed to chemotherapy were treated in the advanced setting 
with olaparib or the physician’s choice of one of three chemotherapeutic agents.  The 
study met its primary endpoint of PFS by blinded independent central review (Robson et 
al. 2017).  There was no statistically significant improvement in OS based on the final 
OS analysis (Robson et al. 2019).


Ipatasertib—F. Hoffmann-La Roche Ltd
62/Protocol CO40016, Version 11 (Cohort C)
3.3.2
Rationale for the China Extension Phase
To characterize the efficacy and safety profile of ipatasertib in combination with
paclitaxel in a Chinese population to support a regulatory submission in China, a China 
extension phase may be included in the study. This study will initially enroll 
approximately 249 patients with TNBC and 201 patients with HR/HER2breast cancer 
across all sites in a global enrollment phase. If at least 1 patient is enrolled in China
(mainland China, Hong Kong, or Taiwan) during the global enrollment phase, additional 
Chinese patients may be subsequently enrolled at CFDA-recognized sites in an 
extended enrollment phase as needed, to enroll a total of up to 90 patients with TNBC
and up to 120 patients with HR/HER2breast cancer, constituting the analysis 
population of the China subgroup. The China subgroup will include Chinese patients 
enrolled at sites in mainland China, Hong Kong, or Taiwan during both the global 
enrollment phase and the China extension phase. 
3.3.3
Rationale for Ipatasertib and Paclitaxel Combination
Large-scale comprehensive genomic analyses (Cancer Genome Atlas Network 2012; 
Lehmann and Pietenpol 2014; Pereira et al. 2016) have characterized the 
heterogeneous nature of breast cancer and its diverse gene-expression patterns and 
underlying genomic changes.  In breast cancer, Akt is an important node along the 
PI3K/Akt pathway that controls apoptosis and cell growth (Yap et al. 2008), and this 
pathway is known to be highly activated in breast cancers (Cancer Genome Atlas 
Network 2012). 
Upregulation of Akt signaling (whether intrinsic or induced following chemotherapy) 
represents a potentially important survival pathway in response to genotoxic or mitotic 
stress (Xu et al. 2012). Data from nonclinical models of ipatasertib plus microtubule 
inhibitors or DNA-damaging chemotherapy agents showed a clear advantage of the 
combination over respective single-agent treatment (refer to the Ipatasertib Investigator’s 
Brochure for further information). Based on the scientific rationale that PI3K/Akt 
blockade attenuates survival signals associated with mitotic stress from treatment with 
microtubule inhibitors, and the high prevalence of PI3K/Akt pathway activation 
signatures in breast cancers (Cancer Genome Atlas Network 2012), clinical trials 
evaluating the preliminary safety and efficacy of the combination of ipatasertib and 
paclitaxel in breast cancer patients have been conducted. 
Paclitaxel chemotherapy is widely used and is often an appropriate choice of 
chemotherapy in the first-line setting of TNBC or HR/HER2breast cancer populations 
requiring chemotherapy (Cardoso et al. 2017; NCCN 2017).  In these populations, the 
current treatment options provide limited PFS benefit (68 months), and long-term 
treatment is often limited by chemotherapy-associated toxicities.  Due to the high 
prevalence of PI3K/Akt pathway activation and the potential role of inhibition of this 
pathway to counter chemoresistance, Akt inhibition in combination with paclitaxel has 
the potential for transformative benefit in breast cancer.


Ipatasertib—F. Hoffmann-La Roche Ltd
63/Protocol CO40016, Version 11 (Cohort C)
The combination of ipatasertib and paclitaxel has been generally well tolerated. In the 
randomized, placebo-controlled Phase II study (GO29227) in patients with locally 
advanced or metastatic TNBC, ipatasertib was administered 400 mg 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.  The most common adverse events in the ipatasertibpaclitaxel 
arm (incidence of 10% higher than in the placebopaclitaxel arm) were diarrhea, 
nausea, asthenia, and peripheral sensory neuropathy. When grouping the adverse 
event preferred terms with similar medical concepts for basket term analysis, 
asthenia/fatigue and peripheral neuropathy were not significantly different between the 
two arms.
Overall, efficacy results from Study GO29227 support the hypothesis that inhibition of 
Akt signaling may improve the effectiveness of paclitaxel treatment and that patients with 
PI3K/Akt-activated tumors are more sensitive to ipatasertib. The median PFS in the 
unselected ITT population demonstrated a hazard ratio of 0.60 (6.2 months in the 
ipatasertib arm compared with 4.9 months in the control arm) and was more pronounced
in the pre-specified patient population with PIK3CA/AKT1/PTEN-altered tumors (hazard 
ratio0.44, 9 months vs. 4.9 months).
Refer to the Ipatasertib Investigator's Brochure for details on nonclinical and 
clinical studies.
3.3.3.1
Rationale for Immunotherapy in Breast Cancer
CIT has demonstrated significant survival benefits observed across multiple advanced 
malignancies.  Currently, the prevailing CIT approach is to circumvent immune evasion 
mechanisms and reinvigorate anti-tumor responses by identifying and targeting T-cell
co-inhibitory surface receptors such as CTLA-4 and PD-L1/PD-1.  While these targets 
have resulted in remarkable clinical therapeutic success for various cancer indications, 
ongoing research indicates a series of stepwise events necessary for the generation of 
a continuous anti-tumor immune response (Chen and Mellman 2013).  Each event is 
critical for an effective response, and each is also susceptible to several tumor immune 
evasion mechanisms.  Thus, the need to identify and circumvent the various factors 
involved in tumor immune evasion will be critical for propagating the anti-tumor immune 
response and advancing the field of CIT, most likely through combined targeted therapy 
regimens.
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that down-regulates immune responses through binding 


Ipatasertib—F. Hoffmann-La Roche Ltd
64/Protocol CO40016, Version 11 (Cohort C)
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including NSCLC, 
urothelial carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head and neck 
cancer, gastric cancer, breast cancer, and sarcoma.  The combination of atezolizumab 
and nab-paclitaxel has shown encouraging efficacy (Adams et al. 2016) (see 
Atezolizumab Investigator's Brochure for detailed efficacy results).  
3.3.3.2
Rationale for Combining Ipatasertib with Atezolizumab
Recently, the loss of PTEN, a tumor suppressor that regulates PI3K/ Akt pathway activity, 
has emerged as a potential mechanism for resistance to checkpoint inhibitor therapy, 
and inhibition of the PI3K/Akt pathway has shown reversal of Tcell-mediated 
immunotherapy resistance (Peng et al. 2016; George et al. 2017).  Potential impacts of 
Akt inhibition on immune response include the following: 1) improving recognition of 
cancer cells by host immune system and rekindling suppressed immune response (Xue 
et al. 2015); 2) restoring and enhancing physiological functionalities of T cells in the 
tumor microenvironment, in addition to enhancing expansion of tumor-specific 
lymphocytes with memory cell phenotype (Crompton et al. 2015); and 3) promoting the 
generation of superior, stem-like tumor-reactive T cells for adoptive immunotherapy (van 
der Waart et al. 2014).
Due to encouraging data for TNBC seen in both combinations of ipatasertib with 
paclitaxel and atezolizumab with nab-paclitaxel, this study tests the hypothesis of 
improved efficacy with the combination of ipatasertib with atezolizumab and paclitaxel.
3.3.4
Rationale for Starting Dose and Schedule of Ipatasertib
For ipatasertib, the starting dose of 400 mg QD on Days 121 of each 28-day cycle was
selected on the basis of safety and pharmacokinetics data from Arm C of 
Study PAM4983g (Phase Ib trial of ipatasertib combined with paclitaxel; refer to the
Ipatasertib Investigator's Brochure for details). The pharmacokinetics of paclitaxel and 
ipatasertib following co-administration showed no evidence of drugdrug interaction 
(See Section 3.3.8), and 400 mg ipatasertib was better tolerated than 600 mg ipatasertib 
in this combination. 


Ipatasertib—F. Hoffmann-La Roche Ltd
65/Protocol CO40016, Version 11 (Cohort C)
In the randomized, placebo-controlled Phase II study (GO29227) in patients with locally 
advanced or metastatic TNBC, 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 Sections 1.2 and 1.3); 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, the totality of pharmacodynamics data from Phase I (PAM4743g, 
PK/pharmacodynamic analysis) and safety and efficacy data (including exploratory 
exposure-response analyses, data on file) from randomized Phase II studies of 
ipatasertib (Study GO29227 and Study GO27983, which evaluated two dose levels of 
200 mg and 400 mg of ipatasertib in patients with metastatic castration-resistant prostate 
cancer) support the selected starting dose of 400 mg ipatasertib for sufficient pathway 
inhibition and efficacy with a generally acceptable safety profile (refer to the Ipatasertib 
Investigator's Brochure for details). In the ipatasertib + paclitaxel arm of the GO29227 
study, despite dose reduction of ipatasertib that occurred in 21.3% of patients due to 
adverse events, discontinuation of ipatasertib due to any adverse event was 6.1%, and 
the median cumulative dose intensity of both ipatasertib and paclitaxel were maintained 
at 99.0% (ipatasertib) and 100% (paclitaxel). 
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.
3.3.5
Rationale for Treatment with Paclitaxel and Choice of 
Paclitaxel Regimen
Chemotherapy is the primary systemic treatment for patients with advanced TNBC and 
HR/HER2breast cancer for whom endocrine therapy is not suitable (as defined by 
Sponsor; see eligibility criteria).  A variety of chemotherapy choices exist including 
anthracyclines (doxorubicin, epirubicin, and pegylated liposomal doxorubicin), taxanes 
(paclitaxel, docetaxel, and albumin-bound paclitaxel), anti-metabolites (capecitabine and 
gemcitabine), platinums (cisplatin and carboplatin), and non-taxane microtubule 
inhibitors (eribulin and vinorelbine).  Generally, combination chemotherapy is associated 
with higher ORRs than single-agent chemotherapy; however, because of an increase in 
toxicity and little survival benefit, sequential use of single agents is usually preferred 
(Cardoso et al. 2017; NCCN 2017).
Currently, there is no defined standard regimen for paclitaxel in the metastatic setting, as 
paclitaxel can be administered weekly (8090 mg/m2) or every 3 weeks (175 mg/m2) 
(Swanton 2006; Cardoso et al. 2017; NCCN 2017).  Meta-analysis showed no difference 
in PFS (6 studies; 1610 patients; hazard ratio of 1.02; 95% CI: 1.08 to 1.32), while OS 


Ipatasertib—F. Hoffmann-La Roche Ltd
66/Protocol CO40016, Version 11 (Cohort C)
was statistically higher among patients receiving weekly paclitaxel (5 studies; 
1471 patients; hazard ratio of 0.78; 95% CI: 0.67 to 0.89). Furthermore, the incidence of 
serious adverse events, neutropenia, neutropenic fever, and peripheral neuropathy were 
significantly lower in weekly taxane schedules (Mauri et al. 2010).  Neurotoxicity, 
however, is a treatment-limiting toxicity for weekly continuous paclitaxel treatment
(Seidman et al. 2008).  Among weekly paclitaxel regimens that have been studied, 
continuous weekly dosing may be associated with more neurotoxicity than dosing on 
Days 1, 8, and 15 of each 28 day-cycle (Swanton 2006; Miller et al. 2007; Seidman et al. 
2008).
In several recent randomized studies of paclitaxel in combination with targeted agents
versus paclitaxel control, the median PFS seen in HR/HER2patients receiving weekly 
paclitaxel (90 mg/m2 on Days 1, 8, and 15 of each 28-day cycle) in the control arm was
approximately 78 months (E2100, Miller et al. 2007; RIBBON-1, Robert et al. 2011; 
PEGGY, Vuylsteke et al. 2016) in the first-line chemotherapy setting.
In Study GO29227, paclitaxel was administered in a weekly regimen of 80 mg/m2 on 
Days 1, 8, and 15 of each 28-day cycle, which maintains the cumulative dose intensity of 
paclitaxel when administered every 3 weeks (175 mg/m2, as recommended by the 
current prescribing information for paclitaxel IV injection [TAXOLU.S. Package Insert; 
Paclitaxel U.K. Summary of Product Characteristics]).  The control arm 
(paclitaxelplacebo) demonstrated a median PFS of 4.93 months (90% CI: 3.58 to
5.36 months), which is similar to the efficacy seen in the TNBC subgroups of several 
clinical trials using weekly paclitaxel (90 mg/m2 on Days 1, 8, and 15 of each 28-day 
cycle) as the control arm (Miller et al. 2007; Miles et al. 2013; Miles et al. 2017).
The current study will use the same paclitaxel dose and schedule in both treatment arms 
as in Study GO29227. Paclitaxel (80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle) 
is considered an appropriate control arm to study the added effect of ipatasertib in both 
the TNBC and HR/HER2populations as specified.  
3.3.6
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered at a fixed dose of 840 mg Q2W (840 mg on Days 1
and 15 of each 28-day cycle).  The average concentration following the 840-mg Q2W 
dosage is expected to be equivalent to that of 1200 mg Q3W, the approved dosage for 
atezolizumab (TecentriqU.S. Package Insert).  Anti-tumor activity has been observed 
across doses ranging from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the 
maximum tolerated dose of atezolizumab was not reached and no dose-limiting toxicities 
were observed at any dose.  The fixed dose of 1200 mg Q3W (equivalent to an average 
body weightbased dose of 15 mg/kg Q3W) was selected on the basis of both 
nonclinical studies (Deng et al. 2016) and available clinical PK, efficacy, and safety data 
(refer to the Atezolizumab Investigator's Brochure for details).


Ipatasertib—F. Hoffmann-La Roche Ltd
67/Protocol CO40016, Version 11 (Cohort C)
3.3.7
Rationale for Biomarker Assessments
Breast cancer is a heterogeneous disease many distinct subtypes as defined by 
molecular signatures and a diverse array of mutational profiles. In addition to
PIK3CA/AKT1/PTENalteration 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 paclitaxel.
Through the use of NGS, WGS, and/or other methods, the collected DNA from blood 
samples and tumor tissue from this study will be analyzed to identify germline
(e.g., BRCA1/2) and somatic alterations 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, or can increase the knowledge and understanding of 
disease biology.  
In addition, all submitted tumor or blood samples at screening (for randomized patients 
and for patients who are not randomized if approved locally) may be evaluated with the
FMI NGS assay and additional diagnostics testing methods to assist future development 
of alternative diagnostic tests related to PIK3CA/AKT1/PTEN-altered status, or when
a tissue biopsy is not feasible.  It is essential to include samples from randomized 
patients (with PIK3CA/AKT1/PTEN-altered tumors) and patients who are not randomized 
(to obtain control information from PIK3CA/AKT1/ PTEN non-altered tumors). 
3.3.7.1
Rationale for Using Archival Tissue for Examining
PIK3CA/AKT1/PTEN-Altered Tumor 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 35% of triple-negative and 45% of HR/HER2breast cancers
(Pereira et al. 2016). In the Phase II study GO29227, a pre-specified patient population
with PIK3CA/AKT1/PTEN-altered tumors as identified using archival or newly obtained 
biopsy tissue demonstrated a substantial benefit from ipatasertib treatment (hazard 
ratio0.44, 9 months vs. 4.9 months). 
These considerations support the use of archival tissue (i.e., sample from primary breast 
tumor) or a newly obtained biopsy to determine the PIK3CA/AKT1/PTEN-altered status 
of the disease to enrich for a patient population with a higher probability of having a 
clinically meaningful response to ipatasertib combined with paclitaxel. In the current 
study, PIK3CA/AKT1/PTEN-altered tumor status is required for all patients. Earlier 
versions of the protocol required central biomarker testing via an NGS assay (e.g., FMI);
however, Version 5 of the protocol has been amended to allow randomization (and 
stratification) of patients based on the presence of a valid PIK3CA/AKT1/PTEN alteration,
using either central tissueor blood-based assays or local/commercial tissueor 
blood-based assays (using a CLIA or equivalently accredited diagnostic laboratory). Any 
patients enrolled not using the central tissue-based NGS assay will then have this 
alteration assessed within the study (using the central tissue-based NGS assay).


Ipatasertib—F. Hoffmann-La Roche Ltd
68/Protocol CO40016, Version 11 (Cohort C)
Patients with TNBC will be prospectively stratified based on the biomarker results used 
to determine eligibility because of the relatively high proportion of PTEN-inactivating 
alterations (i.e., stratification by PIK3CA/AKT1-activating mutation vs. PTEN-inactivating 
alterations), while patients with HR/HER2breast cancer will not be stratified as such,
since the majority of PIK3CA/AKT1/PTEN alterations in HR-positive disease are
activating mutations of PIK3CA.
In order to obtain the most accurate reflection of the patient’s current disease while 
minimizing burden, a specimen from the most recently obtained tumor tissue is 
requested for the central tissue-based assessment.
3.3.7.2
Rationale for Collection of Blood Samples for Noninvasive 
Disease Monitoring
Circulating tumor DNA (ctDNA) can be detected in the blood of patients with epithelial 
cancers and may have diagnostic and therapeutic significance (Schwarzenbach et al. 
2011).  For example, the mutational status of tumor cells may be obtained through the 
isolation of ctDNA (Maheswaran et al. 2008), and ctDNA has been used to monitor 
treatment effectiveness in melanoma (Shinozaki et al. 2007).  In the current study, blood 
samples will be collected at screening, at time of first tumor assessment, and at the 
study completion/early termination visit to evaluate oncogenic genetic alterations at 
baseline and to assess for the possible emergence of new alteration after treatment with 
ipatasertib and paclitaxel.  Genetic alterations will be evaluated in relevant genes in the 
PI3K/Akt pathway, including but not limited to PIK3CA and AKT1.  Identifying potential 
discordances in the PIK3CA/AKT1 status between tumor samples and ctDNA may help 
clarify the prognostic and predictive significance of PIK3CA/AKT1 mutations in patients 
with breast cancer treated with ipatasertib and paclitaxel.
In addition, a blood sample for central assessment of biomarker eligibility by ctDNA at 
FMI may be submitted at screening for assessment using the Foundation ACT (FACT 
assay).  Because the FACT assay is not expected to detect all alterations that can be 
identified using tissue-based NGS, it is only recommended when timelines for 
turnaround of tumor tissue are anticipated to preclude the patient from screening for
the study.
Furthermore, blood samples from patients in Cohort C will be used to evaluate 
circulating cytokine levels to better understand the systemic immune response to 
atezolizumab with ipatasertib and paclitaxel and its relationship with efficacy.
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 will be analyzed in the 


Ipatasertib—F. Hoffmann-La Roche Ltd
69/Protocol CO40016, Version 11 (Cohort C)
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 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 all patients in this study for potential pharmacogenetic analysis of genes 
or biomarkers that may affect the pharmacokinetics of ipatasertib in combination with 
paclitaxel.  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, he or she 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.
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.


Ipatasertib—F. Hoffmann-La Roche Ltd
70/Protocol CO40016, Version 11 (Cohort C)
3.3.7.4
Rationale for Optional Collection of New Tumor Biopsies at 
Disease Progression for Exploratory Purposes
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 
combination of ipatasertib and paclitaxel is critical for the 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 and paclitaxel, which may potentially influence future 
therapies for patients who progress on a PI3K/Akt inhibitor and may be part of 
a potential substudy.  NGS will be performed by a clinical cancer genomic profiling 
laboratory (e.g., FMI).
For patients who provided an optional biopsy at progression, the investigator may 
request the FMI NGS report of the new biopsy, which will be provided when available.  
Results may not be available for samples that do not meet testing criteria.
3.3.8
Rationale for the Pharmacokinetic Evaluation Schedule
A sparse sampling strategy will be applied in this study.  Samples for PK 
characterization of ipatasertib and its metabolite G-037720 will be collected as outlined 
in Appendix 3.  Samples will be collected on Days 1 and 15 of Cycle 1 and Day 15 of 
Cycle 3.  The sampling schedule is designed to enable characterization of ipatasertib 
independently in patients with TNBC (Cohort A) and HR/HER2breast cancer
(Cohort B) using population PK (popPK) methodology for characterization.  In addition, 
the PK data will allow comparison with single-agent ipatasertib data from the Phase I 
clinical trial (Study PAM4743g) and with ipatasertib data from other trials to evaluate 
whether ipatasertib exposures in patients with breast cancers are altered compared with 
other tumors.
The PK results of paclitaxel and ipatasertib in Study PAM4983g were comparable with 
their respective single-agent data, providing evidence that ipatasertib does not alter 
paclitaxel exposure. Ipatasertib is not expected to alter paclitaxel exposure. Paclitaxel 
is metabolized by CYP2C8 and CYP3A4. In vivo, paclitaxel was not a sensitive 
substrate of CYP3A4, and exposure did not markedly change in combination with the 
potent CYP3A4 inhibitor, ketoconazole (Jamis-Dow et al. 1997; Woo et al. 2003). Given
that ipatasertib is a mild-to-moderate inhibitor of CYP3A4 (Study PAM4743g; see the 
Ipatasertib Investigator’s Brochure for details) and is not an inhibitor of CYP2C8,
ipatasertib was not expected to alter paclitaxel exposure. Therefore, paclitaxel 
pharmacokinetics will not be evaluated in this study.


Ipatasertib—F. Hoffmann-La Roche Ltd
71/Protocol CO40016, Version 11 (Cohort C)
In general, monoclonal antibodies do not impact the hepatic, renal, or biliary elimination 
of small molecules, and there is low risk of drug-drug interactions between monoclonal 
antibodies and small molecules given their distinct routes of elimination (Zhou and 
Mascelli 2011). Atezolizumab is a monoclonal antibody and is not anticipated to have 
any CYP-mediated drug-drug interactions with ipatasertib. Also, ipatasertib is not 
expected to change the clearance of atezolizumab. Sparse sampling of atezolizumab 
and ipatasertib in Cohort C will further allow for comparison with single-agent data from 
other trials.
Any remaining PK samples after evaluation of ipatasertib and its metabolite may be used 
for exploratory evaluation of other analytes related to the administered drugs or 
biomarkers affecting their disposition.  
3.3.9
Rationale for Patient-Reported Outcome Assessments
As metastatic breast cancer is not curable with currently approved and available 
therapies, the main goals of treatment are to prolong survival and maintain or improve 
quality of life (Cardoso et al. 2012).  The HR/HER2breast cancer Cohort (B) may 
include patients with symptomatic visceral metastases (i.e., visceral crisis). Additionally,
a higher proportion of HRpatients have bone metastases compared to other subtypes. 
Both of these characteristics are often associated with pain (Irvin et al. 2011; Wood et al. 
2016); thus, treatment and disease-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 (Cohort B), treatment-related symptoms, and 
their interference with daily life is important to capture and will be assessed using 
validated PRO assessments. 
The European Organisation for Research and Treatment of Cancer Core Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) will be administered to patients to assess 
disease/treatment-related symptoms, functioning, and health-related quality of life
(HRQoL) (see Section 4.5.8.1 and Appendix 7). In addition, selected 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 will be 
collected to assess treatment-related symptoms (see Section 4.5.8.2 and Appendix 9).
The European Quality of Life 5-Dimension, 5-Level questionnaire (EQ-5D-5L; see 
Section 4.5.8.3 and Appendix 8) will be used to derive health states for use in economic 
models.
The EORTC QLQ-C30, select items of the PRO-CTCAE, and EQ-5D-5L will be 
assessed at baseline (Day 1 of Cycle 1); at Day 1 of each subsequent cycle; and at the 
treatment discontinuation visit (see Appendix 1). To minimize burden to patients, only 
the EQ-5D-5L and select scales of the EORTC QLQ-C30 will be administered over the 
phone to patients, or completed at the site, after treatment discontinuation and recorded 


Ipatasertib—F. Hoffmann-La Roche Ltd
72/Protocol CO40016, Version 11 (Cohort C)
on paper (see Appendix 1). As of Protocol CO40016 Version 11 (Cohort C), these 
long-term follow-up assessments are no longer required. The selected scales of the 
EORTC QLQ-C30 to measure disease/treatment-related symptoms are as follows:  the 
global health status/HRQoL (which consists of Questions 29 and 30), pain (Questions 9 
and 19), fatigue (Questions 10, 12 and 18), and dyspnea (Question 8). The EQ-5D-5L 
will be collected to inform pharmacoeconomic modeling and will not be included in the 
Clinical Study Report.
3.3.10
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, skeletal-related 
events (SREs) have previously been used as an endpoint, which consists of one or more 
of the following events to patients: 

Radiation to bone (for pain or impending fracture), pathological fracture, spinal cord 
compression, or surgery to the bone (Coleman et al. 1985)
SREs will be measured as an exploratory endpoint to describe the incidence of these 
events in patient populations with TNBC and HR+/HER2within the study and will 
describe the impact of treatment with ipatasertib in the locally advanced 
unresectable/metastatic breast cancer setting (Hortobagyi et al. 1996). 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 450 patients with PIK3CA/AKT1/PTEN-altered tumors are expected to be 
enrolled in this study (~249 patients with TNBC in Cohort A and ~201 patients with 
HR/HER2– breast cancer in Cohort B) during the global enrollment phase.  Among the 
~249 patients in Cohort A, at least 150 patients with a valid alteration as measured by 
central FMI testing is required. Additionally, approximately 100 patients with TNBC 
without PIK3CA/AKT1/PTEN-altered tumors are expected to be enrolled in Cohort C.
After the global enrollment phase is completed, additional Chinese patients may be 
enrolled in the China extension phase for up to a total of 90 Chinese patients with TNBC 
in Cohort A and up to a total of 120 Chinese patients with HR+/HER2- breast cancer in 
Cohort B. 
4.1.1
Inclusion Criteria
Women or men with locally advanced unresectable or metastatic triple-negative or 
HR+/HER2– adenocarcinoma of the breast who have not received prior systemic 
chemotherapy in this setting and who are candidates for taxane monotherapy may be 
eligible for this study.  In patients with BRCA-associated tumors, platinum chemotherapy 
as potentially the preferred treatment option (Cardoso et al. 2017), or olaparib (Robson 
et al.2019), should be taken into consideration when determining if this study may be 
appropriate for these patients.  Similarly, in patients with TNBC with known PD-L1 


Ipatasertib—F. Hoffmann-La Roche Ltd
73/Protocol CO40016, Version 11 (Cohort C)
positive status, atezolizumab plus nab-paclitaxel may be a preferred treatment option
where approved, which should also be considered when determining suitability of this 
study for these patients (Schmid et al. 2018b). Patients may have received prior 
chemotherapy in the neoadjuvant/adjuvant setting.  Locally advanced unresectable
disease must not be amenable to resection with curative intent.  Patients must have 
sufficient tumor tissues, have a valid result either from the central molecular assessment 
of PIK3CA/AKT1/PTEN-altered status or from an appropriately validated local laboratory 
(see specific guidance within disease-specific inclusion criteria), and comply with all 
eligibility criteria to be enrolled.  
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent Form(s) 

Woman or man age 18 years at the time of signing the Informed Consent Form

Eastern Cooperative Oncology Group Performance Status of 0 or 1 

Adequate hematologic and organ function within 14 days before the first study 
treatment on Day 1 of Cycle 1, defined by the following:
Neutrophils (ANC 1500/L)
Hemoglobin 9 g/dL
Platelet count 100,000/L
Serum albumin 3 g/dL
Total bilirubin 1.5 the upper limit of normal (ULN), with the following 
exception:
–
Patients with known Gilbert syndrome who have serum bilirubin 3ULN 
may be enrolled.
AST and ALT 2.5ULN, with the following exception:
–
Patients with documented liver or bone metastases may have AST and 
ALT 5ULN.
ALP 2ULN, with the following exceptions:
–
Patients with known liver involvement may have ALP 5ULN
–
Patients with known bone involvement may have ALP 7ULN
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. Patients should be on a stable anticoagulant regimen. 


Ipatasertib—F. Hoffmann-La Roche Ltd
74/Protocol CO40016, Version 11 (Cohort C)
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min based on 
Cockcroft−Gault glomerular filtration rate estimation:
(140 −age) (weight in kg) 0.85 (if female)
72 (serum creatinine in mg/dL)
Fasting total glucose 150 mg/dL and HbA1C 7.5%

Life expectancy of at least 6 months

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib/placebo, 5 months after the last dose of atezolizumab, and 6 months 
after the last dose of paclitaxel, whichever occurs later, and agreement to refrain 
from donating eggs during this same period
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year, when 
used consistently and correctly, include combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation, 
progestogen-only hormonal contraception associated with inhibition of 
ovulation, bilateral tubal occlusion, male sterilization, intrauterine 
hormone-releasing system, copper interuterine device, and sexual abstinence.
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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential, men 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 28 days after 
the last dose of ipatasertib or 6 months after the last dose of paclitaxel, 
whichever occurs later.  Men must refrain from donating sperm during this 
same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 28 days after the last dose of ipatasertib or 


Ipatasertib—F. Hoffmann-La Roche Ltd
75/Protocol CO40016, Version 11 (Cohort C)
6 months after the last dose of paclitaxel, whichever occurs later, to avoid 
exposing the embryo.
Examples of contraceptive methods with a failure rate of 1% per year, when 
used consistently and correctly, include combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation, 
progestogen-only hormonal contraception associated with inhibition of 
ovulation, bilateral tubal occlusion, male sterilization, intrauterine 
hormone-releasing system, copper interuterine device, and sexual abstinence.
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.

For any patients enrolled in the extended enrollment phase (i.e., China extension 
phase):  patient is a current resident of mainland China, Hong Kong, or Taiwan, and 
of Chinese ancestry.
Disease-Specific Inclusion Criteria
Patients must meet the following disease-specific criteria for study entry:

Histologically documented TNBC or HR/HER2– adenocarcinoma of the breast that 
is locally advanced or metastatic and is not amenable to resection with curative 
intent
Receptor status at study entry should correspond to the evaluation of the most 
recent biopsy (i.e., recurrent or metastatic tissue where applicable and if safely 
accessible, and nonfine-needle aspiration [FNA] sample), as assessed 
locally (or on-study, if not available locally) according to the ASCO/CAP 
guidelines (see Appendix 5 and Appendix 6 for the 2013 guidelines [includes
recent HER2 testing update [Wolff et al. 2018]):
–
HER2is defined as one of the following:  immunohistochemistry 3or
in situ hybridization positive  
–
ER or PgR positivity is defined as 1% of tumor cell nuclei 
immunoreactive to the respective hormonal receptor
–
TNBC is defined as HER2–, ER–, and PgR– (required for eligibility for 
Cohort A)
–
HR/HER2– is defined as HER2– and ERand/or PgR(required for 
eligibility for Cohort B)

Measurable disease according to RECIST v1.1

Eligible for taxane monotherapy, as per local investigator assessment 
(e.g., absence of rapid clinical progression, life-threatening visceral metastases, or 
the need for rapid symptom and/or disease control which may require combination 
chemotherapy)

HR+/HER2– breast cancer that is not considered appropriate for endocrine-based 
therapy and that meets one of the following inclusion criteria: 


Ipatasertib—F. Hoffmann-La Roche Ltd
76/Protocol CO40016, Version 11 (Cohort C)
–
Patient has recurrent disease (locoregional or metastatic) during adjuvant 
endocrine therapy (i.e., ≤5 years of being on therapy).
–
If patient has de novo metastatic disease, patient has progressive 
disease within 6 months of being on first-line endocrine treatment of 
metastatic disease.
Note that prior treatment with CDK4/6 inhibitors or mTOR inhibitors is allowed. 

Submission of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or 
a minimum of 20 freshly cut unstained, serial tumor slides from the most recently 
collected tumor tissue for central molecular analysis (mandatory NGS testing 
[PIK3CA/AKT1/PTEN-altered status] and for other protocol-mandated secondary 
and exploratory assessments).  Cytologic or FNA samples are not acceptable.  
Tumor tissue from bone metastases that is subject to decalcification is not 
acceptable.
If a newer specimen is either insufficient or unavailable, the patient may still be 
eligible if the patient can provide a tissue block (preferred) or a minimum of 
20 unstained serial slides from an older archival tumor tissue or is willing to 
consent to and undergo an additional pretreatment core or excisional biopsy of
the non-target lesion (if it is assessable and the biopsy can be safely obtained).  
In general, a minimum of three core biopsies for NGS testing are required.
–
If the patient already has PIK3CA/AKT1/PTEN alteration results available 
from the FMI commercial tissue-based NGS assay known as 
FoundationONE CDx, then the FMI CTA does not need to be re-run; in 
this situation FFPE tissue block or 10 freshly cut unstained, serial tumor 
slides from the most recently collected tumor tissue is acceptable for other 
protocol-mandated secondary and exploratory assessments, upon 
approval by the Medical Monitor.
–
Please note, this tumor tissue sample is required to be submitted as 
described above for all patients, i.e., if local assessment of
PIK3CA/AKT1/PTEN alteration status or central ctDNA is used to confirm 
biomarker eligibility (see below), tumor tissue is still required to assess
alteration status centrally

Confirmation of biomarker eligibility, i.e., valid results from either central testing (in 
tumor tissue as detailed above or blood [using FACT assay] tested at FMI) or local 
testing of tumor tissue or blood (using an appropriately validated molecular assay at 
a diagnostic laboratory (CLIA or equivalently accredited)full laboratory report must 
be available and captured within the patient’s source documents to support 
eligibility), demonstrating PIK3CA/AKT1/PTEN-altered status defined as the 
presence of one or more of the following:
AKT1 missense mutations that result in amino acid substitution at the following 
residues E17, L52, or Q79
PIK3CA missense mutations that result in amino acid substitution at the 
following residues R88, G106, K111, G118, N345, C420, E453, E542, E545, 
Q546, M1043, H1047, or G1049


Ipatasertib—F. Hoffmann-La Roche Ltd
77/Protocol CO40016, Version 11 (Cohort C)
PTEN alterations that meet any of the following criteria:
–
Homozygous deletion (copy number of 0)
–
Dominant negative short variant (e.g., C124S, G129E, R130X; 
Papa et al. 2014)
–
Loss of heterozygosity (LOH) with copy number of 1 without concomitant 
single-nucleotide variants
One deleterious short variant (including insertions and deletions; classification 
criteria provided below) with a concomitant loss of the non-mutant PTEN allele 
defined by LOH with copy number of 1 or LOH with copy number 1.  
–
Any protein truncating mutations, including nonsense mutations and 
frameshift indels
–
Any mutations in the consensus splice donor and acceptor sequence that 
disrupts the consensus, including insertions and deletions
–
Any missense or non-frameshift mutation that has been confirmed
somatic as described in the COSMIC database
–
If there are two or more deleterious short variants under LOH, the patient 
will not be eligible for the study.
Please note, for local/commercial testing using tumor tissue or blood, a valid 
result from the most recently collected tumor tissue/blood is preferred, 
however, the patient would still be eligible if a valid result is obtained from 
older archival tissue/blood sample.  
4.1.2
Exclusion Criteria
General Exclusion Criteria
Patients who meet any of the following general criteria will be excluded from study entry:

Inability to comply with study and follow-up procedures

History of malabsorption syndrome or other condition that would interfere with 
enteral absorption or results in the inability or unwillingness to swallow pills 

Active infection requiring systemic anti-microbial treatment (including antibiotics, 
anti-fungals, and anti-viral agents)

Known HIV infection 

Known clinically significant history of liver disease consistent with Child-Pugh 
Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B 
surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current 
drug or alcohol abuse, or cirrhosis 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive hepatitis B core 
antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible.
Patients positive for HCV antibody are eligible only if polymerase chain 
reaction (PCR) is negative for HCV RNA. 


Ipatasertib—F. Hoffmann-La Roche Ltd
78/Protocol CO40016, Version 11 (Cohort C)

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to Day 1 of Cycle 1 or anticipation of need for a major surgical procedure 
during the course of the study 
Placement of a vascular access device is not considered major surgery. 

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 28 days after the last dose of ipatasertib/placebo, 5 months after the last dose 
of atezolizumab, and 6 months after the last dose of paclitaxel, whichever occurs 
later
Women of childbearing potential (who are not postmenopausal with 
12 months of non-therapy induced amenorrhea nor surgically sterile) must 
have a negative serum pregnancy test result either within 96 hours prior to 
initiation of study drug, or within 7 days of Day 1, Cycle 1 (in this case,
confirmed by a negative urine pregnancy test result on Day 1 of Cycle 1 prior 
to dosing).

New York Heart Association Class II, III, or IV heart failure; left ventricular ejection 
fraction 50%; or active ventricular arrhythmia requiring medication

Current unstable angina or history of myocardial infarction within 6 months prior to 
Day 1 of Cycle 1

Congenital long QT syndrome or screening QT interval corrected using Fridericia's 
formula (QTcF) 480 milliseconds 

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)

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
For Cohort C, no chronic corticosteroid use is permitted at baseline with rare 
exceptions.  Refer to Atezolizumab-Specific Exclusion Criteria.

Treatment with approved or investigational cancer therapy within 14 days prior to 
Day 1 of Cycle 1 

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 
Disease-Specific Exclusion Criteria
Patients who meet any of the following disease-specific criteria will be excluded from 
study entry:

History of or known presence of brain or spinal cord metastases, as determined by 
computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during 
screening or prior radiographic assessments  


Ipatasertib—F. Hoffmann-La Roche Ltd
79/Protocol CO40016, Version 11 (Cohort C)
Patients with leptomeningeal carcinomatosis will be excluded.

Any previous chemotherapy for inoperable locally advanced or metastatic TNBC or 
HR/HER2– adenocarcinoma of the breast 
Patients may have received prior neoadjuvant or adjuvant chemotherapy 
and/or radiation treatment for breast adenocarcinoma, provided all 
chemotherapy was completed 12 months prior to recurrence.
Patients with TNBC must not have received any previous systemic therapy for 
inoperable locally advanced or metastatic TNBC, including chemotherapy, 
immune checkpoint inhibitors, or targeted agents.
Chemotherapy does not include HER2-targeted therapy, such as trastuzumab, 
pertuzumab, or neratinib (for cases in which patients had early stage HER2+ 
breast cancer and are entering the study with HER2advanced breast 
cancer).  The minimum 12-month, disease-free inclusion requirement begins 
with the last administration of chemotherapy in the early breast cancer setting. 

Unresolved, clinically significant toxicity from prior therapy, except for alopecia and 
Grade 1 peripheral neuropathy 

Patients who have received palliative radiation treatment to peripheral sites
(e.g., bone metastases) for pain control and whose last treatment was completed 
14 days prior to Day 1 of Cycle 1 may be enrolled in the study if they have 
recovered from all acute, reversible effects (e.g., to Grade 1 or resolved by 
enrollment)

Uncontrolled pleural effusion, pericardial effusion, or ascites
Patients with indwelling catheters (e.g., PleurX) are allowed. 

Uncontrolled tumor-related pain 
Patients requiring narcotic pain medication must be on a 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 
randomization.  Patients should be recovered (e.g., to Grade 1 or resolved) 
from the effects of radiation prior to study enrollment.  There is no required 
minimum recovery period beyond the 14 days required for radiation therapy.
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 randomization. 

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium, 12 mg/dL calcium, or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy 
Patients who are receiving bisphosphonate therapy specifically to prevent 
skeletal events (e.g., bone metastasis, osteoporosis) and who do not have 
a history of clinically significant hypercalcemia are eligible. 


Ipatasertib—F. Hoffmann-La Roche Ltd
80/Protocol CO40016, Version 11 (Cohort C)

Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1, 
except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, or Stage I uterine cancer
For other cancers considered to have a low risk of recurrence, discussion with 
the Medical Monitor is required.
In cases where there is a history of early-stage breast cancer with 
ER/PR/HER2 status differing from the advanced breast cancer for which the 
patient is entering the study, the above language still applies (i.e., any breast 
cancer within the 5 years prior to consent is permitted, provided there is no 
controversy as to the current ER/PR/HER2 status). 
Paclitaxel-Specific Exclusion Criteria
Patients who meet any of the following paclitaxel-specific criteria will be excluded from 
study entry:

Known hypersensitivity or contraindication to any component of the study treatments, 
including the paclitaxel excipient macrogolglycerol ricinoleate

Grade 2 peripheral neuropathy
Ipatasertib-Specific Exclusion Criteria
Patients who meet any of the following ipatasertib-specific criteria will be excluded from 
study entry:

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.

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia

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)

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

Prior treatment with an Akt inhibitor
Note that prior PI3K or mTOR inhibitors are allowed.
Atezolizumab-Specific Exclusion Criteria (Cohort C Only)
Patients who meet any of the following atezolizumab-specific criteria will be excluded 
from study entry:

Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 


Ipatasertib—F. Hoffmann-La Roche Ltd
81/Protocol CO40016, Version 11 (Cohort C)
antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 11 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
a stable dose of thyroid-replacement hormone are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of the following conditions 
are met:
o
Rash must cover 10% of body surface area.
o
Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids.
o
There is no occurrence of acute exacerbations of the underlying 
condition requiring psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, or high-potency 
or oral corticosteroids within the previous 12 months.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan

History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during treatment with 
atezolizumab or within 5 months after the last dose of atezolizumab

History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or recombinant 
human antibodies

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2) within 4 weeks or 5 half-lives of the drug (whichever is 
longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressive medication 
during the course of the study, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study.


Ipatasertib—F. Hoffmann-La Roche Ltd
82/Protocol CO40016, Version 11 (Cohort C)
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
There are 3 cohorts in this study.  The first 2 cohorts, A and B, are randomized, 
double-blind, placebo-controlled cohorts in biomarker-positive populations designed to 
estimate the effect on PFS of the addition of ipatasertib to paclitaxel compared with 
placebo plus paclitaxel. The third cohort (C) has a single-arm open-label design to test 
safety and efficacy of the combination of ipatasertib plus atezolizumab plus paclitaxel in 
a biomarker-negative population.
To enable independent comparisons, patients will be assigned to either Cohort A (TNBC
biomarker-positive), Cohort B (HR/HER2biomarker-positive breast cancer), or Cohort 
C (TNBC biomarker-negative), according to tumor hormone receptor and biomarker 
status and these cohorts will be analyzed independently.
In Cohorts A and B, patients will be allocated to each of the treatment arms through the 
use of a stratified permuted block randomization to ensure within-stratum balance of 
patient characteristics between treatment arms.  Randomization will be stratified by the 
following criteria:  prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region 
(Asia-Pacific vs. Europe vs. North America vs. rest of the world), and tumor
PIK3CA/AKT1/PTEN-alteration status (PIK3CA/AKT1-activating mutations vs. PTEN
alterations with no PIK3CA/AKT1-activating mutations) for Cohort A only, and prior 
PI3K/mTOR inhibitors (yes vs. no) for Cohort B only.  These factors may correlate with 
different prognoses and differential responses to Akt inhibition, or they may reflect 
different regional clinical practices.  
Placebo tablets are identical in shape and color to the ipatasertib tablets, and they are
indistinguishable (see Section 4.3.1.1 for details).  Tablet bottles and drug kits for 
placebo will also be identical to those for ipatasertib, except for the unique kit numbers 
on the kit boxes. 
While PK samples must be collected from patients assigned to the comparator control 
arm to maintain the blinding of treatment assignment, PK assay results for these patients 
are generally not needed for the safe conduct or proper interpretation of this study.  
External laboratories responsible for performing study drug PK assays will be unblinded 
to patients' treatment assignments to identify appropriate samples to be analyzed.  In 
other words, PK samples from patients assigned to the control arm will not be analyzed 
for study drug PK concentration except by request (e.g., to evaluate a possible error in 
dosing). 


Ipatasertib—F. Hoffmann-La Roche Ltd
83/Protocol CO40016, Version 11 (Cohort C)
To further protect the integrity of the study, the results of any patient-specific plasma 
concentration data for ipatasertib will not be made known to either investigators or the 
contract research organizations, and any interim safety analyses will not be made known 
to the investigators or Sponsors. In addition, to minimize potential bias in evaluating 
progression-free survival, the NGS data and status of PTEN alteration versus 
PIK3CA/AKT1 mutation of the tumor samples for those patients testing 
diagnostic-positive will not be disclosed to the investigators/patients prior to RECIST 
progression. The NGS research report (and FACT assay report if performed), when 
available, may be released to patients who are: not randomized into Cohorts A or B nor 
enrolled into Cohort C; randomized into Cohorts A or B or enrolled into Cohort C at the 
time they discontinue all study treatment; or following end of the study, whichever occurs 
earlier (unless required by law), upon request by the investigator, and is not intended for 
treatment decisions.
If unblinding of patients in Cohorts A or B is necessary for patient management (e.g., in 
the case of a serious adverse event for which patient management might be affected by 
knowledge of treatment assignment), the investigator will be able to break the treatment 
code by contacting the IxRS.  An investigator may be permitted to perform 
non-emergency unblinding to enable a patient to switch to an approved therapy. 
However, non-emergency unblinding is not permitted to enable a patient to switch to an 
experimental therapy. The investigator should document and provide an explanation for 
any premature unblinding (e.g., accidental unblinding, unblinding due to a serious 
adverse event or non-emergency unblinding).
As per health authority reporting requirements, the Sponsor will break the treatment 
code for all serious, unexpected suspected adverse reactions (see Section 5.7) that are 
considered by the investigator or Sponsor to be related to study drug.  The patient may 
continue to receive treatment, and the investigator and patient will remain blinded to 
treatment assignment.
The Sponsor will be blinded to treatment assignment until the primary analysis of the 
respective cohort.  The iDMC, iDCC, and the Sponsor-independent PK bioanalytical 
personnel will remain unblinded to the treatment assignment. Except for the conditions 
stated above permitting individual treatment unblinding, the investigators and patients 
will be blinded to treatment assignments until the final analysis of all efficacy endpoints 
of the respective cohort.  
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are ipatasertib, matching 
placebo, atezolizumab, and, dependent on local regulations, paclitaxel.  Paclitaxel is an 
approved treatment for breast cancer and is considered standard of care in some 
countries. Loperamide (racecadotril as used in Europe) is a non-IMP in the study.


Ipatasertib—F. Hoffmann-La Roche Ltd
84/Protocol CO40016, Version 11 (Cohort C)
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Ipatasertib and Placebo
Ipatasertib drug product is intended for oral administration and will be supplied as 
100- and 200-mg tablets.  The ipatasertib placebo tablets 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.
The period between re-dispensing and last tablet consumed should not exceed 
1 month.  The investigational product is for investigational use only and is to be used 
only within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the 
label until dispensed for patient use or returned to the Sponsor.
4.3.1.2
Atezolizumab
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  Although the vial contains approximately 20 mL (1200 mg) 
of atezolizumab solution, only 14 mL (840 mg) should be administered.
For information on the formulation, handling, storage, and preparation of atezolizumab, 
see the pharmacy manual and the Atezolizumab Investigator's Brochure.
4.3.1.3
Paclitaxel
For information on the formulation, packaging, and handling of paclitaxel, see the local 
prescribing information for paclitaxel.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.  The sequence of drug 
administration is ipatasertib/placebo, then atezolizumab (only for patients in Cohort C),
and then paclitaxel.  On non-atezolizumab administration days, the sequence of drug 
administration is ipatasertib/placebo and then paclitaxel.
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 5.1.5.
4.3.2.1
Ipatasertib and Placebo
Study treatment of experimental versus placebo arm will be assigned by an IxRS.  
Ipatasertib/placebo will be administered at the starting dose of 400 mg orally QD, 
beginning on Cycle 1, on Days 121 of each 28-day cycle until the patient experiences 


Ipatasertib—F. Hoffmann-La Roche Ltd
85/Protocol CO40016, Version 11 (Cohort C)
disease progression, intolerable toxicity, or withdraws consent.  Patients will receive 
ipatasertib/placebo prior to the IV infusion of paclitaxel.  
Each dose of ipatasertib/placebo should be taken with a minimum of 3 ounces (90 mL) 
of fluid.  Ipatasertib/placebo may be taken with or without food.  If a dose is missed (not 
taken within 8 hours after the scheduled dosing time), the patient should resume dosing 
with the next scheduled dose.  Missed or vomited doses will not be made up.
On 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).  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 in 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.  Patients will be instructed to bring their bottles of ipatasertib/placebo 
and their medication diaries to each study visit.
4.3.2.2
Atezolizumab
Patients will receive atezolizumab 840 mg administered by IV infusion Q2W (on Days 1 
and 15 [3] days) of each 28-day cycle.  Administration of atezolizumab will be 
performed in a monitored setting where there is immediate access to trained personnel 
and adequate equipment and medicine to manage potentially serious reactions.  For 
anaphylaxis precautions, see Appendix 12.
Atezolizumab infusions will be administered per the instructions outlined in Table 3.


Ipatasertib—F. Hoffmann-La Roche Ltd
86/Protocol CO40016, Version 11 (Cohort C)
Table 3
Administration of First and Subsequent Infusions of 
Atezolizumab
First Infusion
Subsequent Infusions
Premedication should be limited to 
prophylaxis as outlined in Section 4.3.3
for the purpose of preventing rash.
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to 
the infusion.
Atezolizumab should be infused over 
60 (15) minutes.
If clinically indicated, vital signs should 
be measured every 15 (5) minutes) 
during the infusion and at 
30 (10) minutes after the infusion.  
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.
On Day 15 of Cycle 1, premedication may 
be given as prophylaxis as outlined in 
Section 4.3.3 for the purpose of preventing 
rash.
If the patient experienced an infusion-
related reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator.
Vital signs should be recorded within 
60 minutes prior to the infusion.
Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.
If the patient experienced an 
infusion-related reaction with the previous 
infusion or if clinically indicated, vital signs 
should be measured during the infusion 
and at 30 (10) minutes after the infusion.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 15 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure.
No dose modification for atezolizumab is allowed.
4.3.2.3
Paclitaxel
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
and 15 of each 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can be given on 
Day 22.  Calculation of body surface area for the purposes of dosing of paclitaxel should 
be made according to the prescribing information.  If the patient's weight changes by10% 
during the study, the body surface area and drug doses should be recalculated.  
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per 
institutional guidelines and administered after the oral dose of ipatasertib/placebo.  


Ipatasertib—F. Hoffmann-La Roche Ltd
87/Protocol CO40016, Version 11 (Cohort C)
Patients should be monitored during paclitaxel administration per institutional policies.  
Patients may receive anti-emetic and other prophylactic treatments, according to 
institutional practice.
4.3.3
Other Treatments: Premedications and Prophylactic Treatment
Because of the known potential for allergic reactions to paclitaxel and/or the 
Cremophorvehicle, precautions must be taken to decrease the risk of anaphylaxis.  
Patients must be premedicated prior to paclitaxel with dexamethasone, 
diphenhydramine, and an H2-receptor blocker (i.e., ranitidine or famotidine) or per 
institutional practice.  H2-receptor antagonists, such as cimetidine, which are known to 
inhibit cytochrome P450, should be avoided. 
Diarrhea is a common adverse event associated with ipatasertib and/or paclitaxel 
treatment. In this current study, to improve diarrhea management and patient 
experiences, loperamide (2 mg twice a day or 4 mg once a day) will be administered 
daily as prophylaxis for diarrhea in the first cycle if allowed by local guidance. If side 
effects of loperamide are not tolerated, doses may be reduced at any time. Investigators 
are encouraged to continue this dosing for the remainder of the study using their 
discretion based on clinical judgments.
If diarrhea occurs, it should be managed per guidelines in Appendix 13; upon resolution 
or when study treatment is restarted, loperamide prophylaxis should be considered to 
resume and continue based on clinical judgments (if allowed by local guidance).
Due to the risk of rash in Cycle 1, patients in Cohort C should receive the following 
prophylaxis during the first cycle in which all 3 study treatments will be given:  On days 
when patients will receive atezolizumab (typically D1 and D15), patients should receive
at least 10 mg/day prednisone (or equivalent dosing of other steroids, e.g., 
methylprednisolone, prednisolone) as premedication prior to atezolizumab, followed by 
a fixed dose of 10 mg/day prednisone (or equivalent) for 24 consecutive days thereafter, 
unless contraindicated.  If institutional practice prior to paclitaxel is to give at least 10 mg 
prednisone (or equivalent dosing of other steroids) on the day of paclitaxel, then the 
additional 10 mg prophylactic prednisone (or equivalent dosing of other steroids) should 
not be given on that day to prevent rash. Timing of steroid on days when patients will 
receive atezolizumab and paclitaxel is at investigator discretion, as per clinical judgment.  
Unless contraindicated, daily oral antihistamine prophylaxis should be used for at least 
the first cycle. It is suggested that a non-sedating oral antihistamine (such as loratadine, 
cetirizine, fexofenadine) and longer-acting formulation be used.  The daily oral 
antihistamine used for rash prophylaxis may be held on the days of paclitaxel infusion if 
the paclitaxel pre-medication already includes an antihistamine.
4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor, where 
required by local health authority regulations. The study site will acknowledge receipt of 


Ipatasertib—F. Hoffmann-La Roche Ltd
88/Protocol CO40016, Version 11 (Cohort C)
IMPs using the IxRS to confirm the shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.5
Continued Access to Ipatasertib and Atezolizumab
The Sponsor will offer continued access to Sponsor study drugs ipatasertib and/or 
atezolizumab free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Sponsor study drug ipatasertib and/or atezolizumab 
after completing the study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Sponsor study drug treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Sponsor study drugs ipatasertib and/or
atezolizumab after completing the study if any of the following conditions are met:

The Sponsor study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the drug or data suggest that the 
drug is not effective for breast cancer

The Sponsor has reasonable safety concerns regarding the drug as treatment for 
breast cancer

Provision of the drug is not permitted under the laws and regulations of the patient's 
country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


Ipatasertib—F. Hoffmann-La Roche Ltd
89/Protocol CO40016, Version 11 (Cohort C)
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 14 days 
prior to initiation of study drug to the study drug discontinuation visit. All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives, as allowed per local guidelines

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
Palliative radiotherapy is permitted for a preexisting lesion, 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).  Study treatment should 
be suspended during palliative radiotherapy (see Section 4.4.3). 
Treatment with atezolizumab may be continued during palliative radiotherapy.
Treatment with ipatasertib should be temporarily held for at least 7 days before 
and after the procedure (at least 14 days after radiation is recommended).  For 
single-day radiotherapy, this hold may be shorter, if discussed by the 
investigator with, and approved in advance by, the Medical Monitor.  The 
patient may continue ipatasertib treatment after treatment holding has been 
completed and the patient has sufficiently recovered.  

Premedication with antihistamines, antipyretics, and/or analgesics for each
paclitaxel administration

Premedication with corticosteroids and antihistamines prior to administration of 
atezolizumab, as outlined in Section 4.3.3

Prophylaxis use of loperamide (racecadotril as used in Europe) is mandated in the 
first cycle (if allowed by local guidance, except when the Medical Monitor approves 
omission, per Section 1.3), and as clinically indicated in subsequent cycles to 
prevent diarrhea. Patients who experience diarrhea should be on treatment doses 
of loperamide per the management guidelines provided in Appendix 13; please refer 
to that section for additional details.  Patients should be educated/reminded to be 
cognizant of the onset, duration, severity, and frequency of symptoms and the 
medications administered. 

Granulocyte colony-stimulating factor treatment is permitted for patients receiving 
paclitaxel. The primary prophylaxis should be administered per the ASCO, EORTC, 
and European Society for Medical Oncology (ESMO) guidelines; namely, in patients 
who are 60 years of age and/or with comorbidities (Smith et al. 2006; Aapro et al. 
2011).


Ipatasertib—F. Hoffmann-La Roche Ltd
90/Protocol CO40016, Version 11 (Cohort C)
Bisphosphonate therapy or RANKL inhibitor therapy (e.g., zolendronic acid and 
denosumab) used specifically to prevent skeletal events (e.g., bone metastasis, 
osteoporosis) is allowed.

Luteinizing hormone-releasing hormone or gonadotropin-releasing hormone 
agonists for ovarian function preservation are allowed.

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)

Inactivated influenza vaccinations

Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment

Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and per institutional practice.  For example, patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine), or 
equivalent medications per institutional practice.  Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies 
as clinically indicated (e.g., supplemental oxygen and 2-adrenergic agonists).
4.4.2
Cautionary Therapy
Patients who require radiation or surgery as part of medical treatment in the absence of 
radiographic disease progression must exercise caution, and all study treatment should 
be temporarily held for at least 7 days before and after the procedure (at least 14 days 
after radiation is recommended). For minor surgeries or single-day radiotherapy, this 
hold may be shorter, if discussed by the investigator with, and approved in advance by, 
the Medical Monitor.  After the temporary treatment hold is complete, study treatment
may be re-initiated when the patient has sufficiently recovered.
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events (refer to Section 5.1.5 for details). All study 
treatment should be temporarily held during systemic corticosteroids treatment (except 
when corticosteroids are given as pre-medication to paclitaxel).


Ipatasertib—F. Hoffmann-La Roche Ltd
91/Protocol CO40016, Version 11 (Cohort C)
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 CYP3A4. 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.  Therefore,
sensitive CYP3A substrates with narrow therapeutic window should be avoided.  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 a clinical study showed that ipatasertib exposures were reduced by 
~50% when co-administered with enzalutamide, a strong CYP3A inducer.  Strong 
CYP3A inhibitors are expected to increase ipatasertib exposures significantly. 
Therefore, the following drugs should be avoided or used with caution. 

Strong CYP3A4/5 inhibitors, such as, but not limited to, atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin, voriconazole, and/or grapefruit juice 

Strong CYP3A4/5 inducers, such as, but not limited to, rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin

CYP3A4/5 substrates with a narrow therapeutic index, such as, but not limited to, 
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, ergot alkaloids ergotamine, and/or 
dihydroergotamine

Paclitaxel exposures may be increased due to CYP2C8 inhibition; therefore, strong 
and moderate CYP2C8 inhibitors, such as gemfibrozil, teriflunomide, clopidogrel,
and deferasirox should be used with caution during treatment with paclitaxel.
Similarly, CYP2C8 inducers should be avoided or used with caution. 

Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or 
use of sensitive CYP3A substrates with a narrow therapeutic window for medical 
treatment (i.e., an alternative treatment cannot be used) must exercise caution and 
all study treatment should be temporarily held until at least 7 days after the last dose 
of these drugs.  

Patients are permitted to take moderate inhibitors of CYP3A4 with caution.
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. Food and Drug Administration [FDA]):  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm
The above lists of medications are not comprehensive.  The investigator should consult 
the prescribing information when determining whether a concomitant medication can be 


Ipatasertib—F. Hoffmann-La Roche Ltd
92/Protocol CO40016, Version 11 (Cohort C)
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.
4.4.3
Prohibited Therapy
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, 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 4.4.1 for details).

Chronic use of a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A 
substrates with a narrow therapeutic window that are deemed not permissible by the 
Medical Monitor after enrollment (refer to the guidance in Section 4.4.2)

Vaccination with a live vaccine should be avoided in patients receiving paclitaxel 
because of the potential for serious or fatal infections

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 months 
after the last dose of atezolizumab.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin 2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab.

Systemic immunostimulatory agents (including, but not limited to, interferons and
IL-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever is longer)
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab.

Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab.


Ipatasertib—F. Hoffmann-La Roche Ltd
93/Protocol CO40016, Version 11 (Cohort C)
4.4.4
Prohibited Food
Use of the following foods is prohibited as described below:

Consumption of grapefruit juice, a potent CYP3A4 enzyme inhibitor, is prohibited 
during the study treatment period and for 10 days after the last dose of study 
treatment.

Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, is prohibited for 
up to 14 days prior to and during the study treatment period, and for 10 days after 
the last dose of study treatment.
4.4.5
Additional Restrictions
No food or fluids other than water will be allowed for 8 hours prior to each Day 1 study 
visit until after study laboratory samples for fasting glucose and fasting lipid profile, as 
applicable, are obtained (see Appendix 1).
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4.  All activities must be performed and 
documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Voluntary, written, dated, and signed informed consent for participation in the study must 
be obtained before performing any study-related procedures (including screening 
evaluations or submission of archival tissues).  Patients may be first screened for
PIK3CA/AKT1/PTEN-altered status by participating in a separate “biomarker-specific”
screening consent, or this assessment may be made as part of the full eligibility 
evaluation and consent for this study. The biomarker-specific screening consent
specifically allows for the collection and submission of the tumor tissue sample (and 
FACT blood sample if desired) for central FMI biomarker-eligibility testing. Patients with 
confirmed PIK3CA/AKT1/PTEN-altered status by central tissue- or blood-based FMI 
assay must have consented to the full study before performing other study-related 
procedures.  The biomarker-specific screening consent also allows for the collection of 
the associated exploratory blood biomarker sample.  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 


Ipatasertib—F. Hoffmann-La Roche Ltd
94/Protocol CO40016, Version 11 (Cohort C)
exceptional circumstances, after approval by the Medical Monitor.  If
PIK3CA/AKT1/PTEN-altered status has been determined for a patient, a repeat testing 
of the biomarker-specific screening process is not required at re-screening.
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 14 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.
Further, to assess the actual intake of analgesic, anti-histamine, and anti-diarrheal 
medication use taken outside of the clinic/hospital setting, patients will complete
a medication diary each day.  Patients will receive the diary on the first day of each
cycle, with site staff completing information on any prescribed analgesic, anti-histamine,
or anti-diarrheal medications, including the recommended dosage and route of 
administration.  Patients should use the diary to record daily ipatasertib/placebo dosing 
and specifically any anti-diarrheal, anti-histamine, or analgesic medications used 
(prescribed or over-the-counter) taken on that cycle of treatment. The intake of 
analgesic, anti-histamine, and loperamide medication will be reported in the Analgesics 
Medication, Anti-histamine, and Targeted Loperamide Concomitant Medications eCRFs, 
respectively.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.
Limited, targeted, 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
95/Protocol CO40016, Version 11 (Cohort C)
4.5.4
Vital Signs
Vital signs will include measurements of pulse rate, systolic and diastolic blood pressure
while the patient is in a seated position after resting for at least 5 minutes, respiratory 
rate and oral, axillary, or tympanic temperature.
On paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end 
of the infusion.  On days when atezolizumab and paclitaxel are both administered, vital 
signs should also be recorded prior to atezolizumab dosing (and during infusion if 
clinically indicated), per Table 3.
4.5.5
Tumor and Response Evaluations
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response will be assessed by the investigator on the 
basis of physical examinations (with photography measurements) and imaging (CT, MRI, 
and bone scans) through use of RECIST v1.1 criteria (see Appendix 10).  Images for 
tumor assessments will be collected to enable retrospective blinded independent central 
review when needed. As of Protocol CO40016, Version 10 (Cohort C), images for tumor 
assessments will no longer be collected for blinded independent central review. The 
same radiographic procedure used to assess disease sites at screening should be used 
throughout the study (e.g., the same contrast protocol for CT scans).  Assessments 
should be performed by the same evaluator to ensure internal consistency across visits. 
An objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation.  At the investigator’s discretion, and if clinically indicated, CT scans may 
be repeated at any time if progressive disease is suspected, and other methods of 
assessment of measurable disease may be used (e.g., brain scans using CT or MRI) in 
addition to those listed above.  For symptomatic deterioration attributed to disease 
progression, every effort should be made to document progression through use of 
objective criteria per RECIST v1.1.  
Baseline tumor assessments should be performed 28 days before Day 1, Cycle 1.  
CT scans should include chest, abdomen, and pelvic scans; CT scans of the neck 
should be included if clinically indicated.  Screening (or documented standard-of-care) 
bone scans (technetium bone scan) and head scans (CT or MRI) should be performed 
within 6 weeks before Day 1, Cycle 1. For patients in Cohort B (HR/HER2–), screening
head scans will be performed only if clinically indicated.
As of Protocol CO40016 Version 11 (Cohort C), tumor assessments should be 
performed based on a schedule calculated from Cycle 1, Day 1 (study Day 1) with the 
first assessment during Week 8 and per standard of care thereafter, regardless of 
treatment administration timings or prior early/late tumor assessments. Therefore, the 
window for each scan will be the 7 days of the given week.  For patients with known or 
suspected bone metastasis, bone scans should be performed with every other tumor 
assessment starting from Week 16, adhering to the same 7-day window.  Bone disease 


Ipatasertib—F. Hoffmann-La Roche Ltd
96/Protocol CO40016, Version 11 (Cohort C)
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. An 
assessment must be done at the treatment completion visit, unless the most recent 
tumor assessment was completed 6 weeks before the treatment completion visit.  
Patients who discontinue study treatment for any reason other than disease progression 
will continue to undergo tumor response evaluations at disease follow-up visits 
(approximately every 812 weeks) until documented progressive disease per 
RECIST v1.1, elective withdrawal from the study, or study completion or termination (see 
schedule of assessments [Appendix 1 for Cohorts A and B and Appendix 2 for 
Cohort C]). As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up
tumor assessments are no longer required.
A documented standard-of-care tumor assessment performed within 28 days before 
Cycle 1, Day 1 (bone or head scans within 6 weeks prior to Cycle 1, Day 1) may be used 
for the screening assessment, provided it meets the following requirements:

CT scans are the preferred imaging modality for tumor assessments.  Tumor 
assessments should include a diagnostic quality, contrast-enhanced CT scan of the 
chest, abdomen, and pelvis at baseline.  CT scans of the neck should be included if 
clinically indicated.  To be suitable for RECIST assessments, CT scans should have 
a maximum thickness of 5 mm and no gaps.  Subsequent tumor assessments 
should include CT scans of the chest, abdomen, and pelvis and other known sites of 
disease.  

In patients for whom a CT scan is contraindicated because of an allergy to 
IV radiographic contrast, both a CT scan of the chest without contrast and a 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 of the Medical Monitor.  At screening, 
tumor assessments should include a diagnostic quality, contrast-enhanced MRI 
scan of the chest (if approved), abdomen, and pelvis.  MRI scans of the neck should 
be included if clinically indicated.  To be suitable for RECIST assessments, MRI 
scans should ideally have a maximum thickness of 5 mm and minimal gaps.  
Subsequent tumor assessments should include MRI scans of the chest (if approved), 
abdomen, and pelvis, and other known sites of disease. 


Ipatasertib—F. Hoffmann-La Roche Ltd
97/Protocol CO40016, Version 11 (Cohort C)
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Laboratory samples should be drawn according to the schedule of activities (see 
Appendix 1, Appendix 2, Appendix 3, and Appendix 4) and within 48 hours (see below 
for pregnancy test requirements) prior to study drug administration at the clinic; results of 
hematology, chemistry and pregnancy tests should be available to assess the dosing 
decision.  The following tests are essential assessments for Day 1 dosing for every cycle:  
hemoglobin, absolute neutrophil counts, lymphocytes, and platelet count; glucose, 
creatinine, potassium, calcium, total bilirubin, ALP (total ALP), AST, ALT; and a 
pregnancy test. Screening local laboratory assessments obtained within these windows
before Day 1 of Cycle 1 do not have to be repeated on Day 1 of Cycle 1.
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology: hemoglobin, hematocrit, WBC count with differential (i.e., must be 
sufficient for the determination of absolute neutrophil counts, lymphocytes), and 
platelet count

Fasting serum chemistry: glucose (following 8-hour fast, plasma glucose is also 
acceptable per local practice), plus the chemistry panel including BUN or urea, 
bicarbonate, creatinine, sodium, potassium, magnesium, calcium, phosphorus, 
albumin, total bilirubin, ALP (total ALP), AST, ALT, and LDH
For investigational sites in countries where bicarbonate may not be collected as 
part of the standard chemistry panel, bicarbonate will not be measured.

Fasting lipid profile: total cholesterol, high-density lipoprotein, low-density
lipoprotein, triglycerides, performed following 8-hour fast

Glycosylated hemoglobin (HbA1c)

Amylase and lipase

Coagulation: PTT (or aPTT) and INR

Urinalysis (dipstick allowed): pH, specific gravity, glucose, protein, ketones, and 
blood; microscopic examination if clinically indicated

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening. A negative serum pregnancy test must be confirmed either within 
96 hours of Cycle 1, Day 1 study treatment administration, or within 7 days of 
Day 1 of Cycle 1 (in this case, confirmed by a negative urine pregnancy test 
on Day 1 of Cycle 1 prior to dosing).
Urine/serum pregnancy tests will be performed at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.


Ipatasertib—F. Hoffmann-La Roche Ltd
98/Protocol CO40016, Version 11 (Cohort C)

Screening viral serology:  HIV, HBsAg, total hepatitis B core antibody (HBcAb), HCV 
antibody; additional tests for HBV DNA or HCV RNA will be required to confirm 
eligibility in patients with a positive antibody result. 

Home glucose monitoring: 
For any patients who initiate home glucose monitoring (see Table 2 for 
management guidance of fasting hyperglycemia), a glucose log will be made 
available for capturing these results. The blood glucose log should be reviewed 
at each clinic visit (see Appendix 1).
The following samples will be sent to the Sponsor or a designee for analysis:

Plasma samples for PK analysis

Blood samples for exploratory research on biomarkers
Blood will be collected for ctDNA analysis at screening (either as part of the
biomarker-specific screening process or full screening; if screening sample 
used for FACT biomarker eligibility analysis, this sample for exploratory 
biomarker research should be collected prior to dosing of Day 1 of Cycle 1), at 
the time of the first tumor assessment (7 days), and at the study drug 
discontinuation visit. A screening/ Day 1 of Cycle 1sample for all patients will 
be collected and submitted with the tissue (see Section 3.3.7 for the rationale).

Blood samples for whole genome sequencing (if approved locally)

Most recently collected tumor tissue for evaluation of PIK3CA/AKT1/PTEN-altered 
tumor status (using the FMI CTA NGS assay, unless the patient already has an 
available FoundationONE CDxcommercial test confirming biomarker eligibility)
and for exploratory research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
20 slides containing unstained, freshly cut, serial sections should be submitted 
at least 3 weeks prior to planned study randomization date. (As noted in
Section 4.4.1, 10 slides rather than 20, are acceptable in patients already 
qualifying via a commercial FoundationONE CDxresult, with Medical Monitor 
approval.)
Tumor tissue should be of good quality based on total and viable tumor content.  
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.  FNA (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or smears), brushing, cell pellets 
from pleural effusion, and lavage samples are not acceptable.  Tumor tissue 
from bone metastases that are subject to decalcification is not acceptable.
If the submitted tissue is determined to be unsuitable for required testing, 
a pre-treatment tumor biopsy (preferred, a minimum of three core biopsies is 
required for NGS evaluation), or older archival tissue may be submitted to 
obtain a valid result.


Ipatasertib—F. Hoffmann-La Roche Ltd
99/Protocol CO40016, Version 11 (Cohort C)

A blood sample for central assessment of biomarker eligibility by ctDNA at FMI may 
be submitted at screening for assessment using the Foundation ACT (FACT assay,
should generally only be performed when it is anticipated that there will be a 
significant delay to acquisition of existing tumor tissue).  If this assessment is used, 
the blood sample normally collected as part of screening procedures (for exploratory 
biomarker analysis) may be used to perform the FACT assay, with an additional 
sample (approximately 20 mL) collected on Day 1 of Cycle 1 for the purposes of 
exploratory biomarker analysis (see above).  Please note, submission of most
recently collected tumor tissue (as described above) is still an eligibility requirement
but is not in itself required to determine biomarker eligibility if the patient qualifies by 
FACT assay.

Biomarker samples (blood, plasma, and tissue) for mandatory exploratory biomarker 
research include, but not limited to, the following assays and assay platforms:
Single-nucleotide polymorphisms that may impact exposure or other responses, 
or NGS results interpretation 
Somatic mutations and copy-number variations by NGS or PCR-based 
methods in tumor tissue and ctDNA
Expression analysis (e.g., RNASeq) of genes related to PI3K/Akt pathway 
activity, immune infiltration/activation, apoptosis, and breast cancer biology 
(i.e., intrinsic subtypes)
Immunohistochemistry-based analysis or quantitative digital 
immunohistochemistry of tumor suppressors, such as PTEN, and markers of 
immune infiltration and activation, such as CD8 and PD-L1
For patients who are not randomized into Cohorts A or B nor enrolled into Cohort C, if
valid results of the FMI NGS assay (and FACT assay report if performed) are available, 
the investigator may obtain results of this screening assay in the form of a research 
report from FMI, which is available upon request.  A copy of this report(s) may also be 
available upon request by the investigator for patients randomized into Cohorts A or B or 
enrolled into Cohort C, at the time they discontinue all study treatment or following end 
of the study, whichever occurs earlier, unless required by law.
If allowed by local laws, the investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise.  The FMI assay has not been cleared or 
approved by health authorities.  The NGS and FACT reports are generated for research 
purposes and are not provided for the purpose of guiding future treatment decisions.  
Results may not be available for samples that do not meet testing criteria.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.


Ipatasertib—F. Hoffmann-La Roche Ltd
100/Protocol CO40016, Version 11 (Cohort C)
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), 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 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).

Tumor tissue and plasma samples collected for biomarker research will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or 18 months after final closure of the study database, whichever 
occurs first.  For patients who are not randomized into Cohorts A or B or enrolled 
into Cohort C, the remaining archival tissue blocks (if applicable) will be returned to 
the site no later than 6 weeks after eligibility determination. The submitted tissues
may still be analyzed using FMI NGS assays and may be used for future 
development of diagnostic tests related to PIK3CA/AKT1/PTEN-altered status.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples. However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of the analyses, data derived from WGS 
specimens 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.
4.5.7
Electrocardiograms and Cardiac Function Assessment
A cardiac function assessment by echocardiogram or multiple-gated acquisition should 
be performed within 12 weeks of Day 1 of Cycle 1.  Under exceptional circumstances 
cardiac function assessment by methods other than echocardiogram or multiple-gated 
acquisition may be acceptable (e.g., cardiac MRI), if consistent with local standard 
practice, but must be approved by the Medical Monitor.


Ipatasertib—F. Hoffmann-La Roche Ltd
101/Protocol CO40016, Version 11 (Cohort C)
Single 12- lead ECG recordings will be obtained at specified timepoints, as outlined in 
the schedule of activities (see Appendix 1) and may be obtained at unscheduled 
timepoints as indicated.
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws).  Circumstances that may induce changes 
in heart rate, including environmental distractions (e.g., television, radio, conversation) 
should be avoided during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. 
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 
drug discontinuation should be made, as described in Sections 5.2.1 and 4.6.1.  The 
investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia).
4.5.8
Patient-Reported Outcomes
To more fully characterize ipatasertib in combination with paclitaxel compared with 
single-agent paclitaxel (Cohorts A and B) or ipatasertib plus atezolizumab and paclitaxel 
(Cohort C) as a first-line treatment in patients with metastatic breast cancer, PRO data 
will be collected using the following instruments: EORTC QLQ-C30, select items of the 
PRO-CTCAE, and the EQ-5D-5L.
PRO questionnaires scheduled for administration during a clinic visit must be completed 
by the patient at the investigational site at the start of the clinic visit prior to all other 
study assessments and before administration of study treatment. Patients will complete 
paper versions of the questionnaires, which will be provided by site staff. Interviewer 
assessment is allowed but can only be conducted by a member of the clinic staff for 
patients who are unable to complete the measures on their own. Study personnel 
should review all questionnaires for completeness before the patient leaves the 
investigational site. Appropriate translated versions of the local language of the PRO 
measures will be available at the site.


Ipatasertib—F. Hoffmann-La Roche Ltd
102/Protocol CO40016, Version 11 (Cohort C)
To minimize burden to patients, only the EQ-5D-5L and select scales of the EORTC 
QLQ-C30 will be administered over the phone to patients, or completed at the site, after 
treatment discontinuation (due to any reason; see Appendix 1). The following selected 
scales of the EORTC QLQ-C30 will measure disease/treatment-related symptoms:  the 
global health status/HRQoL (which consists of Questions 29 and 30), pain (Questions 9 
and 19), fatigue (Questions 10, 12 and 18), and dyspnea (Question 8) scales. 
Instructions and telephone scripts for administering the PRO assessments via telephone 
interviews (during the post-treatment follow-up period of the study) will be provided when 
available in the local language. As of Protocol CO40016 Version 11 (Cohort C), these 
long-term follow-up assessments are no longer required.
4.5.8.1
EORTC QLQ-C30
The EORTC QLQ-C30 (see Appendix 7) is a validated and reliable self-reported 
measure (Aaronson et al. 1993; Sprangers et al. 1996; Fitzsimmons et al. 1999) 
consisting of 30 questions that assess 5 aspects of patient functioning (physical, 
emotional, role, cognitive, and social), 8 symptoms (fatigue, nausea and vomiting, pain, 
dyspnea, insomnia, appetite loss, constipation, and diarrhea), financial difficulties, and 
global health status (GHS)/quality of life (QoL) with a recall period of the previous week. 
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.
4.5.8.2
PRO-CTCAE
The PRO-CTCAE (see Appendix 9) 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 
stand-alone items (Basch et al. 2014).  PRO-CTCAE will be completed per the Schedule 
of Activities, only when available in the local language of the investigational site.
Symptoms selected for this study include those adverse events experienced at any 
grade that occurred in 20% of patients for either treatment (ipatasertib and/or 
paclitaxel) in previous studies.
Only adverse events that are patient self-reportable (Basch et al. 2014) were selected
for PRO analysis 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 do not have an 
identifiable symptom equivalent in the PRO-CTCAE were also excluded. Based on the 
above criteria, 8 symptomatic adverse events were selected from the PRO-CTCAE item 
bank (i.e., diarrhea, nausea, vomiting, decreased appetite, fatigue, peripheral numbness 
and tingling, mouth sores, and rash); a total of 14 items. 


Ipatasertib—F. Hoffmann-La Roche Ltd
103/Protocol CO40016, Version 11 (Cohort C)
An additional item providing an overall assessment of the burden of side effects will be 
collected in addition to the 14 selected-items of the PRO-CTCAE.
4.5.8.3
EQ-5D-5L
The EQ-5D-5L is a validated self-reported health status questionnaire that is used to
calculate health states for use in health economic analyses (EuroQoL Group 1990; 
Brooks 1996; Herdman et al. 2011; Janssen et al. 2013). There are two components of 
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 visual analog scale that 
measures health state. Published weighting systems allow for the creation of a single 
composite score of the patient’s health status. The EQ-5D-5L takes approximately 
3 minutes to complete. It will be used in this study to inform pharmacoeconomic 
evaluations and, as such, will not be included in the Clinical Study Report 
(see Appendix 8).
4.5.9
Skeletal-Related Events Assessment
For this study, a skeletal-related event (SRE) is defined as either 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 eCRF.  Patients should 
be monitored for any SREs during the treatment and treatment-free follow-up periods of 
the study. As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up 
assessments are no longer required.
4.5.10
Mandatory Samples for Whole Genome Sequencing
At participating sites, blood samples will be collected for DNA extraction to enable WGS
to identify germline mutations and somatic 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, or can increase the knowledge and understanding of 
disease biology.  The blood 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 (Section 4.5.10) will not be applicable at that site.
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  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 of important pathways, guiding the development of new targeted agents.


Ipatasertib—F. Hoffmann-La Roche Ltd
104/Protocol CO40016, Version 11 (Cohort C)
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).
Patient medical information associated with WGS specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
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.
4.5.11
Post-Treatment Follow-Up
At post-treatment follow-up visits, survival follow-up information, subsequent treatment 
and outcome, and PROs will be collected via telephone calls, patient’s medical records, 
and/or clinic visits approximately every 3 months until death, loss to follow-up, or study 
termination by Sponsor.  All patients will be followed for post-treatment follow-up 
information unless the patient requests to be withdrawn from study post-treatment
follow-up; this request must be documented in the source file and signed by the 
investigator. 
For patients who discontinue treatment without evidence of disease progression per 
RECIST v1.1, in addition to post-treatment follow-up, patients will be followed every 
812 weeks for tumor assessments (disease follow-up clinic visits; see Appendix 1) until 
documented progression per RECIST v1.1, elective withdrawal from the study, or study 
completion or termination.  Images for tumor assessments will be collected to enable 
retrospective blinded independent central review when needed. As of 
Protocol CO40016, Version 10 (Cohort C), images for tumor assessments will no longer 
be collected for blinded independent central review.
As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up assessments 
are no longer required.
4.5.12
Optional Samples for Research Biosample Repository
4.5.12.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 


Ipatasertib—F. Hoffmann-La Roche Ltd
105/Protocol CO40016, Version 11 (Cohort C)
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR 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 
(Section 4.5.12) will not be applicable at that site.
4.5.12.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to PI3K/Akt pathway activity, 
immune infiltration/activation, apoptosis, and breast cancer biology:

Leftover blood, serum, plasma, and tumor tissue samples (with the exception of 
remaining archival tissue blocks, which will be returned to sites) and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides)

Optional tumor biopsy tissues obtained at the time of progression (e.g., at the 
study treatment discontinuation visit), if deemed clinically feasible
If performed, these biopsies should be performed within 6 weeks after 
progression or prior to the next anti-cancer therapy, whichever is sooner.  
Samples collected via resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy of the growing 
lesion(s) are preferred.
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via WGS, whole exome sequencing (WES), NGS, or other genomic 
analysis methods. Exploratory research results will not be available to patients or 
investigators. However, patients who provided an optional biopsy at progression may 


Ipatasertib—F. Hoffmann-La Roche Ltd
106/Protocol CO40016, Version 11 (Cohort C)
request the FMI NGS report of the new biopsy; it will be provided when available (results 
may not be available for samples that do not meet testing criteria).
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS, WES, and NGS provide a comprehensive characterization of the genome and 
exome, and, along with clinical data collected in this study, may increase the opportunity 
for developing new therapeutic approaches.  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 of important pathways, guiding the 
development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.12.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, 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 specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.12.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 


Ipatasertib—F. Hoffmann-La Roche Ltd
107/Protocol CO40016, Version 11 (Cohort C)
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate 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 
specimens and data will continue to be used as part of the RBR research.
4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
samples from the RBR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RBR samples have been tested prior to withdrawal of consent, results from those tests 
will remain as part of the overall research data.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples during the study, the investigator must inform 
the Medical Monitor in writing of the patient's wishes through use of the appropriate RBR 
Subject Withdrawal Form and must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples after closure of the site, the investigator must 
inform the Sponsor by emailing the study number and patient number to the following 
email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.12.7
Monitoring and Oversight
RBR specimens 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 specimens 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
108/Protocol CO40016, Version 11 (Cohort C)
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment for 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 determines it is in the best interest of the patient

Withdrawal of consent from the study treatment

Pregnancy

Use of an anti-cancer therapy not required per protocol

Disease progression per investigator’s assessment according to RECIST v1.1 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for a treatment discontinuation visit 28 (3)
days (Cohorts A and B) or 30 (3) days (Cohort C) after the last dose of study drug or 
prior to initiation of new anti-cancer therapy, whichever is sooner (see Appendix 1 for
additional details).
After treatment discontinuation, patients will return to the clinic for disease follow-up (if 
patient did not discontinue due to disease progression per RECIST v1.1), and 
information on survival follow-up, PROs, new anti-cancer therapy and 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 from the study or the 
Sponsor terminates the study).  As of Protocol CO40016 Version 11 (Cohort C), these 
long-term follow-up assessments are no longer required.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

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.  Patients should be asked to return to the clinic for a study treatment 
discontinuation visit (if applicable). The primary reason for withdrawal from the study 
should be documented on the appropriate eCRF.  If a patient requests to be withdrawn 


Ipatasertib—F. Hoffmann-La Roche Ltd
109/Protocol CO40016, Version 11 (Cohort C)
from the study, this request must be documented in the source documents and signed 
by the investigator.  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.
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.  The safety plan for patients in this study is based on clinical experience with 
ipatasertib in completed and ongoing studies.
The anticipated important safety risks and management plan for ipatasertib, 
atezolizumab, and paclitaxel are outlined below.  The identified risks associated with 
ipatasertib treatment include gastrointestinal toxicities (diarrhea, nausea, vomiting, and 
oral mucositis), fatigue/asthenia, rash, erythema multiforme, dehydration, decreased 
appetite, ALT/AST increased, and hyperglycemia. Refer to the Ipatasertib Investigator's 
Brochure for a complete summary of safety information of ipatasertib as a single-agent 
and in combination with chemotherapy and other anticancer therapies. Refer to the 
Atezolizumab Investigator's Brochure for a complete summary of safety information of 
atezolizumab as a single agent and in combination with chemotherapy and other 


Ipatasertib—F. Hoffmann-La Roche Ltd
110/Protocol CO40016, Version 11 (Cohort C)
anti-cancer therapies. Refer to the Paclitaxel Prescribing Information or Summary of 
Product Characteristics for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including investigator’s
assessment of the nature, frequency, and severity of adverse events, as well as 
expedited reporting of protocol-defined adverse events of special interest regardless of 
seriousness.  Vital signs and relevant laboratory values will be monitored at baseline and 
during the study.
Guidelines for managing adverse events, including prophylaxis (for diarrhea), and 
criteria for dose modification (interruption, dose reduction or discontinuation) for the 
management of specific adverse events attributable to ipatasertib/placebo, atezolizumab,
and/or paclitaxel, are summarized in Section 5.1.5.5.  The instructions provided are 
intended to serve as a guideline to improve safety and tolerability for patients to continue 
receiving ongoing treatment.  Suggested dose reductions for ipatasertib/placebo and 
paclitaxel are listed in Table 4 and Table 5. Dose reduction for atezolizumab is not 
allowed. General guidelines for dose modification are provided in Section 5.1.5.1.
The iDMC will be responsible for ongoing monitoring of patient safety in the
double-blinded, randomized Cohorts A and B. 
5.1.1
Risks Associated with Ipatasertib in Combination with 
Paclitaxel
Ipatasertib in combination with paclitaxel has been administered to 61 cancer patients in 
Study GO29227 (LOTUS).  Adverse events related to ipatasertib/placebo whose 
incidences were higher by 10% in patients receiving ipatasertibpaclitaxel versus
placebopaclitaxel were diarrhea (88.5% vs. 16.1%) and nausea (41.0% vs. 19.4%).  
The most frequent Grade3 adverse events (reported in 5% of patients in either 
treatment arm) in patients in the ipatasertibpaclitaxel arm vs placebo + paclitaxel arm 
were diarrhea (14 patients [23.0%], all Grade 3, vs. 0 patients), neutropenia (6 patients
[9.8%] vs. 1 patient [1.6%]), decreased neutrophil count (5 patients [8.2%] vs. 4 patients
[6.5%]), and fatigue (2 patients [3.3 %] vs. 4 patients [6.5%]), respectively.
The incidence of overall neutropenia in the LOTUS Study was similar in both arms (34% 
in the ipatasertibpaclitaxel arm vs. 39% in the placebopaclitaxel arm), but Grade3 
neutropenia, analyzed by grouped terms of similar medical concept, was higher in the 
ipatasertibpaclitaxel arm (18% vs. 8%). Thus, for recurrent Grade 3 neutropenia, 
ipatasertib should be reduced by one dose level when treatment is restarted (refer to the 
management guidelines in Section 5.1.5.5). 
Refer to Section 6 of the Ipatasertib Investigator’s Brochure for a detailed description of
anticipated safety risks for ipatasertib and for further information regarding the 


Ipatasertib—F. Hoffmann-La Roche Ltd
111/Protocol CO40016, Version 11 (Cohort C)
nonclinical and clinical safety evaluation of ipatasertib as a single agent and in 
combination with chemotherapy.
5.1.2
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs, 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, 
hypophysitis, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous reactions.  Immune-mediated 
reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are 
considered to be potential risks for atezolizumab.  Refer to Appendix 14 of the protocol 
and Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for atezolizumab.
5.1.3
Risks Associated with Combination Use of Atezolizumab and 
Ipatasertib
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and ipatasertib: gastrointestinal, dermatologic, hepatic, 
pulmonary, and hyperglycemia events.
5.1.4
Risks Associated with Paclitaxel
In prior clinical trials of paclitaxel, the following safety signals associated with paclitaxel 
were identified:  nausea, vomiting, diarrhea, stomatitis, peripheral neuropathy,
hypersensitivity reactions, and hematologic toxicity.  
To be eligible for the current study, patients must have adequate hematologic function, 
as manifested by measurements of complete blood cell counts.  Furthermore, blood cells 
will be assessed prior to each treatment cycle. 
Adverse events related to paclitaxel in the LOTUS study (GO29227) whose incidences 
were higher by 10% in patients receiving ipatasertibpaclitaxel versus
placebopaclitaxel were diarrhea (78.7% vs. 12.9%), nausea (41.0% vs. 24.2%), and 
peripheral sensory neuropathy (26.2% vs. 16.1%).  Refer to the management guidelines 
in Section 5.1.5.5 for these adverse events.
Patients will be monitored for other paclitaxel-associated adverse events as outlined in 
this section.  For more details regarding the safety profile of paclitaxel, see the Paclitaxel 
Prescribing Information or Summary of Product Characteristics.


Ipatasertib—F. Hoffmann-La Roche Ltd
112/Protocol CO40016, Version 11 (Cohort C)
5.1.5
Management of Patients Who Experience Specific Adverse 
Events
5.1.5.1
Dose Modifications
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided below. There will be no dose modifications for atezolizumab in this study; 
however, treatment may be interrupted/discontinued as needed (see below for details).
Any dose modification should be noted on the corresponding Study Drug Administration 
eCRF.  Cases of accidental overdose or medication error, along with any associated
adverse events, should be reported as described in Section 5.3.5.12.
5.1.5.2
General Guidelines
Dose modifications for paclitaxel chemotherapy will be performed as clinically 
appropriate, based on the investigator’s medical judgment. Details in this section can be 
used as guidance; however, only the specific dose levels shown should be used 
(Table 4 and Table 5).  Reasons for dose modifications (interruption or reduction) and 
discontinuation, the supportive measures taken, and the outcome will be documented in 
the patient's chart and recorded in the eCRF. Reasons for not adhering to the following 
guidance should also be documented in the patient’s chart.
On the planned day of treatment, the general parameters for chemotherapy 
administration include the following:

ANC 1500/L

Platelet count 100,000/L

Grade 2 clinically significant chemotherapy-related gastrointestinal toxicity
General guidelines for dosage/schedule modification are summarized as follows:

If any treatment component is interrupted (dose hold), the study cycle day count 
continues and does not shift; i.e., every cycle contains exactly 28 days. 

Cohorts A and B; if ipatasertib/placebo treatment is interrupted, paclitaxel treatment 
may continue if medically appropriate (per investigator discretion).

Cohorts A and B; if paclitaxel treatment is interrupted, consider delaying the 
ipatasertib/placebo and paclitaxel treatment concurrently for up to 7 days 
(i.e., shifting the 7 days-off week for ipatasertib/placebo so that 21 daily doses in 
every 28 days is maintained), at the discretion of the investigator.  The interrupted 
dose of paclitaxel may be administered later in the same cycle, ideally on Day 22, 
taking into consideration the paclitaxel dosing starting on Day 1 of the next cycle.

Cohort C; if ipatasertib treatment is interrupted, atezolizumab and/or paclitaxel 
treatment may continue if medically appropriate (per investigator discretion).

Cohort C; if atezolizumab treatment is interrupted, ipatasertib and/or paclitaxel 
treatment may continue if medically appropriate (per investigator discretion). 


Ipatasertib—F. Hoffmann-La Roche Ltd
113/Protocol CO40016, Version 11 (Cohort C)

Cohort C; if paclitaxel treatment is interrupted, ipatasertib and/or atezolizumab 
treatment may continue if medically appropriate (per investigator discretion).  
If paclitaxel treatment is interrupted, consider delaying ipatasertib treatment 
concurrently for up to 7 days (i.e., shifting the 7 days-off week for ipatasertib so that 
21 daily doses in every 28 days is maintained), at the discretion of the investigator. 
The interrupted dose of paclitaxel may be administered later in the same cycle, 
ideally on Day 22, taking into consideration the paclitaxel dosing starting on Day 1 of 
the next cycle.

Cohort C; given the complexity of this triple drug combination’s schedule, although 
there are pre-specified windows allowed around dosing days, it is strongly 
suggested that paclitaxel administration only be on Days 1, 8, and 15, (or Day 22 as 
a day to compensate for missed paclitaxel on any of the 3 prior days), and that 
atezolizumab be given on Days 1 or 15.  If dosing is not feasible on those days, it is 
acceptable and encouraged to dose on the next suggested day using above 
guidance.  Sites are encouraged to reach out to the Medical Monitor for any 
guidance on this matter.

If toxicity causes paclitaxel treatment to be omitted, clinic visits (and study 
procedures) associated with the administration of paclitaxel chemotherapy in that 
cycle may also be omitted (e.g., Day 8, Day 15, or Day 22).  However, laboratory 
assessments and clinical visits should be scheduled as needed for follow-up of 
adverse events.  In addition, tumor assessment per standard of care should not be 
delayed.  Once the toxicity has resolved to the required level, study treatment and 
study procedures will be resumed, according to the original study cycle day count; 
i.e., every cycle contains exactly 28 days.

For any concomitant conditions at baseline, dose modifications may apply according 
to the shift in toxicity grade, if the investigator deems it appropriate.  For example, if 
a patient has Grade 1 asthenia at baseline that increases to Grade 2 during 
treatment, this change may be considered a shift of one grade and may be treated 
as Grade 1 toxicity for dose-modification purposes if medically appropriate.

For toxicities assessed by the investigator to be unrelated to study treatment and 
unlikely to develop into serious or life-threatening events, treatment may be 
continued at the same dose without reduction or interruption.  

Dose reductions or interruptions may not be required for anemia (non-hemolytic) if 
satisfactorily managed by transfusions.

If any observed toxicity is attributable to only one drug as assessed by the 
investigator, the dose of the other drug(s) may not require modification.

Dose modifications for isolated abnormal hematologic laboratory values will be 
based on hematologic parameters on days when scheduled labs are due or on days 
when infusions are scheduled (i.e., normal hematologic values on Day 1 should not 
prevent dose modification, if indicated, based on a Day 8, Day 15, or Day 22 
laboratory value).

Patients who require chemotherapy dose reductions and tolerate the reduced dose 
for more than one cycle (28 days) may be allowed to increase back to a 100% dose 


Ipatasertib—F. Hoffmann-La Roche Ltd
114/Protocol CO40016, Version 11 (Cohort C)
at the treating physician's discretion (no specific guidance is provided for ipatasertib 
re-escalation, as it is not permitted).

Study treatment may be interrupted to manage toxicity.  
Paclitaxel or ipatasertib/placebo: a dosing gap of up to 4 consecutive weeks 
(approximately 28 days) is permitted. Dose hold for longer than 4 weeks for 
a treatment-related adverse event will require permanent discontinuation of the 
attributable treatment component and per specific adverse event management 
guidelines in Section 5.1.5.5. 
Cohort C: Atezolizumab may be held for up to 12 weeks.  See additional details in 
Section 5.1.5.4.
As applicable, patients may continue treatment with remaining study drugs
(Cohorts A and B: if paclitaxel has been discontinued, ipatasertib/placebo may be 
continued alone, after discussion with the Medical Monitor)
5.1.5.3
Dosage Modification for Ipatasertib/Placebo and Paclitaxel
If the patient does not tolerate the QD dosing of 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 
(i.e., doses below 200 mg/day of ipatasertib/placebo) will be allowed (see Table 4).
Dose re-escalation is not permitted for ipatasertib/placebo.
To manage paclitaxel-related toxicity, no more than one dose reduction for paclitaxel will 
be allowed (Table 5). Paclitaxel doses other than specified in Table 5 will not be allowed.


Ipatasertib—F. Hoffmann-La Roche Ltd
115/Protocol CO40016, Version 11 (Cohort C)
Table 4
Dose Reductions for Ipatasertib/Placebo 
Dose Level a
Ipatasertib/Placebo
Starting dose
400 mg
First dose reduction
300 mg
Second dose reduction
200 mg
Third dose reduction
Not permitted  
a If the patient continues to experience specified drug-related adverse events after the second 
reduction, the treatment should be discontinued.
Table 5
Dose Reductions for Paclitaxel
Dose Level a
Paclitaxel
Starting dose
80 mg/m2
First dose reduction
65 mg/m2
Second dose reduction
Not permitted 
Third dose reduction
Not Applicable
a If the patient continues to experience specified drug-related adverse events after the dose 
reduction, the treatment should be discontinued.
5.1.5.4
Treatment Interruption
Ipatasertib/placebo treatment may be temporarily interrupted in patients who experience 
toxicity considered to be related to study drug. If ipatasertib/placebo has been withheld 
for 28 consecutive days (as measured from the first day of interruption of scheduled 
ipatasertib dosing) because of treatment-related toxicity, the patient should be 
discontinued from ipatasertib/placebo.  
In Cohorts A and B, if the ipatasertib/placebo is discontinued at any time during the 
study, patients may continue on study with chemotherapy alone (Cohorts A and B).  
In Cohort C, if any of the three study treatments are discontinued, the other study 
treatments may be continued independent of each other (i.e., if the ipatasertib is 
discontinued at any time during the study, patients may have the option of continuing on 
study with atezolizumab and chemotherapy or atezolizumab alone or chemotherapy 
alone).
Ipatasertib/placebo, atezolizumab, and/or paclitaxel treatment may be suspended for 
reasons other than toxicity (e.g., surgical procedures) with Medical Monitor approval.  
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
resuming study treatment after a hold of >28 consecutive days, study drug may be 
restarted with the approval of the Medical Monitor. 
If daily systemic corticosteroids are initiated for treatment of any toxicity or other 
condition, they must be tapered to 10 mg/day oral prednisone or equivalent before 


Ipatasertib—F. Hoffmann-La Roche Ltd
116/Protocol CO40016, Version 11 (Cohort C)
ipatasertib or ipatasertib/placebo can be resumed.  Steroids used as prophylaxis (i.e.,
prior to scans, as protocol-directed rash prophylaxis for patients in Cohort C, or prior to 
paclitaxel or atezolizumab) do not require holding of ipatasertib or ipatasertib/placebo.  
Steroids used on a single day to manage IRRs or allergic reactions similarly do not 
require holding of ipatasertib or ipatasertib/placebo.
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to atezolizumab.  If corticosteroids are initiated for treatment of 
the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks due to atezolizumab-related toxicity (as measured from the first day of 
interruption of scheduled atezolizumab dosing), the patient will be discontinued from 
atezolizumab.  Given that a slow taper of steroids, as directed above, is required by 
protocol, atezolizumab may be withheld for 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can then be resumed after 
being withheld for 12 weeks if the Medical Monitor agrees that the patient is likely to 
derive clinical benefit.  Atezolizumab treatment may be suspended for reasons other 
than toxicity (e.g., surgical procedures) with Medical Monitor’s approval, with acceptable 
length of interruption to be determined by the Medical Monitor based on discussion with 
the investigator.  Following discussion with the Medical Monitor, the investigator may 
determine the acceptable length of treatment interruption based on sound medical and 
clinical judgement, and taking into consideration the overall benefitrisk for the patient. 
5.1.5.5
Adverse Event Management Guidelines
Refer to the following appendices for adverse event management guidelines:

Cohorts A and B:  Appendix 13

Cohort C, Ipatasertib plus Atezolizumab plus Paclitaxel: Appendix 14

Cohort C, Atezolizumab: Appendix 15
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.
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 


Ipatasertib—F. Hoffmann-La Roche Ltd
117/Protocol CO40016, Version 11 (Cohort C)
a pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

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 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
118/Protocol CO40016, Version 11 (Cohort C)
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 (Cohorts A and B)
The following adverse events of special interest apply to Cohort C only:

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 treatment, 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 study treatment is suspected.

Pneumonitis


Ipatasertib—F. Hoffmann-La Roche Ltd
119/Protocol CO40016, Version 11 (Cohort C)

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10 ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, 
influenza-like illness, HLH, and MAS

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)
5.2.4
Selected Adverse Events
Additional data may be analyzed for the following selected adverse events:

Diarrhea

Asthenia (fatigue)

Nausea

Peripheral neuropathy (peripheral sensory neuropathy, neuropathy peripheral, 
peripheral motor neuropathy)

Neutropenia (neutrophil count decreased, febrile neutropenia)

Rash (e.g., maculopapular, erythema, urticarial, dermatitis, rash popular, skin 
exfoliation, toxic skin eruption)

Erythema multiforme

Vomiting

Oral mucositis (stomatitis, mucosal inflammation, mouth inflammation, mouth 
ulceration)

Hyperlipidemia (hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, blood 
cholesterol increased, blood triglycerides increased)

Hepatotoxicity (ALT, AST increased)

Hyperglycemia (blood glucose increased)


Ipatasertib—F. Hoffmann-La Roche Ltd
120/Protocol CO40016, Version 11 (Cohort C)

Pneumonia (lower respiratory tract infection)

Pneumonitis (interstitial lung diseases)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will 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 identified by the investigator 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 for patients in Cohorts A and B will be 
reported until 28 days after the final dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first. For patients in Cohort C, all 
adverse events will be reported until 30 days after the final dose of study treatment or 
until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious 
adverse events and adverse events of special interest will continue to be reported until 
90 days after the final dose of study treatment or until initiation of new systemic 
anti-cancer therapy, whichever occurs first.  
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?" 
Note that PRO questionnaires should not be used as solicitation tools for adverse event 
data collection, nor should the PRO data be used as source documents for adverse 


Ipatasertib—F. Hoffmann-La Roche Ltd
121/Protocol CO40016, Version 11 (Cohort C)
event reporting (see Section 5.3.5.13, Patient-Reported Outcome Data), as this data will 
be collected on separate eCRFs and analyzed separately.  To minimize interference 
between the investigator-assessed adverse event reporting (i.e., NCI CTCAE) and PRO
adverse event data (i.e., PRO NCI-CTCAE), the sites should not attempt to reconcile 
data nor elicit questions based upon the results of the PRO questionnaires.  In the event 
that an investigator becomes aware of PRO data that may be indicative of a serious 
adverse event (SAE) or an adverse event of special interest (AESI), the investigator will 
determine whether the criteria for an SAE or AESI have been met and, if so, will report 
the event on the Adverse Event eCRF.
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 6
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
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 


Ipatasertib—F. Hoffmann-La Roche Ltd
122/Protocol CO40016, Version 11 (Cohort C)
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 7):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 7
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.
There is one eCRF page for recording adverse events or serious adverse events.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.


Ipatasertib—F. Hoffmann-La Roche Ltd
123/Protocol CO40016, Version 11 (Cohort C)
5.3.5.1
Infusion-Related Reactions
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per 
institutional guidelines and administered after the oral dose of ipatasertib or placebo. 
Because of the known potential for allergic reactions to paclitaxel and/or the Cremophor 
vehicle, precautions must be taken to decrease the risk of anaphylaxis. Patients must 
be premedicated prior to paclitaxel per institutional practice with dexamethasone, 
diphenhydramine, and one of the following two H2-receptor blockers: ranitidine or 
famotidine. Other H2-receptor antagonists, such as cimetidine, which are known to 
inhibit cytochrome P450, should be avoided. An H1-receptor antagonist, such as
diphenhydramine 50 mg IV, may be given as well.
Patients should be monitored during paclitaxel administration per institutional policies. 
Patients may receive anti-emetic and other prophylactic treatments (e.g., IV infusions of 
calcium and magnesium to try to decrease any potential peripheral neuropathy) 
according to institutional and/or local standards and per manufacturer’s instructions.
Adverse events that occur during or within 24 hours after study drug administration 
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 infusion-related reaction.
5.3.5.2
Diagnosis versus Signs and Symptoms
If known, a diagnosis should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
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.


Ipatasertib—F. Hoffmann-La Roche Ltd
124/Protocol CO40016, Version 11 (Cohort C)

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.  Details regarding any increases or decreases in severity of selected adverse 
events (e.g., diarrhea, Section 5.2.4) 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

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.


Ipatasertib—F. Hoffmann-La Roche Ltd
125/Protocol CO40016, Version 11 (Cohort C)
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.
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).


Ipatasertib—F. Hoffmann-La Roche Ltd
126/Protocol CO40016, Version 11 (Cohort C)
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 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 underlying breast cancer should be recorded 
on the Study Discontinuation 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.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
During post-treatment follow-up, deaths attributed to progression of underlying breast 
cancer should be recorded only on the Study Discontinuation eCRF.  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.


Ipatasertib—F. Hoffmann-La Roche Ltd
127/Protocol CO40016, Version 11 (Cohort C)
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.  
Hospitalization under the following circumstances should not be reported as an adverse 
event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of progression of the 
underlying disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event but should be reported as a non-serious
adverse event instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours


Ipatasertib—F. Hoffmann-La Roche Ltd
128/Protocol CO40016, Version 11 (Cohort C)
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 or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For ipatasertib/placebo, atezolizumab, and paclitaxel,
adverse events associated with special situations should be recorded as described 
below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.


Ipatasertib—F. Hoffmann-La Roche Ltd
129/Protocol CO40016, Version 11 (Cohort C)

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, atezolizumab, and 
paclitaxel, 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
130/Protocol CO40016, Version 11 (Cohort C)
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.  Because the processes of data 
collection and intent of interpretation of investigator-assessed adverse events (i.e., by 
NCI CTCAE) and patient-reported adverse events (e.g., NCI PRO-CTCAE) are
inherently different, these data sets will not be reconciled by the Sponsor and should not 
be used as source documents for adverse event reporting by the site.  
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)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


Ipatasertib—F. Hoffmann-La Roche Ltd
131/Protocol CO40016, Version 11 (Cohort C)
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, M.D. (Primary)
Mobile Telephone No.:
Medical Monitor/Roche Medical Responsible:
, Ph.D.
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 Adverse Event/Special Situations Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first (Cohorts A and B), 
or for patients in Cohort C, all adverse events will be reported until 30 days after the final 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever 
occurs first, and serious adverse events and adverse events of special interest will 
continue to be reported until 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 


Ipatasertib—F. Hoffmann-La Roche Ltd
132/Protocol CO40016, Version 11 (Cohort C)
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 28 days (90 days for 
patients in Cohort C) after the last 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 28 days after the last 
dose of ipatasertib/placebo, 5 months after the last dose of atezolizumab, or 6 months 
after the last dose of paclitaxel, whichever occurs later.  A Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing 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 ipatasertib or placebo 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 
28 days after the last dose of ipatasertib/placebo or 6 months after the last dose of 
paclitaxel, whichever occurs later.  The investigator should report the pregnancy on the 
paper Clinical Trial Pregnancy Reporting Form and submit the form to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 


Ipatasertib—F. Hoffmann-La Roche Ltd
133/Protocol CO40016, Version 11 (Cohort C)
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
134/Protocol CO40016, Version 11 (Cohort C)
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 28 days after the final 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever 
occurs first for patients in Cohorts A and B; defined as 30 days [all adverse events] or 
90 days [serious adverse events and adverse events of special interest] after the final 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever 
occurs first, for patients in Cohort C), all deaths, regardless of cause, should be reported 
through use of the Long-Term Post-Treatment Follow-Up eCRF and in the Study 
Discontinuation eCRF.
In addition, 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 Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
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

Atezolizumab Investigator’s Brochure

Paclitaxel Summary of Product Characteristics
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.


Ipatasertib—F. Hoffmann-La Roche Ltd
135/Protocol CO40016, Version 11 (Cohort C)
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The three cohorts, Cohort A (TNBC biomarker-positive), Cohort B (HR+/HER2–
biomarker-positive breast cancer), and Cohort C (TNBC biomarker-negative) are three 
independent cohorts and will be analyzed separately for the following reasons:

The three patient populations are distinct patient populations and are expected to 
have different prevalence and PFS and OS expectations, and thus different 
enrollment and analysis timelines. 

The readout from one cohort is independent of the readout of the other cohorts. 

This study is essentially three independent trials running under one protocol for 
operational efficiency.
Therefore, for all analyses described below, these three cohorts will be analyzed 
separately.
The global population will include all patients enrolled during the global enrollment phase 
(including patients enrolled at CFDA-recognized sites during that phase), and the China 
subgroup will include all patients enrolled at CFDA-recognized sites (i.e., during both the 
global enrollment phase and the extended China enrollment phase).  Separate analyses 
will be performed for the global population and the China subgroup.
In general, data will be described and summarized as warranted by sample sizes.  
Continuous variables will be summarized using means, standard deviations, medians, 
and ranges; categorical variables will be summarized using counts and percentages; 
time-to-event data will be summarized using estimates of the median and associated 
confidence intervals.  Listings will be used in place of tables in the event of small sample 
sizes.
The detailed analyses will be outlined in the Statistical Analysis Plan (SAP). The 
analyses specified in the SAP supersede those specified in the protocol for regulatory 
filing purposes.
6.1
DETERMINATION OF SAMPLE SIZE
As described earlier, Cohort A (TNBC biomarker-positive), Cohort B (HR+/HER2–
biomarker-positive breast cancer), and Cohort C (TNBC biomarker-negative) are three
independent cohorts and will be analyzed separately. Cohort A and Cohort B will be 
tested independently with 5% type I error control each. Cohort C is a single-arm cohort 
with no statistical hypothesis testing and will be reported descriptively only.  
For unblinding of Cohort A and Cohort B, in the event that the primary PFS analysis 
timelines for the Cohort A and Cohort B are far apart, after the iDMC's review, the 


Ipatasertib—F. Hoffmann-La Roche Ltd
136/Protocol CO40016, Version 11 (Cohort C)
treatment codes of the cohort whose PFS data are mature earlier will be sent to the 
Sponsor to unblind only that cohort for the primary analysis of PFS.  The Sponsor will 
remain blinded to the treatment assignments of the other cohort. Data from any 
additional patients enrolled within the China extension phase will not be included in the 
analysis of the global study. 
Global Study
For Cohort A, approximately 249 patients with TNBC with PIK3CA/AKT1/PTEN-altered 
tumors will be enrolled and randomized in a 2:1 ratio to the experimental arm (ipatasertib 
400 mg + paclitaxel) and control arm (placebo + paclitaxel).  The sample size of 
249 patients is determined on the basis of the power calculation for the PFS and OS 
endpoints. 
The PFS primary analysis in Cohort A is planned to be conducted after approximately 
125 PFS events in Cohort A have been observed or Cohort A’s last patient in, whichever 
is later.  Data of 125 PFS events allows for 95.5% power to detect an improvement in 
median PFS from 6 months in the placebo + paclitaxel arm to approximately 12 months 
in the ipatasertib + paclitaxel arm (hazard ratio = 0.5) at the 5% level of significance 
(two-sided).  The largest hazard ratio deemed to be statistically significant at the 5% 
level will be approximately 0.69 (with median PFS improvement from 6 months to 
8.7-months).
For Cohort A, the key secondary endpoint, OS, will be tested only if the PFS result is 
statistically significant. The final OS analysis with approximately 188 OS events will 
provide 80% power to detect a hazard ratio of 0.65 (median OS improvement from 16 to 
24.6 months), or 64% power to detect a hazard ratio of 0.7. The largest detectable OS 
hazard ratio (with a log-rank test) will be approximately 0.74 (with median OS 
improvement from 16 months to 21.6 months). 
Assuming a 2-month site ramp-up period and approximately 120150 sites, the 
enrollment duration is projected to be approximately 16 months (from the first patient 
enrolled).  The last PFS event (the 125th PFS event) for the PFS analysis in Cohort A 
(patients with TNBC) is projected to occur approximately 20 months after the first patient 
is enrolled. The last death (the 188th OS event) for the final OS analysis in Cohort A 
(patients with TNBC) is projected to occur approximately 53 months after the first patient 
is enrolled.  
For Cohort B, approximately 201 HR+/HER2– patients with
PIK3CA/AKT1/PTEN-altered tumors will be enrolled and randomized in a 2:1 ratio to the 
experimental arm (ipatasertib 400 mgpaclitaxel) and control arm (placebopaclitaxel).  
The sample size of 201 patients is determined on the basis of the power calculation for 
the primary endpoint, PFS. 


Ipatasertib—F. Hoffmann-La Roche Ltd
137/Protocol CO40016, Version 11 (Cohort C)
The PFS primary analysis in Cohort B is planned be conducted when approximately 
150 PFS events in the Cohort B patients have been observed.  This allows for 80% 
power to detect an improvement in median PFS from 8.5 months in the 
placebopaclitaxel arm to approximately 13.8 months in the ipatasertibpaclitaxel arm 
(hazard ratio = 0.62) at the 5% level of significance (two-sided).  The largest hazard ratio 
deemed to be statistically significant at the 5% level will be approximately 0.71 (with 
median PFS improvement from 8.5 months to 11.93 months).
Assuming a 2-month site ramp-up period and approximately 120150 sites, the 
enrollment duration is projected to be approximately 10 months (from the first patient 
enrolled). The last PFS event (the 150th PFS event) for the PFS analysis in Cohort B 
(patients with HR+/HER2– breast cancer) is projected to occur approximately 30 months 
after the first patient is enrolled.
The above timeline estimates are based on an assumption of an annual loss-to-follow-up 
rate for PFS of 5% and an annual loss-to-follow-up rate for OS of 2%.
For Cohort C, approximately 100 patients with TNBC lacking
PIK3CA/AKT1/PTEN-altered tumors will be enrolled and assigned to a single arm of 
ipatasertib plus atezolizumab plus paclitaxel.  The sample size of 100 patients is 
determined on the basis of having a sufficient number of patients for efficacy signal 
seeking, as well as adding to current knowledge on the safety profile of this combination, 
and not delaying the enrollment of patients with TNBC for Cohorts A and C.  There is no 
formal hypothesis testing planned for this cohort, and the endpoints listed in Section 2
(including PFS, ORR, DOR, 1-year and 2-year landmark PFS and OS) will be reported 
descriptively.
Potential China Extension 
For the potential China extension phase, if at least 1 patient is enrolled into Cohorts A or 
B in mainland China, Hong Kong, or Taiwan during the global enrollment phase, 
additional patients may be enrolled at CFDA-recognized sites in an extended enrollment 
phase for up to a total of 90 Chinese patients with TNBC with
PIK3CA/AKT1/PTEN-altered tumors and up to a total of 120 Chinese patients with 
HR/HER2breast cancer with PIK3CA/AKT1/PTEN-altered tumors; these patients will
constitute an analysis population of a China subgroup. The sample size of this China
subgroup is determined on the basis of showing consistency in the China subgroup for 
the primary endpoint and PFS with the global cohort (see Section 6.9). 
6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment, study discontinuation, and discontinuation reasons will be 
summarized by treatment arm for the two cohorts. In addition, major protocol violations, 
including violations of inclusion and/or exclusion criteria, will be summarized by 
treatment arm for the two cohorts.


Ipatasertib—F. Hoffmann-La Roche Ltd
138/Protocol CO40016, Version 11 (Cohort C)
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.
Descriptive summaries of continuous data will present the group mean, standard 
deviation, median, minimum, and maximum.  Descriptive summaries of discrete data will 
present the category counts as frequencies and percentages.
6.4
EFFICACY ANALYSES
All efficacy analyses will be based on the ITT population (i.e., all randomized patients in 
Cohorts A and B; all enrolled patients in Cohort C) according to the treatment arm to 
which patients are allocated.  DOR analysis will include all patients with an objective 
response.
All primary and secondary endpoints based on tumor burden will be based on 
radiological (or photographical, if applicable) assessments by the local radiologist or 
investigator.
A sensitivity analysis of primary and key secondary efficacy objectives on the basis of 
blinded independent central review assessments will be performed using the same 
methodology as specified for investigator-assessed endpoints.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is investigator-assessed PFS, defined as the time from 
randomization (Cohorts A and B) or enrollment (Cohort C) to the first occurrence of 
disease progression, as determined by the investigator using RECIST v1.1 (see
Appendix 10), or death from any cause, whichever occurs first.  Data for patients who do 
not experience disease progression or death will be censored at the last date of 
evaluable tumor assessment.  For patients who do not have an evaluable tumor 
assessment after randomization/enrollment, the data will be censored at the date of 
randomization plus 1 day.
For Cohort A and Cohort B, PFS will be compared between treatment arms using the 
stratified log-rank test.  The hazard ratio will be estimated using a stratified Cox 
proportional hazards model.  The 95% CI for the hazard ratio will be provided.  The 
stratification factors to be used will be the same as the randomization stratification 
factors.  Results from an unstratified analysis will also be provided.  Sensitivity analyses 
will be conducted to compare PFS between the treatment arms in patients with
PIK3CA/AKT1/PTEN-altered tumors as centrally determined by the FMI CTA.
For each treatment arm in each cohort, Kaplan-Meier methodology will be used to 
estimate the median PFS, and the Brookmeyer-Crowley method will be used to 


Ipatasertib—F. Hoffmann-La Roche Ltd
139/Protocol CO40016, Version 11 (Cohort C)
construct the 95% CI for the median PFS (Brookmeyer and Crowley 1982).  
Kaplan-Meier curves will be produced as well.
6.4.2
Secondary Efficacy Endpoints
The secondary endpoints will be tested in Cohort A and Cohort B separately, and will be 
tested only if the primary analysis of respective PFS in the corresponding cohort reaches 
statistical significance at the level of 5%.  
6.4.2.1
Objective Response Rate with Duration of Response
Objective response is defined as a complete response (CR) or partial response (PR) on 
two consecutive occasions 4 weeks apart, as determined by the investigator through 
the use of RECIST v1.1 (Appendix 10).  Patients without a post-baseline tumor 
assessment will be considered as non-responders.  ORR is defined as the proportion of 
patients who have an objective response.  For each cohort, an estimate of ORR will be 
calculated for each treatment arm, and its 95% CI will be calculated using the 
Blyth-Still-Casella method.  ORR will be compared between treatment arms using the 
stratified Cochran-Mantel-Haenszel test.  The stratification factors to be used will be the 
same as those described for the analysis of the primary endpoint.  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.
DOR is defined as the time from the first occurrence of a documented objective 
response to disease progression, as determined by the investigator through the use of 
RECIST v1.1, or death from any cause, whichever occurs first.  The censoring method 
for DOR will be the same as that for PFS.  For each cohort, the Kaplan-Meier approach 
will be used to estimate the median DOR and the corresponding 95% CIs.  Analysis of 
DOR will include only patients with objective responses. Because of the 
non-randomized nature of this analysis population, the analysis of DOR will be 
considered descriptive.
6.4.2.2
Clinical Benefit Rate
Clinical benefit rate is defined as the proportion of patients who have an objective 
response (CR or PR), or stable disease for at least 24 weeks, as determined by the 
investigator through the use of RECIST v1.1.  For each cohort, clinical benefit rate will 
be analyzed using methods similar to those used for ORR.
6.4.2.3
Overall Survival
OS is defined as the time from randomization (Cohorts A and B) or enrollment (Cohort C) 
to death from any cause.  Data for patients who are not reported as having died at the 
time of analysis will be censored at the date when they were last known to be alive.  
Data for patients who do not have post-baseline information will be censored at the 
randomization (Cohorts A and B) or enrollment (Cohort C) date plus 1 day.  For Cohort A 
and Cohort B, the analyses will be conducted using the stratified two-sided log-rank test, 
and the results from the unstratified log-rank test will also be provided.  For each cohort, 


Ipatasertib—F. Hoffmann-La Roche Ltd
140/Protocol CO40016, Version 11 (Cohort C)
the OS curve for each treatment arm will be estimated by the Kaplan-Meier methodology, 
and the survival rates at landmarks (e.g., 1-year and 2-year OS) will be provided when 
data allow.  The hazard ratio for OS and its 95% CI will be estimated by the Cox 
proportional-hazards models.  
For each cohort, sensitivity analyses will be conducted to compare OS between the 
treatment arms in patients with PIK3CA/AKT1/PTEN-altered tumors as centrally 
determined by the FMI CTA.
6.4.2.4
(Cohort C only) 1-Year PFS and 1-Year OS Rate
For Cohort C, 1-year PFS and 1-year OS rate will be estimated using the Kaplan-Meier 
method, and their 95% CIs will be provided using Greenwood’s formula.
6.4.3
Exploratory Efficacy Endpoints
6.4.3.1
Progression-Free Survival 2 (PFS2)
PFS2 is defined as the time from randomization (or enrollment for Cohort C patients) to 
first objective disease progression on next-line treatment, or death from any cause, 
whichever occurs first. Specifically, next-line therapy is defined as the treatment 
received after the first disease progression. Patients who do not experience disease 
progression on next-line therapy or death will be censored at the last time known to be 
alive and without objective disease progression on next-line therapy. Observations from 
patients who do not have post-baseline information will be censored at the date of 
randomization plus 1 day.  This analysis will be performed as data allows and will be
described in the SAP.
6.4.3.2
Patient Subgroup Analysis in Cohort A
For Cohort A (TNBC), all primary and secondary efficacy endpoints will also be explored 
in two subgroups: patients with tumors that have PIK3CA/AKT1-activating mutations; 
and patients with tumors that have PTEN-alterations but no PIK3CA/AKT1-activating 
mutations.
6.4.4
Time to First Skeletal-Related Event 
Time to first skeletal–related event (SRE) is defined as the time from randomization
(Cohorts A and B) or enrollment (Cohort C) to the first occurrence of an SRE.  An SRE is 
either a pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord 
compression. Patients for whom an SRE has not been observed should be censored at 
the last time known to be alive and without an SRE. This analysis will be performed as 
data allow and will be described in the SAP.
6.4.5
Patient-Reported Outcome Analyses
6.4.5.1
Secondary Patient-Reported Outcome Endpoints
To evaluate patient-reported HRQoL while on study treatment, descriptive analysis of 
the mean and mean change from patients’ baseline GHS/HRQoL scale score, which 
consists of Questions 29 and 30 of the EORTC QLQ-C30; Appendix 7) will be assessed 


Ipatasertib—F. Hoffmann-La Roche Ltd
141/Protocol CO40016, Version 11 (Cohort C)
by cycle and independently within each cohort.  The GHS/HRQoL data will be scored 
and analyzed as described in Section 6.4.5.2 (Exploratory PRO Analyses). To evaluate 
time to deterioration of pain, changes in the pain scale (Questions 9 and 19) of the 
EORTC QLQ-C30 will be assessed. Time to deterioration is defined as the time from 
baseline to the first documentation of at least an 11-point increase on the pain scale 
from baseline. 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 randomization (Cohort B).
An 11-point change is defined as a clinically meaningful difference (Cocks et al. 2012); 
additional sensitivity analyses using different thresholds, and definitions of change (e.g. 
confirmed or permanent changes in pain score) will also be conducted. 
6.4.5.2
Exploratory Patient-Reported Outcome Analyses
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) of linear 
transformed scores will be reported for all scales (symptom, functional domains, and 
single items) of the EORTC QLQ-C30 questionnaire according to the EORTC scoring 
manual guidelines (Fayers et al. 2001) for each assessment timepoint. The mean 
change of the linear transformed scores from baseline (and 95% CI using the normal 
approximation) will also be reported independently for each cohort. Line charts depicting 
the mean changes (and 95% confidence intervals) of items and scales over time will be 
provided for each treatment arm from the baseline assessment. In the event of 
incomplete data, for all questionnaire subscales, 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 subscales with less than 50% of the items 
completed, the subscale will be considered as missing.
The EQ-5D-5L (Appendix 8) will be scored according to its manual, and results will be 
reported separately from the clinical study report. 
PRO completion, compliance rates, and reasons for missing data will be summarized at 
each timepoint by treatment arm for each measure in the ITT population. The 
questionnaire is considered completed if at least one question was completed. The 
compliance rate will be based on the total number of patients expected to complete the 
questionnaire at a particular timepoint.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety-evaluable population for each cohort (i.e., 
all patients who received any study treatment) according to the treatment received.
Safety analyses will be conducted by treatment arms and include frequency, nature, and 
severity of treatment-emergent adverse events, including adverse events leading to 
death, serious adverse events, and adverse events of special interest.  All deaths will be 
summarized.  In addition, adverse events leading to study drug discontinuation and dose 


Ipatasertib—F. Hoffmann-La Roche Ltd
142/Protocol CO40016, Version 11 (Cohort C)
modification will be summarized.  Laboratory measurements outside of the normal range 
will be identified.  Selected laboratory data will be summarized by treatment arm and 
grade compared with baseline.  Relevant vital signs will be presented using summary 
statistics by treatment arm 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 MedDRA 
preferred terms and appropriate MedDRA hierarchy.  Adverse event severity will be 
graded according to NCI CTCAE v4.0.  Multiple occurrences of the same event will be 
counted once at the maximum severity.
6.5.1
Exploratory Safety Analysis
For the PRO-CTCAE analysis (Appendix 9), for each treatment arm and dose, the 
number (percentage) of patients reporting symptoms by “frequency,” ”severity,” 
“interference,” and “presence” category will be reported at each assessment 
independently for each cohort.  A summary table of the percentage of patients reporting 
severity of a symptom as “severe” or “very severe” over the course of the study by 
treatment arm will also be provided.  Finally, a longitudinal analysis of change will be 
employed to understand how symptoms may have changed over the course of treatment.
PRO-CTCAE completion, compliance rates, and reasons for missing data will be 
summarized at each timepoint by treatment arm for each measure in the safety 
population.  The questionnaire is considered completed if at least one question was 
completed.  The compliance rate will be based on the total number of patients expected 
to complete the questionnaire at a particular timepoint.
6.6
PHARMACOKINETIC ANALYSES
Ipatasertib and G-037720 concentrations will be measured on Days 1 and 15 of Cycle 1, 
and on Day 15 of Cycle 3.  Atezolizumab, ipatasertib, and G-037720 plasma 
concentration versus time data, together with information on dosing and patient 
characteristics, will be pooled and analyzed using a popPK analysis approach
independently for each cohort.  Plasma samples will also be used to characterize the 
immunogenicity of atezolizumab. Nonlinear mixed-effect modeling will be used for the 
estimation of popPK parameters for ipatasertib and G-037720.  Covariates such as 
patient demographics (e.g., age, sex, body size), total protein, serum albumin, liver 
function tests (e.g., AST, ALT, alkaline phosphatase), and serum creatinine will be 
tested for significance on PK parameters of interest.
The PK data will be combined with the safety and efficacy (e.g., PFS) data for 
exposureresponse modeling as data permit for each cohort.  PK and 
PK/pharmacodynamic analyses may be reported in separate stand-alone reports.  
Additional analyses may be explored as warranted by the data.


Ipatasertib—F. Hoffmann-La Roche Ltd
143/Protocol CO40016, Version 11 (Cohort C)
6.7
BIOMARKER ANALYSES
The exploratory biomarker endpoints, including the effects of breast intrinsic subtypes 
and expression of tumor suppressors, will be evaluated with appropriate methods in an 
effort to understand the association of these markers with study drug response.
6.8
INTERIM ANALYSES
6.8.1
Planned Interim Safety Analyses
An external iDMC will be set up to evaluate safety data in Cohorts A and B on a periodic
basis. All summaries/analyses by treatment arm for the iDMC's review will be prepared 
by an external iDCC.  Members of the iDMC will be external to the Sponsor and will 
follow a charter that outlines their roles and responsibilities.  Any outcomes of these 
safety reviews that affect study conduct will be communicated in a timely manner to the 
investigators for notification of the IRB/EC. A detailed plan will be included in the iDMC 
Charter.
The iDMC will convene a review of summaries of the safety data by cohort and by 
treatment arm after approximately 50 patients (in total from both cohorts) have competed 
1 treatment cycle and approximately every 6 months thereafter until the time of the 
analysis of the primary efficacy endpoint for both cohorts are complete.  In the absence 
of extenuating circumstances, accrual will not be halted while the safety analysis is 
conducted.  The iDMC will review the available data to make a recommendation as to 
the following: to continue without changes to the protocol, to modify the safety 
monitoring and/or eligibility criteria, to add additional safety reviews to address emerging 
safety issues, or to terminate the study.  In addition, the Sponsor may request ad hoc 
meetings of the iDMCat any time during the study to review ongoing safety summary 
data.
6.8.2
Safety monitoring will be performed on a continual basis by 
the Sponsor for Cohort C.  Planned Interim OS Analysis at PFS 
Primary Analysis
For Cohort A, interim OS will be analyzed at the time of the primary analysis for PFS, 
and final OS will be analyzed at the time that approximately 188 OS events occur or 
around 36 months after the last patient has been enrolled, whichever is earlier.  The 
Lan-DeMets -spending function with an O’Brien-Fleming boundary will be used to 
control the type I error accounting for OS interim and final analyses.  With a sample size 
of 249 patients in Cohort A, it is estimated that there will be approximately 75 OS events 
at the time of PFS primary analysis, and approximately 188 OS events at the final OS 
analysis, with corresponding p-value boundaries of (0.000774, 0.049737).  The 
corresponding hazard ratio boundaries are 0.44 and 0.74 at interim and final analysis, 
respectively. The actual alpha-spending will be adjusted and determined based on the 
actual information fraction at the interim analysis.


Ipatasertib—F. Hoffmann-La Roche Ltd
144/Protocol CO40016, Version 11 (Cohort C)
For Cohort B, interim OS will be analyzed at the time of the primary analysis for PFS, 
and final OS will be at the time that approximately 148 OS events occur or around 
5 years after the last patient has been enrolled, whichever is earlier.  The Lan-DeMets 
spending function with an O’Brien-Fleming boundary will be used to control the type I 
error accounting for OS interim and final analyses.  For Cohort B, it is estimated that 
there will be approximately 81 OS events at the time of PFS primary analysis, and 
approximately 148 OS events at the final OS analysis, with corresponding p-value 
boundaries of (0.00489, 0.04842).  The corresponding hazard ratio boundaries are 0.52 
and 0.71 at interim and final analysis, respectively. The actual alpha-spending will be 
adjusted and determined based on the actual information fraction at the interim analysis.
Further details can be found in the SAP. 
6.8.3
Optional Interim Analyses
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct an optional interim efficacy analysis, prior to the time of the 
primary analysis for PFS, with each cohort considered independently.  For example, 
availability of clinical trial results for a specific external competitor molecule during the 
course of 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 two molecules.  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 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 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 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 


Ipatasertib—F. Hoffmann-La Roche Ltd
145/Protocol CO40016, Version 11 (Cohort C)
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.
After the primary analysis for PFS, additional OS interim analyses may be conducted to 
provide additional OS data, per the recommendation from health authorities. If 
conducted, the Lan-DeMets -spending function with an O’Brien-Fleming boundary will 
be used to control the overall type I error for OS accounting for the additional OS interim 
analyses.
6.9
CHINA SUBGROUP ANALYSES
After enrollment for the global study is completed, additional Chinese patients may 
continue to be recruited into the China extension cohorts. A total of up to 90 Chinese 
patients with TNBC with PIK3CA/AKT1/PTEN-altered tumors and up to 120 Chinese 
patients with HR+/HER2breast cancer with PIK3CA/AKT1/PTEN-altered tumors from 
China (mainland China, Hong Kong or Taiwan) may be enrolled, including Chinese
patients enrolled within the global study population and the China extension phase,
combined.  The objective of the China subgroup analyses is to assess the efficacy and 
safety of ipatasertib + paclitaxel versus placebo + paclitaxel in a patient population from 
China, including those enrolled originally during the global phase and the China
extension phase. 
The analysis of PFS among Chinese patients with TNBC will be performed when 
approximately 50 PFS events have occurred in patients with TNBC from the China 
subgroup. A total of 50 PFS events in the China subgroup will provide approximately 
91% probability of observing at least 50% of the risk reduction in PFS expected to be 
observed in the global population, assuming that the true PFS hazard ratio in the China 
subgroup is the same as the target PFS hazard ratio in the global population.  The 
analysis of PFS among Chinese patients with HR+/HER2- breast cancer will be 
performed when approximately 65 PFS events have occurred in patients with
HR+/HER2- breast cancer from the China subgroup. A total of 65 PFS events in the 
China subgroup will provide approximately 89% probability of observing at least 50% of 
the risk reduction in PFS expected to be observed in the global population, assuming
that the true PFS hazard ratio in the China subgroup is the same as the target PFS 
hazard ratio in the global population.
Data from patients in the China extension phase will not be included in the analyses of 
the global phase of the study; instead, data will be combined with data from Chinese 
patients in the global phase of the study and summarized as the China subgroup 
analysis in a separate report.
Details regarding PK analysis for the potential China extension phase will also be 
described in the SAP.


Ipatasertib—F. Hoffmann-La Roche Ltd
146/Protocol CO40016, Version 11 (Cohort C)
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.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff on the eCRFs.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in 
a readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
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, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 


Ipatasertib—F. Hoffmann-La Roche Ltd
147/Protocol CO40016, Version 11 (Cohort C)
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.
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 
IMPs, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results medication inventory records, and images 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.
The Sponsor will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.


Ipatasertib—F. Hoffmann-La Roche Ltd
148/Protocol CO40016, Version 11 (Cohort C)
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 a Child’s Informed Assent Form, biomarker-specific consent or Mobile 
Nursing Informed Consent Form, if applicable) will be provided to each site.  If applicable, 
it will be provided in a certified translation of the local language.  The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
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.


Ipatasertib—F. Hoffmann-La Roche Ltd
149/Protocol CO40016, Version 11 (Cohort C)
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.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.


Ipatasertib—F. Hoffmann-La Roche Ltd
150/Protocol CO40016, Version 11 (Cohort C)
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 Roche policy on study data publication 
(see Section 9.5).
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.
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, 


Ipatasertib—F. Hoffmann-La Roche Ltd
151/Protocol CO40016, Version 11 (Cohort C)
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 120150 sites globally will participate to enroll approximately 450 patients
during the global enrollment phase.  Enrollment will occur through an IxRS.  
After global enrollment is completed (i.e., after approximately 450 patients), as needed,
up to 210 Chinese patients may be enrolled in total (between Cohorts A and B; 
combining Chinese patients enrolled in the global enrollment phase and those enrolled 
in the China extension phase).
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An iDMC will be employed to monitor and evaluate patient safety (Cohorts A and B)
throughout the study.  Tumor response and progression will be evaluated by an 
independent review committee as needed. Membership and procedures for each of 
these committees will be detailed in a charter.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public 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
Study Information at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf


Ipatasertib—F. Hoffmann-La Roche Ltd
152/Protocol CO40016, Version 11 (Cohort C)
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Ipatasertib—F. Hoffmann-La Roche Ltd
153/Protocol CO40016, Version 11 (Cohort C)
10.
REFERENCES
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use 
of granulocyte-colony stimulating factor to reduce the incidence of 
chemotherapy-induced febrile neutropenia in adult patients with 
lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47:832.
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:36576.
Adams S, Diamond JR, Hamilton EP, et al. Phase Ib trial of atezolizumab in combination 
with nab-paclitaxel in patients with metastatic triple-negative breast cancer 
(mTNBC) [absract]. J Clin Oncol 2016;34(suppl; abstr 1009).  
[ASCO/CAP] American Society of Clinical Oncology/College of American Pathologists. 
Guideline recommendations for immunohistochemical testing of estrogen and 
progesterone receptors in breast cancer (unabridged version) [resource on the 
Internet]. 2010 [cited 8 March 2019]. Available from: 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.
[ASCO/CAP] American Society of Clinical Oncology/College of American Pathologists. 
Recommendations for human epidermal growth factor receptor 2 testing in breast 
cancer [resource on the Internet]. 2013 [cited 8 March 2019]. Available from: 
https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-
guidelines/recommendations-for-human-epidermal-growth-factor-2-testing-in-
breast-cancer.
Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute’s 
patient-reported outcomes version of the common terminology criteria for adverse 
events (PRO-CTCAE). J Natl Cancer Inst 2014;106:111. doi: 10.1093/jnci/dju244.
Bellacosa A, Kumar CC, Di Critofano A, et al. Activation of AKT kinases in cancer: 
implications for therapeutic targeting. Adv Cancer Res 2005;94:2986. 
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on 
tumor-specific T cells as a mechanism of immune evasion: implications for tumor 
immunotherapy. Cancer Immunol Immunother 2005;54:30714.
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T cell exhaustion: an 
update on implications for chronic infections and tumor evasion. Cancer Immunol 
Immunother 2007;56:73945.
Brognard J, Clark AS, Ni Y, et al. Akt/protein kinase B is constitutively active in 
non-small cell lung cancer cells and promotes cellular survival and resistance to 
chemotherapy and radiation. Cancer Res 2001;61:398697.


Ipatasertib—F. Hoffmann-La Roche Ltd
154/Protocol CO40016, Version 11 (Cohort C)
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:2941.
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372.
Brugge J, Hung MC, Mills GB.  A new mutational AKTivation in the PI3K pathway. 
Cancer Cell 2007;12:1047.
Butte MJ, Keir ME, Phamduy TB. Programmed death-1 ligand 1 interacts specifically 
with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 
2007;27:11122.
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast 
tumours. Nature 2012;490:6170. 
Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus 
guidelines for Advanced Breast Cancer (ABC 3). Ann Oncol 2017;28:1633.
Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol 2012;23(Suppl 7):vii119.
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation 
immunotherapy-inhibiting programmed death-ligand 1 and programmed death-1. 
Clin Cancer Res 2012;18:65807.
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 
2013;39:110.
Clark AS, West K, Streicher S, et al. Constitutive and inducible Akt activity promotes 
resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol 
Cancer Ther 2002;1:70717.
Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for interpreting change 
scores for the European Organisation for the Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30. Eur J Cancer 2012;48(11):171321.
Coleman RE and Rubens RD. Bone metastases and breast cancer. Cancer Treat Rev. 
1985;12(4):25170.
Crompton JG, Sukumar M, Roychoudhuri R, et al. Akt inhibition enhances expansion of 
potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res 
2015;75:296305.
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:134152; discussion 13536.
Deng R, Bumbaca D, Pastuskovas CV, et al. Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 
monoclonal antibody, an immune checkpoint inhibitor. MAbs 2016;8:593603.


Ipatasertib—F. Hoffmann-La Roche Ltd
155/Protocol CO40016, Version 11 (Cohort C)
EuroQoL Group. EuroQoLa new facility for the measurement of health-related quality 
of life. Health Policy 1990;16:199208.
Fayers PM, Aaronson NK, Bjordal K, et al. on behalf of the EORTC Quality of Life Group. 
The EORTC QLQ-C30 scoring manual (3rd ed). Brussels: European Organisation 
for Research and Treatment of Cancer, 2001.
Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a multicentre, 
open-label, phase 2 randomised controlled trial. Lancet 2016;387:183746.
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 
2015;136:E35986.
George S, Miao D, Demetri GD, et al.  Loss of PTEN is associated with resistance to 
anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. 
Immunity 2017;46:197204.
Gubser PM, Bantug GR, Razik L, et al. Rapid effector function of memory CD8+ T cells 
requires an immediate-early glycolytic switch. Nat Immunol 2013;14:106472.
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality 
of life (QoL) questionnaire module to supplement the EORTC core cancer QoL 
questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study 
Group on Quality of Life. Eur J Cancer 1999;35:93941.
Hales RK, Banchereau J, Ribas A, et al. Assessing oncologic benefit in clinical trials of 
immunotherapy agents. Ann Oncol 2010;21:194451.  
Harb WA. Management of patients with hormone receptorpositive breast cancer with 
visceral disease: challenges and treatment options. Cancer Manag Res 
2015;7:3746.  
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of the EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. N Engl J Med 2010;363:71123.
Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal 
complications in patients with breast cancer and lytic bone metastases. Protocol 
19 Aredia Breast Cancer Study Group. N Engl J Med. 1996;335(24):178591.
Irvin W Jr, Muss HB, Mayer DK. Symptom management in metastatic breast cancer. 
Oncologist 2011;16:120314.
Isakoff SJ, Infante JR, Juric D, et al. Phase Ib dose-escalation study of the Akt inhibitor 
ipatasertib with paclitaxel in patients with advanced solid tumors. Annals of 
Oncology 2014;25 (suppl_4):iv148. 


Ipatasertib—F. Hoffmann-La Roche Ltd
156/Protocol CO40016, Version 11 (Cohort C)
Jamis-Dow CA, Pearl ML, Watkins PB, et al. Predicting drug interactions in vivo from 
experiments in vitro. Human studies with paclitaxel and ketoconazole. Am J Clin 
Oncol 1997;20:5929.
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res 2013;22:171727.
Jemal A, Bray F, Center MM, et al. Global cancer statistics. Cancer J Clin 
2011;61:6990.
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration
resistant prostate cancer. N Engl J Med 2010;363:41122.
Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. 
Annual Rev Immunol 2008;26:677704.
Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies 
for triple-negative breast cancer subtypes. J Pathol 2014;232:14250.
Lin J, Sampath D, Nannini MA, et al. Targeting activated Akt with GDC-0068, a novel 
selective Akt inhibitor that is efficacious in multiple tumor models.  Clin Cancer Res 
2013;19:176072.
Lin K, Lin J, Wu WI, et al. An ATP-site on-off switch that restricts phosphatase 
accessibility of Akt. Sci Signal 2012;5:ra37.
LoRusso PM. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol 
2016;34:380315.
Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in 
circulating lung-cancer cells. N Engl J Med 2008;359:36677. 
Manning BD and Cantley LC. AKT/PKB signaling: navigating downstream. Cell 
2007;129:126174.
Mauri D, Kamposioras K, Tsali L, et al. Overall survival benefit for weekly vs. three-
weekly taxanes regimens in advanced breast cancer: a meta-analysis. Cancer 
Treat Rev 2010;36:6974.
Miles DW, Cameron D, Bondarenko I, et al. Bevacizumab plus paclitaxel versus placebo 
plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer 
(MERiDiAN): a double-blind placebo-controlled randomised phase III trial with 
prospective biomarker evaluation. Eur J Cancer 2017;70:146155.
Miles DW, Diéras V, Cortés J, et al. First-line bevacizumab in combination with 
chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup 
analyses of data from 2447 patients. Ann Oncol 2013;24:277380.
Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone 
for metastatic breast cancer. N Engl J Med 2007;357:266676.


Ipatasertib—F. Hoffmann-La Roche Ltd
157/Protocol CO40016, Version 11 (Cohort C)
Millis SZ, Gatalica Z, Winkler J, et al. Predictive biomarker profiling of > 6000 breast 
cancer patients shows heterogeneity in TNBC, with treatment implications. Clin 
Breast Cancer 2015;15:47381.e3. 
Nanda R, Chow LQ, Dees EC. Pembrolizumab in patients with advanced triple-negative 
breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 2016;34:24607.
[NCCN] National Comprehensive Cancer Network. NCCN Guidelines: Breast Cancer, 
Version 1 [resource on the Internet]. 2017 [cited 12 March 2017]. Available from: 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast.
O’Dwyer PJ and Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT) 1A1 
and irinotecan: practical pharmacogenomics arrives in cancer therapy. 
J Clin Oncol 2006;24:45348.
Paclitaxel U.K. Summary of Product Characteristics, Hospira UK Ltd. 2016. Available 
from: https://www.medicines.org.uk/emc/medicine/15842.
Papa A, Wan L, Bonora M, et al. Cancer-associated PTEN mutants act in a dominant-
negative manner to supress PTEN protein function. Cell 2014;157:595610. 
Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated 
immunotherapy. Cancer Discov. 2016;6:20216. 
Pereira B, Chin SF, Rueda OM, et al. The somatic mutation profiles of 2,433 breast 
cancers refines their genomic and transcriptomic landscapes. Nat Commun 
2016;7:11479.
Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-
controlled, phase III trial of chemotherapy with or without bevacizumab for first-line 
treatment of human epidermal growth factor receptor 2-negative, locally recurrent 
or metastatic breast cancer. J Clin Oncol 2011;29:125260.
Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients 
with a Germline BRCA Mutation. N Engl J Med 2017;377:52333.
Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability 
results: Olaparib versus chemotherapy treatment of physician's choice in patients 
with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann 
Oncol 2019;30(4):55866.
Rodler E, Korde L, Gralow J. Current treatment options in triple negative breast cancer. 
Breast Dis 2010;32:99122.
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:190920.


Ipatasertib—F. Hoffmann-La Roche Ltd
158/Protocol CO40016, Version 11 (Cohort C)
Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic TNBC (mTNBC): 
long-term clinical outcomes and biomarker analyses [abstract]. Presented at 
American Association for Cancer Research 108th Annual Meeting, April 15, 2017; 
abstract 2986.
Schmid P, Abraham J, Chan S et al. AZD5363 plus paclitaxel versus placebo plus 
paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): 
a randomised, double-blind, placebo-controlled, phase II trial. J Clin Oncol
2018a;36:1007.
Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced 
triple-negative Breast Cancer. N Engl J Med 2018b;379:210821.
Schwarzenbach H, Hoon DSB, Pantel K. Cell-free nucleic acids as biomarkers in cancer 
patients. Nat Rev Cancer 2011;11:42637.
Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly 
compared with every-3-weeks paclitaxel for metastatic breast cancer, with 
trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab 
or not in HER-2 nonoverexpressors: final results of cancer and leukemia group B 
protocol 9840. J Clin Oncol 2008;26:16429.
Shinozaki M, O’Day SJ, Kitago M, et al. Utility of circulating B-RAF DNA mutation in 
serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer 
Res 2007;13:206874.
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice 
guideline. J Clin Oncol 2006;24:3187205.
Solit DB, Basso AD, Olshen AB, et al. Inhibition of heat shock protein 90 function down-
regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 2003;63:213944.
Sprangers MA, Groenvold M, Arraras JI, et al. The European Organization for Research 
and Treatment of Cancer breast cancer-specific quality-of-life questionnaire 
module: first results from a three-country field study. J Clin Oncol 
1996;14:275668. 
Swanton C. Chemotherapy and metastatic breast cancer. In: Swanton C, Johnston SRD, 
editors. Handbook of Metastatic Breast Cancer, 1st ed. Abingdon, Oxon: Informa 
Healthcare, 2006:3360.
TAXOL(paclitaxel) INJECTION, Bristol-Myers Squibb. 2011 [cited 20 March 2017]. 
Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf.
Tokunaga E, Oki E, Egashira A, et al. Deregulation of the Akt pathway in human cancer. 
Curr Cancer Drug Targets 2008;8:2736.


Ipatasertib—F. Hoffmann-La Roche Ltd
159/Protocol CO40016, Version 11 (Cohort C)
Tutt A, Ellis P, Kilbum L, et al. Abstract S301: the TNT trial: a randomized phase III trial 
of carboplatin (C) compared with docetaxel (D) for patients with metastatic or 
recurrent locally advanced triple-negative or BRCA1/2 breast cancer 
(CRUK/07/012). Cancer Res 2015;75(9 Suppl):S301.
Turner N, Alacon E, Armstrong A, et al. BEECH: A randomised phase 2 study assessing 
the efficacy of AKT inhibitor AZD5363 combined with paclitaxel in patients with 
ER+ve advanced or metastatic breast cancer, and in a PIK3CA mutant 
subpopulation. Ann Oncol 2017;28(5 Suppl): v74108.
van der Waart AB, van de Weem NM, Maas F, et al. Inhibition of Akt signaling promotes 
the generation of superior tumor-reactive T cells for adoptive immunotherapy. 
Blood 2014;124:3490500.
Vuylsteke P, Huizing M, Petrakova K, et al. Pictilisib PI3Kinase inhibitor (a 
phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of 
hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast 
cancer: interim analysis of the multicentre, placebo-controlled, phase II 
randomised PEGGY study. Ann Oncol 2016;27:205966.
Wallin JJ, Guan J, Prior WW, et al. Nuclear phospho-Akt increase predicts synergy of 
PI3K inhibition and doxorubicin in breast and ovarian cancer. Sci Transl Med 
2010;2:48ra66.
Wolff AC, Hale Hammond ME, Allison KH, 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;36:210522.
Woo JS, Lee CH, Shim CK, et al. Enhanced oral bioavailability of paclitaxel by 
coadministration of the P-glycoprotein inhibitor KR30031. Pharm Res 2003; 
20:2430.
Wood R, de Courcy J, Mitra D, and Iyer S. Patient reported pain severity and 
interference in HR/HER2advanced/metastatic breast cancer in real world 
settings. Ann Oncol 2016;27(suppl_6).
Xu N, Lao Y, Zhang Y, et al. Akt: a double-edged sword in cell proliferation and genome 
stability. J Oncol 2012;2012:951724. doi: 10.1155/2012/951724.
Xue G, Zippelius A, Wicki A, et al. Integrated Akt/PKB signaling in immunomodulation 
and its potential role in cancer immunotherapy. J Natl Cancer Inst 2015;107:110.
Yan Y, Serra V, Prudkin L, et al. Evaluation and clinical analyses of downstream targets 
of the Akt inhibitor GDC-0068. Clin Cancer Res 2013;19:697686.
Yang J, Riella LV, Chock S. The novel costimulatory programmed death ligand 1/B7.1 
pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 
2011;187:11139.


Ipatasertib—F. Hoffmann-La Roche Ltd
160/Protocol CO40016, Version 11 (Cohort C)
Yang SX, Polley E, Lipkowitz S. New insights on PI3K/AKT pathway alterations and 
clinical outcomes in breast cancer. Cancer Treat Rev 2016;45:8796.
Yap TA, Garrett MD, Walton MI, et al. Targeting the PI3K-AKT-mTOR pathway: progress, 
pitfalls, and promises. Curr Opin Pharmacol 2008;8:393412.


Ipatasertib—F. Hoffmann-La Roche Ltd
161/Protocol CO40016, Version 11 (Cohort C)
Appendix 1
Schedule of Activities: Cohorts A and B
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening
Safety 
Eligibility 
or 
Baseline
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycles 5
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Signed informed 
consent(s) d
x
Demographics, 
medical history, 
prior cancer 
treatment
x
Tumor tissue 
sample submission 
x e
Confirmation of 
biomarker eligibility 
(local or central 
testing) 
x ii
Blood sample for 
biomarkers f
x f
x f
x f
x f
Viral serology g
x
Blood sample for 
WGS h
x
Complete physical 
examination
x
x


Appendix 1
Schedule of Activities: Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
162/Protocol CO40016, Version 11 (Cohort C)
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening
Safety 
Eligibility 
or 
Baseline
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycles 5
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Limited physical 
examination
x
x
x
x
x
x
x
x
x
x
x
Weight 
x
x
x
x
x
x
Height
x
Vital signs i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance 
Status
x
x
x
x
x
x
x
ECHO or MUGA 
scan
x j
12-Lead 
electrocardiogram k
x
x
Hematology l
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
INR and PTT (or 
aPTT)
x
x
Fasting serum 
chemistry n
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
Fasting lipid profile, 
amylase, lipase
x
x o
x o
x
HbA1C
x
x o
x o
x
Urinalysis
x
As clinically indicated
x
Pregnancy test p
x
x p
x
x
x
x
x
Tumor 
assessments q
x
Per standard of care r
x s
x t
Bone scan
x u
Every 16 weeks based on starting date of C1D1
x u
x t


Appendix 1
Schedule of Activities: Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
163/Protocol CO40016, Version 11 (Cohort C)
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening
Safety 
Eligibility 
or 
Baseline
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycles 5
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Head scan (CT or 
MRI scan)
x v
Prophylaxis 
anti-diarrheal (2 mg 
BID loperamide or 
equivalent) w
If side effects are not tolerated, doses may be reduced. After 1 cycle without any 
diarrhea, continuation is at physician's discretion. If diarrhea occurs, it should be 
managed per guidelines in Appendix 13; anti-diarrheal treatment should also be 
resumed with loperamide prophylaxis as needed.
Ipatasertib/placebo 
dispension/
accountability
x x
x
x
x
x
Paclitaxel 
administration y
x x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Record 
cancer-related 
radiotherapy and 
surgical procedures z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events bb, z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x cc
x cc
EORTC QLQ-C30 
dd
x
x
x
x
x
x
x ee
PRO-CTCAE dd
x
x
x
x
x
x
EQ-5D-5L dd
x
x
x
x
x
x
x ee
PK samples ff
x
x
x
Survival and 
anti-cancer therapy 
follow-up z
x gg


Appendix 1
Schedule of Activities: Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
164/Protocol CO40016, Version 11 (Cohort C)
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening
Safety 
Eligibility 
or 
Baseline
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycles 5
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Tumor tissue 
sample obtained at 
time of progression 
(optional) hh
x hh
Patient diary 
(medication, dosing 
log, Kit ID)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
BIDtwice a day; CT computed tomography; ctDNAcirculating tumor DNA; Dday; ECHOechocardiogram; ECOGEastern Cooperative 
Oncology Group; EORTCEuropean Organisation for the Research and Treatment of Cancer; FNAfine-needle aspiration; HER2human 
epidermal growth factor receptor 2; HRhormone receptor; MUGAmultiple-gated acquisition; MRImagnetic resonance imaging; 
NGSnext-generation sequencing; PKpharmacokinetic; PROpatient-reported outcome; PRO-CTCAEPatient-Reported Outcomes version of 
the Common Terminology Criteria for Adverse Events; QD once a day; RECISTResponse Evaluation Criteria in Solid Tumors; SDDV study 
drug discontinuation visit; TNBCtriple-negative breast cancer; Treat.treatment; WGSwhole genome sequencing. 
Notes:  Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within the screening safety eligibility/ 
baseline window specified for each assessment.  Screening assessments are to be performed after informed consent and generally within 28 days 
preceding Day 1 of Cycle 1 unless otherwise noted. The safety eligibility/baseline window does not apply to the biomarker-specific screening 
process (i.e., submission of tissue/blood sample for biomarker testing). In addition, patients must have adequate hematologic and organ function 
within 14 days and have a negative pregnancy test (if applicable) prior to the first study treatment on Day 1 of Cycle 1, as defined in Section 4.1.1.  
All assessments or procedures are to be performed predose unless otherwise specified.
a Screening window per individual assessment guidelines detailed, generally within 28 days of Day 1 of Cycle 1 for time-dependent screening 
safety eligibility/baseline assessments.
b Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment period should be performed within3 days of the 
scheduled date or window.  Study assessments may be delayed or moved ahead of the window to accommodate holidays, vacations, and 
unforeseen delays; however, study cycle day count continues without breaks; i.e., every cycle contains exactly 28 days.  
c The study drug discontinuation visit should occur approximately 28 days after the last administration of ipatasertib/placebo or paclitaxel, 
whichever is discontinued last, or prior to initiation of another therapeutic regimen.


Appendix 1
Schedule of Activities: Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
165/Protocol CO40016, Version 11 (Cohort C)
d Patients may be consented for the biomarker-specific process (if enrolling on the basis of central tissue or blood-based FMI testing) using the 
biomarker-specific ICF, followed by (if an alteration is present) full study consent and remaining screening procedures prior to enrollment in the 
study; or, patients may consent using the full study ICF prior to screening and enrollment.  Informed consent must be documented before any 
study-specific screening procedure is performed, and may be obtained more than 28 days before initiation of study treatment.
e Archival tissue (either formalin-fixed paraffin-embedded tumor specimens or a minimum of 20 unstained serial paraffin slides) and an associated 
pathology report must be confirmed to be available prior to entry into the study.  This requirement is required for all patients except those 
enrolled on the basis of PIK3CA/AKT1/PTEN alteration results available from the FMI commercial tissue-based NGS assay known as 
FoundationONE CDx, when a formalin fixed, paraffin embedded tumor (FFPE) tissue block or 10 freshly cut unstained, serial tumor slides from 
the most recently collected tumor tissue is acceptable for other protocol-mandated secondary and exploratory assessments, upon approval by 
the Medical Monitor.  In the absence of archival tissue, newly obtained tissue biopsy samples of non-target lesions (excluding cytology, FNA 
specimens and bone metastasis requiring decalcification) are acceptable (if it is assessable and the biopsy can be safely obtained).  In general, 
a minimum of three core biopsies for NGS testing are required. If PIK3CA/AKT1/PTEN-altered status has been determined for a patient during 
study screening procedures, a repeat biomarker-specific screening is not required.  
f
Blood will be collected for ctDNA analysis at screening (either as part of the biomarker-specific screening process or full screening), at the time 
of the first tumor assessment (7 days), and at the study drug discontinuation visit.  For patients who send a blood sample for FACT assay to 
determine biomarker eligibility, the initial screening blood sample may be used for this purpose, but an additional blood sample taken on Day 1 of 
Cycle 1 will be required for exploratory biomarker assessment. 
g HIV, HBsAg, total hepatitis B core antibody (HBcAb), HCV antibody; additional tests for HBV DNA or HCVRNA will be required to confirm 
eligibility.
h Samples will be collected only at sites with local regulatory authority approval. Sample collection may occur at the same time as other blood 
sampling if preferred (i.e., within 48 hours prior to dosing at the same time as laboratory samples or postdose at the same time as the PK 
sample).
i
Includes pulse rate, respiratory rate, systolic and diastolic blood pressure while patient is in a seated position after resting for 5 minutes, and 
temperature (oral, axillary, or tympanic).  On paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of the infusion.  
From Cycle 5 onward, if paclitaxel treatment has been discontinued, the patient is not required to return to the clinic for Days 8 and 15 vital sign 
assessments.  A telephone call for adverse events and concomitant medication assessment may be performed as clinically indicated.
j
Performed within 12 weeks prior to Day 1 of Cycle 1. Under exceptional circumstances cardiac function assessment by methods other than 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) may be acceptable, if this is consistent with local standard practice (e.g., cardiac 
MRI), but must be approved by the Medical Monitor.
k A single 12-lead ECG measurement at screening and at SDDV visit, and as clinically indicated (refer to Section 4.5.7).
l
Includes WBC count, WBC differential count (including absolute neutrophil counts, lymphocytes), hemoglobin, hematocrit, and platelet count.
m Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic; results should be available to assess dosing; 
with at least 8-hour fasting for glucose measurement as indicated (refer to Section 4.5.6). Glucose logs for any home glucose monitoring 
performed should also be reviewed at clinic visits prior to dosing, and only values which result in intervention recorded within the eCRF.


Appendix 1
Schedule of Activities: Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
166/Protocol CO40016, Version 11 (Cohort C)
n Includes sodium, potassium, bicarbonate, glucose (fasting), BUN/urea, creatinine, calcium, phosphorus, magnesium, total bilirubin, albumin, 
LDH, ALT, AST, and ALP.  For investigational sites in countries where bicarbonate may not be collected as part of the standard chemistry panel, 
bicarbonate will not be measured.  For investigational sites where local practice includes measuring only fasting plasma glucose levels, these 
local assessments may be acceptable to confirm eligibility and should be provided consistently across the study for intra-patient comparability.  
Grade 3 non-hematologic toxicity should be monitored at least weekly.
o Fasting lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides), amylase, lipase, and HbA1c will be assessed 
at screening, every 3 cycles starting on Day 1 of Cycle 3, and at SDDV visit.
p For women of childbearing potential.  A serum pregnancy test is to be performed at screening. A negative serum pregnancy test must be 
obtained either within 96 hours prior to C1D1 study treatment administration, or within 7 days of C1D1 (in this case, confirmed by a negative 
urine pregnancy test prior to C1D1 dosing).  In addition, pregnancy tests (serum or urine) are to be performed within 96 hours of Day 1 of each 
following treatment cycle prior to dosing, and a pregnancy test should be performed when clinically indicated.  If urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test.  For all other women, documentation must be present in medical history confirming that patient 
is not of childbearing potential.
q Tumor assessments performed according to RECIST v1.1.  The method used for a patient (CT or MRI scan or photographic measurements) 
must be the same throughout the study.  An objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation. A missed tumor assessment should be rescheduled as soon as possible.  Images for tumor assessments will be prospectively 
collected to enable retrospective blinded independent central review when needed. As of Protocol CO40016, Version 10 (Cohort C), images for 
tumor assessments will no longer be collected for blinded independent central review.
r
As of Protocol CO40016 Version 11 (Cohort C), tumor assessments (TAs) should be calculated from C1D1 (study Day 1) and completed per 
standard of care.  Therefore, the window for each scan will be the 7 days of the given week. Images for tumor assessments will be prospectively
collected to enable retrospective blinded independent central review when needed. As of Protocol CO40016, Version 10 (Cohort C), images for 
tumor assessments will no longer be collected for blinded independent central review.
s At SDDV visit, tumor assessments should be performed only if not performed within the previous 6 weeks.  If a patient discontinues from the 
study for any reason other than disease progression per RECIST v1.1, every effort should be made to obtain follow-up CT scans to assess 
disease response approximately every 812 weeks until documented progressive disease per RECIST v1.1 (as of Protocol CO40016 
Version 11 [Cohort C] this is no longer required).  Images for tumor assessments will be collected to enable retrospective blinded independent 
central review when needed. As of Protocol CO40016, Version 10 (Cohort C), images for tumor assessments will no longer be collected for 
blinded independent central review.
t
If a patient discontinues from the study for any reason other than disease progression per RECIST v1.1, a disease follow-up clinical visit 
approximately every 812 weeks will be required for tumor assessments until documented progressive disease per RECIST v1.1 (as of 
Protocol CO40016 Version 11 [Cohort C] this is no longer required). Images for tumor assessments will be collected prospectively to enable 
retrospective blinded independent central review when needed. As of Protocol CO40016, Version 10 (Cohort C), images for tumor assessments 
will no longer be collected for blinded independent central review.


Appendix 1
Schedule of Activities: Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
167/Protocol CO40016, Version 11 (Cohort C)
u An initial technetium bone scan should be performed within 6 weeks prior to Day 1 of Cycle 1.  In addition, bone disease identified on bone 
imaging should be evaluated radiographically by CT scan, MRI or X-ray to ascertain the presence of bone destruction versus a healing reaction.  
For patients with known or suspected bone metastasis, bone scans should be performed with every other tumor assessment starting from 
Week 16, adhering to the same 7-day window. If these patients discontinue from the study treatment for any reason other than disease 
progression, they should continue to be followed as clinically indicated, or for approximately every 4 months at disease follow-upuntil 
documented progressive disease per RECIST v1.1. As of Protocol CO40016 Version 11 (Cohort C), this long-term follow-up assessment is no 
longer required. If it is not possible to acquire a technetium bone scan, NaF-PET scans may be considered an alternative, with approval from the 
Medical Monitor.
v Performed within 6 weeks prior to Day 1 of Cycle 1.  Mandatory for Cohort A (TNBC), and as clinically indicated for Cohort B (HR/HER2).
w Administer prophylactic loperamide dose of 2 mg BID or 4 mg QD, if allowed by local guidance.  Refer to Appendix 13 for further diarrhea 
management guidance. 
x 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 3 days after randomization. For patients in Cohort A and Cohort B, who are unblinded and in the placebo paclitaxel arm, placebo no 
longer needs to be dispensed and therefore accounted for.
y If the patient's weight changes by 10% from baseline during the study, the body surface area and drug doses of paclitaxel should be 
recalculated.  
z A skeletal-related event (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 post-treatment 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.
aa At screening and Day 1 of Cycle 1, record all concomitant medications taken between 14 days prior to screening and Day 1 of Cycle 1; at 
subsequent time points, record new concomitant medications and any changes to the daily dosing.  Actual intake of anti-diarrheal, pain 
medication, or pre-medications at each dosage change should be recorded.
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 28 days after the last dose of study 
treatment.  After this period, investigators should report any serious adverse events that are believed to be related to prior treatment with study 
drug.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable 
by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse 
events considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
cc Patients with an unresolved adverse event or serious adverse event will be followed until the event is resolved or stabilized, the patient is lost to 
follow-up, or it has been determined that the study treatment or participation is not the cause of the event. Refer to Section 5.6 for adverse 
events that occur after the adverse event reporting period (defined as 28 days after the last dose of study drug).  An additional adverse event 
follow-up visit may be scheduled (even after the SDDV); follow-up by telephone for adverse event resolution date as applicable.
dd All PRO questionnaires are required to be completed prior to the administration of study treatment and/or prior to any other study assessment(s) 
that could bias patients’ responses.  The EORTC QLQ-C30, PRO-CTCAE, and EQ-5D-5L should be completed on Day 1 of each cycle and at 
the SDDV visit. PRO-CTCAE questionnaires will be completed when available in the local language of the investigational site.


Appendix 1
Schedule of Activities: Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
168/Protocol CO40016, Version 11 (Cohort C)
ee The global health status/HRQoL (which consists of Questions 29 and 30), pain (Questions 9 and 19), fatigue (Questions 10, 12 and 18) and 
dyspnea (Question 8) from the EORTC QLQ-C30 and the EQ-5D-5L will be administered during post-treatment follow-up calls (or visits).  
Questionnaires during the follow-up period do not need to be conducted in person (i.e., do not require an office visit); however, when 
administered via telephone, they must be conducted by interview assessment (using instructions and telephone scripts for administering the 
PRO assessments when available in the local language). These should be conducted prior to the disease follow-up tumor assessment, if 
applicable. As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up assessments are no longer required.
ff See Appendix 3 for schedule of PK assessments.
gg Information about survival, subsequent anti-cancer therapies and associated response, progression date, and most recent tumor assessment
date will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (1 month) until death, loss 
to follow up, or study termination by the Sponsor, unless the patient requests to be withdrawn from follow-up; this request must be documented 
in the source documents and signed by the investigator. As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up
assessments are no longer required.
hh Tumor biopsy collection is optional for study participation.  For patients who sign an Optional Research Biosample Repository Informed Consent 
Form and if tumor biopsies can be obtained with minimal risk and discomfort to the patient, a tumor biopsy would be collected at the time of 
progression within 6 weeks of the progression assessment and prior to initiation of a new anti-cancer therapy; tumor biopsy of the growing lesion 
is preferred.
ii Biomarker eligibility (i.e., presence of PIK3CA/AKT1/PTEN alteration) may be determined using central testing at FMI (from tumor tissue sample 
provided [CTA] or blood samples provided for ctDNA analysis [FACT assay]) or local/commercial testing using an appropriately validated 
molecular-based assay at an accredited diagnostic laboratory (CLIA accredited or equivalent).  If local/commercial assessment of
PIK3CA/AKT1/PTEN alteration status or central ctDNA is used to confirm biomarker eligibility, tumor tissue is still required to confirm alteration 
status centrally, with the exception of the commercial FoundationONE CDxassay, which would allow for a reduced tissue requirement (see 
Section 4.1.1), randomization should proceed based on the local result with no requirement to wait for central confirmation of biomarker eligibility.  
For all local/commercial molecular testing results used to determine biomarker eligibility a full laboratory report must be available and captured 
within the patient’s source documents to support enrollment, key details of the test and result used to confirm biomarker eligibility should be 
entered into the eCRF.  


Ipatasertib—F. Hoffmann-La Roche Ltd
169/Protocol CO40016, Version 11 (Cohort C)
Appendix 2
Schedule of Activities:  Cohort C
Screening (Day 28 to 
Day –1)
Treatment Cycles (28-Day Cycles) a
SDDV b
Post-
Treat. 
Follow-
Up
Cycles 
1 and 2
Cycle 3
Cycle 4
Cycles 5
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Biomarker
-Specific 
Screening
Safety 
Eligibility or 
Baseline
Signed informed 
consent(s) c
x
Viral serology d
x
Demographics, medical 
history, prior cancer treatment
x
Tumor tissue sample 
submission at screening
x e
Blood sample for WGS f
x
Blood sample for biomarkers
x
x ii
Complete physical 
examination g
x
x
Limited physical examination
x
x
x
x
x
x
x
x
x
Weight 
x
x
x
x
x
x
Height
x
Vital signs h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x
x
ECHO or MUGA scan
x i
12-Lead ECG j
x
x
Hematology k
x
x l
x l
x l
x l
x l
x l
x l
x l
x l
x l
x l
x l
x
INR and PTT (or aPTT)
x
x
Fasting serum chemistry m
x
x l
x l
x l
x l
x l
x l
x l
x l
x l
x l
x l
x l
x


Appendix 2
Schedule of Activities: Cohort C (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
170/Protocol CO40016, Version 11 (Cohort C)
Screening (Day 28 to 
Day –1)
Treatment Cycles (28-Day Cycles) a
SDDV b
Post-
Treat. 
Follow-
Up
Cycles 
1 and 2
Cycle 3
Cycle 4
Cycles 5
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
TSH, free T3 (or total T3), 
free T4 n
x
x
x
x n
x
Fasting lipid profile, amylase, 
lipase
x
x o
xo
x
HbA1C o
x
x
x
x
x
x
Urinalysis
x
As clinically indicated
x
Pregnancy test p
x
x p
x
x
x
x
Tumor assessments q
x
x r
x r
x s
xs
Bone scan
x t
See footnote "t"
x t
x t
Head scan (CT or MRI scan)
x u
Prophylaxis with 10 mg 
prednisone (or equivalent) for 
24 consecutive days hh
x
x
Daily antihistamine 
prophylaxis hh
x
x
x
Prophylaxis anti-diarrheal 
(2 mg BID loperamide or 
equivalent, as allowed per 
local guidelines, 2 mg after 
each loose watery stool, and 
up to 16 mg per day, or per 
local guidelines)
If side effects are not tolerated, doses may be reduced. After 1 cycle 
without any diarrhea, continuation is at physician's discretion. If 
diarrhea occurs, it should be managed per guidelines in Appendix 14; 
anti-diarrheal treatment should also be resumed with loperamide 
prophylaxis as needed.
Ipatasertib 
dispension/accountability
x v
x
x
x
Atezolizumab administration
x v
x 
x 
x
x
x
x
x
Paclitaxel administration w
x v
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Activities: Cohort C (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
171/Protocol CO40016, Version 11 (Cohort C)
Screening (Day 28 to 
Day –1)
Treatment Cycles (28-Day Cycles) a
SDDV b
Post-
Treat. 
Follow-
Up
Cycles 
1 and 2
Cycle 3
Cycle 4
Cycles 5
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Record cancer-related 
medications and surgical 
procedures
x
x
x
Concomitant medications x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events y
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x z
x z
EORTC QLQ-C30 dd, ee
x
x
x
x
x
x ee
PRO-CTCAE dd
x
x
x
x
x
EQ-5D-5L dd, ee
x
x
x
x
x
x ee
PK and ADA samples aa
x 
x bb
x
x
x
x ff
x cc
Tumor tissue sample 
obtained at time of 
progression (optional) gg
x gg
Patient diary (medication, 
dosing log, Kit ID)
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; BIDtwice a day; CT computed tomography; Dday; Discon.discontinuation; ECHO echocardiogram; 
ECOGEastern Cooperative Oncology Group; FNAfine-needle aspiration; HbA1C glycosylated hemoglobin; HBcAb hepatitis B core antibody; 
HBsAghepatitis B surface antigen; HCVhepatitis C virus; MRImagnetic resonance imaging; MUGAmultiple-gated acquisition; 
NGSnext-generation sequencing; PKpharmacokinetic; RECIST Response Evaluation Criteria in Solid Tumors; T3triiodothyronine;
T4thyroxine; Treat.treatment; TSHthyroid-stimulating hormone; WGSwhole genome sequencing. 
Notes:  Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within the screening window 
(Days 28 to 1) may be used for the study.  Screening assessments are to be performed within 28 days preceding Day 1 of Cycle 1 unless 
otherwise noted, and patients must have adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of 
Cycle 1, as defined in Section 4.1.1.  All assessments or procedures are to be performed predose unless otherwise specified.
a Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment period should be performed within3 days of the 
scheduled date.  Study assessments may be delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays; however, study cycle day count continues without breaks.  
b The study drug discontinuation visit should occur approximately 30 days after the last administration of ipatasertib, atezolizumab, paclitaxel, 
whichever is discontinued last, or prior to initiation of another therapeutic regimen.


Appendix 2
Schedule of Activities: Cohort C (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
172/Protocol CO40016, Version 11 (Cohort C)
c The Informed Consent Form for Cohort C may be signed only when a patient who initially screens for Cohort A (with TNBC) does not qualify for 
Cohort A (i.e., lack of PIK3CA/AKT1/PTEN alteration validated by central tumor tissue testing using the Foundation Medicine Clinical Trial 
Algorithm).
d HIV, HBsAg, total HBcAb, HCV antibody. If HCV antibody is positive, then need to test HCV RNA to confirm that HCV RNA is undetectable.
e Archival tissue (either formalin-fixed, paraffin-embedded tumor specimens or a minimum of 20 unstained serial paraffin slides) and an associated 
pathology report must be confirmed to be available prior to entry into the study.  In the absence of archival tissue, newly obtained tissue biopsy 
samples of non-target lesions (excluding cytology, FNA specimens and bone metastasis requiring decalcification) are acceptable (if it is 
assessable and the biopsy can be safely obtained).  In general, a minimum of three core biopsies for NGS testing are required.
f
Samples will be collected on Day 1 of Cycle 1 only and only at sites with local regulatory authority approval.
g Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  
h Includes pulse rate, respiratory rate, systolic and diastolic blood pressure while patient is in a seated position after resting for 5 minutes, and 
temperature (oral, axillary, or tympanic).  On paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of the infusion.  
On days when atezolizumab and paclitaxel are both administered vital sign should also be recorded prior to atezolizumab dosing (and during 
infusion if clinically indicated). From Cycle 5 onward, if paclitaxel treatment has been discontinued, the patient is not required to return to the 
clinic for Day 8 and Day 15 vital sign assessments.  However, if atezolizumab administration continues on these days then patient continue to 
have vital signs monitored when they present for atezolizumab infusions. A telephone call for adverse events and concomitant medication 
assessment may be performed as clinically indicated.
i
Performed within 12 weeks prior to Day 1 of Cycle 1. If the left ventricular ejection fraction (LVEF) result as assessed by either of these imaging 
modalities is felt to be inconsistent with the clinical picture, then the investigator may choose an alternative modality (i.e., cardiac MRI), if this is 
consistent with local standard practice.
j
A single 12-lead ECG measurement at screening and at the treatment discontinuation visit, and as clinically indicated (refer to Section 4.5.7).
k Includes WBC count, WBC differential count (including ANCs, lymphocytes), hemoglobin, hematocrit, and platelet count. Hematology 
assessments to be conducted per local guidelines prior to each chemotherapy dosing.
l
Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic; results should be available to assess dosing; 
with at least 8-hour fasting for glucose measurement as indicated.
m Includes sodium, potassium, bicarbonate, glucose (fasting), BUN/urea, creatinine, calcium, phosphorus, magnesium, total bilirubin, albumin, 
LDH, ALT, AST, and ALP.  For investigational sites in countries where bicarbonate may not be collected as part of the standard chemistry panel, 
bicarbonate will not be measured.  Grade 3 non-hematologic toxicity should be monitored at least weekly.  Chemistry evaluation to be 
conducted per local guidelines.
n TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 1 and every 
third cycle thereafter (i.e., Cycles 4, 7, 10, etc.).


Appendix 2
Schedule of Activities: Cohort C (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
173/Protocol CO40016, Version 11 (Cohort C)
o Fasting lipid profile, amylase, and lipase will be assessed at screening, every 3 cycles starting on Day 1 of Cycle 3, and at treatment 
discontinuation visit.  HbA1C will be assessed at the beginning of each cycle, with the exception of Cycle 1 (the screening value may be used in 
place of Cycle 1 testing). 
p For women of childbearing potential.  A serum pregnancy test is to be performed at screening and within 96 hours of Day 1, Cycle 1.  In addition, 
pregnancy tests (serum or urine) are to be performed within 48 hours of Day 1 of each treatment cycle, and a pregnancy test should be 
performed when clinically indicated.  If urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  For all other women, 
documentation must be present in medical history confirming that patient is not of childbearing potential.
q Tumor assessments performed according to RECIST v1.1.  The method used for a patient (CT or MRI scan or photographic measurements) 
must be the same throughout the study.  An objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation. A missed tumor assessment should be rescheduled as soon as possible.  Images for tumor assessments will be collected to 
enable retrospective independent central review when needed. As of Protocol CO40016, Version 10 (Cohort C), images for tumor assessments 
will no longer be collected for blinded independent central review.
r
As of Protocol CO40016 Version 11 (Cohort C), tumor assessments (TAs) should be calculated from C1D1 (study Day 1) and completed per 
standard of care.  Therefore, the window for each scan will be the 7 days of the given week.  Images for tumor assessments will be prospectively
collected to enable retrospective blinded independent central review when needed. As of Protocol CO40016, Version 10 (Cohort C), images for 
tumor assessments will no longer be collected for blinded independent central review.
s At treatment discontinuation visit, tumor assessments should be performed only if not performed within the previous 6 weeks.  If a patient 
discontinues from the study for any reason other than disease progression per RECIST v1.1, every effort should be made to obtain follow-up CT 
scans to assess disease response approximately every 812 weeks until documented progressive disease per RECIST v1.1, elective withdrawal 
from the study, or study completion or termination (as of Protocol CO40016 Version 11 [Cohort C] this is no longer required). Images for 
tumor assessments will be collected to enable retrospective blinded independent central review when needed. As of Protocol CO40016, Version 
10 (Cohort C), images for tumor assessments will no longer be collected for blinded independent central review.
t
An initial technetium bone scan should be performed within 6 weeks prior to Day 1 of Cycle 1.  In addition, bone disease identified on bone 
imaging should be evaluated radiographically by CT scan, MRI or X-ray to ascertain the presence of bone destruction versus a healing reaction.  
For patients with known or suspected bone metastasis, follow-up bone scans should be performed during Days 16–28 of every fourth cycle 
(every 16 weeks) and at the study termination visit. If it is not possible to acquire a technetium bone scan, NaF-PET scans may be considered 
an alternative, with approval from the Medical Monitor. If a patient discontinues from the study for any reason other than disease progression 
per RECIST v1.1, patients with bone metastases should continue to have bone scans during the follow-up phase, approximately every 16 weeks.
As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up assessments are no longer required.
u Performed within 6 weeks prior to Day 1 of Cycle 1.
v Patients should receive their first dose of study drug on the day of enrollment, if possible.  If this is not possible, the first dose should occur no 
later than 3 days after enrollment. Please note the specific instructions for corticosteroid prophylaxis in section 4.3.3, applicable to days in which 
the patient will receive both atezolizumab and paclitaxel.  


Appendix 2
Schedule of Activities: Cohort C (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
174/Protocol CO40016, Version 11 (Cohort C)
w If the patient's weight changes by 10% from baseline during the study, the body surface area and drug doses of paclitaxel should be 
recalculated.
x At screening and Day 1 of Cycle 1, record all concomitant medications taken between 14 days prior to screening and Day 1 of Cycle 1; at 
subsequent timepoints, record new concomitant medications and any changes to the daily dosing.  Actual intake of anti-diarrheal, pain 
medication, or premedications at each dosage change should be recorded. 
y 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 last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  Investigators should report any serious adverse events and 
adverse events of special interest that are believed to be related to prior treatment with study drug until 90 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  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.  
z Patients with an unresolved adverse event or serious adverse event will be followed until the event is resolved or stabilized, the patient is lost to 
follow-up, or it has been determined that the study treatment or participation is not the cause of the event.  Refer to Section 5.6 for adverse 
events that occur after the adverse event reporting period (defined as 30 days after the last dose of study drug for all adverse events, and 
90 days for serious adverse events and adverse events of special interest).  An additional adverse event follow-up visit may be scheduled (even 
after the treatment discontinuation visit); follow-up by telephone for adverse event resolution date as applicable.
aa See Appendix 4 for a schedule of PK assessments.
bb This sampling of PK and ADA does not need to be conducted on Cycle 2, Day 15.
cc Discontinuation sample of PK and ADA must be within 30 days of the last dose.
dd All PRO questionnaires are required to be completed prior to the administration of study treatment and/or prior to any other study assessment(s) 
that could bias patients’ responses.  The EORTC QLQ-C30, PRO-CTCAE, and EQ-5D-5L should be completed on Day 1 of each cycle and at 
the SDDV visit.  PRO-CTCAE questionnaires will be completed when available in the local language of the investigational site.
ee The global health status/HRQoL (which consists of Questions 29 and 30), pain (Questions 9 and 19), fatigue (Questions 10, 12, and 18) and 
dyspnea (Question 8) from the EORTC QLQ-C30 and the EQ-5D-5L will be administered during post-treatment follow-up calls (or visits).  
Questionnaires during the follow-up period do not need to be conducted in person (i.e., do not require an office visit); however, when 
administered via telephone, they must be conducted by interview assessment (using instructions and telephone scripts for administering the 
PRO assessments when available in the local language). These should be conducted prior to the disease follow-up tumor assessment, if 
applicable. As of Protocol CO40016 Version 11 (Cohort C), these long-term follow-up assessments are no longer required.
ff For Cycles 8, 12, and 16.
gg Tumor biopsy collection is optional for study participation.  For patients who sign an Optional Research Biosample Repository Informed Consent 
Form and if tumor biopsies can be obtained with minimal risk and discomfort to the patient, a tumor biopsy would be collected at the time of 
progression within 6 weeks of the progression assessment and prior to initiation of a new anti-cancer therapy; tumor biopsy of the growing lesion 
is preferred.


Appendix 2
Schedule of Activities: Cohort C (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
175/Protocol CO40016, Version 11 (Cohort C)
hh First cycle (or first 28 days of triplet combination dosing) only:  On days when patients will receive atezolizumab (typically Days 1 and 15), 
patients should receive at least 10 mg/day prednisone (or equivalent) as premedication prior to atezolizumab, followed by 10 mg/day prednisone
(or equivalent) for 24 consecutive days thereafter, unless contraindicated.  If institutional practice prior to paclitaxel is to give at least 10 mg/day 
prednisone on the day of paclitaxel, then the additional 10 mg prophylactic prednisone should not be given on that day to prevent rash.  Unless 
contraindicated, daily oral antihistamine prophylaxis should be used for at least the first cycle. It is suggested that a non-sedating oral 
antihistamine (such as loratadine, cetirizine, fexofenadine) and longer acting formulation be used.  The daily oral antihistamine used for rash 
prophylaxis may be held on the days of paclitaxel infusion if the paclitaxel pre-medications already includes an antihistamine.  
ii Applicable to Cycle 1 only.


Ipatasertib—F. Hoffmann-La Roche Ltd
176/Protocol CO40016, Version 11 (Cohort C)
Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Samples: 
Cohorts A and B
Visit
Timepoint
Sample Type
Cycle 1, Day 1
13 hours post-
ipatasertib/placebo
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 1, Day 15 a
Predose b
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 1, Day 15 a
13 hours post-
ipatasertib/placebo
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 3, Day 15 a
Predose b
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 3, Day 15 a
24 hours post-
ipatasertib/placebo
Plasma sample for 
ipatasertib/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, 
the sample collection may be delayed to another day when at least 3 consecutive 
days of ipatasertib/placebo dosing have been administered. 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
177/Protocol CO40016, Version 11 (Cohort C)
Appendix 4
Schedule of Pharmacokinetic and Immunogenicity, Samples:  
Cohort C
Visit
Time
Sample
Day 1 of Cycle 1
Prior to start of first atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
30 (10) minutes after end of 
atezolizumab infusion
Atezolizumab PK (serum)
13 hours post-
ipatasertib/placebo
Plasma sample for ipatasertib and 
G-037720
Day 15 of Cycle 1
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Prior to ipatasertib dose
Plasma sample for ipatasertib and 
G-037720
13 hours after ipatasertib dose
Plasma sample for ipatasertib and 
G-037720
Day 1 of Cycle 2
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 3
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 15 of Cycle 3
Prior to ipatasertib dose
Plasma sample for ipatasertib and
G-037720
24 hours after ipatasertib
Plasma sample for ipatasertib and 
G-037720
Day 1 of Cycle 4
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 8
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycles 12 and 16
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Treatment discontinuation visit 
(30 days after last dose)
At visit
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
ADAanti-drug antibody; 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 ipatasertib administration should also be 
recorded for the day of PK sampling.  PK sampling timepoint should be accurately reported.  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, the sample collection may be delayed to another day when at least 3 consecutive 
days of ipatasertib/placebo dosing have been administered. The sampling can be done any day after 
Day 12 of the relevant cycle corresponding with a planned ipatasertib/placebo dosing day.  Prior to start of 
atezolizumab and ipatasertib dose 0 to 3 hours prior to dosing of the drug(s) on the day of the visit.


Ipatasertib—F. Hoffmann-La Roche Ltd
178/Protocol CO40016, Version 11 (Cohort C)
Appendix 5
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations


Ipatasertib—F. Hoffmann-La Roche Ltd
179/Protocol CO40016, Version 11 (Cohort C)
Appendix 5
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations (cont.)
The complete guideline recommendations can be downloaded from: 
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


Ipatasertib—F. Hoffmann-La Roche Ltd
180/Protocol CO40016, Version 11 (Cohort C)
Appendix 6
ASCO/CAP HER2 Test Guideline Recommendations 


Ipatasertib—F. Hoffmann-La Roche Ltd
181/Protocol CO40016, Version 11 (Cohort C)
Appendix 6
ASCO/CAP HER2 Test Guideline Recommendations (cont.)


Ipatasertib—F. Hoffmann-La Roche Ltd
182/Protocol CO40016, Version 11 (Cohort C)
Appendix 6
ASCO/CAP HER2 Test Guideline Recommendations (cont.)


Ipatasertib—F. Hoffmann-La Roche Ltd
183/Protocol CO40016, Version 11 (Cohort C)
Appendix 6
ASCO/CAP HER2 Test Guideline Recommendations (cont.)


Ipatasertib—F. Hoffmann-La Roche Ltd
184/Protocol CO40016, Version 11 (Cohort C)
Appendix 6
ASCO/CAP HER2 Test Guideline Recommendations (cont.)
The most current guideline recommendations can be downloaded from: 
https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-
guidelines/recommendations-for-human-epidermal-growth-factor-2-testing-in-breast-
cancer








Ipatasertib—F. Hoffmann-La Roche Ltd
188/Protocol CO40016, Version 11 (Cohort C)
Appendix 7
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to be 
completed in this study.
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health.  Please answer all of the questions 
yourself by circling the number that best applies to you.  There are no "right" or "wrong" answers.  
The information that you provide will remain strictly confidential.
Not at
A
Quite
Very
All
Little
a Bit
Much
1.
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4 
5.
Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
6.
Were you limited in doing either your work or other daily activities? 1
2
3
4
7.
Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4
10.
Did you need to rest?
1
2
3
4
11.
Have you had trouble sleeping?
1
2
3
4
12.
Have you felt weak?
1
2
3
4
13.
Have you lacked appetite?
1
2
3
4
14.
Have you felt nauseated?
1
2
3
4
15.
Have you vomited?
1
2
3
4
16.
Have you been constipated?
1
2
3
4


Ipatasertib—F. Hoffmann-La Roche Ltd
189/Protocol CO40016, Version 11 (Cohort C)
Appendix 7
European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (cont.)
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
17.
Have you had diarrhea?
1
2
3
4
18.
Were you tired?
1
2
3
4
19.
Did pain interfere with your daily activities?
1
2
3
4
20.
Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21.
Did you feel tense?
1
2
3
4
22.
Did you worry?
1
2
3
4
23.
Did you feel irritable?
1
2
3
4
24.
Did you feel depressed?
1
2
3
4
25.
Have you had difficulty remembering things?
1
2
3
4
26.
Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27.
Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28.
Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent


Ipatasertib—F. Hoffmann-La Roche Ltd
190/Protocol CO40016, Version 11 (Cohort C)
Appendix 8
EuroQol 5-Dimension Questionnaire, 
Five-Level Version (EQ-5D-5L)
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to be 
completed in this study.


Ipatasertib—F. Hoffmann-La Roche Ltd
191/Protocol CO40016, Version 11 (Cohort C)
Appendix 8
EuroQol 5-Dimension Questionnaire, 
Five-Level Version (EQ-5D-5L) (cont.)




Ipatasertib—F. Hoffmann-La Roche Ltd
193/Protocol CO40016, Version 11 (Cohort C)
Appendix 9
Selected items from the Patient-Reported Outcomes version of 
the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) (cont.)


Ipatasertib—F. Hoffmann-La Roche Ltd
194/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
Measurability of Tumor at Baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable 
or non-measurable as described below.
a. Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow up, 
only the short axis will be measured and followed.  See also notes below on 
“Baseline Documentation of Target and Non-Target Lesions” for information on 
lymph node measurement.
b. Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumors: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:22847.
2 For consistency within this document, the section numbers and cross-references to 
other sections within the article have been deleted and minor formatting changes have 
been made.


Ipatasertib—F. Hoffmann-La Roche Ltd
195/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
c. Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions.  However, 
these techniques can be used to confirm the presence or disappearance of 
bone lesions.

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
Target Lesions:  Specifications by Methods of Measurements 
a. Measurement of Lesions
All measurements should be recorded in metric notation, with use of 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
196/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
b. Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will be considered measurable only 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 a chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thicknesses greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 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 whether substitution of these other approaches is possible and, 
if not, the patient should be considered not evaluable from that point forward.  Care must 
be taken in measurement of target lesions on a different modality and interpretation of 
non-target disease or new lesions since the same lesion may appear to have a different 
size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.


Ipatasertib—F. Hoffmann-La Roche Ltd
197/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Tumor Response Evaluation
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
Baseline Documentation of Target and Non-Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to 
a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is 10 mm by 
CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance, the next largest lesion that can be measured reproducibly 
should be selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node that is reported as being 20 mm30 mm has 
a short axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 
20 mm should be recorded as the node measurement.  All other pathological nodes 
(those with short axis 10 mm but 15 mm) should be considered non-target lesions.  
Nodes that have a short axis of 10 mm are considered non-pathological and should not 
be recorded or followed.


Ipatasertib—F. Hoffmann-La Roche Ltd
198/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases, “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
Response Criteria
a. Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
–
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
–
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
–
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b. Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 


Ipatasertib—F. Hoffmann-La Roche Ltd
199/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of 10 mm.
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and below measurable limit (BML) 
should be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well and BML should also be ticked.)
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion.
c. Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although some non-target lesions may actually be
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the time points specified in the protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
–
All lymph nodes must be non-pathological in size (10 mm short axis).


Ipatasertib—F. Hoffmann-La Roche Ltd
200/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)

Non-CR/Non-PD:  persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
–
The appearance of one or more new lesions is also considered progression.
d. Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden on the basis of the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease; that is, an increase in tumor burden representing an 
additional 73% increase in volume (which is equivalent to a 20% increase in diameter in 
a measurable lesion).  Examples include an increase in a pleural effusion from “trace” to 
“large” or an increase in lymphangitic disease from localized to widespread or may be 
described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  Although it would be ideal to have objective criteria apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.
e. New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 


Ipatasertib—F. Hoffmann-La Roche Ltd
201/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
should be unequivocalthat is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
Evaluation of Response
a. Time Point Response (Overall Response)
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.
Table 1 Time Point 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
202/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Table 2 Time Point Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised.
b. Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered not evaluable at that time point unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm
with three measured lesions, and during the study, only two lesions were assessed but 
those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, 
the response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess,” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that time point.


Ipatasertib—F. Hoffmann-La Roche Ltd
203/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Table 3 Best Overall Response When Confirmation Is Required
Overall Response 
at First Time Point
Overall Response at 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
PR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first time point, any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first time point.  Under these circumstances, the original CR should be changed to PR and 
the best response is PR.
c. Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 


Ipatasertib—F. Hoffmann-La Roche Ltd
204/Protocol CO40016, Version 11 (Cohort C)
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
progression even after discontinuation of treatment.  Symptomatic deterioration is not 
a descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1–3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment.  If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


Ipatasertib—F. Hoffmann-La Roche Ltd
205/Protocol CO40016, Version 11 (Cohort C)
Appendix 11
Preexisting Autoimmune Diseases and Immune Deficiencies
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with 
a medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life-threatening 
skin adverse reaction while receiving another immunostimulatory anti-cancer agent.  The
Medical Monitor is available to advise on any uncertainty over autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison disease
Ankylosing spondylitis
Anti-phospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating 
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Goodpasture syndrome
Graves disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cholangitis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


Ipatasertib—F. Hoffmann-La Roche Ltd
206/Protocol CO40016, Version 11 (Cohort C)
Appendix 12
Anaphylaxis Precautions
EQUIPMENT NEEDED

Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, IV, and/or endotracheal use in accordance with 
standard practice

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.


Ipatasertib—F. Hoffmann-La Roche Ltd
207/Protocol CO40016, Version 11 (Cohort C)
Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B
Guidelines for management of specific adverse events are provided in the subsections 
below.
DIARRHEA MANAGEMENT GUIDELINES
Specific guidelines for managing diarrhea to improve safety and tolerability are provided
in Table 1.  In this study, all patients should receive loperamide (2 mg oral twice a day or 
4 mg once a day) 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, and the prophylaxis dose may be adjusted as necessary, using their discretion 
based on clinical judgment and per local guidance. 
Treatment modifications for diarrhea (any grade), when it occurs, should be instituted as 
early as possible.  Guidelines for treatment of diarrhea following the prophylactic dose of 
loperamide (where allowed) includes use of loperamide 2 mg every 4 hours or after each 
loose, watery stool, up to the maximum total dose of 16 mg/day or per institutional 
guidelines and standard of care, including, but not limited to, additional therapy with 
Lomotil(diphenoxylate and atropine), codeine, or octreotide.  Duration of diarrhea may 
be minimized by taking ipatasertib/placebo with food, avoiding lactose-containing foods, 
and hydrating with 810 glasses per day (~12 oz/glass) of electrolyte-containing clear
liquid, such as broth or low-calorie drinks.  
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 
diarrhea to receive instructions of treatment and prevention of dehydration so that 
patients can be promptly and appropriately managed. Educational materials will be
provided to investigators and patients outlining these guidelines. 
Dose intensity of paclitaxel should be maintained as tolerated.  Dose reductions of 
ipatasertib/placebo will be by one level at a time (i.e., 400 to 300 mg; 300 to 200 mg) as 
outlined in Section 5.1.5.3 and Table 4.  If Grade ≥2 diarrhea persists following dose 
reductions of ipatasertib/placebo to 200 mg daily and with maximum treatment for 
diarrhea, ipatasertib/placebo should be discontinued.  Paclitaxel dose reduction or 
discontinuation should be considered if diarrhea persists even after ipatasertib/placebo 
discontinuation.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
208/Protocol CO40016, Version 11 (Cohort C)
Table 1
Diarrhea Management Guidelines
Severity of Diarrhea a
Management Guideline
Prevention

All patients are mandated to receive loperamide (2 mg 
BID or 4 mg QD) as prophylaxis for diarrhea in the first 
cycle, if allowed by local guidance.  If there are clinical 
concerns that preclude the use of loperamide 
prophylaxis in Cycle 1, discussion with the 
Medical Monitor is required.  Loperamide dose 
adjustment 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 with 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.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
209/Protocol CO40016, Version 11 (Cohort C)
Table 1
Diarrhea Management Guidelines (cont.)
Severity of Diarrhea a
Management Guideline
Grade 2
Increase of 46 stools per day 
over baseline; moderate increase 
in ostomy output compared with 
baseline

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 5.1.5.3) for recurrent Grade 2 
diarrhea.

When study treatment is resumed, loperamide 
prophylaxis should also be resumed and continues as 
clinically indicated, if allowed by local guidance.
Grade 3
Increase of 7 stools per day over 
baseline; incontinence; 
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 and paclitaxel until diarrhea 
improves to Grade 1 or better.  Ipatasertib/placebo 
should be reduced by one dose level (see Section 
5.1.5.3) when treatment is restarted.  Consider resuming 
paclitaxel at the same dose.

For recurrent Grade 3 diarrhea, reduce 
ipatasertib/placebo dose by one additional dose level 
(see Section 5.1.5.3).  Consider reducing paclitaxel by 
one dose level when treatment is restarted (see Section 
5.1.5.3).

When study treatment is resumed, loperamide 
prophylaxis should also be resumed and continues as 
clinically indicated, if allowed by local guidance.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
210/Protocol CO40016, Version 11 (Cohort C)
Table 1
Diarrhea Management Guidelines (cont.)
Severity of Diarrhea a
Management Guideline
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.

Interrupt paclitaxel until diarrhea improves to Grade 1
or better.  Consider resuming paclitaxel by one dose 
level lower or discontinuing paclitaxel per investigator's 
discretion (see Section 5.1.5.3).
ADLactivities of daily living; BIDtwice a day; NCI CTCAE v4.0 National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; QD once a day.
a Diarrhea, as defined by NCI CTCAE v4.0, a disorder characterized by frequent and watery 
bowel movements.
FASTING HYPERGLYCEMIA
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours.
Dose modification guidelines for fasting hyperglycemia attributable to study treatment 
are outlined below (see Table 2) and are intended to provide guidance for fasting 
glucose measurements assessed in the clinic.  Decisions regarding study treatment 
should be made on fasting levels drawn in the clinic whenever possible.
Home glucose measurements 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 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 judgement) and glucose should be monitored closely to 
minimize the risk of hypoglycemia.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
211/Protocol CO40016, Version 11 (Cohort C)
Table 2
Fasting Hyperglycemia Management Guidelines
Severity of Fasting 
Hyperglycemia
Management Guideline
Grade 1:  fasting 
glucose value ULN to 
160 mg/dL 
(8.9 mmol/L) a

Monitor fasting glucose per protocol

Consider initiating home glucose monitoring 
Grade 2:  fasting 
glucose value 160 to 
250 mg/dL (8.913.9 
mmol/L) a

Interruption of ipatasertib/placebo until fasting hyperglycemia 
resolves to Grade 1 or better.

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 (refer to 
Table 4).

If the patient previously 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.
Grade 3:  glucose value 
250 to 500 mg/dL 
(13.927.8 mmol/L) a

Interrupt ipatasertib/placebo dosing until fasting hyperglycemia 
resolves to Grade 1 or better.

Initiate home glucose monitoring

Treat hyperglycemia as medically appropriate.  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.

If Grade 3 fasting hyperglycemia recurs, the dose of 
ipatasertib/placebo should be reduced by one dose level when 
treatment is restarted.  
Grade 4:  glucose 
value 500 mg/dL
(27.8 mmol/L); 
life-threatening 
consequences a

Interrupt ipatasertib/placebo dosing until resolution to Grade 1 or 
better.

Treat hyperglycemia as medically appropriate.  

Initiate home glucose monitoring

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 if and when treatment
is restarted.

If Grade 4 hyperglycemia recurs, permanently discontinue 
ipatasertib/placebo.
ULNupper limit of normal.
a
For all grades, the patient should receive education on a diabetic diet.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
212/Protocol CO40016, Version 11 (Cohort C)
NEUTROPENIA AND/OR THROMBOCYTOPENIA
Addition of hematopoietic growth factors is allowed.  If a dose delay is required as 
a result of neutropenia at any grade, patients should receive prophylactic granulocyte 
colony-stimulating factor or granulocyte-macrophage colony-stimulating factor per 
institutional standards.  Patients should be counseled as to the risk of fever and infection 
and to the importance of contacting their treating physician immediately if these 
conditions occur so that they can be promptly and appropriately managed.  Dosage 
modification guidelines for neutropenia and/or thrombocytopenia attributable to 
ipatasertib/placebo and/or paclitaxel are outlined in Table 3.
Table 3
Neutropenia and Thrombocytopenia Management Guidelines
Severity of Neutropenia 
and/or Thrombocytopenia
Management Guideline
Grade 2

Ipatasertib/placebo may be continued at the original dose. 
Paclitaxel may be held and can then be administered at the previous 
dose, when ANC has recovered to 1500/L and when the platelet 
count has recovered to 100,000/L.  If clinically appropriate based 
on the investigator’s medical judgment, paclitaxel may be 
administered up to 14 days (2 doses), even with Grade 2 
neutropenia, without a dose reduction, as long as G-CSF is used to 
manage the neutropenia.  If the hematologic criteria do not recover 
to Grade1 or better within the 14-day window of treating for ongoing 
Grade 2 neutropenia, the subsequent paclitaxel dose(s) must be 
held until recovery of hematological criteria to Grade 1 or better.
Grade 3

Ipatasertib/placebo and paclitaxel should both be held until recovery
to Grade 1 and if clinically appropriate based on the investigator’s 
medical judgment to Grade 2 as long as G-CSF is used to manage 
the neutropenia. Please see guidelines in this table regarding 
treatment for ongoing Grade 2 hematological toxicities.  
o
First episode:  If recovery is to Grade 1, resume the original 
dose.  If recovery to Grade 1 is achieved with the use of G-CSF, 
then continued use of G-CSF is recommended once dosing of 
the study drug is resumed.  If recovery is to Grade 2, follow the 
guidance above. 
o
Recurrent episode: Ipatasertib/placebo and paclitaxel should be 
reduced by one dose level when treatment is restarted.  If 
patient has had more than three Grade 3 neutropenia episodes 
on study, despite the above dose reduction to 65 mg/m2, the 
paclitaxel dose should be permanently discontinued, but the 
patient may continue to receive ipatasertib/placebo following 
discussion with the Medical Monitor. 

Following a treatment hold of up to 4 weeks, if recovery to Grade 2 
or better neutropenia does not occur, the patient will permanently 
discontinue paclitaxel but may continue ipatasertib/placebo following 
discussion with the Medical Monitor.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
213/Protocol CO40016, Version 11 (Cohort C)
Table 3
Neutropenia and Thrombocytopenia Management Guidelines
(cont.)
Severity of Neutropenia 
and/or Thrombocytopenia
Management Guideline
Febrile neutropenia and 
Grade 4 neutropenia

Paclitaxel and ipatasertib/placebo should be held until recovery to 
Grade 1, and if clinically appropriate based on the investigator’s 
medical judgment to Grade 2, as long as G-CSF is used to 
manage the neutropenia.  Please see guidelines in this table 
regarding treatment for ongoing Grade 2 hematological toxicities.  
First episode:  Ipatasertib/placebo and paclitaxel should be 
reduced by one dose level when treatment is restarted.  
Recurrent episode:  Ipatasertib/placebo and paclitaxel should 
be discontinued. 

Following a treatment hold of up to 4 weeks, if recovery to 
Grade 2 or better neutropenia does not occur, the patient will 
permanently discontinue paclitaxel and ipatasertib/placebo 
treatment.
ANCabsolute neutrophil count; G-CSFGranulocyte-colony stimulating factor.
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 4).  For persistent nausea and/or 
vomiting attributable to ipatasertib/placebo, dosage modification guidelines are outlined
in Section 5.1.5.3, Table 4, and Table 4). 
Table 4
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 and paclitaxel 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 5.1.5.3) when treatment 
is restarted.  Paclitaxel dose may be reduced by one level if 
recurrent Grade 3 nausea or vomiting occurs after dose reduction of 
ipatasertib/placebo has occurred (see Section 5.1.5.3).


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
214/Protocol CO40016, Version 11 (Cohort C)
RASH
Ipatasertib/placebo should be permanently discontinued for rash associated with 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, 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 5 (see Section 5.1.5.3 and Table 4 for dose modifications).
Table 5
Rash Management Guidelines
Severity of Rash
Management Guideline
Grade 1

Continue study drugs. 

Consider topical corticosteroids.
Grade 2

Interrupt ipatasertib/placebo treatment until resolution to Grade1 or better
or the toxicity is no longer clinically significant. 

Treat rash with topical corticosteroids.

Consider treatment of rash with oral corticosteroids.
Grade 3

Interrupt ipatasertib/placebo 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 within 28 days, following completion of the steroid taper, 
ipatasertib/placebo may be resumed at one dose level below the previous 
dose (see Section 5.1.5.3).

If recovery of the skin toxicity to Grade1 or better does not occur or skin 
toxicity remains clinically significant continuously for 4 weeks, or Grade 3 
rash recurs, permanently discontinue ipatasertib/placebo.
Grade 4

Administration of systemic steroids (oral or intravenous) is recommended.  
Consider dermatological consultation and skin biopsy.  Ipatasertib/placebo 
should be permanently discontinued.
PNEUMONITIS
Pneumonitis is not known to be causally related to any of the study drugs; however, it
has been observed with other drugs treating pathways similar to ipatasertib. Every effort
should be made to determine the etiology of dyspnea and changes in pulmonary function
(see Table 6).


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
215/Protocol CO40016, Version 11 (Cohort C)
Table 6
Pneumonitis Management Guidelines
Severity of 
Pneumonitis
Management Guideline
Grade 1

Continue study drugs.

Perform CT scan and PFTs.  Repeat CT scan every 8 weeks until a return 
to baseline.
Grade 2

If infectious etiology is ruled out or if improvement is not evident with broad 
spectrum antibiotics, prescribe corticosteroids as clinically indicated.

Interrupt ipatasertib/placebo and paclitaxel treatment until improvement to 
Grade1 or better.  Consider resuming ipatasertib/placebo and paclitaxel at 
same dose level or one dose level below (see Section 5.1.5.3) per 
investigator's assessment.

Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return 
to baseline.

For recurrent Grade 2 pneumonitis, ipatasertib/placebo must be resumed at 
one dose level below the previous dose (see Section 5.1.5.3).  Consider 
resuming paclitaxel at same dose or one dose below (see Section 5.1.5.3) 
per investigator's assessment.

Discontinue ipatasertib/placebo if recovery to Grade1 or better is not 
evident within 28 days.  Paclitaxel dose should be resumed at one dose 
level below previous dose (see Section 5.1.5.3) or discontinued per 
investigator's assessment.
Grade 3

If infectious etiology is ruled out or if improvement is not evident with broad 
spectrum antibiotics, prescribe corticosteroids as clinically indicated.

Interrupt ipatasertib/placebo and paclitaxel treatment until improvement to 
Grade1 or better.  Resume ipatasertib/placebo and paclitaxel at one dose 
level below previous dose (see Section 5.1.5.3) per investigator’s 
assessment.  If recovery to Grade1 or better is not evident within 28 days, 
discontinue study treatments.  

Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return 
to baseline.  Bronchoscopy is recommended.

For recurrent non-infectious Grade 3 pneumonitis events, 
ipatasertib/placebo and paclitaxel should be permanently discontinued.
Grade 4

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 paclitaxel.

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.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
216/Protocol CO40016, Version 11 (Cohort C)
MUCOSITIS
Mouthwash such as magic mouth wash (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 7.
Table 7
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 5.1.5.3).  The dose of paclitaxel 
may be maintained or reduced by one level for subsequent cycles per 
investigator's discretion (see Section 5.1.5.3).
Grade 3

Hold ipatasertib/placebo and paclitaxel until recovery to Grade 2 or better.  
If the mucositis resolves to Grade 2 or better during the current cycle, the 
dose of ipatasertib/placebo should be reduced by one dose level (see 
Section 5.1.5.3).  The dose of paclitaxel may be maintained or reduced by 
one dose level for subsequent cycles per investigator's discretion (see 
Section 5.1.5.3).

If recovery of mucositis to Grade 2 or better does not occur within a 
maximum of 4 weeks, the patient will permanently discontinue paclitaxel 
and ipatasertib/placebo.
HEPATOTOXICITY
Permanently discontinue ipatasertib for any patients who develop a concurrent 
elevation of ALT and/or AST greater than 3 ULN 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.  Dosage modification and symptom 
management guidelines for hepatotoxicity, attributable to study treatment are shown 
below (see Table 8).


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
217/Protocol CO40016, Version 11 (Cohort C)
Table 8
Hepatotoxicity Management Guidelines
Severity of LFT Elevation
Management Guideline
Grade 1 
AST or ALT baseline 3 ULN if 
baseline was normal; 
1.53.0 baseline if baseline was 
abnormal
or 
T bilirubin baseline 1.5 ULN 
was normal; 1.01.5 baseline if 
baseline was abnormal

Continue study drugs.
Grade 2 
AST or ALT 3–5 ULN if baseline 
was normal; 3–5 baseline if baseline 
was abnormal
or
T 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 5–20 ULN if 
baseline was normal; 5–20 baseline 
if baseline was abnormal
or
T bilirubin 3–10 ULN if baseline 
was normal; 3–10 baseline if 
baseline was abnormal

Immediately interrupt ipatasertib.

On return of LFTs to baseline or to AST and ALT 
2.5 ULN and total bilirubin 1.5 ULN 
levels, restart ipatasertib/ at previous dose 

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.  On return of LFTs to baseline or AST 
and ALT 2.5 ULN and total bilirubin 
1.5 ULN levels, restart ipatasertib, reducing 
the dose by one level 

Further Grade 3 occurrences must result in 
permanent discontinuation of ipatasertib.
Grade 4
AST or ALT 20 ULN if baseline 
was normal; 20 baseline if 
baseline was abnormal
or
T bilirubin 10 ULN if baseline 
was normal; 10 baseline if 
baseline was abnormal

Permanently discontinue ipatasertib.
LFT liver function test; QD once daily; T=total; ULN upper limit of normal.


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
218/Protocol CO40016, Version 11 (Cohort C)
PERIPHERAL NEUROPATHY
If Grade 3 peripheral neuropathy attributable to paclitaxel develops in patients, 
paclitaxel should be held until the neuropathy recovers to Grade 2 or better, or resolution 
such that the peripheral neuropathy is no longer clinically significant.  During this time, 
patients may continue ipatasertib/placebo at the discretion of the investigator.  If the 
peripheral neuropathy recovers to Grade 2 or better within 4 weeks or resolution such 
that the peripheral neuropathy is no longer clinically significant, dosing of paclitaxel may 
resume reduced by one dose level (see Section 5.1.5.3).  If recovery of the peripheral 
neuropathy to Grade 2 or better does not occur within a maximum of 4 weeks, the 
patient will permanently discontinue paclitaxel but may continue the ipatasertib/placebo. 
HYPERSENSITIVITY 
If a hypersensitivity reaction due to infusion of paclitaxel develops in patients, treatment 
for the hypersensitivity reaction, including the possibility of rechallenging with the 
attributable chemotherapy agent, in presence of premedication for paclitaxel 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., ipatasertib/placebo).
OTHER NON-HEMATOLOGIC TOXICITIES
If other Grade 3 non hematologic toxicities not described above develop in patients, 
treatment with ipatasertib/placebo and/or paclitaxel 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 paclitaxel).  Grade 3 non-hematologic toxicity should be 
monitored at least weekly.
If the toxicity resolves to Grade 1 or better within 2 weeks, treatment may resume with 
the attributable agent.
If the toxicity resolves to Grade 1 or better in 24 weeks, the dose of the attributable 
drug should be reduced by one level per the suggested guidelines in Section 5.1.5.3.
Depending on the nature and the severity of the adverse event, if recovery to Grade 1 or 
better takes 4 weeks, treatment may resume with the attributable agent with dose 
reduction, or the attributable agent may be permanently discontinued, at the discretion of 
the investigator and after discussion with the Medical Monitor.  
For Grade 3 toxicities associated primarily with laboratory abnormalities only
(e.g., elevation of ALT, AST, lipase, or amylase, or decreases in phosphorus without 
clinical or other evidence of pancreatitis or other hepatic dysfunction), study treatment 


Appendix 13
Guidelines for Management of Adverse Events for Patients in 
Cohorts A and B (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
219/Protocol CO40016, Version 11 (Cohort C)
may continue without interruption and/or dose reduction at the discretion of the
investigator per institutional practice.


Ipatasertib—F. Hoffmann-La Roche Ltd
220/Protocol CO40016, Version 11 (Cohort C)
Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel)
Guidelines for the management of patients who experience specific adverse events are 
provided in Appendix 15 and Table 1, as outlined below:

Table 1 provides guidelines for the management of patients who experience the 
following potential overlapping toxicities:  gastrointestinal, dermatologic, hepatic, 
pulmonary, and hyperglycemia events.  It is recommended that study treatments be 
withheld or discontinued per the guidelines in Table 1.  For these potential 
overlapping toxicities, guidelines in Table 1 should be followed instead of guidelines 
in Appendix 15.

Table 1 provides guidelines for the management of patients who experience 
adverse events associated with ipatasertib.  It is recommended that atezolizumab 
and/or ipatasertib be withheld or discontinued per the guidelines in Table 1.

Appendix 15 provides guidelines for the management of patients who experience 
atezolizumab-associated IRRs and immune-mediated adverse events.  It is 
recommended that atezolizumab be withheld or discontinued per the guidelines in 
Appendix 15 and that ipatasertib be withheld or discontinued per the guidelines in 
Table 1.
For cases in which management guidelines are not covered in Table 1 or Appendix 15, 
patients should be managed and treatments should be withheld or discontinued as
deemed appropriate by the investigator according to best medical judgment.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
221/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel
Event
Action to Be Taken
Infusion-related 
reactions and 
anaphylaxis
Follow guidelines for atezolizumab in Appendix 15.
Withhold ipatasertib/placebo.
For anaphylaxis precautions, see Appendix 12.
For severe hypersensitivity reactions, permanently discontinue atezolizumab and ipatasertib/placebo.
Gastrointestinal toxicity
General guidance
For all patients, dispense loperamide 4 mg once per day as prophylaxis for diarrhea in the first cycle.
After the first cycle, continue this dosing for the remainder of the study as clinically indicated.
Thoroughly evaluate all events of diarrhea or colitis for more common etiologies other than drug-induced 
effects.
For diarrhea that persists for more than 5 days, despite treatment with anti-diarrheal agent(s) and/or with dose 
hold of ipatasertib/placebo, consult with gastroenterologists to rule out the risk of colitis and infection.  Educate 
patients on the symptoms and importance of early reporting of diarrhea and provide instructions for treatment 
and prevention of dehydration so that patients can be promptly and appropriately managed.  (Educational 
materials will be provided to investigators and patients outlining these guidelines.)
For events of significant duration or magnitude or associated with signs of systemic inflammation or acute 
phase reactants (e.g., increased C-reactive protein, platelet count, or bandemia), perform sigmoidoscopy (or
colonoscopy, if appropriate) with colonic biopsy, with three to five specimens for standard paraffin block to 
check for inflammation and lymphocytic infiltrates to confirm colitis diagnosis.
Administer anti-diarrheal agents and other supportive care per institutional guidelines or per suggested 
supportive care outlined below:
Medication
As early as possible, institute treatment modifications for diarrhea (any grade) when it occurs.  Guidelines for 
treatment of diarrhea, following the prophylactic dose of loperamide 4 mg initial daily dose, include use of 
loperamide 2 mg after each loose watery stool, up to the maximum total dose of 16 mg/day or per institutional 
guidelines and standard of care, including, but not limited to, additional therapy with diphenoxylate and atropine, 
codeine, or octreotide.  Please note that loperamide prophylaxis alone is not sufficient if diarrhea occurs despite 
prophylaxis; if diarrhea occurs while on loperamide prophylaxis, loperamide use should be increased as noted 
above, or additional medications added. 


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
222/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity (cont.)
General guidance 
(cont.)
Medication (cont.)
- To minimize duration of diarrhea, encourage taking ipatasertib/placebo with food, avoiding lactose-containing 
foods, and hydrating with 810 glasses per day (approximately 12 oz/glass) of electrolyte-containing clear 
liquid, such as broth and Gatorade® drinks.
- Reduce dose of ipatasertib/placebo by one level at a time (i.e., from 400 to 300 mg; from 300 to 200 mg) as 
outlined in Table 4.  If Grade 2 diarrhea persists following dose reductions of ipatasertib/placebo to 200 mg 
daily and with maximum treatment for diarrhea, discontinue ipatasertib/placebo. 
Oral Supplementation
- Initiate potassium and/or magnesium if serum levels are less than the lower limit of normal.
- Consider rehydration therapy with oral electrolyte solution for Grade 1 diarrhea or vomiting.
Dietary Modifications
- Instruct patient to eat small meals and eliminate lactose-containing products from diet.
- Suggest diet of bananas, rice, apples, and toast, while avoiding fiber from vegetables and other fruits.
- Encourage adequate hydration with salt-containing liquids (e.g., broth, sports drinks such as Gatorade®).
Diarrhea, Grade 1 
Continue atezolizumab and ipatasertib/placebo.
Initiate supportive care and monitor patient closely.
Investigate etiology, referring patient to gastrointestinal specialist for evaluation of possible colitis if appropriate.
Upon resolution, loperamide prophylaxis can be considered and continued as clinically indicated, if allowed by 
local guidance.  Please note, loperamide prophylaxis is to be taken throughout at least the first cycle.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
223/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity (cont.)
Diarrhea, Grade 2
Withhold atezolizumab and ipatasertib/placebo.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs) while investigating etiology.
Investigate etiology, referring patient to GI specialist for evaluation of possible colitis, including biopsy if 
appropriate.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at a fixed dose.  If not, 
permanently discontinue atezolizumab and contact Medical Monitor. a, b, c
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 Table 4) for recurrent Grade 2 diarrhea.
When study treatment 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.
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to 
be reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on 
an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated,  they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
mediated event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
224/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Diarrhea, Grade 3
Withhold ipatasertib/placebo, atezolizumab, and paclitaxel.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs) while investigating etiology.
Investigate etiology, referring patient to GI specialist for evaluation of possible colitis, including biopsy if 
appropriate.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at a fixed dose.  If not, 
permanently discontinue atezolizumab and contact Medical Monitor. a, b, c
Interrupt ipatasertib/placebo and paclitaxel until diarrhea improves to Grade 1 or better.  Ipatasertib/placebo 
should be reduced by one dose level (see Table 4) when treatment is restarted.  Consider resuming paclitaxel 
at the same dose.
For recurrent Grade 3 diarrhea, reduce ipatasertib/placebo dose by one additional dose level (see Table 4).  
Consider reducing paclitaxel by one dose level when treatment is restarted (see Table 5).
When study treatment 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.
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to 
be reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on 
an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event. The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
225/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Diarrhea, Grade 4 
Permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. c
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs) while investigating etiology.
Rule out bowel perforation.
Investigate etiology, referring patient to GI specialist for evaluation of possible colitis, including biopsy if 
appropriate.
Interrupt paclitaxel until diarrhea improves to Grade 1 or better.  Consider resuming paclitaxel by one dose level 
lower or discontinuing paclitaxel per investigator's discretion (see Table 5).
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to 
be reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on 
an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated,  they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
226/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Gastrointestinal 
toxicity (cont.)
Colitis, Grade 1
Continue atezolizumab and ipatasertib/placebo.
Initiate supportive care and monitor patient closely. 
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy if symptoms persist for 5 days.
Colitis, Grade 2
Withhold atezolizumab and ipatasertib/placebo.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy.
For recurrent events or events that persist 5 days, initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at a fixed dose.  If not, 
permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. a, b, c
If event resolves to Grade 1 or better within 28 days, resume ipatasertib/placebo with the dose reduced by one 
level.  If not, permanently discontinue ipatasertib/placebo.
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to 
be reduced to the equivalent of 10 mg/day oral prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
227/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity (cont.)
Colitis, Grade 3
Withhold atezolizumab and ipatasertib/placebo.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at a fixed dose.  If not, 
permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. a, b, c
If event resolves to Grade 1 or better within 28 days, resume ipatasertib/placebo with dose reduced by one 
level.  If not, permanently discontinue ipatasertib.
Colitis, Grade 4
Permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. c
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.
If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to 
be reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on 
an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
mediated event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of benefitrisk 


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
228/Protocol CO40016, Version 11 (Cohort C)
and documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
229/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Endocrine disorders
Asymptomatic 
hypothyroidism
Follow guidelines for atezolizumab in Appendix 15.
Continue ipatasertib/placebo.
Symptomatic 
hypothyroidism
Follow guidelines for atezolizumab in Appendix 15.
Continue ipatasertib/placebo.
Asymptomatic 
hyperthyroidism
Thyroid-stimulating hormone 0.1 mU/L and 0.5 mU/L:
Follow guidelines for atezolizumab in Appendix 15.
Continue ipatasertib/placebo.
Thyroid-stimulating hormone 0.1 mU/L:
Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism
Follow guidelines for atezolizumab in Appendix 15.
Continue ipatasertib/placebo.
For life-threatening immune- mediated hyperthyroidism, withhold ipatasertib/placebo.  If event becomes 
clinically manageable within 28 days, resume ipatasertib/placebo with the dose reduced by one level (see 
Table 4).  If not, permanently discontinue ipatasertib/placebo.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
230/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Endocrine disorders (cont.)
Symptomatic adrenal 
insufficiency, Grade 2, 
3, or 4
Follow guidelines for atezolizumab in Appendix 15.
Continue ipatasertib/placebo.
Hyperglycemia, 
general guidance
Thoroughly evaluate all events of hyperglycemia for more common etiologies other than drug-induced effects.
Investigate for diabetes.  If patient has Type 1 diabetes, treat as Grade 3 event.  
In workup, include confirmation of fasting blood glucose, urinary glucose and ketones, arterial blood gas, serum 
bicarbonate, hemoglobin A1C, C-peptide levels, anti-islet antibodies, and anti-GAD65 antibody.
Treat hyperglycemia per institutional guidelines with fluid replacement, insulin, and correction of electrolyte 
abnormalities.  
Hyperglycemia
Grade 1, fasting 
glucose value 
ULN to 160 mg/dL 
(8.9 mmol/L)
Continue atezolizumab and ipatasertib/placebo.
Provide patient with education on a diabetic diet and consider home glucose monitoring.
Consider oral anti-diabetic medications (e.g., metformin) or insulin replacement, guided by etiology of 
hyperglycemia. 
Hyperglycemia
Grade 2, fasting 
glucose value 
160250 mg/dL 
(8.913.9 mmol/L)
Withhold atezolizumab and ipatasertib/placebo dosing until fasting glucose value resolves to Grade 1.  
(Investigate for diabetes. If patient has Type 1 diabetes, treat as a Grade 3 event. If patient does not have 
Type 1 diabetes, treat as per institutional guidelines.)
Encourage a diabetic diet and initiate home glucose monitoring.
Start oral anti-diabetic medications (e.g., metformin) or insulin replacement, guided by etiology of hyperglycemia.
If patient is already on an oral anti-diabetic medication, the dose of ipatasertib/placebo should be reduced by one 
dose level (refer to Table 4).
If the patient previously 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.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
231/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Endocrine disorders (cont.)
Hyperglycemia
Grade 3, glucose 
value 
250500 mg/dL 
(13.927.8 mmol/L)
Withhold atezolizumab and ipatasertib/placebo dosing until fasting glucose value resolves to Grade 1 and 
contact Medical Monitor.
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).
Encourage a diabetic diet and initiate home glucose monitoring.
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.
If hyperglycemia Grade 3 recurs, the dose of ipatasertib/placebo should be reduced by one dose level (see 
Table 1) when treatment is restarted.
Resume atezolizumab when symptoms resolve and glucose levels are stable.
Hyperglycemia
Grade 4, 
glucose value 
500 mg/dL 
(27.8 mmol/L); 
life-threatening 
consequences
Withhold atezolizumab and ipatasertib/placebo dosing until fasting glucose value resolves to Grade 1. 
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).
Assess for volume depletion and appropriate intravenous or oral hydration.
Encourage a diabetic diet and initiate home glucose monitoring.
Upon recovery of fasting glucose to Grade 1, reduce ipatasertib/placebo by one dose level (see Table 4) 
when treatment is restarted.
Resume atezolizumab when symptoms resolve and glucose levels are stable.
If hyperglycemia Grade 4 recurs, permanently discontinue ipatasertib/placebo and atezolizumab and contact 
Medical Monitor.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
232/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Pulmonary events
General guidance
Thoroughly evaluate all pulmonary events for other commonly reported etiologies, such as 
pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic obstructive 
pulmonary disease, or pulmonary hypertension.
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with the 
administration of atezolizumab.
Pulmonary event, 
Grade 1
Continue atezolizumab and ipatasertib/placebo.
Re-evaluate on serial imaging.
Consider patient referral to pulmonary specialist.
For Grade 1 pneumonitis, consider withholding atezolizumab.
Pulmonary event, 
Grade 2
Withhold atezolizumab and ipatasertib/placebo.
Refer patient to pulmonary and infectious disease specialists and consider bronchoscopy or BAL. 
If bronchoscopy is consistent with immune-mediated etiology, Initiate treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at a fixed dose.  If not, 
permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. a, b, c
If event resolves to Grade 1 or better within 28 days, resume ipatasertib/placebo at current dose.
For recurrent events, treat as a Grade 3 or 4 event.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
233/Protocol CO40016, Version 11 (Cohort C)
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to 
be reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on 
an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefit-risk and documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
234/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Pulmonary events (cont.)
Pulmonary event, 
Grade 3 or 4
Permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. c
Refer patient to pulmonary and infectious disease specialists and consider Bronchoscopy or BAL.
If bronchoscopy is consistent with immune-mediated etiology initiate treatment with corticosteroids 
1−2 mg/kg/day oral prednisone or equivalent. 
If pulmonary event does not improve within 48 hours or worsens, consider adding an immunosuppressive agent.
When event resolves to Grade 1 or better, taper corticosteroids over 1 month.
Hepatic events
AST/ALT ULN to 
3ULN with total 
bilirubin 2ULN
Continue atezolizumab and ipatasertib/placebo.
Monitor LFTs d until values resolve to within normal limits or to baseline values.
BALbronchoscopic alveolar lavage; LFT liver function test; ULNupper limit of normal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated
event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.
d The LFT panel should include AST, ALT, alkaline phosphatase, and total bilirubin.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
235/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Hepatic events (cont.)
AST/ALT 3ULN 
to5ULN with total 
bilirubin 2ULN
Continue atezolizumab and ipatasertib/placebo.
Monitor LFTs d, f every 4872 hours until decreasing and then weekly until return to baseline.  
Consider patient referral to a hepatologist e and liver biopsy.
Suspected immune-mediated events of 5 days' duration:
Withhold atezolizumab for up to 12 weeks after event onset.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
If atezolizumab is withheld and event resolves to AST/ALT 3 ULN with total bilirubin 2 ULN within 
12 weeks, resume atezolizumab at a fixed dose.  If not, permanently discontinue atezolizumab and 
ipatasertib/placebo and contact Medical Monitor. a, b, c
BALbronchoscopic alveolar lavage; LFT liver function test; ULNupper limit of normal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to 
be reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.
d The LFT panel should include AST, ALT, alkaline phosphatase, and total bilirubin.
e When the cause of the hepatic event is unclear, suggested workup may include a review of symptoms, concomitant drug use (including 
nonprescription medications and herbal and dietary supplement preparations), alcohol use, recreational drug use, and special diets; 
ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and 
biliary tract disease; reviewing exposure to environmental chemical agents and additional tests to evaluate liver function (e.g., INR, 
direct bilirubin).
f
In instances when patients have baseline elevation of LFTs clinical judgement should be used when determining appropriate frequency 
for monitoring LFTs (e.g., patients with documented liver or bone metastases may have baseline AST/ALT 5 ULN); monitoring of 
LFTs for such patients may be as per clinical judgement until a threshold of ALT/AST 5 ULN.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
236/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Hepatic events (cont.)
AST/ALT 5ULN to 
10ULN with total 
bilirubin ULN to 
2ULN
Continue atezolizumab and ipatasertib/placebo.
Monitor LFTs d every 4872 hours until decreasing and then weekly until return to baseline.  
Consider patient referral to hepatologist e and liver biopsy.
Suspected immune-mediated events:
Withhold atezolizumab.
Consider initiation of treatment with 12 mg/kg/day oral prednisone or equivalent.
If corticosteroids are initiated and event does not improve within 48 hours, consider adding an immunosuppressive 
agent.
If event resolves to AST/ALT 3 ULN with total bilirubin 2 ULN within 12 weeks, resume atezolizumab at 
a fixed dose.  If not, permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. 
a ,b, c
AST/ALT ULN to 
3ULN with total 
bilirubin 2ULN
Investigate causes for elevated bilirubin and initiate treatment as indicated per institutional guidelines.
Use best medical judgment when determining whether to continue study treatment.
LFTliver function test; ULNupper limit of normal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated
event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of benefit-risk and
documented by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
d The LFT panel should include AST, ALT, alkaline phosphatase, and total bilirubin.
e When the cause of the hepatic event is unclear, suggested workup may include a review of symptoms, concomitant drug use (including 
nonprescription medications and herbal and dietary supplement preparations), alcohol use, recreational drug use, and special diets; ruling 
out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract 
disease; reviewing exposure to environmental chemical agents and additional tests to evaluate liver function (e.g., INR, direct bilirubin).


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
237/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Hepatic events (cont.)
AST/ALT 3to 
10ULN with total 
bilirubin 2ULN
Withhold atezolizumab and ipatasertib/placebo.
Monitor LFTs d every 4872 hours until decreasing and then monitor weekly.
Refer patient to hepatologist e and consider liver biopsy.
Consider initiation of treatment with 12 mg/kg/day oral prednisone or equivalent.
If corticosteroids are initiated and event does not improve within 48 hours, consider adding an immunosuppressive 
agent.
If event resolves to AST/ALT 3 ULN with total bilirubin 2 ULN within 12 weeks, resume atezolizumab at 
a fixed dose.  If not, permanently discontinue atezolizumab and contact Medical Monitor. a, b, c
If event resolves to AST/ALT 3 ULN with total bilirubin 2 ULN within 28 days, resume ipatasertib/placebo 
with dose reduced by one level (see Table 4).  If not, permanently discontinue ipatasertib/placebo.
Permanently discontinue atezolizumab and ipatasertib/placebo for life-threatening hepatic events and contact the 
Medical Monitor.
LFTliver function test; ULNupper limit of normal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated 
event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
d The LFT panel should include AST, ALT, alkaline phosphatase, and total bilirubin.
e When the cause of the hepatic event is unclear, suggested workup may include a review of symptoms, concomitant drug use (including 
nonprescription medications and herbal and dietary supplement preparations), alcohol use, recreational drug use, and special diets; ruling 
out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract 
disease; reviewing exposure to environmental chemical agents and additional tests to evaluate liver function (e.g., INR, direct bilirubin).


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
238/Protocol CO40016, Version 11 (Cohort C)
Event
Action to Be Taken
Hepatic events (cont.)
AST/ALT 10ULN
Permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor. c
Monitor LFTs d every 4872 hours until decreasing and then monitor weekly.
Refer patient to hepatologist e and consider liver biopsy.
Consider administering 12 mg/kg/day oral prednisone or equivalent.  
If corticosteroids are initiated and event does not improve within 48 hours, consider adding an immunosuppressive 
agent or escalating the corticosteroid dose.
When event resolves to AST/ALT 3 ULN with total bilirubin 2 ULN, taper corticosteroids over 1 month.
LFTliver function test; ULNupper limit of normal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated 
event.  The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
d The LFT panel should include AST, ALT, alkaline phosphatase, and total bilirubin.
e When the cause of the hepatic event is unclear, suggested workup may include a review of symptoms, concomitant drug use (including 
nonprescription medications and herbal and dietary supplement preparations), alcohol use, recreational drug use, and special diets; ruling 
out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract 
disease; reviewing exposure to environmental chemical agents and additional tests to evaluate liver function (e.g., INR, direct bilirubin).


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
239/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Dermatologic toxicity
General guidance

Consider having a dermatologist evaluate persistent and/or severe rash or pruritus.

Unless contraindicated, daily oral antihistamine prophylaxis should be used for at least the first cycle.  It is 
suggested that a non-sedating oral antihistamine (such as loratadine, cetirizine, fexofenadine) and longer-acting 
formulation be used.  The daily oral antihistamine used for rash prophylaxis may be held on the days of paclitaxel 
infusion if the paclitaxel premedication already includes an antihistamine.  

For the first 28-day cycle of triplet study drug combination:  On days when patients will receive atezolizumab
(typically, Days 1 and 15), patients should receive at least 10 mg prednisone (or equivalent) as premedication prior 
to atezolizumab, followed by 10 mg/day prednisone (or equivalent) for 24 consecutive days thereafter, unless 
contraindicated.  If institutional practice prior to paclitaxel is to give at least 10 mg/day prednisone on the day of 
paclitaxel, then the additional 10 mg prophylactic prednisone should not be given on that day to prevent rash.  
Timing of steroid on days when patients will receive atezolizumab and paclitaxel is at Investigator discretion, as per 
clinical judgement.  

Ipatasertib/placebo 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, including erythema multiforme, attributable to ipatasertib/placebo 
are shown below.

Although uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic 
epidermal necrolysis have been reported with atezolizumab, and atezolizumab should be permanently 
discontinued for confirmed cases (see Appendix 15).
Dermatologic event, 
Grade 1

Consider referring patient to a dermatologist. 

Continue atezolizumab and ipatasertib/placebo.

Initiate supportive care (e.g., topical corticosteroids and continue antihistamine administration).  

Consider treatment with 10 mg/day oral prednisone/or equivalent.
Dermatologic event, 
Grade 2

Consider referring patient to dermatologist for evaluation and perform a biopsy, if appropriate.

Continue topical corticosteroids and antihistamine administration

Consider treatment with 10 mg/day oral prednisone or equivalent; treatment with a higher steroid dose may be
necessary as clinically indicated.

If unresponsive to topical corticosteroids, consider oral prednisone


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
240/Protocol CO40016, Version 11 (Cohort C)

Ipatasertib/placebo: Interrupt ipatasertib/placebo treatment until resolution to Grade 1 or better or the toxicity is no 
longer clinically significant. If steroid dose is 10 mg/day, ipatasertib/placebo may be resumed if clinically
appropriate.

Atezolizumab: If steroid dose is 10 mg/day, atezolizumab should be continued.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
241/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Dermatologic toxicity (cont.)
Dermatologic event, 
Grade 3

Withhold atezolizumab and ipatasertib/placebo.

Refer patient to dermatologist.  Perform a biopsy if appropriate.

If no prior steroid treatment has been initiated, consider treatment with 10 mg/day oral prednisone or equivalent.

If prior oral steroid treatment or no improvement within 48 hours, consider, increasing prednisone or equivalent 
dose to 12 mg/kg/day.

Atezolizumab:  if event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at a fixed dose.  If 
not, permanently discontinue atezolizumab and contact Medical Monitor. Only restart atezolizumab (if steroid 
dose is 10 mg/day). a, b, c

Ipatasertib/placebo:  If event resolves to Grade 1 or better or the toxicity is no longer clinically significant, 
resume ipatasertib/placebo at the same dose or dose reduced by one level if considered medically appropriate.  
Only restart ipatasertib/placebo if steroid dose is 10 mg/day oral prednisone.  If not, permanently discontinue 
ipatasertib/placebo.
Dermatologic event, 
Grade 4

Permanently discontinue atezolizumab and ipatasertib/placebo and contact Medical Monitor.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune- mediated
event.  The decision to re-challenge patients with atezolizumab should be based on investigator’s assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
242/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Neutropenia 
Grade 2

Ipatasertib/placebo may be continued at the original dose.

Withhold the taxane until ANC has recovered to 1500/mL.
If clinically appropriate based on the investigator’s medical judgment, the taxane may be administered up to 
14 days (2 doses), even with Grade 2 neutropenia, without a dose reduction, as long as G-CSF is used to 
manage the neutropenia.

If neutropenia does not recover to Grade 1 or better within the 14-day window of treating for ongoing Grade 2 
neutropenia, the subsequent taxane dose(s) must be held until recovery to Grade 1 or better.

If event resolves, administer the taxane at the previous dose.
Grade 3

Withhold ipatasertib/placebo and taxane until recovery to Grade 1 and, if clinically appropriate based on the 
investigator’s medical judgment, to Grade 2 as long as G-CSF is used to manage the neutropenia.  Please 
see guidelines in this table regarding treatment for ongoing Grade 2 neutropenia. 
First episode:  If recovery is to Grade 1, resume the original dose.  If recovery to Grade 1 is achieved with 
the use of G-CSF, then continued use of G-CSF is recommended once dosing of the study drug is 
resumed. If recovery is to Grade 2, follow the guidance above. 
Recurrent episode:  Ipatasertib/placebo and taxane should be reduced by one dose level when treatment is 
restarted.  If patient has had more than three Grade 3 neutropenia episodes during the study, despite the 
maximum dose reduction to 65 mg/m2 for paclitaxel, the taxane should be permanently discontinued, but 
the patient may continue to receive ipatasertib/placebo following discussion with the Medical Monitor. 

Following a treatment hold of 4 weeks, if recovery of neutropenia to Grade 2 or better has not occurred, the 
patient will permanently discontinue taxane but may continue ipatasertib/placebo following discussion with 
the Medical Monitor.
G-CSFgranulocyte colony-stimulating factor.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
243/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Neutropenia (cont.)
Febrile neutropenia 
and Grade 4 
neutropenia

All study treatment should be withheld until recovery to Grade 1, and if clinically appropriate based on the 
investigator’s medical judgment to Grade 2, as long as G-CSF is used to manage the neutropenia.  Please see 
guidelines in this table regarding treatment for ongoing Grade 2 neutropenia. 
- First episode:  Ipatasertib/placebo and taxane should be reduced by one dose level when treatment is 
restarted. 
- Recurrent episode:  Ipatasertib/placebo and taxane should be discontinued.  Atezolizumab maybe continued 
after discussion with the Medical Monitor

Following a treatment hold of up to 4 weeks, if recovery to Grade 2 or better neutropenia does not occur, the 
patient will permanently discontinue all treatment.
Ipatasertib/placebo-related toxicities not described above
Grade 3

Withhold ipatasertib/placebo.  Continue atezolizumab.

If the toxicity resolves to Grade 1 or better within 2 weeks, treatment may resume with ipatasertib/placebo at 
the prior dose level.

If the toxicity resolves to Grade 1 or better within 24 weeks, the dose of the ipatasertib/placebo should be 
reduced by one level per the suggested guidelines in Table 4.

Depending on the nature and the severity of the adverse event, if recovery to Grade 1 or better takes 
4 weeks, treatment may resume with the ipatasertib/placebo with dose reduction, or the ipatasertib/placebo 
may be permanently discontinued, at the discretion of the investigator
G-CSFgranulocyte colony-stimulating factor.


Appendix 14
Adverse Event Management Guidelines for Patients in Cohort C 
(Ipatasertib Plus Atezolizumab Plus Paclitaxel) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
244/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab Plus Paclitaxel (cont.)
Event
Action to Be Taken
Atezolizumab-related toxicities not described in Appendix 15
Grade 3

Follow guidelines for atezolizumab in Appendix 15

Withhold ipatasertib/placebo until resolution to Grade 1.

If the toxicity resolves to Grade 1 or better within 2 weeks, treatment with ipatasertib/placebo may resume at 
the prior dose level.

If the toxicity resolves to Grade 1 or better within 24 weeks, the dose of ipatasertib/placebo should be 
reduced by one level per the suggested guidelines in Table 4.

Depending on the nature and the severity of the adverse event, if recovery to Grade 1 or better takes 
4 weeks, treatment may resume with ipatasertib/placebo with dose reduction, or ipatasertib/placebo may be 
permanently discontinued, at the discretion of the investigator


Ipatasertib—F. Hoffmann-La Roche Ltd
245/Protocol CO40016, Version 11 (Cohort C)
Appendix 15
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications. Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with atezolizumab 
should be based on investigator's assessment of benefitrisk and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in
Appendix 14.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
246/Protocol CO40016, Version 11 (Cohort C)
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Appendix 14.
GASTROINTESTINAL EVENTS
Immune-mediated related colitis has been associated with the administration of 
atezolizumab.  Management guidelines for diarrhea or colitis are provided in 
Appendix 14.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 1.  For events of hyperglycemia, see 
Appendix 14.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
247/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism
Continue atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH closely.
Symptomatic 
hypothyroidism
Withhold atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH closely.
Consider patient referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:
Continue atezolizumab.

Monitor TSH every 4 weeks. 

Consider patient referral to endocrinologist.
TSH 0.1 mU/L:
Follow guidelines for symptomatic hyperthyroidism.
Consider patient referral to endocrinologist.
Symptomatic 
hyperthyroidism
Withhold atezolizumab.
Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed.
Consider patient referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator’s assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
248/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist.
Perform appropriate imaging.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on investigator’s assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
249/Protocol CO40016, Version 11 (Cohort C)
Table 1
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist.
Perform brain MRI (pituitary protocol).
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
Initiate hormone replacement if clinically indicated.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to endocrinologist.
Perform brain MRI (pituitary protocol).
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge
patients with atezolizumab should be based on investigator’s assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 2.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
250/Protocol CO40016, Version 11 (Cohort C)
Table 2
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 
Continue atezolizumab.
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.
If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical Monitor.c
Refer patient to ophthalmologist.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.  
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge
patients with atezolizumab should be based on investigator’s assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
251/Protocol CO40016, Version 11 (Cohort C)
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis 
may also be a clinical manifestation of myositis and should be managed accordingly.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 3.
Table 3
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 2-4
Permanently discontinue atezolizumab and contact Medical Monitor. a
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over
1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator’s assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
252/Protocol CO40016, Version 11 (Cohort C)
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines, anti-
pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole 
(dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential 
for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T-cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 4.
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  
If a patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
253/Protocol CO40016, Version 11 (Cohort C)
Table 4
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome
Event
Management
Grade 1 a
fever b with or 
without 
constitutional 
symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration.

In case of rapid decline or prolonged CRS (2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2.
For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs 
and/or CRS.
Grade 2 a
fever b with 
hypotension not 
requiring 
vasopressors
and/or
hypoxia 
requiring 
low-flow oxygen
d by nasal 
cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  If 
no improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS as described in this appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. 

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab, and contact Medical Monitor. e

If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
anti-pyretics, and/or analgesics and monitor closely for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
254/Protocol CO40016, Version 11 (Cohort C)
Table 4
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Event
Management
Grade 3 a
fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
hypoxia requiring 
high-flow oxygen
d by nasal 
cannula, face 
mask, 
non-rebreather
mask, or 
Venturi-mask

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
hypoxia requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
BiPAP, intubation 
and mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor 
other organ function closely.  Manage constitutional symptoms and 
organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
255/Protocol CO40016, Version 11 (Cohort C)
Table 4
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level positive 
airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive airway pressure; 
CRScytokine release syndrome; CTCAECommon Terminology Criteria for Adverse Events; 
eCRFelectronic Case Report Form; HLHhemophagocytic lymphohistiocytosis; 
ICUintensive care unit; IRRinfusion-related reaction; MASmacrophage activation 
syndrome; NCCNNational Cancer Comprehensive Network; NCINational Cancer Institute.
Note:  These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with 
CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at6 L/min, and high flow is defined as oxygen 
delivered at6 L/min.
e
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the event.  The decision to re-challenge patients with atezolizumab 
should be based on investigator’s assessment of benefitrisk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.   For subsequent infusions, administer oral premedication with antihistamines, anti-
pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication with 
corticosteroids and extending the infusion time may also be considered after assessing the 
benefitrisk ratio.
f
Refer to Riegler et al. (2019).
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 5.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
256/Protocol CO40016, Version 11 (Cohort C)
Table 5
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0ULN:
Continue atezolizumab.
Monitor amylase and lipase weekly.
For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Asymptomatic with amylase and/or lipase 2.05.0ULN:
Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Monitor amylase and lipase every other day.
If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator’s assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
257/Protocol CO40016, Version 11 (Cohort C)
Table 5
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator’s assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
258/Protocol CO40016, Version 11 (Cohort C)
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limited, with or without pruritus.  Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab.  
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated. Management guidelines for dermatologic 
events deemed solely related to atezolizumab are provided in Table 6. For management 
of events that are related to ipatasertib, paclitaxel, or combination therapy, refer to 
guidelines in Appendix 13, Table 3.
Table 6
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 
Continue atezolizumab.
Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 
Continue atezolizumab.
Consider patient referral to dermatologist for evaluation and, if indicated, 
biopsy.
Initiate treatment with topical corticosteroids.
Consider treatment with higher-potency topical corticosteroids if event does 
not improve.
If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day.
Dermatologic 
event, Grade 3 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to dermatologist for evaluation and, if indicated, biopsy.
Initiate treatment with 10 mg/day oral prednisone or equivalent, increasing 
dose to 12 mg/kg/day if event does not improve within 4872 hours.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor. c
Dermatologic 
event, Grade 4
Permanently discontinue atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator’s assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
259/Protocol CO40016, Version 11 (Cohort C)
Table 6
Management Guidelines for Dermatologic Events (cont.)
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome 
or toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist, or urologist as relevant) for 
evaluation and, if indicated, biopsy.

Follow the applicable treatment and management guidelines 
above.

If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge
patients with atezolizumab should be based on investigator’s assessment of benefitrisk
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 7.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
260/Protocol CO40016, Version 11 (Cohort C)
Table 7
Management Guidelines for Neurologic Disorders
Event
Management
Immune-
mediated
neuropathy, 
Grade 1
Continue atezolizumab.
Investigate etiology.
Immune-
mediated
neuropathy, 
Grade 2 
Withhold atezolizumab for up to 12 weeks after event onset. a
Investigate etiology and refer patient to neurologist.
Initiate treatment as per institutional guidelines.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-
mediated
neuropathy, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Refer patient to neurologist.
Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade)
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to neurologist.
Initiate treatment as per institutional guidelines.
Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator’s 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
261/Protocol CO40016, Version 11 (Cohort C)
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 8.
Table 8
Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades
Permanently discontinue atezolizumab and contact Medical Monitor. a
Refer patient to neurologist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent 
upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator’s assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 9.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
262/Protocol CO40016, Version 11 (Cohort C)
Table 9
Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1
Continue atezolizumab.
Monitor kidney function, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline 
values. 
Renal event, 
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to renal specialist.
Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. 
Refer patient to renal specialist and consider renal biopsy.
Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator’s 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of 
atezolizumab.  Myositis or inflammatory myopathies are a group of disorders sharing the 
common feature of inflammatory muscle injury; dermatomyositis and polymyositis are 
among the most common disorders.  Initial diagnosis is based on clinical (muscle 
weakness, muscle pain, skin rash in dermatomyositis), biochemical (serum creatine 
kinase increase), and imaging (electromyography/MRI) features, and is confirmed with 
a muscle biopsy. Patients with possible myositis should be referred to a rheumatologist 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
263/Protocol CO40016, Version 11 (Cohort C)
or neurologist.  Patients with possible myositis should be monitored for signs of 
myocarditis.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 10.
Table 10 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-
mediated
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator’s 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
264/Protocol CO40016, Version 11 (Cohort C)
Table 10 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-
mediatedmyositis, 
Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-
mediated
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
265/Protocol CO40016, Version 11 (Cohort C)
Table 10
Management Guidelines for Immune-Mediated Myositis 
(cont.)
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be based on an assessment of benefitrisk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on investigator’s 
assessment of benefitrisk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed.
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)


Appendix 15 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
266/Protocol CO40016, Version 11 (Cohort C) 
• 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
• 
Ferritin > 684 mg/L (684 ng/mL) 
• 
At least two of the following: 
– 
Platelet count ≤ 181 × 109/L (181,000/µL) 
– 
AST ≥ 48 U/L 
– 
Triglycerides > 1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 11. 
Table 11 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
• Permanently discontinue atezolizumab and contact Medical Monitor. 
• Consider patient referral to hematologist. 
• Initiate supportive care, including intensive care monitoring if indicated 
per institutional guidelines. 
• Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
• If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti−programmed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:502−4. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:190−6. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465−77. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
267/Protocol CO40016, Version 11 (Cohort C)
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.

SAP_001.pdf: 
 
Official Title: 
 
A Double-Blind, Placebo-Controlled, Randomized Phase III Study of 
Ipatasertib in Combination With Paclitaxel as a Treatment for Patients 
With Pik3ca/Akt1/Pten-Altered, Locally Advanced or Metastatic, Triple-
Negative Breast Cancer or Hormone Receptor-Positive, HER2-
Negative Breast Cancer 
NCT Number: NCT03337724 
Document Dates: SAP Version 2: 12-March-2020 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Ipatasertib—F. Hoffmann-La Roche Ltd
6WDWLVWLFDO $QDO\VLV 3ODQ CO40016
STATISTICAL ANALYSIS PLAN
TITLE:
A DOUBLE-BLIND, PLACEBO-CONTROLLED,
RANDOMIZED PHASE III STUDY OF IPATASERTIB IN
COMBINATION WITH PACLITAXEL AS A TREATMENT FOR
PATIENTS WITH PIK3CA/AKT1/PTEN-ALTERED, LOCALLY
ADVANCED OR METASTATIC, TRIPLE-NEGATIVE BREAST
CANCER OR HORMONE RECEPTOR–POSITIVE,
HER2-NEGATIVE BREAST CANCER
PROTOCOL NUMBER:
CO40016
STUDY DRUG:
Ipatasertib (RO5532961, GDC-0068)
VERSION NUMBER:
2
IND NUMBER:
133823
EUDRACT NUMBER:
2017-001548-36
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
See electronic date stamp below.
DATE AMENDED:
Version 1: 6 February 2020
Date and Time(UTC)        Reason for Signing
Name
12-Mar-2020 09:25:50
Company Signatory


Ipatasertib—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan CO40016
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
Study CO40016 Statistical Analysis Plan (SAP) has been amended primarily to 
incorporate the Health Authority (HA) feedback. 
Changes to the SAP, along with the rationales, are summarized below.

Section 4.4.1 To avoid the potential risk of over-stratification (Akazawa et al. 1997), 
additional wording describing the stratificiation factors to be used in the stratified 
analysis have been added to allow leaving out stratification factors causing too 
sparse stratum in the stratified analysis. The following wording is added “If at least 
one stratum (i.e., a combination of stratification factor levels across all stratification 
factors) has fewer than 10 progression free survival (PFS) events across treatment 
arms, the stratification factor which contains the level with the smallest number of 
patients will be removed from the stratified analyses. The removal of the 
stratification factors will continue until there is no stratum with fewer than 10 PFS 
events. The final set of stratification factors used in stratified analyses will be 
applied to all endpoints where stratified analyses are planned”.

Section 4.4.3.1 Per Food and Drug Administration’s (FDA) recommendation, the 
method to calculate 95% confidence interval of objective response rate (ORR) has 
been changed from Blyth-Still-Casella method to the more conservative Clopper 
Person method.

Section 4.4.6.1 Additional sensitivity analysis on PFS excluding patients who 
enrolled on the basis of a non-clinical trial assay (CTA) result has been added to 
support Foundation Medicine, Inc. (FMI) companion diagnostics filing. This analysis 
is aimed to further demonstrate the clinical utility of the FMI CTA.

Section 4.4.2 Overall survival has been labeled as a key secondary endpoint per the 
FDA’s suggestion given that this endpoint is type I error controlled. The analysis 
methods for this endpoint remain unchanged.

Section 4.4.5.1.1 The following covariates has been added to the mixed-effects
model covariates: prior adjuvant/neoadjuvant chemotherapy, prior therapy with a 
phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR)
inhibitor, and bone metastases, since these factors may correlate with 
Patient-Reported Outcomes (PROs). Brain metastases has been removed from the 
covariates, since it is part of trial exclusion criteria.

Section 4.4.6.4 Text referring to the supplemental PRO analysis document (Anchor-
Based Method to Assess Within-Patient Meaningful Change in the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
Core 30 [EORTC QLQ-C30] Pain Scale) has been added in this main SAP. 
Cumulative distribution function (CDF) curves to support the pain analysis will be 
produced and reported as part of the supplementary PRO anchoring SAP, therefore 
reference to CDF curves has been removed from section 4.4.5.1.2.


Ipatasertib—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan CO40016

Section 4.4.5.2 Time to first opioid use analysis has been added per previous HA
feedback on PRO pain analysis.

Sections 4.4.5.1.1 and 4.4.5.2.1 Text has been added to clarify that line charts will 
be provided only for 5 key scales to focus visualizations on key variables, tables for 
all 15 instrument scale will still remain to be provided.
Additional minor changes have been made to improve clarity and consistency.


Ipatasertib—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan CO40016
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 7
2.
STUDY DESIGN........................................................................................... 7
2.1
Protocol Synopsis.................................................................. 10
2.2
Outcome Measures ............................................................... 10
2.3
Determination of Sample Size ............................................... 14
3.
STUDY CONDUCT..................................................................................... 16
3.1
Randomization....................................................................... 16
3.2
Independent Review Facility.................................................. 16
3.3
Data Monitoring ..................................................................... 17
4.
STATISTICAL METHODS .......................................................................... 17
4.1
Analysis Populations ............................................................. 17
4.1.1
Randomized/ITT Population .................................................. 17
4.1.2
Pharmacokinetic-Evaluable Population ................................. 18
4.1.3
Safety Population .................................................................. 18
4.1.4
PRO-(valuable 3opulation.................................................... 18
4.2
Analysis of Study Conduct..................................................... 18
4.3
Analysis of Treatment Group Comparability .......................... 18
4.4
Efficacy Analysis.................................................................... 19
4.4.1
Primary Efficacy Endpoint...................................................... 19
4.4.2
Key Secondary Efficacy Endpoints........................................ 19
4.4.3
Other Secondary Efficacy Endpoints ..................................... 20
4.4.3.1
Objective Response Rate with Duration of 
Response .............................................................................. 20
4.4.3.2
Clinical Benefit Rate .............................................................. 21
4.4.4
Exploratory Efficacy Endpoints.............................................. 21
4.4.4.1
Progression-Free Survival 2 (PFS2)...................................... 21
4.4.4.2
Time to First Skeletal-Related Event ..................................... 21
4.4.4.3
Time to First Objective Response.......................................... 22
4.4.5
Patient-Reported Outcome Analyses .................................... 22


Ipatasertib—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan CO40016
4.4.5.1
Secondary Patient-Reported Outcome Endpoints................. 22
4.4.5.2
Exploratory Patient-Reported Outcome Analyses ................. 24
4.4.6
Sensitivity Analyses............................................................... 24
4.4.6.1
Sensitivity Analyses of Progression-Free Survival................. 24
4.4.6.2
Sensitivity Analyses of Objective Response Rate ................. 25
4.4.6.3
Sensitivity Analyses of Duration of Response ....................... 26
4.4.6.4
Sensitivity Analyses of Time to Deterioration in 
Pain ....................................................................................... 26
4.4.7
Subgroup Analyses ............................................................... 26
4.5
Pharmacokinetic Analyses..................................................... 27
4.6
Safety Analyses..................................................................... 28
4.6.1
Exposure of Study Medication............................................... 28
4.6.2
Adverse Events ..................................................................... 28
4.6.3
Laboratory Data..................................................................... 29
4.6.4
ECOG Performance Status ................................................... 29
4.6.5
Electrocardiograms................................................................ 29
4.6.6
Exploratory Patient-Reported Safety Outcome 
Analyses................................................................................ 29
4.6.6.1
Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) ........................................................... 29
4.7
Exploratory Biomarker Analyses............................................ 31
4.8
Missing Data.......................................................................... 31
4.9
Interim Analyses .................................................................... 32
4.9.1
Planned Interim Safety Analysis............................................ 32
4.9.2
Planned Interim OS Analysis at PFS Primary 
Analysis ................................................................................. 32
4.9.3
Optional Interim Analysis....................................................... 33
5.
REFERENCES ........................................................................................... 34


Ipatasertib—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan CO40016
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints (Applicable for 
Both Cohort A and Cohort B, Unless Otherwise Stated)............. 12
Table 2
Summary of Overall Survival Interim and Final Analysis: 
Cohort A...................................................................................... 33
Table 3
Summary of Overall Survival Interim and Final Analysis: 
Cohort B...................................................................................... 33
LIST OF FIGURES
Figure 1
Study Schema (Cohort A and B)................................................. 10
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 35
Appendix 2
Schedule of Assessments........................................................... 51
Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples..................................................................... 61


Ipatasertib—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan CO40016
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study CO40016 Cohorts A and B, the two double-blind 
placebo-controlled randomized cohorts. Cohort C is an open-label single-arm cohort, 
the analysis for Cohort C is not covered in this SAP, but has been described in the 
protocol.
2.
STUDY DESIGN
The two randomized, double-blind, placebo-controlled cohorts in this Phase III study are
designed to evaluate the efficacy of ipatasertibpaclitaxel (IpatPac) versus 
placebopaclitaxel (PboPac) in patients with histologically confirmed, locally advanced 
or metastatic triple-negative breast cancer (advanced TNBC; Cohort A) and in patients 
with locally advanced or metastatic hormone receptor (HR)/human epidermal growth 
factor receptor 2 (HER2)breast adenocarcinoma (advanced HR/HER2- BC; Cohort B) 
who are not suitable for endocrine therapy.  Each cohort is independent with separate 
analyses, but with a single screening process to identify, allocate, and subsequently 
stratify on the basis of histologic and diagnostic status.  Patients must have measurable 
disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) and a tumor with alteration of phosphatidylinositol-4,5bisphosphate 
3 kinase catalytic subunit alpha (PIK3CA) and/or protein kinase B (AKT1) and/or 
phosphatase and tensin homolog (PTEN) as determined by any blood- or tissue-based 
molecular diagnostic assay (using a Clinical Laboratory Improvement Amendments
[CLIA] or equivalently accredited diagnostic laboratory).  This alteration status is 
hereafter referred to as PIK3CA/AKT1/PTEN-altered (see Section 4.1.1 of the Study 
Protocol for Disease-Specific Inclusion Criteria).  Pathological determination of estrogen 
receptor (ER), progesterone receptor (PgR), and HER2 status based on local 
assessment according to American Society of Clinical Oncology (ASCO) and College of 
American Pathologists (CAP) guidelines (see Appendix 3 and Appendix 4 of the Study 
Protocol) will be applied for cohort assignment by an interactive voice or Web-based 
response system (IxRS), with subsequent randomization within each cohort based on 
the appropriate stratification factors for the different cohorts.  Patients who have 
unknown tumor ER, PgR, HER2, or PIK3CA/AKT1/PTEN-altered status and for whom 
determination of status is not possible are not eligible for this study.
Treatment benefit in patients with PIK3CA/AKT1/PTEN-altered tumors will be 
independently compared in patients with advanced TNBC (Cohort A) and in patients with 
advanced HR/HER2BC.  The study schema is shown in Figure 1.
Approximately 249 patients with advanced TNBC and 201 patients with advanced 
HR/HER2BC will be enrolled at approximately 120150 centers worldwide during the 
global enrollment phase.  Patients will be assigned to either Cohort A (advanced TNBC) 
or Cohort B (advanced HR/HER2BC) according to the most recent locally assessed 


Ipatasertib—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan CO40016
pathologically documented receptor status, in their recurrent or metastatic tumor where 
applicable (i.e., for patients with locally advanced BC, this would not apply) and if safely 
accessible, per ASCO/CAP guidelines (see Appendix 3 and Appendix 4 of the Study 
Protocol for the 2013 guidelines [includes recent HER2 testing update [Wolff et al. 2018]) 
and randomly assigned in a 2:1 ratio to the experimental arm (Ipat 400 mgPac) or 
control arm (PboPac).  Randomization will be stratified by the following factors:  prior 
adjuvant/neoadjuvant chemotherapy (yes vs. no), region (Asia-Pacific vs. Europe vs. 
North America vs. rest of the world), tumor PIK3CA/AKT1/PTEN alteration status 
(PIK3CA/AKT1-activating mutations vs. PTEN alterations with no 
PIK3CA/AKT1-activating mutations; Cohort A only), and prior therapy with a 
phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitor 
(yes vs. no; Cohort B only).
Given the probability of PIK3CA/AKT1/PTEN-non-altered status (approximately 80%85% 
for TNBC and 50%60% for HR+/HER2- BC by blood-based NGS assay, such as FACT, 
and 55%65% by tissue-based NGS, such as FMI CTA), it remains an option to use the 
biomarker-specific ICF/screening process first, prior to other study screening procedures 
for those patients who require central testing of biomarker status.  Patients will also be 
given the option of providing a tissue biopsy sample obtained at disease progression for 
exploratory analyses; this decision will not affect overall study eligibility.  
All eligible patients will receive paclitaxel chemotherapy (80 mg/m2 IV) on Days 1, 8, 
and 15 of each 28-day cycle and either ipatasertib at a dose of 400 mg administered 
orally once a day (QD) on Days 121 of each 28-day cycle (experimental arm) or 
placebo orally QD on Days 121 of each 28-day cycle (control arm).  Study treatment 
will continue until disease progression, intolerable toxicity, elective withdrawal from the 
study, or study completion or termination.  Upon treatment discontinuation, patients will 
be followed every 3 months for survival, patient-reported outcomes (PROs)
(see Section 4.5.8 of the Study Protocol), and new anti-cancer therapy and outcome 
(therapy/procedures, doses, start and stop date, best responses, most recent tumor 
assessment date, and progression date).
Tumor measurement for disease evaluation will be performed every 8 weeks, regardless 
of whether patients receive study treatment during the treatment cycle.  For estimation of 
progression-free survival (PFS), objective response rate (ORR), and duration of 
response (DOR), tumor response will be based on RECIST v1.1.  For patients who 
discontinue treatment without evidence of disease progression per RECIST v1.1, in 
addition to post-treatment follow-up, patients will be followed every 812 weeks for 
tumor assessments until documented progression per RECIST v1.1, elective withdrawal 
from the study, or study completion or termination.  Images for tumor assessments for all 
patients are prospectively collected to enable retrospective blinded independent central 
review when needed.


Ipatasertib—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan CO40016
The pharmacokinetics of ipatasertib and its metabolite G-037720 will be assessed in all 
patients receiving ipatasertib.  Safety will be evaluated on an ongoing basis in this study 
through the monitoring of all serious and non-serious adverse events (AEs) and will be 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).
An independent Data Monitoring Committee (iDMC) will periodically evaluate the safety 
of ipatasertib or placebo combined with paclitaxel.  The analysis supporting iDMC review 
has been conducted by an independent Data Coordinating Center (iDCC) and provided 
to the iDMC.  Interactions between the iDMC and Sponsor will be carried out as
specified in the iDMC Charter.
No interim analysis of the primary efficacy endpoint PFS is planned.  One interim overall 
survival (OS) analysis (at the time of the primary analysis for PFS) for each cohort is 
planned as described in Section 6.8.2 of the Study Protocol. Analysis of safety and 
efficacy for each cohort will be performed independently.
Crossover is not allowed.
There is no China Extension phase.


Ipatasertib—F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan CO40016
Figure 1
Study Schema (Cohort A and B) 
BCbreast cancer; Dday; EUEurope; HER2human epidermal growth factor receptor 2; 
HRhormone receptor; LA locallyadvanced; MBCmetastatic breast cancer; NA= North 
America; POby mouth; Rrandomization; RoWRest of the World; TNBCtriple-negative 
breast cancer; Y/Nyes or no.
Note: 
(1) If allowed locally, prophylaxis loperamide is mandated in Cycle 1, dose adjustment is as 
necessary, and continuation is per investigator judgment.
(2) Study Schema for Cohort C is not included, but can be found in the protocol.
a PIK3CA/AKT1 mutant versus PTEN-altered (and non-PIK3CA/AKT1 mutant).
b If applicable, patients will return to the clinic every 812 weeks for tumor assessments 
(disease follow-up visit) until disease progression, elective withdrawal from study, or study 
completion or termination.  
c The originally planned potential China Extension phase is removed.
d A lower number of slides may be required if FoundationONE CDxis commercially already 
run and used for biomarker qualification.
e
Patients with HR+/HER2breast cancer who are not suitable candidates for endocrine therapy 
and who meet one of the following criteria:  the patient has recurrent disease (locoregional or 
metastatic) during adjuvant endocrine therapy (i.e., ≤5 years of being on therapy), or if the 
patient has de novo metastatic disease, patient has progressive disease within 6 months of 
being on first-line endocrine treatment of metastatic disease.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  Detailed schedule of Assessments in 
Appendix 2 and Appendix 3.
2.2
OUTCOME MEASURES
This SAP provides details of the planned analyses and statistical methods for Cohorts A 
and B that will independently evaluate the safety, efficacy, and pharmacokinetics of 
IpatPac compared with PboPac in patients with PIK3CA/AKT1/PTEN-altered tumors.  
One cohort will be a first-line treatment in patients with advanced TNBC, and the second 


Ipatasertib—F. Hoffmann-La Roche Ltd
11/Statistical Analysis Plan CO40016
will be a first-chemotherapy treatment in patients with advanced HR/HER2BC who 
are not appropriate candidates for endocrine therapy.  Patients will be enrolled based on 
central or local/commercial determination of PIK3CA/AKT1/PTEN-altered status by 
blood or tissue, with central assessment of PIK3CA/AKT1/PTEN-altered status in tumor 
tissue performed in any patients enrolled using alternative methods and will be allocated 
to one of the cohorts based on hormone-receptor status.  Patients with HER2-positive 
tumors are not eligible.  The reason that the two patient populations will be evaluated
separately is that advanced TNBC and advanced HR/HER2BCs have different 
biologies that manifest clinically with different prognoses and response to treatment, and 
molecularly with distinct molecular profiles with dissimilar oncogenic drivers.  The two 
populations have different prevalence and PFS and OS expectations, and thus different 
enrollment and analysis timelines.
The two independent target patient populations for this study are premenopausal and 
postmenopausal female and male patients with measurable, advanced TNBC and 
HR/HER2BC who have not received chemotherapy in either of these settings.  
Patients must be appropriate candidates for taxane monotherapy.  In particular, patients 
with advanced HR/HER2BC should be suitable for treatment with chemotherapy 
(e.g., experiencing symptomatic visceral disease or demonstrated insensitivity to 
endocrine therapy).  Prior neoadjuvant and/or adjuvant chemotherapy is allowed, 
provided it has been concluded at least 12 months before the diagnosis of advanced 
disease.
Patients with PIK3CA/AKT1/PTEN-altered tumors (as defined in Section 3.1.1 and
Section 4.1.1 of the Study Protocol) will be assigned to Cohort A (advanced TNBC) or 
Cohort B (advanced HR/HER2BC) based on their hormone receptor status (as 
evaluated locally, or on study, only if local evaluation is not available, with additional 
slides submitted for this purpose) and randomized with a 2:1 ratio to the experimental 
versus control arm.  All primary, secondary, exploratory, and safety objectives will be 
assessed independently for each cohort (i.e., Cohort A:  patients with advanced TNBC 
with PIK3CA/AKT1/PTEN-altered tumors and Cohort B:  patients with advanced 
HR/HER2BC with PIK3CA/AKT1/PTEN-altered tumors).
The primary endpoint for the Cohort A (advanced TNBC) is PFS.  The primary endpoint 
for Cohort B (advanced HR/HER2BC) is also PFS. The primary analysis for each 
cohort will be independent and triggered by cohort-specific events and will also be 
independent of the readout of the other cohort (refer to Section 6 of the Study Protocol).  
The secondary endpoints for each cohort will be tested if the primary analysis of the 
respective PFS reaches statistical significance at the level of 5%.
Specific objectives and corresponding endpoints for each cohort will be analyzed 
independently following cohort-specific statistical analysis plans, and are outlined in
Table 1.


Ipatasertib—F. Hoffmann-La Roche Ltd
12/Statistical Analysis Plan CO40016
Table 1
Objectives and Corresponding Endpoints (Applicable for Both 
Cohort A and Cohort B, Unless Otherwise Stated)
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of IpatPac
compared with PboPac
PFS, defined as the time from randomization to 
the first occurrence of disease progression, as 
determined locally by the investigator through 
the use of RECIST v1.1, or death from any 
cause, whichever occurs first
Secondary Efficacy Objectives:
To evaluate the efficacy of IpatPac
compared with PboPac
Key Secondary Endpoint:
OS, defined as the time from randomization to 
death from any cause 
Other Secondary Endpoints:
Objective response rate, defined as a CR or 
PR on two consecutive occasions 4 weeks 
apart, as determined locally by the investigator
through the use of RECIST v1.1
Duration of response, defined as the time from 
the first occurrence of a documented objective 
response to disease progression, as 
determined locally by the investigator through 
use of RECIST v1.1, or death from any cause, 
whichever occurs first
Clinical benefit rate, defined as an objective 
response (CR or PR), or stable disease for at 
least 24 weeks, as determined locally by the 
investigator through the use of RECIST v1.1
To evaluate PROs of GHS/HRQoL associated 
with IpatPac compared with Pbo+Pac
Mean and mean changes from baseline 
GHS/HRQoL score as measured by the 
GHS/HRQoL scale (Questions 29 and 30) of 
the EORTC QLQ-C30, by cycle
To evaluate PROs of disease-related pain of 
IpatPac compared with PboPac (Cohort B 
only) 
Time to deterioration in pain, defined as the 
first minimally important increase of 11 points 
from the baseline pain scale score (Questions 
9 and 19) of the EORTC QLQ-C30
Exploratory Efficacy Objectives:
To evaluate the efficacy of IpatPac
compared with PboPac in advanced TNBC 
(Cohort A only) patients with tumors that have 
the following:
-
PIK3CA/AKT1-activating mutations 
-
PTEN alterations (and no 
PIK3CA/AKT1-activating mutations) 
PFS
Objective response rate
Duration of response
Clinical benefit rate
OS 


Ipatasertib—F. Hoffmann-La Roche Ltd
13/Statistical Analysis Plan CO40016
Table 1
Objectives and Corresponding Endpoints (Applicable for Both 
Cohort A and Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Exploratory Efficacy Objectives: (cont.)
To evaluate PROs of function and 
disease/treatment-related symptoms 
associated with IpatPac compared with 
PboPac
Mean and mean changes from baseline scores 
in functional (i.e., role, physical, cognitive,
emotional, and social) and disease/treatment-
related symptoms by cycle as assessed by the 
functional and symptom scales of the EORTC 
QLQ-C30
To collect utilities for pharmacoeconomic 
modeling 
Health states for utility assessment and the VAS 
as measured by the EQ-5D-5L questionnaire for 
modeling
To evaluate the clinical benefit
PFS2, defined as the time from randomization 
to first objective disease progression on next-
line treatment, or death from any cause, 
whichever occurs first
Time to first skeletal–related event (SRE), 
defined as the time from randomization to the 
occurrence of an SRE.  An SRE is either a 
pathologic fracture, radiation therapy to the 
bone, surgery to the bone, or spinal cord 
compression.
To evaluate analgesic use in IpatPac and 
PboPac treatment arms (Cohort B only)
Change in use of opioid analgesics during 
treatment, as measured by the intake of 
analgesic treatments
Safety Objective:
To evaluate the safety of IpatPac compared 
with PboPac
Incidence of adverse events as assessed by the 
investigator, with severity determined through 
the use of NCI CTCAE v4.0 
Incidence of prespecified adverse events 
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Exploratory Safety Objective:
To collect PROs regarding key symptomatic 
adverse events of IpatPac compared with 
PboPac
Selected items from the PRO-CTCAE capturing 
patients' rating of the presence, severity, 
frequency, and/or interference of diarrhea, 
nausea, vomiting, decreased appetite, fatigue, 
neuropathy, mouth sores, and rash symptoms 
and an additional item regarding bother due to 
side effects of treatment


Ipatasertib—F. Hoffmann-La Roche Ltd
14/Statistical Analysis Plan CO40016
Table 1
Objectives and Corresponding Endpoints (Applicable for Both 
Cohort A and Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Pharmacokinetic Objective:
To characterize the pharmacokinetics of 
ipatasertib and its metabolite (G-037720) 
when administered in combination with 
paclitaxel
Plasma concentration of ipatasertib and 
G-037720 at specified timepoints for analysis 
using population PK methodology
Exploratory Pharmacokinetic Objective:
To evaluate potential relationships between 
ipatasertib exposure, efficacy, and safety of 
IpatPac compared with PboPac
Relationship between ipatasertib PK and 
efficacy endpoints 
Relationship between ipatasertib PK and safety 
endpoints 
Exploratory Biomarker Objectives:
To evaluate predictive or prognostic 
biomarkers (plasma or tissue) associated 
with disease activity status or response to 
treatment 
To identify possible mechanisms of 
resistance to study treatments through the 
comparative analysis of potential biomarkers 
in pretreatment and post-progression biopsy 
tissue samples and in blood 
To evaluate alternative diagnostics testing 
methods for PIK3CA/AKT1/PTEN-altered 
status
Relationship between tissue- and blood-based 
biomarkers and patient clinical features (e.g., 
baseline features) and outcome (e.g., duration 
of PFS)
Change in mutation and copy number in 
oncogenes, tumor suppressors, and/or other 
genes associated with disease progression by 
DNA sequencing 
Change in levels of tumor suppressors, 
immune checkpoints, mitotic index, apoptotic 
index, and/or immune-cell infiltration by 
immunohistochemistry
Associations of BC subtypes defined by 
molecular signatures with patient outcomes
Association of BRCA1/2 genetic alterations 
and homologous repair deficiency with patient 
outcomes
BCbreast cancer; BRCA breast and ovarian cancer susceptibility gene; CR complete 
response; 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; GHSglobal health status; HRQoLhealth-related quality of life;
IpatPac ipatasertib + paclitaxel; NCI CTCAE v4.0National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0; OSoverall survival; 
PKpharmacokinetics; PFSprogression-free survival; PboPac placebo + paclitaxel;
PRpartial response; PRO patient-reported outcome; PRO-CTCAEPatient-Reported 
Outcomes Version of the Common Terminology Criteria for Adverse Events; RECIST 
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; TNBCtriple-negative breast 
cancer; VASvisual analog scale.
2.3
DETERMINATION OF SAMPLE SIZE
As described earlier, Cohort A (patients with advanced TNBC) and Cohort B (patients 
with advanced HR/HER2BC) are two independent cohorts and will be analyzed 
separately.  Each cohort will be tested independently with 5% type I error control. In the 


Ipatasertib—F. Hoffmann-La Roche Ltd
15/Statistical Analysis Plan CO40016
event that the primary PFS analysis timelines for the advanced TNBC and 
HR/HER2cohorts are far apart, the treatment codes of the cohort whose PFS data 
are mature earlier will be sent to the Sponsor to unblind only that cohort for the primary 
analysis of PFS. The Sponsor will remain blinded to the treatment assignments of the 
other cohort.
For Cohort A, approximately 249 patients with advanced TNBC with 
PIK3CA/AKT1/PTEN-altered tumors will be enrolled and randomized in a 2:1 ratio to the 
experimental arm (Ipat 400 mg Pac) and control arm (PboPac). The sample size of 
249 patients is determined on the basis of the power calculation for the PFS and OS 
endpoints.
The PFS primary analysis in Cohort A is planned be conducted after approximately 
125 PFS events in Cohort A have been observed or last patient in, whichever is later. 
This allows for at least 95.5% power to detect an improvement in median PFS from 
6 months in the PboPac arm to approximately 12 months in the IpatPac arm (hazard 
ratio 0.5) at the 5% level of significance (two-sided). The largest hazard ratio deemed 
to be statistically significant at the 5% level will be approximately 0.69 (with median PFS 
improvement from 6 months to 8.7 months).
For Cohort A, the key secondary endpoint, OS, will be tested only if the PFS result is 
statistically significant.  The final OS analysis with approximately 188 OS events will 
provide 80% power to detect a hazard ratio of 0.65 (median OS improvement from 16 to 
24.6 months), or 64% power to detect a hazard ratio of 0.7 (median OS improvement 
from 16 to 22.9 months).  The largest detectable OS hazard ratio (with a log-rank test) 
will be approximately 0.74 (with median OS improvement from 16 months to 
21.6 months).
Assuming a 2-month site ramp-up period and approximately 120150 sites, the 
enrollment duration is projected to be approximately 16 months (from the first patient 
enrolled).  The last PFS event (the 125th PFS event) for the PFS analysis in Cohort A is 
projected to occur approximately 20 months after the first patient is enrolled.  The last 
death (the 188th OS event) for the final OS analysis in Cohort A is projected to occur 
approximately 53 months after the first patient is enrolled.
For Cohort B, approximately 201 patients with advanced HR/HER2 BC with 
PIK3CA/AKT1/PTEN-altered tumors will be enrolled and randomized in a 2:1 ratio to the 
experimental arm (Ipat 400 mg Pac) and control arm (PboPac).  The sample size of 
201 patients is determined on the basis of the power calculation for the primary endpoint, 
PFS.
The PFS primary analysis in Cohort B is planned be conducted when approximately 
150 PFS events in the Cohort B patients have been observed.  This allows for 80% 
power to detect an improvement in median PFS from 8.5 months in the PboPac arm to 


Ipatasertib—F. Hoffmann-La Roche Ltd
16/Statistical Analysis Plan CO40016
approximately 13.8 months in the IpatPac arm (hazard ratio0.62) at the 5% level of 
significance (two-sided).  The largest hazard ratio deemed to be statistically significant at 
the 5% level will be approximately 0.71 (with median PFS improvement from 8.5 months 
to 11.93 months).
Assuming a 2-month site ramp-up period and approximately 120-150 sites, the 
enrollment duration is projected to be approximately 10 months (from the first patient 
enrolled).  The last PFS event (the 150th PFS event) for the PFS analysis in Cohort B 
(patients with advanced HR/HER2 BC) is projected to occur approximately 
30 months after the first patient is enrolled.
For both Cohort A and B, the above timeline estimates are based on an assumption of 
an annual loss-to-follow-up rate for PFS of 5% and an annual loss-to-follow-up rate for 
OS of 2%.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Patients will be assigned to either Cohort A (advanced TNBC) or Cohort B (advanced 
HR/HER2BC) according to the most recent locally assessed pathologically 
documented receptor status in their recurrent or metastatic tumor per ASCO/CAP 
guidelines and randomly assigned in a 2:1 ratio to the experimental arm 
(Ipat 400 mgPac) or control arm (PboPac).  Randomization will be stratified by the 
following factors:  prior adjuvant/neoadjuvant treatment including chemotherapy (yes vs. 
no), region (Asia-Pacific vs. Europe vs. North America vs. rest of the world), tumor 
PIK3CA/AKT1/PTEN alteration status (PIK3CA/AKT1-activating mutations vs. PTEN
alterations with no PIK3CA/AKT1-activating mutations; Cohort A only), and prior therapy 
with a PI3K or mTOR inhibitor (yes vs. no; Cohort B only).
3.2
INDEPENDENT REVIEW FACILITY
The imaging data used for tumor assessment are collected by the Sponsor from all 
patients to enable retrospective independent central review of response endpoints by an 
Independent Review Committee (IRC). An independent imaging group will be used to 
evaluate tumor assessments for determination of progression and objective response 
according to RECIST v1.1. Imaging data (computed tomography/Magnetic resonance 
imaging (MRI)/bone scans) will be acquired according to a standard protocol and will be 
forwarded to the independent reviewers. Investigator tumor assessments will not be 
reconciled with the IRC tumor assessments. IRC data will be used in the sensitivity 
analyses to support the findings of the investigator assessed outcomes. Further details 
will be included in the IRC Charter. Details of imaging handling procedures are also 
described in a separate laboratory manual.


Ipatasertib—F. Hoffmann-La Roche Ltd
17/Statistical Analysis Plan CO40016
3.3
DATA MONITORING
An iDMC has been evaluating safety during the study on a regular basis. Members of 
the iDMC are external to the Sponsor and follow a separate iDMC Charter that outlines 
their roles and responsibilities, as well as a detailed monitoring plan. The iDMC will 
meet approximately every 6 months from the point of first patient in to review unblinded 
safety and study conduct data prepared by an independent Data Coordinating Center 
(iDCC). The safety data will include demographic data, AEs, serious adverse events
(SAEs), and relevant laboratory data.
Following each data review, the iDMC will provide recommendations to the Sponsor as 
to whether the study should continue or be amended, or whether the study should be 
stopped on the basis of safety (i.e., evidence of harm). The Sponsor’s Data Review 
Board (DRB; a group consisting of employees of the Sponsor empowered to make 
critical decisions) will decide on the basis of the iDMC’s recommendations. The final 
decision will rest with the Sponsor.
Any outcomes of these safety reviews that affect study conduct will be communicated in 
a timely manner to the investigators for notification of the Institutional Review 
Boards/Ethics Committees (IRBs/ECs).
4.
STATISTICAL METHODS
The analyses outlined in this SAP supersede those specified in the protocol for 
regulatory filing purposes.
The two cohorts, Cohort A (patients with advanced TNBC) and Cohort B (patients with 
advanced HR/HER2BC), are two independent cohorts and will be analyzed 
separately for the following reasons:

The two patient populations are in two different disease settings with different 
prevalence and different PFS and OS expectations, and thus different enrollment 
and analysis timelines.

The readout from one cohort is independent of the readout of the other cohort.

Cohorts A and B are essentially two independent trials running under one protocol 
for operational efficiency.
Therefore, for all analyses described below, these two cohorts will be analyzed 
separately.
4.1
ANALYSIS POPULATIONS
4.1.1
Randomized/ITT Population
The randomized population, which is also referred as the intent-to-treat (ITT) population,
is defined as all randomized patients, whether or not the patient received the assigned 
treatment. All efficacy analyses will be performed in the ITT population, unless 


Ipatasertib—F. Hoffmann-La Roche Ltd
18/Statistical Analysis Plan CO40016
otherwise specified. The ITT patients will be analyzed according to the treatment arm 
assigned at randomization by IxRS.
4.1.2
Pharmacokinetic-Evaluable Population
Pharmacokinetic (PK) analyses will be based on PK observations from all patients who 
received ipatasertib treatment with evaluable PK samples.
4.1.3
Safety Population
The safety population is defined as patients who received any amount of study treatment. 
All safety analyses will be performed in the safety population, unless otherwise specified. 
Patients will be analyzed according to the treatment group associated with the actual 
regimen received. Patients who were randomized to the study but who did not receive 
any study drug will not be included in the safety population.
4.1.4
PRO-evaluable population 
The patient-reported outcome (PRO)-evaluable population includes all randomized 
patients who have a baseline and at least 1 post-baseline PRO assessment. The 
PRO-evaluable patients will be analyzed according to the treatment arm assigned at 
randomization by IxRS.
Analyses for PRO efficacy endpoints will be performed in the PRO-evaluable population, 
unless otherwise specified. PRO-CTCAE will be analyzed in the safety population by 
treatment groups according to treatment received.
4.2
ANALYSIS OF STUDY CONDUCT
Patient enrollment, treatment discontinuation, treatment discontinuation reasons, study 
discontinuation, and study discontinuation reasons will be summarized by treatment arm 
for the two cohorts in the ITT population.  In addition, major protocol violations, including 
violations of inclusion and/or exclusion criteria, will be summarized by treatment arm for 
the two cohorts.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
The treatment group comparability will be evaluated in the ITT population in each cohort. 
Demographics summaries, stratification factors, medical history, and other baseline 
disease characteristics will be compared between the treatment arms in each cohort. 
Baseline values are the last available data obtained prior to the patient receiving the first 
dose of any study treatments on Cycle 1, Day 1 visits unless otherwise noted.
Descriptive summaries of continuous data will present the group mean, standard 
deviation, median and ranges. Descriptive summaries of discrete data will present the 
category counts as frequencies and percentages.


Ipatasertib—F. Hoffmann-La Roche Ltd
19/Statistical Analysis Plan CO40016
Previous and concomitant cancer therapy will also be summarized, including 
radiotherapy and surgery, as well as subsequent anti-cancer therapy. Previous and 
concurrent diseases and medication will also be summarized.
4.4
EFFICACY ANALYSIS
All efficacy analyses will be based on the ITT population (i.e., all randomized patients) 
according to the treatment arm to which patients are randomized, unless otherwise 
specified. 
All primary and secondary RECIST-based endpoints are as per local radiologist or 
investigator assessment.
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is investigator-assessed PFS, defined as the time from 
randomization to the first occurrence of disease progression, as determined by the 
investigator using RECIST v1.1, or death from any cause, whichever occurs first.
Data for patients who do not experience disease progression or death will be censored 
at the last date of evaluable tumor assessment. For patients who do not have an 
evaluable tumor assessment after randomization, the data will be censored at the date 
of randomization plus 1 day.
For each cohort, PFS will be compared between treatment arms using the stratified 
log-rank test.  The hazard ratio will be estimated using a stratified Cox proportional 
hazards model.  The 95% CI for the hazard ratio will be provided.  To avoid the potential 
risk of over-stratification (Akazawa et al. 1997), if at least one stratum (i.e., a 
combination of stratification factor levels across all stratification factors) has fewer than 
10 PFS events across treatment arms, the stratification factor which contains the level 
with the smallest number of patients will be removed from the stratified analyses. The 
removal of the stratification factors will continue until there is no stratum with fewer than 
10 PFS events. The final set of stratification factors used in stratified analyses will be 
applied to all endpoints where stratified analyses are planned. Values for the 
stratification factors will be recorded in the IxRS at the time of randomization. Results 
from an unstratified analysis will also be provided.  Kaplan-Meier methodology will be 
used to estimate the median PFS 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 median PFS for each treatment arm (Brookmeyer and Crowley 1982).
4.4.2
Key Secondary Efficacy Endpoints
Overall survival is a key secondary endpoint and will be formally tested with 5% alpha in 
each cohort only if the primary analysis of respective PFS in the corresponding cohort 
reaches statistical significance at the level of 5% to maintain the overall type I error of 5% 
in each cohort.  The alpha spending between interim and final analysis is described in 
Section 4.9.2.


Ipatasertib—F. Hoffmann-La Roche Ltd
20/Statistical Analysis Plan CO40016
OS is defined as the time from randomization to death from any cause.  Data for patients 
who are not reported as having died at the time of analysis will be censored at the date 
when they were last known to be alive.  Data for patients who do not have post-baseline 
information will be censored at the randomization date plus 1 day.  The analyses will be 
conducted using the stratified two-sided log-rank test, and the results from the 
unstratified log-rank test will also be provided.  The stratification factors to be used will 
be the same as the randomization stratification factors.  For each cohort, the OS curve 
for each treatment arm will be estimated by the Kaplan-Meier methodology, and the 
survival rates at landmarks (e.g., 1-year and 2-year OS) will be provided when data 
allow.  The hazard ratio for OS and its 95% CI will be estimated by the Cox 
proportional-hazards models.
4.4.3
Other Secondary Efficacy Endpoints
The following secondary endpoints will also be tested only if the primary analysis of 
respective PFS in the corresponding cohort reaches statistical significance at the level of 
5%.
4.4.3.1
Objective Response Rate with Duration of Response
ORR analysis will be performed among patients with measurable disease at baseline.
Objective response is defined as a complete response (CR) or partial response (PR) on 
two consecutive occasions4 weeks apart, as determined by the investigator through 
the use of RECIST v1.1. Patients without a post-baseline tumor assessment will be 
considered as non-responders.  Objective response rate (ORR) is defined as the 
proportion of patients who have an objective response.  Analysis of ORR will be 
performed among patients with measurable disease at baseline. For each cohort, an 
estimate of ORR will be calculated for each treatment arm, and its 95% CI will be 
calculated using the Clopper-Pearson method.  ORR will be compared between 
treatment arms using the stratified Cochran-Mantel-Haenszel test.  The stratification 
factors to be used will be the same as those described for the analysis of the primary 
endpoint.  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.
DOR analysis will be performed on all patients with an objective response. DOR is 
defined as the time from the first occurrence of a documented objective response to 
disease progression, as determined by the investigator through the use of RECIST v1.1, 
or death from any cause, whichever occurs first.  The censoring method for DOR will be 
the same as that for PFS.  For each cohort, the Kaplan-Meier approach will be used to 
estimate the median DOR and the corresponding 95% CIs.  Analysis of DOR will include 
only patients with objective responses.  Because of the non-randomized nature of this 
analysis population, the analysis of DOR will be considered descriptive without formal 
hypothesis testing.


Ipatasertib—F. Hoffmann-La Roche Ltd
21/Statistical Analysis Plan CO40016
4.4.3.2
Clinical Benefit Rate
Clinical benefit rate is defined as the proportion of patients who have clinical benefit with 
measurable disease at baseline. Having clinical benefit is defined as having an 
objective response (CR or PR), or stable disease for at least 24 weeks, as determined 
by the investigator through the use of RECIST v1.1.  For each cohort, clinical benefit rate 
will be analyzed using methods similar to those used for ORR.
4.4.4
Exploratory Efficacy Endpoints
4.4.4.1
Progression-Free Survival 2 (PFS2)
PFS2 is defined as the time from randomization to first objective disease progression on 
next-line treatment, or death from any cause, whichever occurs first. Specifically, 
next-line therapy is defined as the treatment received after the first disease progression. 
Patients who do not experience disease progression on next-line therapy or death will be 
censored at the last time known to be alive and without objective disease progression on 
next-line therapy. Observations from patients who do not have post-baseline information 
will be censored at the date of randomization plus 1 day.
PFS2 will be compared between the two treatment arms using the same method as the 
primary endpoint of PFS. This analysis will be performed as data allows.
4.4.4.2
Time to First Skeletal-Related Event
A skeletal-related event (SRE) is defined as either a pathologic fracture, radiation 
therapy to the bone, surgery to the bone, or a spinal cord compression. Any 
cancer-related radiation or surgery to the bone (on-study treatment and during 
post-treatment follow-up), or adverse events with diagnosis of pathologic fracture or 
spinal cord compression, will be assessed according to the SRE criteria. Descriptive 
statistics of the number and percentage of patients with SRE will be summarized by 
treatment arm in each cohort.
Time to first SRE is defined as the time from randomization to the first occurrence of an 
SRE.  Censoring rules will be applied as follows:

Observations from patients who do not have post-baseline information will be 
censored at the date of randomization plus 1 day.

Patients for whom an SRE has not been observed will be censored at the last time 
known to be alive and without an SRE.

Observations from patients who died before having an event will be censored on the 
date of death.

Observations from patients who discontinued study without experiencing an SRE 
will be censored on the date of study discontinuation.
The time from randomization to first SRE will be compared between the two treatment 
arms using a unstratified log-rank test for the ITT population as data allow. The hazard 


Ipatasertib—F. Hoffmann-La Roche Ltd
22/Statistical Analysis Plan CO40016
ratio, including a 95% CI, of the experimental arm compared with the control arm will be 
estimated using a unstratified Cox proportional hazards model.
4.4.4.3
Time to First Objective Response 
Among patients with objective responses, the time from randomization to first objective 
response will be compared between the two treatment arms. Objective response is 
defined in Section 4.4.3.1. Because of the non-randomized nature of this analysis 
population, this analysis will be considered descriptive without formal hypothesis testing. 
Summary statistics (mean, SD, median, and range) will be calculated for the two 
treatment arms.
4.4.5
Patient-Reported Outcome Analyses
The European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) (version 3) data will be scored according to 
the EORTC scoring manual (Fayers et al. 2001).  Missing data will be assessed and 
reported by cycle.  In the event of incomplete data, if the scale has more than 50% of the 
constituent items completed, a pro-rated score will be computed consistent with the 
scoring manual and validation papers of the measure.  For subscales with less than 50% 
of the items completed, the subscale will be considered missing.
Completion analysis will be performed for the overall EORTC QLQ-C30 questionnaire by 
treatment arm for the two cohorts in the ITT population.  Completion rates will be 
summarized by number and proportion of patients among those expected to complete 
the QLQ-C30 at each time point.  Reasons for non-completion will be summarized at 
each time point by treatment arm for the two cohorts.
4.4.5.1
Secondary Patient-Reported Outcome Endpoints
4.4.5.1.1
Patient-Reported Outcomes of Global Health Status/ Quality of 
Life–EORTC Data
A secondary patient-reported endpoint is mean and mean changes from baseline score 
of global health status/quality of life (GHS/QoL). Summary statistics (number of patients, 
mean, SD, median, and range) of linearly transformed absolute scores and mean 
changes from baseline will be calculated for the GHS/QoL (Q29 and Q30) scale of the 
EORTC QLQ-C30 at each assessment time point for each arm within each cohort, in the
PRO-evaluable population. Line charts depicting the mean changes (and 95% 
confidence intervals) of GHS/QoL over time will be provided for the treatment arm from 
the baseline assessment. A 10-point change will be used to identify clinically meaningful 
change from baseline within each treatment arm on the GHS/QoL scale (Osoba et al. 
1998).
A longitudinal analysis will be conducted to estimate the effect difference on PRO
repeated responses over a selected period of time and between the treatment arms
within each cohort. A mixed-effects model on a set of covariates (prior 
adjuvant/neoadjuvant chemotherapy, prior therapy with a phosphoinositide 3-kinase 


Ipatasertib—F. Hoffmann-La Roche Ltd
23/Statistical Analysis Plan CO40016
[PI3K] or mTOR inhibitor, baseline domain score, age group, race group, baseline 
Eastern Cooperative Oncology Group [ECOG] status, bone metastases, treatment, 
analysis visit, treatment interaction with analysis visit, and baseline measurement 
interaction with analysis visit) will be conducted. This analysis will be conducted in the 
PRO-evaluable population. Time points with less than 20% patients who completed 
GHS/QoL scale during the treatment period, where all subsequent time points during the 
treatment period also have less than 20% completion will be excluded. Change from 
baseline at subsequent cycles will be presented by treatment arm and will include least 
squares mean (LS Mean), difference in LS Mean between the two treatment arms, and 
95% CIs for the differences. The standard error will also be calculated for each LS 
Mean.
4.4.5.1.2
Patient-Reported Outcomes of disease-related pain-EORTC 
Data (Cohort B only)
A secondary patient-reported endpoint is time to deterioration (TTD) in pain. A 11-point 
change in pain scale (items 9 and 19 of the EORTC QLQ-C30) is defined as the 
minimally important difference (MID) (Cocks et al. 2012).  The time to deterioration (TTD) 
in pain scale is defined as the time from randomization to the first time the patient’s pain 
scale score shows a11-point increase from the baseline scale score, confirmed by the 
following:
1.
The initial score increase of11-points from baseline is followed by a confirmation 
of a score increase11-points from baseline
2.
The score increase of 11-points from baseline must be held for at least two 
consecutive assessments
Visit summary and change from baseline analyses will be performed for the pain scale of 
EORTC QLQ-C30 (Q9 and Q19) for each arm within each cohort, in the PRO-evaluable 
population. Time to deterioration in pain will be compared between the treatment arms
using the same method as the primary endpoint of PFS (Section 4.4.1), in the ITT 
population. 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 baseline assessment or without a post-baseline assessment will be censored at 
randomization plus 1 day.
Permanent deterioration is defined as a confirmed 11-point increase from baseline in 
pain scale of EORTC QLQ-C30 [Q9 and Q19], that is not followed by a score less than 
an 11-point increase from baseline at any subsequent assessments. Time to permanent 
deterioration in pain may also be compared between the treatment arms using the same 
method as the primary endpoint of PFS as data allow, in the ITT population. 


Ipatasertib—F. Hoffmann-La Roche Ltd
24/Statistical Analysis Plan CO40016
4.4.5.2
Exploratory Patient-Reported Outcome Analyses
4.4.5.2.1
Patient-Reported Outcomes of Functional and 
Disease/Treatment Symptoms-EORTC Data 
Summary statistics (mean, SD, median, and range) of linearly transformed absolute
scores and mean changes from baseline (and 95% CIs) will be calculated for 
disease/treatment-related symptom items and scales and all functional (i.e., physical, 
role, emotional, cognitive, and social) scales of the EORTC QLQ-C30 at each 
assessment timepoint for each arm within each cohort, in the PRO-evaluable population.
Handling of missing data, and the descriptive analyses for mean change from baseline 
of these exploratory endpoints (Cocks et al. 2012) will be analogous to the secondary 
PRO endpoint of GHS/QoL (see Section 4.4.5.1.1 for further details).
Additionally, longitudinal analyses will be conducted in the PRO-evaluable population for
the physical and role functional scales, and disease/treatment-related symptom items 
and scales of: pain (Questions 9 and 19), fatigue (Questions 10, 12 and 18), and 
dyspnea (Question 8), analogous to the secondary PRO endpoint of GHS/QoL 
(see Section 4.4.5.1.1 for further details).
Line charts depicting the mean changes (and 95% confidence intervals) of items and 
scales over time will be provided for each treatment arm from the baseline assessment 
for key functional scales and symptom items (i.e., physical functioning, role functioning, 
diarrhea, and pain).
In support of the secondary patient-reported endpoint TTD in pain, and to further 
elucidate pain treatment effects, an exploratory analysis for time to first opioid use for 
cancer related pain may be performed in ITT population as data allows. Opioid
medication intake as per the study medication diary will be analyzed for analgesia 
producing opioids, coded as per the standardized drug grouping (SDG) for the World 
Health Organization (WHO) Drug Dictionary. The use of the SDG will allow for the 
inclusion of opioids known to produce analgesia, and exclusion of opioids that do not 
produce analgesia.
4.4.6
Sensitivity Analyses
4.4.6.1
Sensitivity Analyses of Progression-Free Survival
PFS censoring for missing visits
An analysis of PFS censoring for missing visits will be performed. Data for patients with 
a PFS event who missed two or more scheduled assessment immediately prior to the 
PFS event will be censored at the last tumor assessment prior to the missed visits.
PFS by IRC
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for primary PFS endpoint on the basis of investigator 
assessment.


Ipatasertib—F. Hoffmann-La Roche Ltd
25/Statistical Analysis Plan CO40016
PFS censoring for non-protocol therapy
Non-protocol therapy (NPT) is defined as any anti-cancer therapy other than study 
treatment. The impact of NPT on the primary endpoint of investigator-assessed PFS by 
RECIST v1.1 will be evaluated. A sensitivity analysis will be performed where patients 
who received NPT before a PFS event occurred will be censored at the last tumor 
assessment date before the patient received NPT.
PFS in tissue-based FMI CTA confirmed patients
An analysis of PFS may be performed in the patients with FMI confirmed 
PIK3CA/AKT1/PTEN-altered tumors. This analysis will use the same methodology as 
specified for the analysis of PFS in the ITT population
PFS in patients with clinical benefit 
An analysis of PFS will be performed in patients with clinical benefit using the same 
methodology as specified for PFS in the ITT population. Clinical benefit is defined in 
Section 4.4.5.1.1.
PFS using stratification factors reported on eCRF
A stratified analysis will be performed on PFS using the same stratification factors for the 
primary PFS analysis but based on values collected on the electronic Case Report Form 
(eCRF) when available.
PFS excluding patients enrolled on the basis of a local test/commercial result
demonstrating PIK3CA/AKT1/PTEN-altered status
An analysis of PFS result will be performed excluding patients whose biomarker elibility
of demonstrating PIK3CA/AKT1/PTEN-altered status was determined by a local 
test/commercial result at the time of enrollment (regardless of their tissue-based FMI 
CTA results available post-enrollment). This analysis will use the same methodology as 
specified for the analysis of PFS in the ITT population.
Additional sensitivity analyses may be considered if appropriate.
4.4.6.2
Sensitivity Analyses of Objective Response Rate
ORR by IRC
An analysis of ORR on the basis of the IRC assessments will be performed among 
patients with measurable disease at baseline according to the assessment by the IRC 
and using the same methodology as specified for ORR on the basis of investigator 
assessment.


Ipatasertib—F. Hoffmann-La Roche Ltd
26/Statistical Analysis Plan CO40016
4.4.6.3
Sensitivity Analyses of Duration of Response
DOR by IRC
An analysis of DOR on the basis of the IRC assessments will be performed using the 
same methodology as specified for DOR on the basis of investigator assessment. 
Objective response is according to the assessment by the IRC.
4.4.6.4
Sensitivity Analyses of Time to Deterioration in Pain
In addition to the time to deterioration in pain base-case analysis of 11-points, as per 
Section 4.4.5.1.2, sensitivity analyses using the different thresholds of 10 and 20 points 
will be performed in order to explore the more conservative value of 20 representing the 
upper bound of the medium threshold range as specified in Cocks et al. (2012), and the 
value of 10 as cited in Osoba et al. (1998). Additional supplemental analysis will also be 
performed using anchor-based methods to assess within-patient meaningful change in 
the EORTC QLQ-C30 pain scale, by utilizing within trial EQ-5D-5L Pain/Discomfort item 
data to derive additional EORTC QLQ-C30 clinically meaningful thresholds for use within 
the TTD analysis ( refer to CO40016 (IPATunity130) Cohort B Supplemental Analyses 
document).
4.4.7
Subgroup Analyses
To assess the consistency of study results in subgroups defined by demographic and 
baseline characteristics, PFS in these subgroups will be examined. OS in these 
subgroups will be examined only if data allows. Summaries of PFS and OS (the latter if
data allows), including unstratified HRs estimated from Cox proportional hazards models 
and Kaplan-Meier estimates of the median, will be produced separately for each level of 
the categorical variables. 
PFS will be evaluated in the subgroups based on the following characteristics in both 
Cohort A and B:

Age group at randomization 

Prior adjuvant/neoadjuvant chemotherapy 

Regions

Race 

Number of sites of metastases at baseline 

Disease free interval

ECOG at Enrollment

Stage at initial diagnosis 
For Cohort A (advanced TNBC), PFS will also be explored in the subgroups based on 
the following characteristics: 

PIK3CA/AKT1-activating mutations vs. PTEN alterations but no 
PIK3CA/AKT1-activating mutations. 


Ipatasertib—F. Hoffmann-La Roche Ltd
27/Statistical Analysis Plan CO40016

PD-L1 status (PD-L1 stained tumor infiltrating tumor cells [IC]1% of tumor area)

Chemotherapy-free interval
For Cohort B (advanced HR/HER2 BC), PFS will also be explored in relevant 
subgroups dependent on selected baseline characteristic

Number of lines of prior endocrine treatment in the advanced setting 

Menopausal status at baseline 

Prior PI3K/mTOR inhibitor use 

Prior CDK4/6 inhibitor use
OS in the above subgroups may be explored if data allows.
Additionally, for cohort A (advanced TNBC), ORR will be explored in the following 
subgroups:

PIK3CA/AKT1-activating mutations vs. PTEN alterations but no 
PIK3CA/AKT1-activating mutations. 
4.5
PHARMACOKINETIC ANALYSES
Ipatasertib and its metabolite (G-037720) levels will be measured on Day 1 and Day 15 
of Cycle 1, and on Day 15 of Cycle 3.  Patients who receive at least one dose of 
ipatasertib with evaluable PK data will be included in the analysis. Plasma 
concentrations of ipatasertib will be tabulated and summarized (mean, standard 
deviation, coefficient of variation, median, range, geometric mean, and geometric mean 
coefficient of variation) by cycle, as appropriate.
Exploratory analyses including population pharmacokinetics with covariate analysis, 
exposure-safety and exposure-efficacy analyses will be conducted if appropriate and 
reported in separate stand-alone reports. The details of analyses methods will be 
included in the separate reports.


Ipatasertib—F. Hoffmann-La Roche Ltd
28/Statistical Analysis Plan CO40016
4.6
SAFETY ANALYSES
All safety analyses will be based on the safety-evaluable population according to the 
treatment received.  Safety analyses will be conducted by treatment groups and include 
incidence, severity, and seriousness of adverse events, deaths, and clinically significant 
laboratory measurements.
4.6.1
Exposure of Study Medication
Study treatment exposure, including treatment duration, dose intensity, and total 
cumulative dose, will be summarized with descriptive statistics. Reasons for 
discontinuation from study treatment will be summarized.
4.6.2
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to the NCI CTCAE v4.0.  
Adverse events will be summarized by mapped term, appropriate thesaurus level and 
NCI CTCAE grade.
After informed consent has been obtained but prior to initiation of study drug, only SAEs
caused by a protocol-mandated intervention should be reported, e.g., SAEs related to 
invasive procedures such as biopsies.
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 28 days after the last dose of study. After this period, investigators should 
report any SAEs and adverse events of special interest (AESI) that are believed to be 
related to prior treatment with study drug. 
Summary tables of the following will be provided for each cohort independently, 
including, but not limited to:

SAEs 

AEs leading to study treatment discontinuation 

AEs leading to dose reduction 

AEs leading to dose interruption 

Treatment-related AEs

Treatment-related SAEs  

Severe adverse events (Grade 3 or higher) 

AEs leading to death 

AEs by highest NCI CTCAE Grade 

Selected AE (including sponsor-defined AESI)


Ipatasertib—F. Hoffmann-La Roche Ltd
29/Statistical Analysis Plan CO40016
A summary table of common AEs, i.e., those occurring in at least 10% of patients in 
either treatment group will be provided.
Multiple occurrences of the same event will be counted once at the maximum severity. 
All listings of AEs will include all AEs with onset on or after the first study drug treatment 
up to the data cutoff date. 
All deaths and causes of death will be summarized.
Time to the first onset and duration of first AEs of interest (e.g., rash, hyperglycemia, and 
diarrhea) may be summarized descriptively if data allows.
4.6.3
Laboratory Data
Laboratory data will be classified according to NCI CTCAE 4.0 and will be summarized 
descriptively over time including change from baseline by cohort. Highest NCI CTCAE 
grade post-baseline will also be reported and shift tables from baseline to worst value 
during the study post-baseline will be presented by cohort. Summary statistics (number 
of patients, mean, SD, median, and range) of absolute values and mean changes from 
baseline will be calculated for HbA1c and triglycerides at each assessment time point for 
each group within each cohort. 
A Hy’s law analysis will be provided. The potential Hy’s law quadrant is defined as 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increases above 
3-fold the upper limit of normal (ULN) with concomitant total bilirubin increases above 
2-fold the ULN.
4.6.4
ECOG Performance Status
ECOG performance status will also be summarized over time (shift from baseline to the 
worst post-baseline value).
4.6.5
Electrocardiograms
The ECG of patients will be summarized at baseline and study drug discontinuation 
visits.
4.6.6
Exploratory Patient-Reported Safety Outcome Analyses
4.6.6.1
Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE)
Eight symptomatic adverse events were selected from the PRO-CTCAE item bank (i.e., 
diarrhea, nausea, vomiting, decreased appetite, fatigue, peripheral numbness and 
tingling, mouth sores, and rash); a total of 14 items, an additional item providing an 
overall assessment of the burden of side effects will be collected.
The number and proportion of patients who complete the Patient-Reported Outcomes 
version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) will be 


Ipatasertib—F. Hoffmann-La Roche Ltd
30/Statistical Analysis Plan CO40016
summarized by treatment group at each time point in the safety population within each 
cohort.  The questionnaire is considered completed if at least one attribute is assessed 
for any patient-reported AE.  The compliance proportion will be based on the total 
number of patients expected to complete the questionnaire at a particular time pointi.e., 
those patients who had the opportunity to complete the questionnaire.
For the PRO-CTCAE analysis, for each treatment group, the number (percentage) of 
patients reporting symptoms by “frequency”, ”severity”, “interference” and “presence” 
category will be reported at each assessment independently for each cohort.
The following terms are used in the description of PRO-CTCAE data:

SOC (System Organ Class): Reflecting the overall system organ class containing a 
selected AE, e.g., pain, mood, respiratory

Item: Corresponds to each AE selected from the PRO-CTCAE item library

Attribute: There are four possible attributes for each selected AE, including 
presence (yes/no), severity, frequency and interference with daily life.
The attributes of frequency, severity and interference with daily life are based on scores 
of 0-4. These numeric scores are used interchangeably with the following category 
labels:

Frequency:
–
0: Never
–
1: Rarely
–
2: Occasionally
–
3: Frequently
–
4: Almost constantly

Severity:
–
0: None
–
1: Mild
–
2: Moderate
–
3: Severe
–
4: Very severe

Interference with daily life:
–
0:  Not at all
–
1: A little bit
–
2: Somewhat
–
3: Quite a bit


Ipatasertib—F. Hoffmann-La Roche Ltd
31/Statistical Analysis Plan CO40016
–
4: Very much
The numeric scores indicate an ordinal, rather than continuous, outcome, therefore 
analysis will focus on frequency counts and percentages; no other summary statistics 
will be provided. Frequency counts and percentages are used to summarize each 
attribute descriptively, for each symptom item, each attribute is analyzed separately; 
there is no composite scoring mechanism for PRO-CTCAE.
There will be no imputation for missing data, and all available data will be summarized 
(i.e., there is no requirement for a minimum number of attributes to be completed at each 
visit).
Descriptive statistics of the number and percentage of patients with each score will be 
summarized by attribute, for each visit, by treatment group and cohort. The worst 
post-baseline score will be summarized per treatment group within each cohort, for each 
individual attribute and AE, and shift tables will be provided per treatment group. A 
summary table of the percentage of patients reporting severity of symptoms as “severe” 
or “very severe” over the course of the study by treatment group will also be provided.
Change from baseline in PRO-CTCAE attribute scores will be summarized at each visit, 
where change from baseline is calculated as the post-baseline score minus the score 
assigned to the same attribute at the baseline assessment timepoint. Negative values 
will be mapped to a category of “Improvement”, zero values will be mapped to “No 
Change”, and positive values will be mapped to “Worsening”. The number and 
percentage of patients within each of these categories will be summarized by attribute, 
visit and treatment group.
Stacked barplots of the scores for each attribute at each visit will also be provided, per 
treatment group, as well as stacked bar charts illustrating the change from baseline (as 
per description above).
PRO-CTCAE scores at baseline and all post-baseline visits will also be listed, by 
treatment group.
4.7
EXPLORATORY BIOMARKER ANALYSES
Exploratory biomarker analyses (in tumor tissues and plasma, whole blood, or serum) 
will be performed in an effort to understand the association of these markers with study 
drug response, including efficacy and/or adverse events. Results will be performed as 
data allow and will be presented in a separate report.
4.8
MISSING DATA
In safety analyses, all deaths are included, from all sources, regardless of completeness 
of death date; patients who died with only a partial death date available will be included.


Ipatasertib—F. Hoffmann-La Roche Ltd
32/Statistical Analysis Plan CO40016
In efficacy analyses, a death is considered an event if and only if a complete death date 
is available; patients who died with only a partial death date available will be censored.
4.9
INTERIM ANALYSES
4.9.1
Planned Interim Safety Analysis
An external iDMC has been be set up to evaluate safety data on a periodic basis. All 
summaries/analyses by treatment group for the iDMC's review will be prepared by an 
external iDCC. Members of the iDMC will be external to the Sponsor and will follow a 
charter that outlines their roles and responsibilities. Any outcomes of these safety 
reviews that affect study conduct will be communicated in a timely manner to the 
investigators for notification of the IRB/EC. A detailed plan will be included in the iDMC 
Charter.
The iDMC will convene a review of summaries of the safety data by cohort and by 
treatment group after approximately 50 patients (in total from both cohorts) have 
competed one treatment cycle and approximately every 6 months thereafter until the 
time of the analysis of the primary efficacy endpoint for both cohorts are complete.  In 
the absence of extenuating circumstances, accrual will not be halted while the safety 
analysis is conducted.  The iDMC will review the available data to make a 
recommendation as to the following: to continue without changes to the protocol, to 
modify the safety monitoring and/or eligibility criteria, to add additional safety reviews to 
address emerging safety issues, or to terminate the study.  In addition, the Sponsor may 
request ad hoc meetings of the iDMC at any time during the study to review ongoing 
safety summary data.
4.9.2
Planned Interim OS Analysis at PFS Primary Analysis
For Cohort A, interim OS will be analyzed at the time of the primary analysis for PFS, 
and final OS will be analyzed at the time that approximately 188 OS events occur or 
around 36 months after the last patient has been enrolled, whichever is earlier.  The 
Lan-DeMets -spending function with an O’Brien-Fleming boundary will be used to 
control the type I error accounting for OS interim and final analyses. With a sample size 
of 249 patients in Cohort A, it is estimated that there will be approximately 75 OS events 
at the time of PFS primary analysis, and approximately 188 OS events at the final OS 
analysis, with corresponding p-value boundaries of (0.000774, 0.049737). The 
corresponding hazard ratio boundaries are 0.44 and 0.74 at interim and final analysis, 
respectively. The actual alpha-spending will be adjusted and determined based on the 
actual information fraction at the interim analysis.
For Cohort B, interim OS will be analyzed at the time of the primary analysis for PFS, 
and final OS will be at the time that approximately 148 OS events occur, or around 5 
years after the last patient has been enrolled, whichever is earlier.  The Lan-DeMets 
-spending function with an O’Brien-Fleming boundary will be used to control the type I 
error accounting for OS interim and final analyses.  For cohort B, it is estimated that 


Ipatasertib—F. Hoffmann-La Roche Ltd
33/Statistical Analysis Plan CO40016
there will be approximately 81 OS events at the time of PFS primary analysis, and 
approximately 148 OS events at the final OS analysis, with corresponding p-value 
boundaries of (0.004895, 0.048427).  The corresponding hazard ratio boundaries are 
0.52 and 0.71 at interim and final analysis, respectively. The actual alpha-spending will 
be adjusted and determined based on the actual information fraction at the interim 
analysis. 
Table 2
Summary of Overall Survival Interim and Final Analysis: Cohort A
Analysis of OS
Projected 
Number of 
Deaths
Efficacy Stopping Boundary a
Estimated 
Timing b
Interim analysis
75
p0.000774 or observed HR0.44
20 months
Final analysis
188
p0.049737 or observed HR0.74
53 months
HRhazard ratio; OS overall survival.
a p-value will be based on two-sided log rank test. 
b Time from randomization of first patient to data cutoff.
Table 3
Summary of Overall Survival Interim and Final Analysis: Cohort B
Analysis of OS
Projected 
Number of 
Deaths
Efficacy Stopping Boundary a
Estimated 
Timing0b
Interim analysis
81
p0.004895 or observed HR0.52
30 months
Final analysis
148
p0.048427or observed HR0.71
63 months
HRhazard ratio; OS overall survival.
a p-value will be based on two-sided log rank test. 
b Time from randomization of first patient to data cutoff. 
4.9.3
Optional Interim Analysis
Currently, there is no plan for optional interim analysis for this study as described in 
Protocol Section 6.8.3. Optional OS interim analyses could be performed per health 
authority request, and in such a case the p-value boundaries will be adjusted accordingly 
using Lan-DeMets -spending function with an O’Brien-Fleming boundary to control the 
overall typeI error at 0.05 for each cohort.


Ipatasertib—F. Hoffmann-La Roche Ltd
34/Statistical Analysis Plan CO40016
5.
REFERENCES
Akazawa K, Nakamura T, Palesch Y. Power of logrank test and Cox regression model in 
clinical trials with heterogeneous samples. Statistics in medicine. 1997 
16(5):583-97
Brookmeyer R and Crowley JA. Confidence interval for the median survival time. 
Biometrics 1982;38:29-41.
Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for interpreting change 
scores for the european organisation for the research and treatment of cancer 
quality of life questionnaire core 30. Eur J Cancer. 2012;48(11):1713-21.
DeMets DL and Lan KK. Interim analysis: the alpha spending function approach. Stat 
Med 1994;13:1341-52; discussion 1353-6.
Fayers PM, Aaronson NK, Bjordal K, et al. On behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 scoring manual (3rd ed). Brussels: European 
Organisation for Research and Treatment of Cancer 2001.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality of life score. J Clin Oncol 1998;16:139-44
Wolff AC, Hale Hammond ME, Allison KH, 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;36:210522.


Ipatasertib—F. Hoffmann-La Roche Ltd
35/Statistical Analysis Plan CO40016
Appendix 1
Protocol Synopsis
TITLE:
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED 
PHASE III STUDY OF IPATASERTIB IN COMBINATION WITH 
PACLITAXEL AS A TREATMENT FOR PATIENTS WITH 
PIK3CA/AKT1/PTEN-ALTERED, LOCALLY ADVANCED OR 
METASTATIC, TRIPLE-NEGATIVE BREAST CANCER OR 
HORMONE RECEPTOR–POSITIVE, HER2-NEGATIVE BREAST 
CANCER
PROTOCOL NUMBER:
CO40016
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-001548-36
IND NUMBER:
133823
TEST PRODUCT:
Ipatasertib (RO5532961, GDC-0068)
PHASE:
III
INDICATION:
Locally advanced or metastatic triple-negative breast cancer with 
PIK3CA/AKT1/PTEN-altered tumor and no prior chemotherapy in the 
advanced setting
Locally advanced or metastatic hormone receptor–positive, 
HER2-negative breast cancer with PIK3CA/AKT1/PTEN-altered 
tumor and no prior chemotherapy in the advanced setting
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This protocol encompasses two studies, or cohorts, of different patient populations that will 
independently evaluate the safety, efficacy, and pharmacokinetics of ipatasertib in combination 
with paclitaxel (ipatasertib + paclitaxel) compared with placebo plus paclitaxel (placebo + 
paclitaxel) in patients with PIK3CA/AKT1/PTEN-altered tumors.  One cohort will be a first-line 
treatment in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), 
and the second will be a first-chemotherapy treatment in patients with advanced hormone 
receptorpositive, human epidermal growth factor receptor 2negative (HR/HER2) breast 
cancer who are not appropriate candidates for endocrine therapy.  Patients will be screened for 
PIK3CA/AKT1/PTEN-altered tumors and will be allocated to one of the cohorts based on 
hormone-receptor status.  HER2-positive patients are not eligible.  The reason that the two 
patient populations will be evaluated separately is that TNBC and HR/HER2breast cancers 
have different biologies that manifest clinically in different prognoses and response to treatment, 
and molecularly with distinctly different molecular profiles with dissimilar oncogenic drivers.  The 
two populations have different prevalences and progression-free survival (PFS) and overall 
survival (OS) expectations, and thus different enrollment and analysis timelines.  
The two independent target patient populations for this study are premenopausal and 
postmenopausal female and male patients with measurable, locally advanced or metastatic 
TNBC and HR/HER2breast cancer who have not received chemotherapy in either of these
settings.  Patients must be appropriate candidates for taxane monotherapy.  In particular, 


Ipatasertib—F. Hoffmann-La Roche Ltd
36/Statistical Analysis Plan CO40016
patients with HR/HER2breast cancer should be suitable for treatment with chemotherapy 
(e.g., demonstrated insensitivity to endocrine therapy).  Prior adjuvant or neoadjuvant 
chemotherapy is allowed, provided it has been concluded at least 12 months before disease 
recurrence.
Patients with PIK3CA/AKT1/PTEN-altered tumors will be assigned to Cohort A (TNBC) or 
Cohort B (HR/HER2breast cancer) based on their hormone receptor status (as evaluated 
locally, or on study, only if local evaluation is not available, with additional slides submitted for 
this purpose) and randomized with a 2:1 ratio to the experimental versus control arm.  All 
primary, secondary, exploratory, and safety objectives will be assessed independently for each 
cohort (i.e., Cohort A:  patients with TNBC with PIK3CA/AKT1/PTEN-altered tumors and Cohort 
B:  patients with HR/HER2breast cancer with PIK3CA/AKT1/PTEN-altered tumors). 
The primary endpoint for the Cohort A (TNBC) is PFS.  The primary endpoint for Cohort B 
(HR/HER2breast cancer) is also PFS. The primary analysis for each cohort will be 
independent and triggered by cohort-specific events and will also be independent of the readout 
of the other cohort.  The secondary endpoints for each cohort will be tested if the primary 
analysis of the respective PFS reaches statistical significance at the level of 5%.  
Specific objectives and corresponding endpoints for each cohort will be analyzed independently 
following cohort-specific statistical analysis plans, and are outlined in the table, below.
Table 1
Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated)
Objectives
Corresponding Endpoints
Primary Efficacy Objective:
To evaluate the efficacy of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel  
PFS, defined as the time from randomization to 
the first occurrence of disease progression, as 
determined locally by the investigator through 
the use of RECIST v1.1, or death from any 
cause, whichever occurs first
Secondary Efficacy Objectives:
To evaluate the efficacy of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel 
Objective response rate, defined as a CR or 
PR on two consecutive occasions 4 weeks 
apart, as determined locally by the investigator
through the use of RECIST v1.1
Duration of response, defined as the time from 
the first occurrence of a documented objective 
response to disease progression, as 
determined locally by the investigator through 
use of RECIST v1.1, or death from any cause, 
whichever occurs first
Clinical benefit rate, defined as an objective 
response (CR or PR), or stable disease for at 
least 24 weeks, as determined locally by the 
investigator through the use of RECIST v1.1
OS, defined as the time from randomization to 
death from any cause


Ipatasertib—F. Hoffmann-La Roche Ltd
37/Statistical Analysis Plan CO40016
Table 1 Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Secondary Efficacy Objectives:
To evaluate PROs of GHS/HRQoL associated 
with ipatasertib + paclitaxel compared with 
placebo + paclitaxel  
Mean and mean changes from baseline 
GHS/HRQoL score as measured by the 
GHS/HRQoL scale (Questions 29 and 30) of 
the EORTC QLQ-C30, by cycle
To evaluate PROs of disease-related pain of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel (Cohort B only) 
Time to deterioration in pain, defined as the 
first minimally important increase of ≥11 points 
from the baseline pain scale score (Questions 
9 and 19) of the EORTC QLQ-C30
Exploratory Efficacy Objectives:
To evaluate the efficacy of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel in TNBC (Cohort A only) 
patients with tumors that have the following:
-
PIK3CA/AKT1-activating mutations 
-
PTEN alterations (and no PIK3CA/AKT1-
activating mutations) 
PFS
Objective response rate
Duration of response
Clinical benefit rate
OS 
To evaluate PROs of function and 
disease/treatment-related symptoms 
associated with ipatasertib + paclitaxel 
compared with placebo + paclitaxel 
Mean and mean changes from baseline scores 
in functional (i.e., role, physical, cognitive,
emotional, and social) and disease/treatment-
related symptoms by cycle as assessed by the 
functional and symptom scales of the EORTC 
QLQ-C30
To collect utilities for pharmacoeconomic 
modeling 
Health states for utility assessment and the VAS 
as measured by the EQ-5D-5L questionnaire for 
modeling
To evaluate the clinical benefit
PFS2, defined as the time from randomization 
to first objective disease progression on next-
line treatment, or death from any cause, 
whichever occurs first
Time to first skeletal–related event (SRE), 
defined as the time from randomization to the 
occurrence of an SRE.  An SRE is either a 
pathologic fracture, radiation therapy to the 
bone, surgery to the bone, or spinal cord 
compression.


Ipatasertib—F. Hoffmann-La Roche Ltd
38/Statistical Analysis Plan CO40016
Table 1 Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated) (cont.)
Objectives
Corresponding Endpoints
Exploratory Efficacy Objectives (cont.):
To evaluate analgesic use in ipatasertib + 
paclitaxel and placebo + paclitaxel treatment 
arms (Cohort B only)
Change in use of opioid and non-opioid 
analgesics during treatment, as measured by 
the intake of analgesic treatments
Safety Objective:
To evaluate the safety of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel 
Incidence of adverse events as assessed by the 
investigator, with severity determined through 
the use of NCI CTCAE v4.0 
Incidence of prespecified adverse events 
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results
Exploratory Safety Objective
To collect PROs regarding key symptomatic 
adverse events of ipatasertib + paclitaxel 
compared with placebo + paclitaxel 
Selected items from the PRO-CTCAE 
capturing patients' rating of the presence, 
severity, frequency, and/or interference of 
diarrhea, nausea, vomiting, decreased appetite, 
fatigue, neuropathy, mouth sores, and rash 
symptoms and an additional item regarding 
bother due to side effects of treatment
Pharmacokinetic Objective:
To characterize the pharmacokinetics of 
ipatasertib and its metabolite (G-037720) 
when administered in combination with 
paclitaxel
Plasma concentration of ipatasertib and 
G-037720 at specified timepoints for analysis 
using population PK methodology
Exploratory Pharmacokinetic Objective:
To evaluate potential relationships between 
ipatasertib exposure, efficacy, and safety of 
ipatasertib + paclitaxel compared with 
placebo + paclitaxel 
Relationship between ipatasertib PK and 
efficacy endpoints 
Relationship between ipatasertib PK and safety 
endpoints 


Ipatasertib—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan CO40016
Table 1 Objectives and Corresponding Endpoints (Applicable for Both Cohort A and 
Cohort B, Unless Otherwise Stated) (cont.)
Exploratory Biomarker Objectives:
To evaluate predictive or prognostic 
biomarkers (plasma or tissue) associated 
with disease activity status or response to 
treatment 
To identify possible mechanisms of 
resistance to study treatments through the 
comparative analysis of potential biomarkers 
in pretreatment and post-progression biopsy 
tissue samples and in blood 
To evaluate alternative diagnostics testing 
methods for PIK3CA/AKT1/PTEN-altered 
status
Relationship between tissue- and blood-based 
biomarkers and patient clinical features (e.g., 
baseline features) and outcome (e.g., duration 
of PFS)
Change in mutation and copy number in 
oncogenes, tumor suppressors, and/or other 
genes associated with disease progression by 
DNA sequencing 
Change in levels of tumor suppressors, 
immune checkpoints, mitotic index, apoptotic 
index, and/or immune-cell infiltration by 
immunohistochemistry
Associations of breast cancer subtypes 
defined by molecular signatures with patient 
outcomes
Association of BRCA1/2 genetic alterations 
and homologous repair deficiency with patient 
outcomes
BRCAbreast and ovarian cancer susceptibility gene; CR complete response; 
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; GHSglobal health status; HRQoLhealth-related quality of life; NCI CTCAE 
v4.0National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0; 
OSoverall survival; PKpharmacokinetics; PFSprogression-free survival; PRpartial 
response; PRO patient-reported outcome; PRO-CTCAEPatient-Reported Outcomes Version 
of the Common Terminology Criteria for Adverse Events; RECIST v1.1Response Evaluation 
Criteria in Solid Tumors, Version 1.1; TNBCtriple-negative breast cancer; VASvisual analog 
scale.
Study Design
Description of Study
This two-cohort, randomized, double-blind, placebo-controlled Phase III study is designed to 
evaluate the efficacy of ipatasertib + paclitaxel versus placebo + paclitaxel in patients with 
histologically confirmed, locally advanced or metastatic TNBC and in patients with locally 
advanced or metastatic HR/HER2breast adenocarcinoma who are not suitable for endocrine 
therapy.  Each cohort will be independent with separate analyses, but with a single screening 
process to identify, allocate, and subsequently stratify on the basis of histologic and diagnostic 
status.  Patients must have measurable disease as defined by Response Evaluation Criteria in 
Solid Tumors, Version 1.1 (RECIST v1.1) and a PIK3CA/AKT1/PTEN-altered tumor as 
determined either centrally or using local/commercial molecular testing, by a clinical cancer 
genomic profiling laboratory (e.g., Foundation Medicine, Inc. [FMI]) or a CLIA [or equivalently 
accredited] diagnostic laboratory).  Tumor PIK3CA/AKT1/PTEN-altered status is defined as the 
presence of PTEN alterations or PIK3CA/AKT1-activating mutations as determined by any 
blood- or tissue-based molecular assay (see Disease-Specific Inclusion Criteria for further 
details).  Pathological determination of estrogen receptor (ER), progesterone receptor (PgR), 
and HER2 status based on local assessment according to American Society of Clinical 
Oncology (ASCO) and College of American Pathologists (CAP) guidelines will be applied for 
cohort assignment by an interactive voice or Web-based response system (IxRS), with 
subsequent randomization within each cohort based on the appropriate stratification factors for 
the different cohorts.  Patients who have unknown tumor ER, PgR, HER2, or 


Ipatasertib—F. Hoffmann-La Roche Ltd
40/Statistical Analysis Plan CO40016
PIK3CA/AKT1/PTEN-altered status and for whom determination of status is not possible are not 
eligible for this study.
If a patient will screen for biomarker eligibility with the tissue-based FMI CTA, time for tumor 
tissue retrieval, shipping, and turnaround of eligibility results should be taken into account when 
screening patients (and submitted sample should be sufficient per protocol requirements to 
have maximum likelihood that a valid result can be obtained).
As the FACT assay is not able to detect all qualifying alterations that may be identified using the 
FMI CTA, tissue submission should not be delayed as patients may qualify by the latter, rather 
than by FACT.  FACT testing at FMI may not necessarily be faster than the FMI CTA and, 
therefore, should only be performed when it is anticipated that there will be a significant delay to 
acquisition of existing tumor tissue.
If local/commercial testing is available, demonstrating a qualifying alteration, or if this result is 
obtained, these results may be used to determine biomarker eligibility.  However, please note, 
for patients not enrolled on the basis of the FMI tissue-based CTA (e.g., local/commercial tests 
or blood-based FACT assay), submission of tumor tissue is still required, but randomization 
should proceed based on the local result with no requirement to wait for central assessment of 
biomarker eligibility.
Treatment benefit in patients with PIK3CA/AKT1/PTEN-altered tumors will be independently 
compared in patients with triple-negative receptor status and in patients with HR/HER2status.
Approximately 249 patients with TNBC and 201 patients with HR/HER2breast cancer will be 
enrolled at approximately 120150 centers worldwide during the global enrollment phase.  
Patients will be assigned to either Cohort A (TNBC) or Cohort B (HR/HER2breast cancer) 
according to the most recent locally assessed pathologically documented receptor status, in 
their recurrent or metastatic tumor where applicable (i.e., for patients with locally advanced 
breast cancer , this would not apply) and if safely accessible, per ASCO/CAP guidelines, and 
randomly assigned in a 2:1 ratio to the experimental arm (ipatasertib 400 mg + paclitaxel) or 
control arm (placebo + paclitaxel).  Randomization will be stratified by the following factors:  
prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region (Asia-Pacific vs. Europe vs. North 
America vs. rest of the world), tumor PIK3CA/AKT1/PTEN-alteration status (PIK3CA/AKT1-
activating mutations vs. PTEN alterations with no PIK3CA/AKT1-activating mutations; Cohort A 
only), and prior therapy with a phosphoinositide 3-kinase (PI3K) or mTOR inhibitor (yes vs. no; 
Cohort B only).
Potential China Extension Phase
After completion of the global enrollment phase, as needed, additional patients may be enrolled 
at China Food and Drug Administration (CFDA)-recognized sites in an extended enrollment 
phase to ensure a total of up to 90 patients with TNBC and up to 120 patients with HR/HER2
breast cancer, constituting the analysis population of a China subgroup.  For each of Cohort A 
and Cohort B, patients from the China extension phase will be randomized in a 2:1 ratio to the 
two treatment arms, the same as during the global enrollment phase.  Any Chinese patients 
enrolled in the China extension phase will undergo the same schedule of assessments and will 
receive study treatment as in the global study cohorts. 
The China subgroup includes all Chinese patients enrolled in the global study cohorts and the 
China extension phase.  The China subgroup analysis will be performed and summarized 
separately.  The Chinese patients enrolled in the global study cohorts will be analyzed together 
with all other patients enrolled in the global study, and will be reported in the global study clinical 
study report.
All patients must consent to provide sufficient archival tissue or newly obtained tumor biopsy 
tissue for central molecular evaluation as well as have a valid result of PIK3CA/AKT1/PTEN-
altered status (local result or centrally tested) to be eligible for enrollment.  Given the probability 
of PIK3CA/AKT1/PTEN non-altered status (approximately 80%85% for TNBC and 50%60% 
for HR positive by blood-based NGS assay such as FACT and 55%65% by tissue-based NGS 
such as FMI CTA), it remains an option to use the biomarker-specific ICF/screening process 
first, prior to other study screening procedures for those patients who require central testing of 
biomarker status. It is advised that even if the patient will screen for biomarker eligibility on the 
basis of the FACT (or other blood-based) NGS assay, that tissue be submitted as quickly as 
possible as it is expected that the blood-based FACT assay will not detect all alterations that 


Ipatasertib—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan CO40016
can be identified using tissue-based NGS; i.e., even if there is biomarker ineligibility based on 
the blood-based assay, the patient may still qualify on the basis of the tissue-based assay.  
Patients will also be given the option of providing a tissue biopsy sample obtained at disease 
progression for exploratory analyses; this decision will not affect overall study eligibility.  
Patients who are not randomized in the study may receive a copy of the FMI NGS (and FACT 
assay report if performed) research report (if available) for their tumor upon request.  A copy of 
this report(s) may also be available upon request by the investigator for randomized patients, at 
the time they are documented to have disease progression (per RECIST v1.1 criteria), or 
following end of the study, whichever occurs earlier, unless required by law.  The research 
report(s) may be obtained by the investigator, via the Sponsor study team, and will describe 
results from investigational tests that are not intended to be used to guide future treatment 
decisions. 
All eligible patients will receive paclitaxel chemotherapy (80 mg/m2 IV) on Days 1, 8, and 15 of 
each 28-day cycle and either ipatasertib at a dose of 400 mg administered orally once a day 
(QD) on Days 121 of each 28-day cycle (experimental arm) or placebo orally QD on 
Days 121 of each 28-day cycle (control arm).  Study treatment will continue until disease 
progression, intolerable toxicity, elective withdrawal from the study, or study completion or 
termination.  Upon treatment discontinuation, patients will be followed every 3 months for 
survival, PROs, and new anti-cancer therapy and outcome (therapy/procedures, doses, start 
and stop date, best responses, most recent tumor assessment date, and progression date). 
Tumor measurement for disease evaluation will be performed every 8 weeks, regardless of 
whether patients receive study treatment during the treatment cycle.  For estimation of PFS, 
objective response rate (ORR), and duration of response (DOR), tumor response will be based 
on RECIST v1.1.  For patients who discontinue treatment without evidence of disease 
progression per RECIST v1.1, in addition to post-treatment follow-up, patients will be followed 
every 812 weeks for tumor assessments until documented progression per RECIST v1.1, 
elective withdrawal from the study, or study completion or termination.  Images for tumor 
assessments for all patients will be prospectively collected to enable retrospective blinded 
independent central review when needed.
The pharmacokinetics of ipatasertib and its metabolite G-037720 will be assessed in all patients 
receiving ipatasertib.  Safety will be evaluated on an ongoing basis in this study through the 
monitoring of all serious and non-serious adverse events and will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 
(NCI CTCAE v4.0).
An independent Data Monitoring Committee (iDMC) will periodically evaluate the safety of 
ipatasertib or placebo combined with paclitaxel.  The analysis supporting iDMC review will be 
conducted by an independent Data Coordinating Center (iDCC) and provided to the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC Charter. 
No interim analysis of the primary efficacy endpoint PFS is planned.  One interim OS analysis 
(at the time of the primary analysis for PFS) for each cohort is planned.   
Analysis of safety and efficacy for each cohort will be performed independently.
Crossover is not allowed.
Number of Patients
Approximately 450 patients with PIK3CA/AKT1/PTEN-altered tumors are expected to be 
enrolled in this study (~249 patients with TNBC in Cohort A and ~201 patients with HR/HER2–
breast cancer in Cohort B) during the global enrollment phase.
After the global enrollment phase is completed, additional Chinese patients may be enrolled in 
the China extension phase for up to a total of 90 Chinese patients with TNBC in Cohort A and 
up to a total of 120 Chinese patients with HR+/HER2breast cancer in Cohort B.
Target Population
Inclusion Criteria
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent Form(s) 


Ipatasertib—F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan CO40016

Woman or man age18 years at the time of signing the Informed Consent Form

Eastern Cooperative Oncology Group Performance Status of 0 or 1 

Adequate hematologic and organ function within 14 days before the first study treatment on 
Day 1 of Cycle 1, defined by the following:
Neutrophils (ANC 1500/L)
Hemoglobin 9 g/dL
Platelet count 100,000/L
Serum albumin 3 g/dL
Total bilirubin 1.5 the upper limit of normal (ULN), with the following exception:
–
Patients with known Gilbert syndrome who have serum bilirubin 3 ULN may 
be enrolled.
AST and ALT 2.5 ULN, with the following exception:
–
Patients with documented liver or bone metastases may have AST and ALT 
5 ULN.
ALP 2 ULN, with the following exceptions: 
–
Patients with known liver involvement may have ALP 5 ULN
–
Patients with known bone involvement may have ALP 7 ULN
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.
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min based on 
Cockcroft−Gault glomerular filtration rate estimation:
(140 − age) (weight in kg) 0.85 (if female)
72 (serum creatinine in mg/dL)
Fasting total glucose 150 mg/dL and HbA1C 7.5%

Life expectancy of at least 6 months

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year 
during the treatment period and for at least 28 days after the last dose of 
ipatasertib/placebo and 6 months after the last dose of paclitaxel, whichever occurs later, 
and agreement to refrain from donating eggs during this same period
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year, when used 
consistently and correctly, include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion, 
male sterilization, intrauterine hormone-releasing system, copper uterine devices, and 
sexual abstinence.
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 


Ipatasertib—F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan CO40016
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men 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 28 days after the last dose of 
ipatasertib or 6 months after the last dose of paclitaxel, whichever occurs later.  Men 
must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for 28 days after the last dose of ipatasertib or 6 months after 
the last dose of paclitaxel, whichever occurs later, to avoid exposing the embryo.
Examples of contraceptive methods with a failure rate of 1% per year, when used 
consistently and correctly, include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion, 
male sterilization, intrauterine hormone-releasing system, copper uterine devices, and 
sexual abstinence.
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.

For any patients enrolled in the extended enrollment phase (i.e., China extension phase):  
patient is a current resident of mainland China, Hong Kong, or Taiwan, and of Chinese 
ancestry.
Disease-Specific Inclusion Criteria
Patients must meet the following disease-specific criteria for study entry:

Histologically documented TNBC or HR/HER2– adenocarcinoma of the breast that is 
locally advanced or metastatic and is not amenable to resection with curative intent
Receptor status at study entry should correspond to the evaluation of the most recent 
biopsy (i.e., recurrent or metastatic tissue where applicable and if safely accessible, 
and nonfine-needle aspiration [FNA] sample), as assessed locally (or on-study, if not 
available locally) according to the ASCO/CAP guidelines:  
HER2is defined as one of the following:  immunohistochemistry 3or in situ 
hybridization positive  
ER or PgR positivity is defined as 1% of tumor cell nuclei immunoreactive to the 
respective hormonal receptor
TNBC is defined as HER2–, ER–, and PgR– (required for eligibility for Cohort A)
HR/HER2– is defined as HER2– and ERand/or PgR(required for eligibility for 
Cohort B)

Measurable disease according to RECIST v1.1

Eligible for taxane monotherapy, as per local investigator assessment (e.g., absence of 
rapid clinical progression, life-threatening visceral metastases, or the need for rapid 
symptom and/or disease control which may require combination chemotherapy)

HR+/HER2– breast cancer that is not considered appropriate for endocrine-based therapy 
and that meets one of the following inclusion criteria:

Patient has recurrent disease (locoregional or metastatic) during adjuvant 
endocrine therapy (i.e., ≤5 years of being on therapy).

If patient has de novo metastatic disease, patient has progressive disease 
within 6 months of being on first-line endocrine treatment of metastatic disease.
Note that prior treatment with CDK4/6 inhibitors or mTOR inhibitors is allowed.


Ipatasertib—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan CO40016

Submission of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or a minimum 
of 20 freshly cut unstained, serial tumor slides from the most recently collected tumor tissue 
for central molecular analysis (mandatory NGS testing [PIK3CA/AKT1/PTEN-altered status] 
and for other protocol-mandated secondary and exploratory assessments).  Cytologic or 
FNA samples are not acceptable.  Tumor tissue from bone metastases that is subject to 
decalcification is not acceptable.
If a newer specimen is either insufficient or unavailable, the patient may still be eligible 
if the patient can provide a tissue block (preferred) or a minimum of 20 unstained 
serial slides from an older archival tumor tissue or is willing to consent to and undergo 
an additional pretreatment core or excisional biopsy of the non-target lesion (if it is 
assessable and the biopsy can be safely obtained).  In general, a minimum of three 
core biopsies for NGS testing are required.
If the patient already has PIK3CA/AKT1/PTEN alteration results available from the 
FMI commercial tissue-based NGS assay known as FoundationONE CDx, then the 
FMI clinical trial assay (CTA) does not need to be rerun; in this situation 
formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or 10 freshly 
cut unstained, serial tumor slides from the most recently collected tumor tissue is 
acceptable for other protocol-mandated secondary and exploratory assessments, 
upon approval by the Medical Monitor.
Please note, this tumor tissue sample is required to be submitted as described above 
for all patients (i.e., if local assessment of PIK3CA/AKT1/PTEN alteration status or 
central ctDNA is used to assess biomarker eligibility (see below), tumor tissue is still 
required to assess alteration status centrally.)

Confirmation of biomarker eligibility, i.e., valid results from either central testing (in tumor 
tissue as detailed above or blood [using FACT assay]tested at FMI) or local/commercial 
testing of tumor tissue or blood (using an appropriately validated molecular assay at a
diagnostic laboratory [full laboratory report must be available and captured within the 
patient’s source documents to support eligibility]) demonstrating PIK3CA/AKT1/PTEN-
altered status defined as the presence of one or more of the following:
AKT1 missense mutations that result in amino acid substitution at the following
residues E17, L52, or Q79
PIK3CA missense mutations that result in amino acid substitution at the following 
residues R88, G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, 
H1047, or G1049
PTEN alterations that meet any of the following criteria:
Homozygous deletion (copy number of 0)
Dominant negative short variant (e.g., C124S, G129E, R130X)
Loss of heterozygosity (LOH) with copy number of 1 without concomitant single-
nucleotide variants
One deleterious short variant (including insertions and deletions; classification criteria 
provided below) with a concomitant loss of the non-mutant PTEN allele defined by 
LOH with copy number of 1 or LOH with copy number 1.  
o
Any protein truncating mutations, including nonsense mutations and frameshift 
indels
o
Any mutations in the consensus splice donor and acceptor sequence that 
disrupts the consensus, including insertions and deletions
o
Any missense or non-frameshift mutation that has been confirmed somatic as 
described in the COSMIC database
o
If there are two or more deleterious short variants under LOH, the patient will 
not be eligible for the study.
Please note, for local/commercial testing using tumor tissue or blood, a valid result 
from the most recently collected tumor tissue/blood is preferred, however, the patient 


Ipatasertib—F. Hoffmann-La Roche Ltd
45/Statistical Analysis Plan CO40016
would still be eligible if a valid result is obtained from older archival tissue/blood 
sample.  
Exclusion Criteria
General Exclusion Criteria
Patients who meet any of the following general criteria will be excluded from study entry:

Inability to comply with study and follow-up procedures

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills 

Active infection requiring systemic anti-microbial treatment (including antibiotics, anti-
fungals, and anti-viral agents)

Known HIV infection 

Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] 
or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive hepatitis B core antibody [HBcAb] test, 
accompanied by a negative HBV DNA test) are eligible.
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
is negative for HCV RNA. 

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
Day 1 of Cycle 1 or anticipation of need for a major surgical procedure during the course of 
the study 
Placement of a vascular access device is not considered major surgery. 

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
28 days after the last dose of ipatasertib/placebo and within 6 months after the last dose of 
paclitaxel, whichever occurs later 
Women of childbearing potential (who are not postmenopausal with 12 months of 
non-therapy induced amenorrhea nor surgically sterile) must have a negative serum 
pregnancy test result either within 96 hours prior to initiation of study drug, or within 
7 days of Day 1, Cycle 1 (in this case, confirmed by a negative urine pregnancy test 
result on Day 1 of Cycle 1 prior to dosing).

New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction 
50%; or active ventricular arrhythmia requiring medication

Current unstable angina or history of myocardial infarction within 6 months prior to Day 1 of 
Cycle 1

Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF) 480 milliseconds 

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)

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 approved or investigational cancer therapy within 14 days prior to Day 1 of 
Cycle 1 

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 


Ipatasertib—F. Hoffmann-La Roche Ltd
46/Statistical Analysis Plan CO40016
Disease-Specific Exclusion Criteria
Patients who meet any of the following disease-specific criteria will be excluded from study 
entry:

History of or known presence of brain or spinal cord metastases, as determined by 
computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during 
screening or prior radiographic assessments  
Patients with leptomeningeal carcinomatosis will be excluded.

Any previous chemotherapy for inoperable locally advanced or metastatic TNBC or 
HR/HER2– adenocarcinoma of the breast 
Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or 
radiation treatment for breast adenocarcinoma, provided all chemotherapy was 
completed 12 months prior to recurrence.
Patients with TNBC must not have received any previous systemic therapy for 
inoperable locally advanced or metastatic TNBC, including chemotherapy, immune 
checkpoint inhibitors, or targeted agents.
Chemotherapy does not include HER2-targeted therapy, such as trastuzumab, 
pertuzumab, or neratinib (for cases in which patients had early stage HER2+ breast 
cancer and are entering the study with HER2advanced breast cancer).  The 
minimum 12-month, disease-free inclusion requirement begins with the last 
administration of chemotherapy in the early breast cancer setting.

Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 
peripheral neuropathy 

Patients who have received palliative radiation treatment to peripheral sites (e.g., bone 
metastases) for pain control and whose last treatment was completed 14 days prior to Day 
1 of Cycle 1 may be enrolled in the study if they have recovered from all acute, reversible 
effects (e.g., to Grade 1 or resolved by enrollment)

Uncontrolled pleural effusion, pericardial effusion, or ascites
Patients with indwelling catheters (e.g., PleurX) are allowed. 

Uncontrolled tumor-related pain 
Patients requiring narcotic pain medication must be on a 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 
randomization.  Patients should be recovered (e.g., to Grade 1 or resolved) from the 
effects of radiation prior to study enrollment.  There is no required minimum recovery 
period beyond the 14 days required for radiation therapy.
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 randomization. 

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium, 12 mg/dL calcium, or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy 
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events (e.g., bone metastasis, osteoporosis) and who do not have a history of 
clinically significant hypercalcemia are eligible. 

Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer
For other cancers considered to have a low risk of recurrence, discussion with the 
Medical Monitor is required.


Ipatasertib—F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan CO40016
In cases where there is a history of early-stage breast cancer with ER/PR/HER2 
status differing from the advanced breast cancer for which the patient is entering the 
study, the above language still applies (i.e., any breast cancer within the 5 years prior 
to consent is permitted, provided there is no controversy as to the current 
ER/PR/HER2 status.)
Ipatasertib-Specific Exclusion Criteria
Patients who meet any of the following ipatasertib-specific criteria will be excluded from study 
entry:

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.

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia

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)

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

Prior treatment with an Akt inhibitor
Note that prior PI3K or mTOR inhibitors are allowed.
Paclitaxel-Specific Exclusion Criteria
Patients who meet any of the following paclitaxel-specific criteria will be excluded from study 
entry:

Known hypersensitivity or contraindication to any component of the study treatments, 
including the paclitaxel excipient macrogolglycerol ricinoleate

Grade 2 peripheral neuropathy
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later.
Length of Study
The total length of the study, from screening of the first patient to the end of the study (excluding 
the potential China extension phase), is expected to be approximately 53 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is ipatasertib, matching placebo, and, 
dependent on local regulations, paclitaxel.  Paclitaxel is an approved treatment for breast 
cancer and is considered standard of care in some countries.  Loperamide is a non-IMP in the 
study.
Each dose of ipatasertib should be taken with a minimum of 3 ounces (90 mL) of fluid.  
Ipatasertib may be taken with or without food.  If a dose is missed (not taken within 8 hours after 
the scheduled dosing time), the patient should resume dosing with the next scheduled dose.  
Missed or vomited doses will not be made up.
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
and 15 of each 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can be given on 
Day 22.  Calculation of body surface area for the purposes of dosing of paclitaxel should be 
made according to the prescribing information.  If the patient's weight changes by 10% during 
the study, the body surface area and drug doses should be recalculated.  


Ipatasertib—F. Hoffmann-La Roche Ltd
48/Statistical Analysis Plan CO40016
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per institutional 
guidelines and administered after the oral dose of ipatasertib/placebo.  
Because of the known potential for allergic reactions to paclitaxel and/or the 
Cremophorvehicle, precautions must be taken to decrease the risk of anaphylaxis.  Patients 
must be premedicated prior to paclitaxel with dexamethasone, diphenhydramine, and an 
H2-receptor blocker (i.e., ranitidine or famotidine) or per institutional practice.  H2-receptor 
antagonists, such as cimetidine, which are known to inhibit cytochrome P450, should be avoided.
Comparator
The ipatasertib placebo tablets 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.  Placebo will be administered at the starting dose of 400 mg orally QD, 
beginning on Cycle 1, on Days 121 of each 28-day cycle until the patient experiences disease 
progression, intolerable toxicity, or withdraws consent.  Patients will receive placebo prior to the 
IV infusion of paclitaxel.
Each dose of placebo should be taken with a minimum of 3 ounces (90 mL) of fluid.  Placebo 
may be taken with or without food.  If a dose is missed (not taken within 8 hours after the 
scheduled dosing time), the patient should resume dosing with the next scheduled dose.  
Missed or vomited doses will not be made up.
Non-Investigational Medicinal Products
Loperamide is a non-investigational medicinal product (non-IMP) in the study.  All patients 
should receive loperamide (2 mg oral twice a day or 4 mg once a day) 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, and the prophylaxis dose may be adjusted as 
necessary, using their discretion based on clinical judgment and per local guidance.
Statistical Methods
The two cohorts, Cohort A (patients with TNBC) and Cohort B (patients with HR+/HER2– breast 
cancer), are two independent cohorts and will be analyzed separately for the following reasons:

The two patient populations are in two different disease settings with different prevalence 
and different PFS and OS expectations, and thus different enrollment and analysis timelines. 

The readout from one cohort is independent of the readout of the other cohort. 

This study is essentially two independent trials running under one protocol for operational 
efficiency.
Therefore, for all analyses described below, these two cohorts will be analyzed separately.
The global population will include all patients enrolled during the global enrollment phase 
(including patients enrolled at CFDA-recognized sites during that phase), and the China 
subgroup will include all patients enrolled at CFDA-recognized sites (i.e., during both the global 
enrollment phase and the extended China enrollment phase).  Separate analyses will be 
performed for the global population and the China subgroup.
Primary Analysis
The primary efficacy endpoint is investigator-assessed PFS, defined as the time from 
randomization to the first occurrence of disease progression, as determined by the investigator 
using RECIST v1.1, or death from any cause, whichever occurs first.  Data for patients who do 
not experience disease progression or death will be censored at the last date of evaluable 
tumor assessment.  For patients who do not have an evaluable tumor assessment after 
randomization, the data will be censored at the date of randomization plus 1 day.
For each cohort, PFS will be compared between treatment arms using the stratified log-rank 
test.  The hazard ratio will be estimated using a stratified Cox proportional hazards model.  The 
95% CI for the hazard ratio will be provided.  The stratification factors to be used will be the 
same as the randomization stratification factors.  Results from an unstratified analysis will also 
be provided.  Kaplan-Meier methodology will be used to estimate the median PFS 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 median PFS for each treatment arm.


Ipatasertib—F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan CO40016
For each cohort, sensitivity analyses will be conducted to compare PFS between the treatment 
arms in patients with PIK3CA/AKT1/PTEN-altered tumors as centrally determined by the FMI 
CTA.
Determination of Sample Size
As described earlier, Cohort A (patients with TNBC) and Cohort B (patients with HR+/HER2–
breast cancer) are two independent cohorts and will be analyzed separately.  Each cohort will 
be tested independently with 5% type I error control.  In the event that the primary PFS analysis 
timelines for the TNBC and HR+/HER2– cohorts are far apart, the treatment codes of the cohort 
whose PFS data are mature earlier will be sent to the Sponsor to unblind only that cohort for the 
primary analysis of PFS.  The Sponsor will remain blinded to the treatment assignments of the 
other cohort. Data from any additional patients enrolled within the China extension phase will 
not be included in the analysis of the global study.
Global Study
For Cohort A, approximately 249 patients with TNBC with PIK3CA/AKT1/PTEN-altered tumors 
will be enrolled and randomized in a 2:1 ratio to the experimental arm (ipatasertib 400 mg + 
paclitaxel) and control arm (placebo + paclitaxel).  The sample size of 249 patients is 
determined on the basis of the power calculation for the PFS and OS endpoints. 
For Cohort B, approximately 201 HR+/HER2– patients with PIK3CA/AKT1/PTEN-altered 
tumors will be enrolled and randomized in a 2:1 ratio to the experimental arm (ipatasertib 
400 mg + paclitaxel) and control arm (placebo + paclitaxel).  The sample size of 201 patients is 
determined on the basis of the power calculation for the primary endpoint, PFS. 
Potential China Extension 
For the potential China extension phase, if at least 1 patient is enrolled in mainland China, Hong 
Kong, or Taiwan during the global enrollment phase, additional patients may be enrolled at 
CFDA-recognized sites in an extended enrollment phase for up to a total of 90 Chinese patients 
with TNBC with PIK3CA/AKT1/PTEN-altered tumors and up to a total of 120 Chinese patients 
with HR/HER2breast cancer with PIK3CA/AKT1/PTEN-altered tumors; these patients will 
constitute an analysis population of a China subgroup.  The sample size of this China subgroup 
is determined on the basis of showing consistency in the China subgroup for the primary 
endpoint and PFS with the global cohort.
Planned Interim Safety Analysis
An external iDMC will be set up to evaluate safety data on a periodic basis.  All 
summaries/analyses by treatment arm for the iDMC's review will be prepared by an external 
iDCC.  Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  Any outcomes of these safety reviews that affect study 
conduct will be communicated in a timely manner to the investigators for notification of the 
IRB/EC.  A detailed plan will be included in the iDMC Charter.
The iDMC will convene a review of summaries of the safety data by cohort and by treatment 
arm after approximately 50 patients (in total from both cohorts) have competed 1 treatment 
cycle and approximately every 6 months thereafter until the time of the analysis of the primary 
efficacy endpoint for both cohorts are complete.  In the absence of extenuating circumstances, 
accrual will not be halted while the safety analysis is conducted.  The iDMC will review the 
available data to make a recommendation as to the following: to continue without changes to 
the protocol, to modify the safety monitoring and/or eligibility criteria, to add additional safety 
reviews to address emerging safety issues, or to terminate the study.  In addition, the Sponsor 
may request ad hoc meetings of the iDMC at any time during the study to review ongoing safety 
summary data.
Planned Interim OS Analysis at PFS Primary Analysis
For Cohort A, interim OS will be analyzed at the time of the primary analysis for PFS, and final 
OS will be analyzed at the time that approximately 188 OS events occur or around 36 months 
after the last patient has been enrolled, whichever is earlier.  The Lan-DeMets -spending 
function with an O’Brien-Fleming boundary will be used to control the type I error accounting for 
OS interim and final analyses.  With a sample size of 249 patients in Cohort A, it is estimated 
that there will be approximately 75 OS events at the time of PFS primary analysis, and 
approximately 188 OS events at the final OS analysis, with corresponding p-value boundaries of 
(0.000774, 0.049737).  The corresponding hazard ratio boundaries are 0.44 and 0.74 at interim 


Ipatasertib—F. Hoffmann-La Roche Ltd
50/Statistical Analysis Plan CO40016
and final analysis, respectively. The actual alpha-spending will be adjusted and determined 
based on the actual information fraction at the interim analysis.
For Cohort B, interim OS will be analyzed at the time of the primary analysis for PFS, and final 
OS will be at the time that approximately 148 OS events occur, or around 5 years after the last 
patient has been enrolled, whichever is earlier.  The Lan-DeMets -spending function with an 
O’Brien-Fleming boundary will be used to control the type I error accounting for OS interim and 
final analyses. For Cohort B, it is estimated that there will be approximately 81 OS events at the 
time of PFS primary analysis, and approximately 148 OS events at the final OS analysis, with 
corresponding p-value boundaries of (0.00489, 0.04842).  The corresponding hazard ratio 
boundaries are 0.52 and 0.71 at interim and final analysis, respectively. The actual alpha-
spending will be adjusted and determined based on the actual information fraction at the 
interim analysis. 
Further details can be found in the SAP.
Optional Interim Analyses
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct an optional interim efficacy analysis, prior to the time of the primary analysis 
for PFS, with each cohort considered independently.  For example, availability of clinical trial 
results for a specific external competitor molecule during the course of 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 two molecules.  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 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 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 the primary endpoint of PFS to determine the critical value for stopping 
for positive efficacy at the interim analysis.  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.
After the primary analysis for PFS, additional OS interim analyses may be conducted to provide 
additional OS data, per the recommendation from health authorities.  If conducted, the Lan-
DeMets -spending function with an O’Brien-Fleming boundary will be used to control the 
overall type I error for OS accounting for the additional OS interim analyses.
.


Ipatasertib—F. Hoffmann-La Roche Ltd
51/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening 
Safety 
Eligibility 
or 
Baseline
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1
D8 D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Signed informed 
consent(s) d
x
Demographics, 
medical history, prior 
cancer treatment
x
Tumor tissue sample 
submission 
x e
Confirmation of 
biomarker eligibility 
(local or central 
testing) 
x ii
Blood sample for 
biomarkers f
x f
x f
x f
x f
Viral serology g
x
Blood sample for 
WGS h
x
Complete physical 
examination
x
x


Ipatasertib—F. Hoffmann-La Roche Ltd
52/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening 
Safety 
Eligibility 
or 
Baseline
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1
D8 D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Limited physical 
examination
x
x
x
x
x
x
x
x
x
x
x
Weight 
x
x
x
x
x
x
Height
x
Vital signs i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance 
Status
x
x
x
x
x
x
x
ECHO or MUGA 
scan
x j
12-Lead 
electrocardiogram k
x
x
Hematology l
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
INR and PTT (or 
aPTT)
x
x
Fasting serum 
chemistry n
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
Fasting lipid profile, 
amylase, lipase
x
x o
x o
x


Ipatasertib—F. Hoffmann-La Roche Ltd
53/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening 
Safety 
Eligibility 
or 
Baseline
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1
D8 D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
HbA1C
x
x o
x o
x
Urinalysis
x
As clinically indicated
x
Pregnancy test p
x
x p
x 
x
x
x
x
Tumor 
assessments q
x
Every 8 weeks based on starting date of C1D1 r
x s
x t
Bone scan
x u
Every 16 weeks based on starting date of C1D1
x u
x t
Head scan (CT or 
MRI scan)
x v
Prophylaxis 
anti-diarrheal (2 mg 
BID loperamide or 
equivalent) w
If side effects are not tolerated, doses may be reduced. After 1 cycle without any 
diarrhea, continuation is at physician's discretion. If diarrhea occurs, it should be 
managed per guidelines in Section 5.1.3.5; anti-diarrheal treatment should also 
be resumed with loperamide prophylaxis as needed.
Ipatasertib/placebo 
dispension/
accountability
x x
x
x
x
x


Ipatasertib—F. Hoffmann-La Roche Ltd
54/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening 
Safety 
Eligibility 
or 
Baseline
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1
D8 D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Paclitaxel 
administration y
x x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Record cancer-related 
radiotherapy and 
surgical procedures z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events bb, z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x cc
x cc
EORTC QLQ-C30 dd
x
x
x
x
x
x
x ee
PRO-CTCAE dd
x
x
x
x
x
x
EQ-5D-5L dd
x
x
x
x
x
x
x ee
PK samples ff
x
x
x
Survival and 
anti-cancer therapy 
follow-up z
x gg


Ipatasertib—F. Hoffmann-La Roche Ltd
55/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
Screening a
Treatment Cycles (28-Day Cycles) b
SDDV c
Post-
Treat. 
Follow-
Up
Biomarker
-Specific 
Screening 
Safety 
Eligibility 
or 
Baseline
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1
D8 D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Tumor tissue sample 
obtained at time of 
progression 
(optional) hh
x hh
Patient diary 
(medication, dosing 
log, Kit ID)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
BIDtwice a day; CTcomputed tomography; ctDNAcirculating tumor DNA; Dday; ECHOechocardiogram; ECOGEastern Cooperative 
Oncology Group; EORTC QLQ-C30European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30; 
EQ-5D-5L= European Quality of Life 5-Dimension, 5-Level questionnaire; FNAfine-needle aspiration; HER2human epidermal growth factor 
receptor 2; HRhormone receptor; MUGAmultiple-gated acquisition; MRImagnetic resonance imaging; NGSnext-generation sequencing; 
PKpharmacokinetic; PROpatient-reported outcome; PRO-CTCAEPatient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events; QDonce a day; RECISTResponse Evaluation Criteria in Solid Tumors; SDDVstudy drug discontinuation visit; TNBCtriple-
negative breast cancer; Treat.treatment; WGSwhole genome sequencing. 
Notes:  Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within the screening safety eligibility/ 
baseline window specified for each assessment.  Screening assessments are to be performed after informed consent and generally within 28 days 
preceding Day 1 of Cycle 1 unless otherwise noted. The safety eligibility/baseline window does not apply to the biomarker-specific screening 
process (i.e., submission of tissue/blood sample for biomarker testing).  In addition, patients must have adequate hematologic and organ function 
within 14 days and have a negative pregnancy test (if applicable) prior to the first study treatment on Day 1 of Cycle 1, as defined in Section 4.1.1.  
All assessments or procedures are to be performed predose unless otherwise specified.
a Screening window per individual assessment guidelines detailed, generally within 28 days of Cycle 1 Day 1 for time-dependent screening safety 
eligibility/baseline assessments.


Ipatasertib—F. Hoffmann-La Roche Ltd
56/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
b Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment period should be performed within 3 days of the 
scheduled date or window.  Study assessments may be delayed or moved ahead of the window to accommodate holidays, vacations, and 
unforeseen delays; however, study cycle day count continues without breaks; i.e., every cycle contains exactly 28 days.  
c The study drug discontinuation visit should occur approximately 28 days after the last administration of ipatasertib/placebo or paclitaxel, 
whichever is discontinued last, or prior to initiation of another therapeutic regimen.
d Patients may be consented for the biomarker-specific process (if enrolling on the basis of central tissue or blood-based FMI testing) using the 
biomarker-specific ICF, followed by (if an alteration is present) full study consent and remaining screening procedures prior to enrollment in the 
study; or, patients may consent using the full study ICF prior to screening and enrollment.  Informed consent must be documented before any 
study-specific screening procedure is performed, and may be obtained more than 28 days before initiation of study treatment.
e Archival tissue (either formalin-fixed paraffin-embedded tumor specimens or a minimum of 20 unstained serial paraffin slides) and an associated 
pathology report must be confirmed to be available prior to entry into the study.  This requirement is required for all patients except those 
enrolled on the basis of PIK3CA/AKT1/PTEN alteration results available from the FMI commercial tissue-based NGS assay known as 
FoundationONE CDx, when a formalin fixed, paraffin embedded tumor (FFPE) tissue block or 10 freshly cut unstained, serial tumor slides from 
the most recently collected tumor tissue is acceptable for other protocol-mandated secondary and exploratory assessments, upon approval by 
the Medical Monitor.  In the absence of archival tissue, newly obtained tissue biopsy samples of non-target lesions (excluding cytology, FNA 
specimens and bone metastasis requiring decalcification) are acceptable (if it is assessable and the biopsy can be safely obtained).  In general, 
a minimum of three core biopsies for NGS testing are required.  If PIK3CA/AKT1/PTEN-altered status has been determined for a patient during 
study screening procedures, a repeat biomarker-specific screening is not required.
f
Blood will be collected for ctDNA analysis at screening (either as part of the biomarker-specific screening process or full screening), at the time 
of the first tumor assessment (7 days), and at the study drug discontinuation visit.  For patients who send a blood sample for FACT assay to 
determine biomarker eligibility, the initial screening blood sample may be used for this purpose, but an additional blood sample taken on Cycle 1, 
Day 1 will be required for exploratory biomarker assessment. 
g HIV, HBsAg, total hepatitis B core antibody (HBcAb), HCV antibody; additional tests for HBV DNA or HCVRNA will be required to confirm 
eligibility.
h Samples will be collected only at sites with local regulatory authority approval. Sample collection may occur at the same time as other blood 
sampling if preferred (i.e., within 48 hours prior to dosing at the same time as laboratory samples or postdose at the same time as the PK 
sample).
i
Includes pulse rate, respiratory rate, systolic and diastolic blood pressure while patient is in a seated position after resting for 5 minutes, and 
temperature (oral, axillary, or tympanic).  On paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of the infusion.  
From Cycle 5 onward, if paclitaxel treatment has been discontinued, the patient is not required to return to the clinic for Day 8 and Day 15 vital 
sign assessments.  A telephone call for adverse events and concomitant medication assessment may be performed as clinically indicated.


Ipatasertib—F. Hoffmann-La Roche Ltd
57/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
j
Performed within 12 weeks prior to Day 1, Cycle 1.  Under exceptional circumstances cardiac function assessment by methods other than 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) may be acceptable, if this is consistent with local standard practice (e.g., cardiac 
MRI), but must be approved by the Medical Monitor.
k A single 12-lead ECG measurement at screening and at SDDV visit, and as clinically indicated (refer to Section 4.5.7).
l
Includes WBC count, WBC differential count (including absolute neutrophil counts, lymphocytes), hemoglobin, hematocrit, and platelet count.
m Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic; results should be available to assess dosing; 
with at least 8-hour fasting for glucose measurement as indicated (refer to Section 4.5.6). Glucose logs for any home glucose monitoring 
performed should also be reviewed at clinic visits prior to dosing, and only values which result in intervention recorded within the eCRF.
n Includes sodium, potassium, bicarbonate, glucose (fasting), BUN/urea, creatinine, calcium, phosphorus, magnesium, total bilirubin, albumin, 
LDH, ALT, AST, and ALP.  For investigational sites in countries where bicarbonate may not be collected as part of the standard chemistry panel, 
bicarbonate will not be measured.  For investigational sites where local practice includes measuring only fasting plasma glucose levels, these 
local assessments may be acceptable to confirm eligibility and should be provided consistently across the study for intra-patient comparability.  
Grade 3 non-hematologic toxicity should be monitored at least weekly.
o Fasting lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides), amylase, lipase, and HbA1c will be assessed 
at screening, every 3 cycles starting on Day 1 of Cycle 3, and at SDDV visit.
p For women of childbearing potential.  A serum pregnancy test is to be performed at screening.  A negative serum pregnancy test must be 
obtained either within 96 hours prior to C1D1 study treatment administration, or within 7 days of C1D1 (in this case, confirmed by a negative 
urine pregnancy test prior to C1D1 dosing).  In addition, pregnancy tests (serum or urine) are to be performed within 96 hours of Day 1 of each 
following treatment cycle prior to dosing, and a pregnancy test should be performed when clinically indicated.  If urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test.  For all other women, documentation must be present in medical history confirming that patient 
is not of childbearing potential.
q Tumor assessments performed according to RECIST v1.1.  The method used for a patient (CT or MRI scan or photographic measurements) 
must be the same throughout the study.  An objective response should be confirmed by repeat assessments 4 weeks after initial documentation. 
A missed tumor assessment should be rescheduled as soon as possible.  Images for tumor assessments will be prospectively collected to 
enable retrospective blinded independent central review when needed.
r
Tumor assessments (TAs) should be calculated from C1D1 (study Day 1) and completed during Week 8 and every 8 weeks thereafter.  
Therefore, the window for each scan will be the 7 days of the given week.  Images for tumor assessments will be prospectively collected to 
enable retrospective blinded independent central review when needed.


Ipatasertib—F. Hoffmann-La Roche Ltd
58/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
s At SDDV visit, tumor assessments should be performed only if not performed within the previous 6 weeks.  If a patient discontinues from the 
study for any reason other than disease progression per RECIST v1.1, every effort should be made to obtain follow-up CT scans to assess 
disease response approximately every 812 weeks until documented progressive disease per RECIST v1.1.  Images for tumor assessments will 
be collected to enable retrospective blinded independent central review when needed.
t
If a patient discontinues from the study for any reason other than disease progression per RECIST v1.1, a disease follow-up clinical visit 
approximately every 812 weeks will be required for tumor assessments until documented progressive disease per RECIST v1.1.  Images for 
tumor assessments will be collected prospectively to enable retrospective blinded independent central review when needed.
u An initial technetium bone scan should be performed within 6 weeks prior to Day 1 of Cycle 1.  In addition, bone disease identified on bone 
imaging should be evaluated radiographically by CT scan, MRI or X-ray to ascertain the presence of bone destruction versus a healing reaction.  
For patients with known or suspected bone metastasis, bone scans should be performed with every other tumor assessment starting from 
Week 16, adhering to the same 7-day window.  If these patients discontinue from the study treatment for any reason other than disease 
progression, they should continue to be followed as clinically indicated, or for approximately every 4 months at disease follow-upuntil 
documented progressive disease per RECIST v1.1.  If it is not possible to acquire a technetium bone scan, NaF-PET scans may be considered 
an alternative, with approval from the Medical Monitor.
v Performed within 6 weeks prior to Day 1 of Cycle 1.  Mandatory for Cohort A (TNBC), and as clinically indicated for Cohort B (HR/HER2).
w Administer prophylactic loperamide dose of 2 mg BID or 4 mg QD, if allowed by local guidance.  Refer to Section 5.1.3.5.1. for further diarrhea 
management guidance. 
x 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 3 days after randomization.
y If the patient's weight changes by 10% from baseline during the study, the body surface area and drug doses of paclitaxel should be 
recalculated.  
z A skeletal-related event (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 post-treatment 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.
aa At screening and Day 1 of Cycle 1, record all concomitant medications taken between 14 days prior to screening and Day 1 of Cycle 1; at 
subsequent time points, record new concomitant medications and any changes to the daily dosing.  Actual intake of anti-diarrheal, pain 
medication, or pre-medications at each dosage change should be recorded. 


Ipatasertib—F. Hoffmann-La Roche Ltd
59/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
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 28 days after the last dose of study 
treatment.  After this period, investigators should report any serious adverse events that are believed to be related to prior treatment with study 
drug.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable 
by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse 
events considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
cc Patients with an unresolved adverse event or serious adverse event will be followed until the event is resolved or stabilized, the patient is lost to 
follow-up, or it has been determined that the study treatment or participation is not the cause of the event. Refer to Section 5.6 for adverse 
events that occur after the adverse event reporting period (defined as 28 days after the last dose of study drug).  An additional adverse event 
follow-up visit may be scheduled (even after the SDDV); follow-up by telephone for adverse event resolution date as applicable.
dd All PRO questionnaires are required to be completed prior to the administration of study treatment and/or prior to any other study assessment(s) 
that could bias patients’ responses.  The EORTC QLQ-C30, PRO-CTCAE, and EQ-5D-5L should be completed on Day 1 of each cycle and at 
the SDDV visit.  PRO-CTCAE questionnaires will be completed when available in the local language of the investigational site.
ee The global health status/HRQoL (which consists of Questions 29 and 30), pain (Questions 9 and 19), fatigue (Questions 10, 12 and 18) and 
dyspnea (Question 8) from the EORTC QLQ-C30 and the EQ-5D-5L will be administered during post-treatment follow-up calls (or visits).  
Questionnaires during the follow-up period do not need to be conducted in person (i.e., do not require an office visit); however, when 
administered via telephone, they must be conducted by interview assessment (using instructions and telephone scripts for administering the 
PRO assessments when available in the local language). These should be conducted prior to the disease follow-up tumor assessment, if 
applicable.
ff See Appendix 2 for schedule of PK assessments.
gg Information about survival, subsequent anti-cancer therapies and associated response, progression date, and most recent tumor assessment 
date will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (1 month) until death, loss 
to follow up, or study termination by the Sponsor, unless the patient requests to be withdrawn from follow-up; this request must be documented 
in the source documents and signed by the investigator. 
hh Tumor biopsy collection is optional for study participation.  For patients who sign an Optional Research Biosample Repository Informed Consent 
Form and if tumor biopsies can be obtained with minimal risk and discomfort to the patient, a tumor biopsy would be collected at the time of 
progression within 6 weeks of the progression assessment and prior to initiation of a new anti-cancer therapy; tumor biopsy of the growing lesion 
is preferred.


Ipatasertib—F. Hoffmann-La Roche Ltd
60/Statistical Analysis Plan CO40016
Appendix 2
Schedule of Assessments (cont.)
ii
Biomarker eligibility (i.e., presence of PIK3CA/AKT1/PTEN alteration) may be determined using central testing at FMI (from tumor tissue 
sample provided [CTA] or blood samples provided for ctDNA analysis [FACT assay]) or local/commercial testing using an appropriately validated 
molecular-based assay at an accredited diagnostic laboratory (CLIA accredited or equivalent).  If local/commercial assessment of 
PIK3CA/AKT1/PTEN alteration status or central ctDNA is used to confirm biomarker eligibility, tumor tissue is still required to confirm alteration 
status centrally, with the exception of the commercial FoundationONE CDxassay, which would allow for a reduced tissue requirement
(See Section 4.1.1 ), randomization should proceed based on the local result with no requirement to wait for central confirmation of biomarker 
eligibility.  For all local/commercial molecular testing results used to determine biomarker eligibility a full laboratory report must be available and 
captured within the patient’s source documents to support enrollment, key details of the test and result used to confirm biomarker eligibility should 
be entered into the eCRF.


Ipatasertib—F. Hoffmann-La Roche Ltd
61/Statistical Analysis Plan CO40016
Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples
Visit
Timepoint
Sample Type
Cycle 1, Day 1
13 hours post-
ipatasertib/placebo
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 1, Day 15 a
Predose b
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 1, Day 15 a
13 hours post-
ipatasertib/placebo
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 3, Day 15 a
Predose b
Plasma sample for 
ipatasertib/placebo
and G-037720
Cycle 3, Day 15 a
24 hours post-
ipatasertib/placebo
Plasma sample for 
ipatasertib/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, the sample collection may be delayed 
to another day when at least 3 consecutive days of ipatasertib/placebo dosing have been 
administered.  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.